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 peptldyl nitriles capable of selectively inhibiting dipeptldyl-peptidase I (DPPI), also known as cathepsin C, an enzyme that deaves a dipeptide from the N terminus of a polypeptide chain. BACKGROUND OF THE INVENTION

Dlpeptldyl 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 subunlts. 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-termlnal 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 conjuctlva. 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 celi activation are the serine peptidases of the chymotrypsln 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 Golgl 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 (Adklson et al. 2002, J. Clin. Invest, 109, 363-271; Pham. et al. 2004, J. Immunol, 173,7277-7281).

WO 2009074829 to Astra zeneca discloses peptidyl nitriles and use thereof as dlpeptidyl peptidase Inhibitors. WO 2010128324 and WO 2010142985 to Astrazeneca discloses further nitrile compounds and use thereof as dlpeptidyl peptidase inhibitors. WO 2011019801A1 and WO 2009026197 to Glaxo Group Ltd. disclose cathepsin C inhibitors and their use. WO 2007137738 to Sanofi-Aventis discloses spirocydic nitriles as cathepsin cysteine protease inhibitors. WO 2006034004 to Axys Pharmaceuticals, Inc. discloses a process of preparing cyanomethyl peptide analogs useful as cysteine protease inhibitors. WO 2005028429 to Axys Pharmaceuticals, Inc. discloses haloalkyl containing compounds as cysteine protease. WO 2005025554 to Japan Tobacco Inc. discloses dlpeptidyl peptidase IV inhibitors. WO

2004108661 to Axys Pharmaceuticals, Inc. discloses amldino compounds as cysteine protease inhibitors. WO 2003029200 to Boehringer Ingelheim Pharmaceuticals, Inc discloses compounds useful as reversible Inhibitors of cysteine proteases. Nathalie Méthot, Daniel Guay, Joel Rubin, Diane Ethier, Karen Ortega, Simon Wong, Denis Normandin, Christian Beaulleu, T. Jagadeeswar Reddy, Denis Rlendeau, and M. David Perdval : In Vivo Inhibition of Serine protease Processing Requires a High Fractional Inhibition of Cathepsin C, Mol Pharmacol 73: 1857-1865, 2008 disclose dlpeptlde nltriie cathepsin C inhibitors. Nathalie Methot, Joel Rubin, Daniel Guay, Christian Beaulleu, Diane Ethier T. Jagadeeswar Reddy, Denis Rlendeau, and M. David Perdval: 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 dlpeptlde nltriie cathepsin C inhibitors. The article "In vivo inhibition of serine protease processing requires a high fractional Inhibition of cathepsin" C. Methot N, Guay D, Rubin J, Ethier D, Ortega K, Wong S, Normandln D, Beaulleu C, Reddy TJ, Rlendeau D, Perdval MD. Mol Pharmacol. 2008;73(6): 1857-65 also dlsdose dipeptide nltriie cathepsin C inhibitors. Jon Bondebjerg, Henrlk Fuglsang, Klrsten Rosendal Valeur, John Pedersen and Lars Naerum, Dipeptldyl nitrlles as human dipeptidyl peptidase I Inhibitors, Bioorganic & Medldnal Chemistry Letters 16 (2006) 3614-3617 disclose compounds having a dipeptide nltriie scaffold as Inhibitors of human dipeptidyl peptidase I. Daniel Guay, Christian Beaulleu, T. Jagadeeswar Reddy, Robert Zamboni, Nathalie Methot, Joel Rubin, Diane Ethier and M. David Perdval, Design and synthesis of dipeptidyl nitrlles 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 nitrlles 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

So, in a first aspect the present Invention relates to a compound of formula (I)

wherein 1 represents hydrogen; halogen; hydroxyl; nttro; cyano or mercapto; or R ¹ represents -O- CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ or -C _1-3 -alkyl; which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ or - C _1-3 -alkyl Is optionally substituted with at least one substituent selected from halogen, hydroxyl, nltro, cyano and mercapto;

R ² represents hydrogen; halogen; hydroxyl; nltro; cyano or mercapto; or R ² represents -O-CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ ; cydopropy!, C _1-3 -alkyl; C _2-3 -alkenyl; or C _2-3 -alkynyl; which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ , cydopropyl, C _1-3 alkyl, C _2-3 -alkenyl or C _2-3 -alkynyl Is optionally substituted with at least one substituent selected from halogen, hydroxyl, nltro, cyano and mercapto; or R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at feast 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 selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, - NR ³ R ⁴ , and mercapto; or R ² represents a phenyl ring, which phenyl ring Is optionally substituted with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, cyano, -NR ³ R ⁴ , and mercapto; or R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen atom(s), and which aromatic ring Is optionally substituted with at least one substituent selected from halogen, C _{1 -3} -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-6 -cycloaikyl or C _3-6 -heterocycloalkyl, which C _3-6 -cycloalkyl or C^-heterocycloalkyl Is optionally substituted with at least one substituent selected from halogen, hydroxyl, nltro, cyano and mercapto; D represents an oxygen atom or a sulphur atom;

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 selected from halogen, C _1-3 alk ; optionally substituted with halogen, Q. 6-alkoxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxy!, nitro, cyano, mercapto and trifiuoromethyl;

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 halogen; carboxyl; oxo; hydroxy!; amino; nitro; cyano; mercapto; C ₃ - ₅ -cyc!oa!kyl; C ₂ -6-alkenyl; trifiuoromethyl; trifluoromethoxy; C alkoxy; C _1-6 - thioalkyl; C^-alkylcarbonyl; C _1- e-alkylcarbonyloxy; C _1-6 -aikoxycarbonyi; -NR ³ R ⁴ ; -C(0)NR ⁵ R ⁶ ; -N(R ⁷ )C(0)R ⁸ ; -S-C _1- 3-alkyl; -S(0) ₂ NR ⁹ R ¹⁰ ; -N(R ^u )S(0) ₂ R"; -S(0),R ¹³ wherein a Is 0, 1 or 2; -NHC(-NH)NH ₂ ; -C(-NH)NH ₂ ; benzyfoxy; -S(0) ₂ -(4- R ¹⁹ -piperazln-1 -yl) optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; ~(C _1-2 -alkyi)-4- R ¹⁹ -plpera2in-1 -yl in which the C _{1 -2} -alkyl is optionally substituted with one or more -R ¹⁷ and in which the piperazine ring is optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -N(R ¹⁸ )-4-R ¹⁹ -plperazin-1 -yl; -O-4- R ¹⁹ -plperazln-1 -yl; -C(=0)- 4-R ¹⁹ - piperazin- 1 -yl ; -S(0) ₂ (-Ci^-alkyldiazepanyi) which is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C^-alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and

trifiuoromethyl; 4-(C _1-6 - alkyl)plperazln-1 -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 _1-e -alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifiuoromethyl; plperldinyl which is optionally substituted with -NR ¹⁴ R ¹⁵ or C _1-6 -alkyi optionally substituted with halogen, hydroxyl, C _1-6 -alkoxy, -NR ¹⁴ R ^1S , phenyl, plperldinyl, morphoilnyl or 4- R ¹⁹ - plperazln-1 -yl; -C _1-3 -alkyl-plperidinyl optionally substituted with -NR ¹⁴ R ¹⁵ or d^-alkyl optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ¹⁵ , phenyl, plperldinyl, morphoilnyl or 4- R ¹⁹ -piperazln-1 -yl; C _3-6 -cycloalkyi optionally substituted with - R ¹ R ^1S or C _1- e-alkyl optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ¹⁵ , phenyl, plperldinyl, morphoilnyl or 4- R ¹⁹ - piperazln-1 -yl; and Ci^-alkyl, which C _1- e-alkyl Is optionally substituted with one or more of halogen, amino, cyano, hydroxy, Ci^-alkoxy, -NR ¹⁴ R ^1S , phenyl, morphoilnyl or C _3-6 cycloalkyl, which C _3-6 cydoalkyl Is optionally substituted with -NR ^l4 R ¹⁵ , phenyl, plperldinyl, morphoilnyl or 4-R ¹⁹ -plperazln-1 -yl; with the proviso that when B is phenyl, then B Is substituted with at least one substituent; 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;

R ³ and R* each independently represent hydrogen, C _1-6 -alkyl or C ₃ -s-cycloalkyi, 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 _1-6 -aikyi or C _3-6 -cycioalkyi, 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, Cj.. ₈ ~aSkyi or C _3-6 -cycioalkyi, 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" and R ¹⁵ each Independently represent hydrogen, C _1- e-alkyl or C ₃ ..6"Cycioa!kyl, 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 ^e , R ¹¹ , R ¹² and R ¹³ each independently represent a hydrogen atom or a Ci^-alkyl or C ₃ - ₆ - cydoalkyl;

R ¹⁶ represents a hydrogen atom or C -alkyl;

R ¹⁷ represents halogen, cyano, cyciopropyi or G^-alkyl optionally substituted with halogen, cyano, or cydopropyl optionally substituted with methyl or halogen; or two R" together with the carbon atom(s) to which they are attached form a cyciopropyi;

R ¹⁸ represents a hydrogen atom, or C _1-3 -alkyl optionally substituted with halogen or methyl cydopropyl, wherein methyl cyciopropyi Is optionally substituted with methyl or halogen;

R ¹⁹ represents C ₃ . _s -cycloa!kyi, -C _1-3 -alkyl-C ₃ - _s -cycloaikyl or Ci. ₆ -alkyl; and R ²⁰ each independently represent halogen, hydroxy), cyano, mercapto, amino or C _{1 -6} -alkyl optionally substituted with halogen, hydroxy!, cyano, amino or mercapto; as well as stereoisomers, pharmaceutically acceptable salts, solvates, and hydrates thereof, is provided.

In a further aspect, the invention relates to a pharmaceutical composition comprising, as an active substance, a compound of formula (I), (Π) or (III) as defined herein together with a pharmaceutically acceptable adjuvant, carrier or diluent. The Invention relates In a further aspect to a compound of formula (Ij, (II) or (III) as defined herein for use In medicine. In a further aspect, the invention relates to a method for the treatment of aliments, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II) or (III) as defined herein or of a composition as defined herein. In a further aspect, the invention relates to the use of a compound of formula (I), (II) or (III) as defined herein for the preparation of a medicament. In a further aspect, the Invention relates to a method For modulating DPPI levels in a subject In need thereof comprising administering to said subject an amount of a compound of formula (I), (II) or (III) as defined herein or a composition as defined herein in an amount effective to modulate said DPPI levels in said subject. In a further aspect, the invention relates to a combination of a compound of formula (I), (II) or (HI) 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 chemok!ne receptor function; and an inhibitor of kinase function.

DETAILED DISCLOSURE OF THE INVENTION Disclosed herein is a compound of the formula (I)

wherein R ¹ represents hydrogen; halogen; hydroxyl; nitro; cyano or mercapto; or R ¹ represents -O- CH ₃ ; -O-C2H5; -S-CH ₃ ; -S-C ₂ H ₅ or -d- ₃ -alkyl; which -O -CH ₃ , -O -C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ or - C _{1 -3} -alkyl Is optionally substituted with at least one substftuent selected from halogen, hydroxyl, nitro, cyano and mercapto; R ² represents hydrogen; halogen; hydroxyl; nitro; cyano or mercapto; or R ² represents -O-CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ ; cyciopropyl, C _1-3 -alkyl; C _2-3 -alkenyl; or C _2-3 -aikynyl; which -0~CH ₃ , -O-C ₂ H ₅ , -S-CH _3f -S-C ₂ H ₅ , cydopropyl, C _1-3 -alkyl, C _2-3 -alkenyl or C _2-3 -alkynyl is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nitro, cyano and mercapto; or R ² represents a 5-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 substltuent selected from halogen, C _{1 -3} -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, - NR ³ R ⁴ , and mercapto; or R ² represents a phenyl ring, which phenyl ring is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, cyano, -NR ³ R ⁴ , and mercapto; or R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen atom(s), and which aromatic ring Is optionally substituted with at least one substltuent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto; or R ^x and R ² together with the carbon atom to which they are attached form C _3-6 -cycloalkyi or C _3-e -heterocydoalkyl, which C _3-6 ~cyc!oaikyl or C _M -heterocydoalkyl Is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nitro, cyano and mercapto;

D represents an oxygen atom or a sulphur atom; 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 substltuent selected from halogen, C _1-3 -aikyl optionally substituted with halogen, d- 6-alkoxy, trlfiuoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxyl, nitro, cyano, mercapto and trlfluoromethyl;

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 substltuent Q selected from halogen; carboxyl; oxo; hydroxyl; amino; nitro; cyano; mercapto; G^-cydoalkyl; C ₂ . ₆ -alkeny!; trifluoromethyl; trifluoromethoxy; C _1- e-alkoxy; &. _-5 - thloalkyl; Ci^-a!kylcarbonyi; C _1-6 -alkylcarbonyloxy; C _1- e-alkoxycarbonyi; -NR ³ R ⁴ ; -C(0)NR ⁵ R ⁶ ; -N(R ⁷ )C(0)R ⁸ ; -S-C _1- 3-a!kyi; -S(0) ₂ NR ⁹ R ¹⁰ ; -N(R ^U )S(0) ₂ R"; -S(0).R ¹³ wherein a Is 0, 1 or 2; -NHC(=NH)NH ₂ ; -C(-NH)NH ₂ ; benzyloxy; -S(0) ₂ -(4- R ¹⁹ -plperazln-1-yl) optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -(C _1-2 -alkyl)-4- R ¹⁹ -plperazln-1-yl In which the Ci. ₂ -alkyl Is optionally substituted with one or more -R ¹⁷ and in which the plperazlne ring is optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -N(R ¹⁸ )-4-R ¹⁹ -piperazin-1-yl; -O-4- R ¹⁹ -plperazin-1-yl; -C(=0)- 4-R ¹⁹ -piperazln-1-yl; -S(0) ₂ (-Ci.6- aiky!diazepany!) which is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, Ci^-alkoxy, trifluoromethoxy, hydroxy!, nitro, cyano, mercapto and

trifluoromethyl; 4-(Ci.. _e - alkyl)piperazin-1-yl which is optionally substituted at a carbon atom with at least one substituent selected from halogen, d _-3 -alkyl optionally substituted with halogen, d-e-aikoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifluoromethyl; plperidinyl which is optionally substituted with -NR ¹⁴ R ¹⁵ or C -alkyi optionally substituted with halogen, hydroxyl, C -alkoxy, -NR ¹⁴ R ^1S , phenyl, plperidinyl, morphollnyl or 4- R ¹⁹ - plperazin-l-yl; -C _1-3 -alkyl-plperidinyl optionally substituted with -NR ¹⁴ R ¹⁵ or Cn-alkyl optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ¹⁵ , phenyl, plperidinyl, morphoiiny! or 4- R ¹⁹ -plperazln-1-yl; C _3-6 -cycloaikyl optionally substituted with -NR ¹⁴ R ¹⁵ or C^-alkyl optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ^1S , phenyl, piperidlnyl, morphollnyl or 4- R ¹⁹ - piperazln-1-yl; and C^-alkyl, which C _1-6 -alkyl is optionally substituted with one or more of halogen, amino, cyano, hydroxy, C _1- e-alkoxy, -NR ¹⁴ R ¹⁵ , phenyl, morphollnyl or C _3-6 cydoalkyl, which C3_e cydoalkyl is optionally substituted with -NR ¹⁴ R ¹⁵ , phenyl, plperidinyl, morphollnyl or 4-R ¹⁹ -plperazln-1-yl; with the proviso that when B is phenyl, then 8 Is substituted with at least one substituent;

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 ^IE )S(0 ₂ )-, d-j-alkylene, ethenylene or ethynylene;

R ³ and R ⁴ each Independently represent hydrogen, C _1-6 -aikyi or C _3-6 -cycioalS yl, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocydic ring;

R ⁵ and R ⁶ each Independently represent hydrogen, C^-alkyl or C _3-6 -cycioalkyi, 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 _1-6 -alkyl or C ₃ - _s -cycioaikyl, 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 _1- «-alkyl or C _3-6 -cycloaikyl, 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", R ¹² and R ¹³ each Independently represent a hydrogen atom or a C^-alkyl or C ₃ . _s ~ cydoalkyl;

R ¹⁶ represents a hydrogen atom or Ci^-alkyl; R ¹⁷ represents halogen, cyano, cydopropyl or C _h alkyl optionally substituted with halogen, cyano, or cydopropyl optionally substituted with methyl or halogen; or two R ¹⁷ together with the carbon atom(s) to which they are attached form a cydopropyl;

R ¹⁸ represents a hydrogen atom, or C _1-3 -alkyl optionally substituted with halogen or methyl cydopropyl, wherein methyl cydopropyl is optionally substituted with methyl or halogen; R ¹⁹ represents C ₃ . ₅ -cydoalkyl, -C _1-3 -alkyi-C ₃ . ₅ -cycloaikyl or d.-g-alkyi; and

R ²⁰ each Independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci^-alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, pharmaceutically acceptable salts, solvates, and hydrates thereof.

In a further aspect dislosed herein, is a compound of above formula I, wherein R ¹ represents hydrogen, halogen, hydroxy!, nitro, cyano, or mercapto, or R ¹ represents -Q-CH ₃ , -O-C ₂ H ₅ , - S-CH ₃ , -S-QtHj or -C _a-3 -alkyl, which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H _S or -d _-3 -alkyl is optionally substituted with at least one substttuent selected from halogen, hydroxyl, nitro, cyano and mercapto;

R ² represents hydrogen, halogen, hydroxyl, nitro, cyano, or mercapto, or R ² represents -O-CH ₃ , -0-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H _S , cydopropyl or C _1-3 -alkyl, which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ , cydopropyl or C _1-3 -alkyl Is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nitro, cyano and mercapto, or R ² represents a 5-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 optionaiiy substituted with at least one substituent selected from halogen, d- ₃ -alkyi optionally substituted with halogen, carboxyl, hydroxy!, nitro, cyano, -NR ³ R ⁴ , and mercapto, or R ^z represents a phenyl ring, which phenyl ring Is optionally substituted with at least one substituent selected from halogen, C _1-3 - alkyl optionally substituted with halogen, carboxyl, hydroxyl, cyano, -NR ³ R ⁴ , and mercapto; or R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen atom(s), and which aromatic ring is optionally substituted with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto; or R ¹ and R ^l together form C _3-6 -cycloaikyl or C _3-6 -heterocycloalkyl, which C _3-6 -cycioalkyl or C ₃ . 6-heterocydoaikyl Is optionally substituted with at least one substituent selected from halogen, hydroxyl, nitro, cyano and mercapto;

D represents an oxygen atom or a sulphur atom;

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 selected from halogen, Ci _-3 -alkyl, which C _1-3 -alkyl is optionally substituted with halogen, C _1-6 -aikoxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxyl, nitro, cyano, mercapto and trifluoromethyl; B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionaiiy 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 selected from halogen; carboxyl; hydroxyl; amino; nitro; cyano;

mercapto; C _3-6 -cycioaikyi; C ₂ . ₅ -a!kenyi; trifluoromethyl; trifluoromethoxy; C _1-6 -alkoxy; Ci+- thloalkyl; C _1-e -alkylcarbonyl; Ci^-alkylcarbonyloxy; C _1-6 -alkoxycarbonyl; -NR ³ R ⁴ ; -C(0)NR ⁵ R ⁶ ; -N(R ⁷ )C(0)R ⁸ ; -S-C _1- 3-alkyl; -S(0) ₂ NR ⁹ R ¹⁰ ; -N(R ^u )S(0) ₂ R ¹² ; -S(0).R ¹³ wherein a Is 0, 1 or 2; -NHC(=NH)NH ₂ ; -C(=NH)NH ₂ ; benzyloxy; -S(0) ₂ -(4-(Ca-«-alkyl)plperazln-1-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 _1-6 -alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifluoromethyl; -(C ₁ . ₂ -alky1)-4-R ¹⁹ -plperazin-1-yl in which the Ci. ₂ -alkyl is optionally substituted with one or more -R ¹⁷ ; -N(R ^1B )-4-R ¹⁹ -plperazln-1-yl; -O-4- R ¹ *- piperaz!n-1-yl; -C("0)-4-R ¹⁹ -plperazin-1-yl; -S(0) ₂ -(4-(C ₃ - ₅ -cycloalkyl)plperazln-1-yl); - S(0) ₂ -(4-(C _3-5 -cycloalkyl-C ₁ - ₃ -alkyl)plperazln-1-yl); -S(0) ₂ (-C ₁ .«-alkyldiazepanyl ) which Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, Ci. ₆ -alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifiuoromethyl; 4-(C _1-6 - alkyi)plperazln-1 -yl which Is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, d-e-alkoxy, trifiuoromethoxy, hydroxy!, nitro, cyano, mercapto and trifiuoromethyl; piperidinyl which is optionally substituted with -NR ¹⁴ R ¹⁵ or d-e- alkyfand wherein d-e-aikyl is optionally substituted with halogen, hydroxyl, d. ₆ -alkoxy, - NR ^W R ¹⁵ , phenyl or morphollnyl; with the proviso that when B is phenyl, then B is substituted with at least one substituent;

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;

R ³ and R ⁴ each Independently represent hydrogen, d-e-a!kyl or C ₃ . _e -cycloa!kyi, 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 ^s and R ⁶ each independently represent hydrogen, d-«-alkyl or C _3-6 -cycioaikyi, 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 -a!ky! or C _3-6 -cycioa!kyi, 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 ^1S each Independently represent hydrogen, d-e-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 d-e-alkyl or C _3-6 - cydoalkyl; R" represents a hydrogen atom or d-e-aikyl;

R ¹⁷ represents a hydrogen atom, halogen, or C _1-3 -alkyl optionally substituted with halogen or methylcydopropyl, wherein methylcyclopropyl is optionally substituted with methyl or halogen; R represents a hydrogen atom, or C _1-3 -aikyl optionally substituted with halogen or methyl cydopropyl, wherein methyl cyclopropyl Is optionally substituted with methyl or halogen; and 1 ⁹ represents -C _1-3 -a Iky I -C _3-5 -cycloa I ky I or C _1-3 -alkyl; as well as stereoisomers, a pharmaceutically acceptable salts, solvates, and hydrates thereof, is provided.

In a further aspect disclosed herein, is a compound of the formula (I) wherein

R ¹ represents hydrogen, halogen, hydroxyl, nltro, cyano, or mercapto, or Rl represents -O- CH ₃ , -O-C ₂ H ₅ , -S~CH ₃ , -S-CjHs or -do-alkyl, which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H _S or - C _1- 3-alkyl is optionally substituted with halogen, hydroxyl, nltro, cyano and mercapto; R ² represents hydrogen, halogen, hydroxyl, nitro, cyano, or mercapto, or R ² represents -O- CH ₃ , -O-C ₂ H ₅ , -S-CHj, -S-C ₂ H ₅ , cyclopropyl or C,- ₃ -alkyl, which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , - S-C ₂ H _S , cyclopropyl or C _1- j-alkyl is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nltro, cyano and mercapto or R ² represents a 5-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 substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto; or R ¹ and R ² together form C _3-6 -cyc!oalkyi or C _3-6 -heterocyc!oa!kyi, which C cydoalkyl or C ₃ . _e -heterocycloalkyl is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nitro, cyano and mercapto;

D represents an oxygen atom or a sulphur atom;

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 substltuent selected from halogen, Ci _-3 -alkyl, which C _1-3 -alkyl is optionally substituted with halogen, Ci. ₆ -alkoxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxyl, nltro, cyano, mercapto and trifiuoromethyl; 8 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 selected from halogen, carboxyl, hydroxyl, amino, nltro, cyano, mercapto, C ₃ .. ₆ -cycioalkyi, C ₂ „ ₆ -alkenyi, trifiuoromethyl, tr!flucromethoxy, Cj. ₆ -alkoxy, C _1-6 - thioalkyl, Ci. ₆ -alkylcarbonyl, C _1- g-aikylcarbonyioxy, C _1-6 -alkoxycarbonyi, -NR ³ R ⁴ , -C(0)NR ⁵ R ⁶ , -N(R ⁷ )C(0)R ⁸ , -S-C _1- a-alkyl, -S(O) ₂ NR ⁹ R ⁱ⁰ , -N(R ^u )S(0) ₂ R ¹² , -S(0).R ¹³ wherein a Is 0, 1 or 2, - NHC(=NH)NH ₂ , -C(»NH)NH ₂ , benzyloxy, -S(0) ₂ (C _1-6 -N-alkyipiperazinyi), which -S(0) ₂ (C«-N- alkylplperazlnyl) Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyI optionally substituted with halogen, C _1- e-alkoxy,

trlfluoromethoxy, hydroxyl, nltro, cyano, mercapto and trifiuoromethyl, -5(0) ₂ .(C _1-6 -N- alkyldlazepanyl), which -S(0) ₂ (C _1-6 -N- alkyldiazepanyi) Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C _1-e -alkoxy, trlfluoromethoxy, hydroxyl, nltro, cyano, mercapto and

trifiuoromethyl, d^-N- alkylplperazlnyl, which C _x . ₆ -N- alkylpiperazinyl Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C^-alkoxy, trlfluoromethoxy, hydroxyl, nltro, cyano, mercapto and trifiuoromethyl, plpet dlnyl, which plperidlnyl is optionally substituted with - NR ¹ R ¹⁵ or C -g-alkyl, and Q^-alkyl, which Q-e-alkyi Is optionally substituted with halogen, hydroxyl, C alkoxy, -NR ¹ R ¹⁵ , phenyl or morphoi!nyl; with the proviso that when B Is phenyl, then B Is substituted with at least one substituent;

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^-alkylene, ethenylene or ethynylene;

R ³ and R ⁴ each Independently represent hydrogen, C^-alkyl or C ₃ - ₆ -cycioaikyl, 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 ^s and R ^e each Independently represent hydrogen, C _1-s -a!kyl or C _3-6 -cycioalkyi, 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 -aikyl or C _3-6 -cycioa!kyi, 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-g-alkyl or C _3-6 -cycioalkyl, 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 _1-6 -a!kyl or C _3-6 - cycfoaiky!; and R ¹⁶ represents a hydrogen atom or C _1-6 -alkyl; as well as stereoisomers, a pharmaceutically acceptable salts, solvates, and hydrates thereof, is provided.

In a further aspect, disclosed herein is a compound of the formula (II)

wherein

R ¹ represents hydrogen; halogen; hydroxyl; nitro; cyano or mercapto; or R ¹ represents -O- CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ or -Ci _-3 -alkyl; which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ or - C _1-3 -alkyl Is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nltro, cyano and mercapto;

R ² represents hydrogen; halogen; hydroxyl; nltro; cyano or mercapto; or R ² represents -O-CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H _S ; cydopropyl, Ci _-3 -alkyl; C _2-3 -alkenyl; or C _2-3 -alkynyl; which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H _S , cydopropyl, C _1-3 -aikyl, C _2-3 ~aikenyl or C _2-3 -alkynyl Is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nitro, cyano and mercapto; or R ² represents a 5-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 selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxy!, nitro, cyano, - NR ³ R ⁴ , and mercapto; or R ² represents a phenyl ring, which phenyl ring Is optionally substituted with at least one substituent selected from halogen, Q^-alkyl optionally substituted with halogen, carboxyl, hydroxyl, cyano, -NR ³ R ⁴ , and mercapto; or R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen atom(s), and which aromatic ring is optionally substituted with at least one substituent selected from halogen, Ci _-3 -a!kyi optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ . _e -cycloaikyl or C _3-6 -heterocycioalkyl, which C _3-e -cycioalkyi or C ₃ -6~heterocycloaikyl is optionally substituted with at least one substituent selected from halogen, hydroxy!, nitro, cyano and mercapto;

D represents an oxygen atom or a sulphur atom;

B represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionaily comprises at least one ring heteroatom selected from a nitrogen atom, an oxygen atom and a sulphur atom, and which aromatic ring system Is optionaily substituted with at least one substituent Q selected from halogen; carboxyl; oxo; hydroxyl; amino; nitro; cyano; mercapto; C ₃ .. ₆ -cycioaikyl; C ₂ . ₆ -alkeny!; trifluoromethyl; trifiuoromethoxy; Q _t - ₆ -alkoxy; C^- thloalkyl; Ci. ₆ -alkylcarbonyl; C _1-6 -a!kylcarbonyloxy; d-e-alkoxycarbonyl; -NR ³ R ⁴ ; -C(0)NR ⁵ R ⁶ ; -N(R ⁷ )C(0)R ^e ; -S-d-a-alkyl; -S(0) ₂ NR ⁹ R ¹⁰ ; -N(R ⁿ )S(0) ₂ R ¹² ; -S(0),R ¹³ wherein a is 0, 1 or 2; -NHC(==NH)NH ₂ ; -C(=NH)NH ₂ ; benzyioxy; -S(0) ₂ -(4- R ¹⁹ -piperazin-1 -yl) optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -(C _1-2 -alkyl)-4- R ¹⁹ -piperazln-1 -yl In which the Ci. ₂ -alkyl is optionally substituted with one or more -R ¹⁷ and in which the plperazine ring is optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -N(R ⁱ⁸ )-4-R ⁱ⁹ -piperazin-1 -yi; -O-4- R ¹⁹ -plperazln-1 -yl; -C(«0)- 4-R ⁱ⁹ -piperazin-1 -yi; -S(0) ₂ (-Ci. ₆ -alkyldiazepany!) which is optionally substituted at a carbon atom with at least one substituent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, C _{1 -6} -aikoxy, trifiuoromethoxy, hydroxyl, nitro, cyano, mercapto and

trifluoromethyl; 4-(Ci. ₆ - alkyl)plperazin-1 -yl which Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C^-alkoxy, trifiuoromethoxy, hydroxy!, nitro, cyano, mercapto and trifluoromethyl; piperfdinyl which Es optionally substituted with -NR ^w R ¹⁵ or Ci ₆ -a!kyi optionally substituted with halogen, hydroxyl, C _1-6 -aikoxy, -NR ¹⁴ R ^1S , phenyl, piperidlnyl, morpholinyi or 4- R ¹⁹ - plperazln-1 -yl; -C _1-3 -alkyl-plperidinyi optional!y substituted with -NR ¹⁴ R ¹⁵ or Ci^-alkyl optionally substituted with halogen, hydroxyl, -NR ¹ R ¹⁵ , phenyl, piperidlnyl, morpholinyi or 4- R ¹⁹ -p!perazin-1 -yl; C ₃ .. ₆ -cycloaikyl optionally substituted with -NR ¹⁴ R ¹⁵ or C _1- e-alkyl optionally substituted with halogen, hydroxy!, -NR ¹⁴ R ^1J , phenyl, p!peridinyl, morphollnyl or 4- R ¹⁹ - plperazin-1 -yl; and C _t -e-alkyl, which d^-alkyl is optionally substituted with one or more of halogen, amino, cyano, hydroxy, Ci-g-alkoxy, -NR ¹⁴ R ^1S , phenyl, morpholinyl or C _3-6 cycioalkyi, which C _3-6 cycioalkyi Is optionally substituted with -NR ¹⁴ R ^1S , phenyl, plpei dlnyl, morphollnyl or 4-R ¹⁹ -plperazin-1 -yl; with the proviso that when B is phenyl, then B is substituted with at least one substituent;

X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, ~S(0 ₂ )-, -N(R ¹⁸ )-, - 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; R ³ and R ⁴ each independently represent hydrogen, C _1-6 -aikyi or C _3-6 -cycloaikyl, 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 ^s and R ⁶ each independently represent hydrogen, Ci. _s -alkyl or C _3-6 -cyc!oaikyl, 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^-alkyl or C _3-6 ~cycioaiky!, 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 _1-6 -aikyl or Cj-g-cycEoaiky!, 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 - cydoalkyl;

R ¹⁶ represents a hydrogen atom or C _1-6 -alkyl; R ¹⁷ represents halogen, cyano, cydopropyl or C _1-3 -alkyl optionally substituted with halogen, cyano, or cydopropyl optionally substituted with methyl or halogen; or two R ¹⁷ together with the carbon atom(s) to which they are attached form a cydopropyl; R represents a hydrogen atom, or Q^-aikyi optionally substituted with halogen or methyl cydopropyl, wherein methyl cyc!opropyi Is optionally substituted with methyl or halogen;

R ¹⁹ represents C ₃ . ₅ -cycloaiky!, -Ci _-3 -8lkyi-C ₃ . ₅ -cycloalkyl or C _1- e-alkyl; and

R ^zo each Independently represent halogen, hydroxy!, cyano, mercapto, amino or Q-g-aiky! optionally substituted with halogen, hydroxy!, cyano, amino or mercapto; as well as stereoisomers, pharmaceutically acceptable salts, solvates, and hydrates thereof.

In a further aspect, disclosed herein Is a compound of the formula (III)

wherein R ¹ represents hydrogen; halogen; hydroxyl; nltro; cyano or mercapto; or R ¹ represents -O- CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ or -d _-3 -alkyl; which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H _S or - C _1-3 -alkyl Is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nltro, cyano and mercapto;

R ² represents hydrogen; halogen; hydroxyl; nltro; cyano or mercapto; or R ² represents -O-CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ ; cydopropyl, C _1- s-alkyl; C _2-3 -alkenyl; or C _2-3 -alkynyl; which -O-CH3, -O-C ₂ H ₅ , -S-CH ₃ , -S-C2H5, cydopropyl, C _1-3 -alkyl, C _2-3 -alkenyl or C _2-3 -alkynyl Is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nltro, cyano and mercapto; or R ² represents a 5-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 substltuent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxy!, nltro, cyano, - NR ³ R ⁴ , and mercapto; or R ² represents a phenyl ring, which phenyl ring is optionally substituted with at least one substituent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxy!, cyano, -N ³ R ⁴ , and mercapto; or R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen atom(s), and which aromatic ring is optionally substituted with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto; or R ¹ and R ² together with the carbon atom to which they are attached form C _3-6 - cycioalkyi or C ₃ - ₆ '-heterocycioa!kyi, which C^-cydoalkyl or C _3-6 ~heterocycloalkyi Is optionally substituted with at least one substituent selected from halogen, hydroxyl, nltro, cyano and mercapto; D represents an oxygen atom or a sulphur atom;

Q is selected from halogen; carboxyl; hydroxyl; amino; nltro; cyano; mercapto; C _3-6 - cyc!oalkyl; C ₂ - ₆ -aikenyl; trifiuoromethyl; trifluoromethoxy; C _1-6 -alkoxy; C _1-s -thloalkyl; C _1-6 - alkylcarbonyl; C _1-6 -alkyicarbonyioxy; C _1-6 -alkoxycarbonyl; -NR ³ R ⁴ ; -C(0)NR ⁵ R ⁶ ; -N(R ⁷ )C(0)R ⁸ ; -S-C _1-3 -alkyl; -S(0) ₂ NR ⁹ R ¹⁰ ; -N(R ⁿ )S(0) ₂ R ¹² ; -S(0).R ¹³ wherein a is 0, 1 or 2;

-NHC(=NH)NH ₂ ; -C(=NH)NH ₂ ; benzyloxy; -S(0) ₂ -(4- R ¹⁹ -plperazln-1 -yl) optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -(d. ₂ -alkyl)-4- R ⁱ⁹ -plperazin-1 -yl in which the C _1-2 -alkyl is optionally substituted with one or more -R ¹⁷ and In which the piperazine ring is optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -N(R ¹⁸ )-4-R ¹⁹ -plperazin-1 -yl; -O-4- R ¹⁹ -plperazln-1 -yl; -C(==Oj- 4-R ⁹ -piperazln-1 -yl; -S(0) ₂ (-C ₁₄ -alkyldlazepanyi) which is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C alkoxy, trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and

trifiuoromethyl; 4-(Ci. ₆ ~ alkyl)piperazln-1 -yl which is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, Ci^-alkoxy, trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and trifiuoromethyl; plperidlnyl which is optionally substituted with -NR ¹⁴ R ¹⁵ or Ci. ₆ -aikyl optionally substituted with halogen, hydroxy), Cj-g-alkoxy, -NR ¹⁴ R ¹⁵ , phenyl, plperidlnyl, morpholiny! or 4- R ¹⁹ - plperazln-1 -yl; -C _1-3 -alkyl-piperidinyl optionally substituted with -NR ¹⁴ R ¹⁵ or Ci. ₆ -alkyi optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ¹⁵ , phenyl, piperldinyl, morpholinyl or 4- R ¹⁹ -piperazln-1 -yl; C cydoalkyl optionally substituted with -NR ¹⁴ R ¹⁵ or Ci. ₆ -aikyl optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ¹⁵ , phenyl, plperidlnyl, morpholinyl or 4- R ¹⁹ - piperazln-1 -yl; and Q-e-alkyl, which Ci. _e -alkyl Is optionally substituted with one or more of halogen, amino, cyano, hydroxy, C _1-6 -a!koxy, -NR ¹⁴ R ^1S , phenyl, morpholinyl or C _3-6 cycioalkyi, which C _3-6 cycioalkyi Is optionally substituted with -NR ¹⁴ R ¹⁵ , phenyl, plperidlnyl, morpholinyl or 4-R ¹⁹ -plperazln-1 -yl; with the proviso thst when B is phenyl, then B is substituted with at ieast one substituent; 3 and R ⁴ each independently represent hydrogen, Ci.. ₆ --alkyi or C ₃ .. ₆ -cycioaiky! _f 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 _1-6 -aikyi or C _3-6 -cycioa!kyl, or R ^s and R ⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

R* and R ¹⁰ each independently represent hydrogen, Ci^-alkyl or C _3-6 -cycioalkyi, 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 ^w and R ^1S each independently represent hydrogen, C^-alkyl or C^-cydoalkyl, or R ¹⁴ and R ^1S together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

R ⁷ , R ^e , R ^u , R ¹² and R ¹³ each independently represent a hydrogen atom or a Ci^-alkyl or C _3-6 - cycloalkyi;

R ¹⁶ represents a hydrogen atom or C^-alkyl;

R ¹⁷ represents halogen, cyano, cydopropyl or C _1-3 -alkyl optionally substituted with halogen, cyano, or cydopropyl optionally substituted with methyl or halogen; or two R ¹⁷ together with the carbon atom(s) to which they are attached form a cydopropyl; R ¹⁸ represents a hydrogen atom, or Ci _-3 -alkyl optionally substituted with halogen or methyl cydopropyl, wherein methyl cydopropyl Is optionally substituted with methyl or halogen;

R ¹⁹ represents C ₃ . _s ~cycloalkyl, -C _1- s-aikyl-Qs-s-cyc!oaikyl or C _1-6 -aIkyi; and

R ²⁰ each Independently represent halogen, hydroxyl, cyano, mercapto, amino or Ci^-alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, pharmaceutically acceptable salts, solvates, and hydrates thereof- The term "DPPI" as used herein Is Intended to mean dipeptldy!-peptldase I (EC 3.4.14.1) also known as cathepsln C, cathepsin J, dipeptldyl amlnopeptldase I and dlpeptidyl transferase. DPPI cleaves a dlpeptide 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. "Enantiomer!caiiy enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomeiically 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 racemlc 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 -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H _S , cydoalkyl, C _1-3 -alkyl, heterocycloalkyi, or an aromatic or non-aromatic ring, may be unsubstituted or substituted with one or more substttuents 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 substttuent and that the substitution results In a stable compound (I.e. one that does not spontaneously undergo transformation such as by rearrangement, cydization, or elimination). In certain embodiments, a single atom may be substituted with more than one substftuent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substttuents 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 or HI may contain one or more asymmetric centers (also referred to as a chlral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chlral centers may also be present In a substltuent such as an alkyl group. Where the

stereochemistry of a chlral center present In Formula I, II or III, 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 or III containing one or more chlral center may be used as racemlc mixtures, enantiomerically enriched mixtures, or as enantiomerically pure Individual stereoisomers.

Individual stereoisomers of a compound according to Formula I, II or III 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 dlastereolsomerlc salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer- specific reagent, for example by enzamatlc oxidation or reduction; or (3) by gas-liquid or liquid chromatography In a chlral enviornment, for example, on a chlral support such as silica with a bound chlral ligand or in the presence of a chlral 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 enantlomer to the other by asymmetric transformation. The compounds according to Formula I, II or III 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 or III, or In any chemical structure illustrated herein, Is not specified, the structure is intended to encompass the trans (E) geometric isomer, the ds (Z) geometric Isomer, and all mixtures thereof. If there is a cycloalkyl or cydoalkenyl group present, some substltuent patterns may result in and axial or an equatorial configuration. Both forms are Induded, unless spedfied otherwise. All tautomeric forms are also included in Formula I, II or III whether such tautomers exist In equilibrium or predominately in one form. In certain embodiments, compounds according to Formula I, II or III 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 or III may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable add addition salts by treatment with a suitable add. Thus, the skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds according to Formula I, II or III may be prepared. Indeed, In certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I, II or III may be preferred over the respective free base or free add because such salts impart greater stability or solubility to the molecule thereby fadlitatlng formulation into a dosage form. Accordingly, the Invention Is further directed to pharmaceutically-acceptable salts of the compounds according to Formula I, II or III.

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 add or free base form with a suitable base or add, 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 appredate 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, Indudlng 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 substttuent 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 _1-6 -aikyi" denotes a straight or branched, saturated hydrocarbon chain having from one to six carbon atoms. Examples of C^-alkyl include methyl, ethyl, propyl, 2-methyl-1- propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dlmethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1- pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n- pentyl, isopentyl, neopentyl and n-hexyl. Examples of C _1-3 -alkyl include e.g. methyl, ethyl and propyl.

The term ^w C _1-3 -alkyiene ^ff as used herein represents a branched or straight hydrocarbon group having from 1 to 3 carbon atoms, e.g. methylene, ethylene, Isopropylene or propylene and the like. The term "C2-e-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. C ₂ . ₆ -alkenyl, C _3-s -alkenyl, and the like. Representative examples are ethenyl (or vinyl), propenyl (e.g. prop-1-enyl, prop-2-enyl), butadlenyf (e.g. buta-1,3-dlenyl), butenyl (e.g. but-1-en-1-yl, but-2-en-1-yl), pentenyl (e.g. pent-1-en-1-yl, pent-2-en-2-yl), hexenyl (e.g. hex-1-en-2-yl, hex-2-en-1-yl), l-ethylprop-2-enyl, i,l-(dlmethyl)prop-2-enyl, l-ethylbut-3-enyl, l,l-(dlmethyl)but-2-enyl, and the like.

The term *C _2-3 -alkyny as used herein represents a hydrocarbon group having from 2 to 3 carbon atoms and at least one triple bond, e.g. ethynyl or propynyl.

The term "Cj-s-cycioalkyi" as used herein represents a saturated monocyclic carbocyclic ring having from 3 to 6 carbon atoms. Representative examples are cydopropyl, cydobutyl, cyclopentyl, cyciohexyl, and the like. The term ^w C _3- rcycloalky as used herein represents a saturated monocyclic carbocyclic ring having from 3 to 7 carbon atoms. Representative examples are cydopropyl, cydobutyl, cydopentyl, cyciohexyl, cycloheptyl and the like.

"C _1- s-thioalkyl" as used herein refers to the radical Ci. ₆ -alkyl-S-. Representative examples are methylthlo, ethylthio, propytthlo (e.g. 1-propylthio, 2-propylthio, 3-propylthlo), butylthio, pentyl thlo, hexylthlo, and the like. " w-heterocycloalky as used herein means a non-aromatic monocyclic or polycydfc 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 azirldinyl, pyrrolidinyl, pyrrolidine, piperidlnyl, piperidino, piperazinyl, plperazlno, morpholinyl, morpholino, thlomorphoiinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyi, and pyranyl.

"C _1- 6-alkoxy" as used herein refers to the radical C _1-6 -aikyi-O-. 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.

"C _1- 6-alkylcarbonyr as used herein refers to the radical d-s-alkyl-C(»0)-. Representative examples are acetyl (methylcarbonyl), proplonyl (ethylcarbonyl), butanoyl (prop-1-y carbonyl, prop-2-ylcarbonyl), and the like.

"C _1- 6-a Iky lea rbony loxy* as used herein refers to the radical Ci. ₆ -a!kyl-C(==O)0-> ^w Ci _-6 -alkoxycarbony!" as used herein refers to the radical C _1-6 -alkoxy-C(=0)-. Representative examples are methoxvea rbonyl , ethoxycarhonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxyca rbonyl, 2-methyl- 2-propoxycarbonyl, 3-methylbutoxyca rbonyl, 1-hexoxyca rbonyl, and the like.

The term "benzyloxy" as used herein refers to the radical C ₆ H ₅ CH ₂ 0-

The term "halogen" or "halo* means fluorine, chlorine, bromine or Iodine.

The term "carboxyi" shall mean the radical -COOH,

The term "ca rbonyl" 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 -CK The term "nitra" shall mean the radical -NO^

The term "cyano" shall mean the radical -CN,

The term "mercapto* shall mean the radical -SH.

The term "amino" shall mean the radical -NH ₂ . Where, for example, two substituents such as R ¹ and R ² both represent a Cus-alkyt group or both represent a C _3-6 -cyc!oalkyi group, the alkyl or cydoalkyl groups may be the same as, or different from, one another.

The term *5-membered aromatic ring" as used herein denotes a radical of a 5-membered aromatic ring optionally comprising at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen atom. In one aspect the term "5-membered aromatic ring" as used herein denotes a radical of an aromatic ring optionally comprising at least one ring heteroatom selected from a nitrogen atom and an oxygen atom. Examples Include but are not limited to five-membered rings with a single heteroatom such as thienyl, thiazolyl, imldazo!yl, pyrazolyl, oxazolyl, pyrrolyl and furanyl. The term "5-membered non-aromatic ring" as used herein denotes a radical of a 5- membered non- aromatic ring optionally comprising at least one ring heteroatom selected from a sulphur atom, a nitrogen atom and an oxygen atom. In one aspect the term "5- membered non-aromatic ring" as used herein denotes a radical of an non-aromatic ring optionally comprising at least one ring heteroatom selected from a nitrogen atom and an oxygen atom. Examples Include but are not limited to five-membered rings with a single heteroatom such as cydopentenyl, cydopentanyl, tetrahydrofuranyl and pyrrolidlnyl.

The term "6-membered aromatic ring which aromatic ring comprises one, two or three nitrogen atom(s)* as used herein denotes a radical of a 6-membered aromatic ring comprising one, two or three nitrogen atom(s). Examples include but are not limited to pyridine, pyrimidine, pyrazine, and pyridazine,

The term, for example, "R ³ and R ⁴ together with the nitrogen to which they are attached, form a 4- to 7-membered ring saturated heterocydlc ring" or "R* and R ¹⁰ together with the nitrogen to which they are attached, form a 4- to 7-membered ring saturated heterocydlc ring" or "R ¹⁴ and R ^1S together with the nitrogen to which they are attached, form a 4- to 7- membered ring saturated heterocyclic ring" as used herein will optionally contain at least one further ring heteroatom selected from nitrogen, oxygen and sulphur (such as preferably contain a single nitrogen ring atom) and represents but are not limited to morphollnyl, plperaz!nyl, plper!d!nyi, pyrrolldinyl, and the like.

For the avoidance of doubt, It should be understood that the definitions of the heterocyclic rings In formula (I) are not Intended to include structures having any 0-0, 0-S or S-S bonds and that a substttuent, 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- membered or 4- to 7-membered saturated heterocyclic rings In formula (I) are not intended to include structures wherein the groups -S-, -O- and -S(O)- are adjacent to each other, i.e, that the rings do not Include any O-O, O-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 poiycyclic (e.g. blcydic 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 (or as also named herein S(=0) ₂ ) are mentioned below. Representative examples are phenyl, naphthyl, pyrrolyl (e.g. pyrrol-1 -yl, pyrrol-2-yl, pymol-3-yl), furanyl (e.g. furan-2-yl, furan-3- yl), thienyl (e.g. thlen-2-yl, thlen-3-yl), oxazolyl (e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), thiazo!yl (e.g. thlazol-2-yl, thlazol-4-yl, thlazol-5-yl), imidazolyl (e.g. imldazol-2-yl, imidazol- 4-yl, lmidazol-5-yl), pyrazolyl (e.g. pyrazol-1 -yl, pyrazol-3-yl, pyrazol-5-yi), isoxazolyl (e.g. isoxazol-3-yl, lsoxazol-4-yl, lsoxazol-5-yl), isothlazolyl (e.g. lsothlazol-3-yl, lsothiazol-4-yl, lsothlazol-5-yl), 1,2,3-triazolyl (e.g. 1,2,3-trlazol-1 -yl, 1 ,2,3-trlazol-4-yl, 1 ,2,3-trlazol-5-yl), 1,2,4-trlazolyl (e.g. 1,2,4-trlazol-1 -yl, 1 ,2,4-trlazol-3-yl, 1 ,2,4-trlazol-5-yl), 1,2,3-oxad!azolyl (e.g. 1 ,2,3-oxadlazol-4-yl, 1 ,2,3-oxadlazol-5-yl), 1,2,4-oxadlazoiyi (e.g. 1 ,2,4-oxadiazo!-3-yl, 1 ,2,4-oxadlazol-5-yl), 1,2,5-oxadiazoiyl (e.g. 1 ,2,5-oxadlazol-3-yl, 1 ,2,5-oxadlazoi-4-yl), 1,3,4- oxadiazoiy! (e.g. 1 ,3,4-oxadiazol-2-yl, 1 ,3,4-oxadiazol-5-yl), 1,2,3-thladlazolyl (e.g. 1,2,3- thiadlazoi-4-yi, 1 ,2,3-thladlazol-5-yl), 1,2,4-thiadlazolyl (e.g. 1 ,2,4-thladlazol-3-yl, 1,2,4- thladlazol-5-yl), 1,2,5-thladlazotyl (e.g. 1 ,2,5-th!adlazoi-3-yl, 1 ,2,5-thladlazol-4-yl), 1,3,4- thiadiazo!yi (e.g. 1,3,4-th ladlazol-2-yl, 1 ,3,4-thiadiazol-5-yl), tetrazolyi (e.g. tetrazol-1 -yl, tetrazol-5-yl), pyranyl (e.g. pyran-2-yl), pyrtdlnyl (e.g. pyridlne-2-yl, pyrldlne-3-yl, pyrldlne- 4-yl), pyridazlnyl (e.g. pyrldazln-2-yl, pyrldazin-3-yl), pyrlmldlnyl (e.g. pyrlmldln-2-yl, pyrimidin-4-yi, pyrimldln-5-yl), pyrazinyl, 1,2,3-triazinyi, 1,2,4-trlazinyl, 1,3,5-triazlnyl, thiadlazlnyl, azepinyl, azecinyi, and the like. Aromatic ring system Is also intended to Include bicycllc 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- 1-yl, lndol-2-yl, lndol-3-yl, lndol-5-yl), Isolndolyl, 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]thlen-3-yl,

benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]thien-3-yl, benzo[c]thlen-5-yl), Indazolyl (e.g. indazol-1 -yl, indazoi-3-yl, indazol-5-yl), Indollzinyl (e.g. indollzin-1 -yl, indollzln-3-yl), benzopyrany! (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yi, benzo[c]pyran-1 -yl,

benzo[c]pyran-7-yl), benzimidazolyl (e.g. benzimldazol-1 -yl, benzlmldazol-2-yl,

benzimldazol-5-yl), benzothiazolyl (e.g. benzot lazol-2-yl, benzothlazol-5-yl),

benzisothlazolyl, benzoxazotyl, benzisoxazolyl, benzoxazinyi, benzotriazolyl, naphthyridinyl (e.g. 1 ,8-naphthyridin-2-yl, l,7-naphthyridin-2-yl, 1 ,6-naphthyrtdln-2-yl), phthalazinyl (e.g. phtha!azln-1 -yl, phthalazin-5-yi), pterldinyi, pur!ny! (e.g. purin-2-yl, purtn-6-yl, purin-7-yl, purln-8-yl, purin-9-yl), quinazolinyi (e.g. quinazolin-2-yl, quinazolin-4-yl, quinazolln-6-yl), dnnollnyl, quinoliny (e.g. quinolin-2-yl, quinolln-3-yl, qulnolln-4-yl, quinolln-6-yl), isoqulnoliny! (e.g. isoquinolin-1 -yl, isoquinolin-3-yi, isoquino!ln-4-yl), quinoxallnyl (e.g.

qulnoxalin-2-yl, quinoxaiin-5-yi), pyrrolopyridinyl (e.g. pyrrolo[2,3-b]pyrldinyl, pyrrolo[2,3- cjpyridinyl, pyrroio[3,2-c]pyi1dinyl), furopyridinyl (e.g. furo[2,3-b]pyridinyl, furo[2,3- c] pyridinyl, uro[3,2-c]pyridinyl), thienopyridinyl (e.g. thleno[2 _f 3-b]pyrtdinyl, thleno[2,3- cjpyridinyl, thleno[3,2-c]pyridlnyl), Imldazopyridinyl (e.g. Smidazo[4,5-b]pyr!diny!, imidazo[4,5-c]pyr1dlnyi, imidazo[1 ,5-a]pyridinyl, lmidazo[1 ,2-a]pyridinyl), Imldazopyrimidinyl (e.g. imidazo[1 ,2-a]pyrimidirtyl, imidazo[3,4-a]pyrjmldinyi), pyrazolopyridlnyl (e.g.

pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridlnyl, pyrazolo[1 ,5-a]pyridlnyl),

pyrazolopyrimid!nyl (e.g. pyrazolo[1 ,5-a]pyrlmldinyl, pyrazolo[3,4-d]pyrimldinyl),

hlazolopyridinyl (e.g. thiazolo[3,2-d]pyrid!nyl), thiazolopyrimidinyl (e.g. thlazolo[5,4- d] pyrimidlnyl), imdazothiazolyl (e.g. imldazo[2,l-b]thiazolyl), triazolopyrldinyl (e.g.

triazolo[4,5-b]pyridinyl), triazolopyiim!dinyl (e.g. 8-azapurinyl), and the like. Aromatic ring system is also Intended to include polycydlc 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), phenoxazlnyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl), acrldlnyl (e.g. acridin-9-yl, acrldin-10- yl), phenothlazinyl (e.g. phenothlazin-10-yl), carbollnyl (e.g. pyrldo[3,4-b]lndol-1 -yl, pyrido[3,4-b]indol-3-yi), phenanthrollnyl (e.g. phenanthrolln-5-yl), and the like. Other representative examples are pyrrollnyl, pyrazollnyl, Imldazolinyl (e.g. 4,5-dihydroimidazol-2- yl, 4,5-dlhydrolmldazol-1 -yl), indolinyl (e.g. 2,3-dihydroindol-1 -yl, 2,3-dlhydrolndol-5-yl), dlhydrobenzofuranyl (e.g. 2 _i 3-dihydrobenzo[b]furan-2-yl, 2,3-dihydrobenzo[b]furan-4-yl), dlhydrobenzothlenyl (e.g. 2,3-dlhydrobenzo[b]thlen-2-yl, 2,3-dihydrobenzo[b]thlen-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-dlhydrobenzo[c]pyran-1 -yl, dihydrobenzo[c]pyran- 7-yl), oxazollnyl (e.g. 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-y1, 4,5-dlhydrooxazol-5- yl), Isoxazolinyl, oxazepinyl, tetrahydroindazolyl (e.g. 4,5,6,7-tetrahydrolndazol-1 -yl, 4.5.6.7- tetrahydrolndazol-3-yl, 4,5,6,7-tetrahydrolndazol-4-yl, 4,5,6,7-tetrahydro!ndazoi-6- yi), tetrahydrobenzimidazolyl (e.g. 4,5,6,7-tetrahydrobenzlmldazol-1 -yl, 4,5,6,7- tetrahydro enzlmidazol-5-yi), tetrahydrolmidazo[4,5-c]pyridyl (e.g. 4,5,6,7- tetrahydrolmldazo[4,5-c]pyrid-1 -yl, 4,5,6,7-tetrahydroimidazo[4,5-c]pyrld-5-y!, 4,5,6,7- tetrahydroimldazo[4,5-c]pyrid-6-yl), etrahydroquinolinyl (e.g. 1,2,3,4-tetrahydroqulnollnyl,

5.6.7.8- tetrahydroqulnolinyl), tetrahydrolsoqu!nolinyl (e.g. 1,2,3,4-tetrahydrolsoqulnolinyl, 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g. 1,2,3,4-tetrahydroqulnoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl), and the like.

In one aspect, the 5- to 10-membered aromatic ring systems Include phenyl, furanyl, pyrazoly!, pyrid!nyl, indolyl, oxazolyl, qulnoiinyl, pyrlmldlnyl, thlenyi, 2,3- dlhydrobenzoxazlnyl, 3,4-dihydrobenzoxazlnyl, benzothlazlnyl, benzoxazollnyl and benzothlazollnyl.

In one aspect, R ¹ represents hydrogen, halogen, hydroxyl, nltro, cyano, or mercapto.

In a further aspect, R ¹ represents hydrogen or halogen,: In a further aspect, R ¹ represents hydrogen..

In one aspect, R ² represents hydrogen, halogen, hydroxyl, nltro, cyano, or mercapto.

In another aspect, R ² represents C, _-3 -alkyl, which C _1-3 -alkyl is optionally substituted with at least one substltuent selected from halogen, hydroxyl, nltro, cyano and mercapto.

In a further aspect, R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring comprises at least one ring heteroatom selected from a sulphur atom, nitrogen atom and an oxygen atom, and which aromatic ring or non-aromatic ring is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, the aromatic ring or non-aromatic ring Is optionally substituted with one to three substituent(s). In a further aspect, the aromatic ring or non-aromatic ring Is un- substituted.

In a further aspect, R ² represents a 5-membered aromatic ring, which aromatic ring comprises at least one ring heteroatom selected from a sulphur atom, nitrogen atom and an oxygen atom, and which aromatic ring Is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, R ² represents a phenyl ring, which phenyl ring is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyi, hydroxy!, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, R ² represents a phenyl ring. In a further aspect, R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen atom(s), and which aromatic ring is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyi optionally substituted with halogen, carboxyi, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, R ² represents optionally substituted pyridine. In a further aspect, R ² represents optionally substituted pyrlmldine. In a further aspect, R ² represents optionally substituted pyrazlne. In yet a further aspect, R ² represents optionally substituted pyrfdazine.

In a further aspect, R ² represents Ci.. ₃ -aikyi>

In a further aspect, R ² represents methyl or ethyl.

In a further aspect, R ² represents cyclopropyl. In a further aspect, R ¹ and R ² together form a cydopropyl.

In a further aspect, R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring comprises at least one oxygen atom, and which aromatic ring or non-aromatic ring Is optionally substituted with at least one substltuent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyi, hydroxyl, nltro, cyano, - NR ³ R ⁴ , and mercapto.

In a further aspect, R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring comprises at least one oxygen atom, and which aromatic ring or non-aromatic ring is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyi, hydroxyl, nltro, cyano, - NR ³ R ⁴ , and mercapto.

In a further aspect, R ² represents furan-2-yl, thiophen-2-yl, or thlazol-2-yl, wherein furan-2- yl, thiophen-2-yl, or thlazol-2-yl is optionally substituted with at least one substltuent selected from halogen, d-j-aiky! optionally substituted with halogen, carboxyi, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, ^? represents furanyl such as furan-2-yl, which Is optionally substituted with at least one substttuent, preferably is un-substttuted or substituted with one to three substituent(s) selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, R ² represents furan-2-yl, which Is un-substttuted or substituted with halogen such as fiuoro.

In a further aspect, R ² represents thlophen-2-yl, which Is optionally substituted with at least one substituent, preferably Is un-substltuted or substituted with one to three substftuent(s) selected from halogen, C _{1 -3} -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto.

In a further aspect, R ² represents thlophen-2-yl, which is optionally substituted with at least one substituent, preferably is un-substltuted or substituted with one to three substituent(s) selected from halogen, C _1- -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, R ² represents thlophen-2-yl, which Is un-substltuted or substituted with halogen such as fiuoro.

In a further aspect, R ² represents thlazol-2-yl, which Is optionally substituted with at least one substituent, preferably is un-substltuted or substituted with one to three substituent(s) selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto.

In a further aspect, R ² represents thiazol-2-yl, which is optionally substituted with at least one substituent, preferably Is un-substituted or substituted with one to three substltuent(s) selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto. In a further aspect, R ² represents thlazol-2-yl, which is un-substltuted or substituted with halogen such as fiuoro.

In one aspect, X Is a single bond.

In one aspect, D represents an oxygen atom. In a further aspect, D represents a sulphur atoms

In one aspect, A represents a 5- to 10-membered aromatic ring system, which aromatic ring system optionally comprises at ieast one ring heteroatom selected from a nitrogen atom, oxygen atom and a sulphur atom, and which aromatic ring system is optionally substituted with at Ieast one substituent selected from halogen, Ci _-3 -alkyl, which C _1-3 -alkyl is optionally substituted with halogen, C _1- e-alkoxy, trifiuoramethoxy, -NR ³ R ⁴ , carboxyl, hydroxyl, nltro, cyano, mercapto and trifluoromethyl .

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 nitrogen, oxygen, sulphur atom(s), and which aromatic ring system is optionally substituted with at Ieast one substituent selected from halogen, d _-3 -alkyi, which C _1-3 -alkyl Is optionally substituted with halogen, Ci^-alkoxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxyl, nltro, cyano, mercapto and trifluoromethyl .

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 Ieast one substituent selected from halogen, C _{1 -3} -alkyl, which Ci _-3 -alkyl is optionally substituted with halogen, C _{1 -s} -a!koxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxy!, nifcro, cyano, mercapto and trifluoromethyl .

In a further aspect, A represents furanylene, benzothiazolene, naphthylene, thienylene, benzotrlazol, 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 one aspect, B represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises at Ieast one, two or three ring heteroatom(s) selected from nitrogen and sulphur, and which aromatic ring system is optionally substituted with at Ieast one substltuent selected from halogen, carboxyl, hydroxy!, amino, nltro, cyano, mercapto, C _M - cycloaikyi, C _2< -alkenyl, trffluoromethyl, trifluoromethoxy, Ci. ₆ -alkoxy, C _1-6 -thloalkyl, C _1-6 - alkylcar onyl, d-«-alkylcarbonyloxy, C^-alkoxycarbonyi, -NR ³ R ⁴ , -C(0)NR ⁵ R ⁶ , -N(R ⁷ )C(0)R ⁸ , -S~Ci.3-a!kyl, -S(0) ₂ NR ⁹ R ¹⁰ , -N(R ^u )S(0) ₂ R ¹² , -S(0) _B R ¹³ wherein a Is 0, 1 or 2, - NHC(=NH)NH ₂ , -C(=NH)NH ₂ , benzyloxy, -S(0) ₂ {C _1-6 -N-alkylplperazlnyl), which -S(Q) ₂ (C _1-6 -N- alkylpfperazinyl) is optionally substituted at a carbon atom with at least one substltuent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, C^-alkoxy,

trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and trffluoromethyl, -S(0) ₂ (C,.«-N- alkyldiazepanyl), which -S(0) ₂ (C _1-6 -N- alkyldlazepanyl) Is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1- j-alkyl optionally substituted with halogen, Ci. ₆ -alkoxy, trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and

trifiuoromethyl, C _x . ₆ -N- alkylpiperazinyl, which C _1-6 -N- alkylplperazlnyl is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C^-alkoxy, trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and trifiuoromethyl, plperldlnyl, which plperidlny! is optionally substituted with - NR ^W R ¹⁵ or C _1- e-alkyl, and C _1-6 -aikyl, which C _1-6 -alkyl is optionally substituted with halogen, hydroxy!, Ci.. ₆ -aikoxy, -NR ¹⁴ R ¹⁵ , phenyl or morphollnyl.

In a further aspect, B represents benzothlazolyl, pyrrolyl, pyrazolyl, Indolyl, thiazolyl, pyridazinyl, phenyl, triazolopyrtdlnyl, or imldazolyl. In another aspect, B represents benzothlazolyl, Indolyl, thiazolyl, pyridazinyl, imidazolyl, or phenyl.

In a further aspect, B represents thiazolyl. In a further aspect, B represents imldazolyl. In a further aspect, B represents phenyl. In a further aspect, B represents benzothlazolyl,

In a further aspect, B represents pyrazolyl.

In a further aspect, B represents pyrrolyl,

In a further aspect, B represents Indolyl. In a further aspect, B represents pyridazinyi.

In a further aspect, B represents triazofopyridinyE. in a further aspect, B represents optionally substituted benzothlazolyl, pyrrolyl, pyrazolyl, Indolyl, thiazolyl, pyrtdazlnyl, phenyl, trfazolopyiidinyl, or fmldazolyl. In a further aspect, B represents optionally substituted thiazolyl.

In a further aspect, B represents optionally substituted Imldazolyl.

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 pyrazo!yi. 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 pyridazinyi.

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 substltuent selected from halogen, cyano, trifluoromethyl, C _1-6 -thioa!kyl, -S(0) ₂ (C ₁ . ₆ -alkyiplperazlnyl), which -S(0) ₂ (C _1-e -N- alkylpiperazlnyl) Is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _r - ₃ ~aikyi optionally substituted with halogen, Ci^-alkoxy,

trtfluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifluoromethyl, C alkylplperazinyl, which d-6- - alkylplperazlnyl Is optionally substituted at a carbon atom with at least one substltuent selected from halogen, d^-alkyi optionally substituted with halogen, C _1-e -alkoxy, trifiuoromethoxy, hydroxy!, nitro, cyano, mercapto and trifluoromethyl, and piperldinyi, which plperidlnyl is optionally substituted with -NR ¹⁴ R ^1S or Ci. _G -alkyl.

In one aspect, a 5- to 10-membered aromatic ring system is

wherein Z is a 5- or 6-membered heterocyclic ring containing 1 - 3 ring heteroatoms independently selected from oxygen, nitrogen and sulphur.

In a further aspect, B represents a 5- to 10-membered aromatic ring system, which aromatic ring system Is substituted with at least one C ₁₄ -alkylplperazlnyl, which C^-N- alkylpiperazinyl Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _{1 -3} -alkyl optionally substituted with halogen, C _1-6 -alkoxy,

trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trlfluoromethyl.

In a further aspect, B represents phenyl substituted with at least one substituent selected from halogen, cyano, trlfluoromethyl, -S(0) ₂ (d-6-alkylplperazlnyl), which -S(Q) ₂ {Ci.. ₆ -N- alkylplperazlnyl) Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C -alkoxy,

trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and trlfluoromethyl, Ci^-alkylpiperazinyl, which d-e- - alkylpiperazlnyl Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _{1 -3} -alkyl optionally substituted with halogen, Ci^-alkoxy, trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and trlfluoromethyl, and plperidlnyl, which piperidinyl is optionally substituted with - R ¹⁴ R ^1S or Ci. ₆ -alkyi, In a further aspect, B represents phenyl substituted with -S(0) ₂ (4-Cm-alkyl-plperazin-1 -yl), which - S(0) ₂ (4-C _1-e -aikyl-piperazin-1 -yl) Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, d. 6-alkoxy, trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and trlfluoromethyl.

In one aspect, Q is at least one substituent selected from halogen; cyano; trlfluoromethyl; - S(0) ₂ -(4-(C ₁ - ₆ -alkyi)-piperazln-1 -yl) optionally substituted at a carbon atom with at least one substituent R ²⁰ ; -(C _1-2 -alkyl)-4-R ⁱ⁹ -plperazln-1 -yl In which the d _-2 -alkyl Is optionally substituted with at least one R ¹⁷ ; 4-(Ci^-alkyl)-plperazln-1 -yl optionally substituted at a carbon atom with at least one substituent R ²⁰ ; and piperidiny! optionally substituted with - NR ¹⁴ R ¹⁵ or d-6-alkyl.

In one aspect, Q represents -S(0) ₂ -{4-(C _1-6 -a!kyi)-p!perazin-1 -yi) optionally substituted at a carbon atom with at least one substituent R ²⁰ . In one aspect, Q represents -S(0) ₂ -(4- (methyl)-plperazin-1 -yl) optionally substituted at a carbon atom with at least one substituent

R ²⁰ .

In one aspect, Q represents 4-(C _1-6 -alkyl)-plperazln-1 -yl optionally substituted at a carbon atom with at least one substituent R ²⁰ . In one aspect, Q represents 4-(methyl)-p!perazin-1 - yi. In one aspect, Q represents -(Ci. ₂ -alkyl)-4-R ¹⁹ -plperazln-1 -yl in which the C _1- 1-aikyl Is optionally substituted with one or more R ¹⁷ . In a further aspect, Ci. ₂ -alkyi Is methyl. In yet a further aspect, Q^-alkyl Is ethyl.

In one aspect, R ¹⁷ is selected from cyano; cyclopropyl; methyl substitueret with cyclopropyl; ethyl substitueret with cydopropyl; and ethyl substitueret with cyclopropyl which cyclopropyl is optionally substitueret with methyl.

In a further aspect, two R ¹⁷ together with the carbon atom to which they are attached form a cydopropyl. In a further aspect, two R ¹⁷ together with the carbon atoms to which they are attached form a cyclopropyl.

In a further aspect, R ¹⁹ is selected from methyl; ethyl; propyl; cydopropyl; cydobutyl;

cydopentyl; isopropyl; methylcydopropyl ; ethylcydopropyl; and propylcydopropyl.

In a further aspect, B represents optionally substituted benzothiazo!yl, pyrrolyl, pyrazolyl, Indolyl, thlazolyl, pyridazinyl, phenyl, triazolopyridinyf, or imidazolyf.

In a further aspect, A and B together represents 4,4'-blphenyl, 4-(thlazol-5-yl)phenyl, 4- (thlazol-4-yl)phenyl, or 4-([1 ,2,4]triazolo[1 ,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'-blphenyl, and wherein B is optionally substituted with -S(0) ₂ (4-Ci. ₆ -alkyl-plperazln-1 -yl), which - S(0) ₂ (4-^. ₆ -alkyl-plperazln-1 -yl) Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C _1- e-alkoxy, trtfluoromethoxy, hydroxy!, nltro, cyano, mercapto and trifiuoromethyl.

In a further aspect, A and B together represents an 4,4'-blphenyl, and wherein B Is substituted with -S(0) ₂ -(4-methyl-plperazin-1-yl). In a further aspect, A and B together represents an 4,4'-biphenyl, and wherein B is substituted with 4-methyl-plperazln-l -yl.

In a further aspect, A and B together represents an 4,4'-blphenyl, and wherein B is substituted with -methyl-4-methyl-piperazin-1-yl.

In a further aspect, A and B together represents an 4,4'-biphenyl, and wherein B Is substituted with -ethyl-4-methyl-plperazin-1-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-plperazln-1-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-1-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-plperazin-1-yl).

In a further aspect, A and B together represents 4-(thlazol-4-yl)phenyl, and wherein B is optionally substituted with 4-methyl-piperazln-1-yl.

In a further aspect, A and B together represents an optionally substituted 4- ([1,2,4]triazolo[1,5-a]pyridine-6-yl)phenyl.

In a further aspect, A and B together represents a 4-[1,2,4]triazolo[1,5-a] and wherein B is optionally substituted with 4-C _1-6 ~aSkyl~piperazin-1-yl.

In a further aspect, A and B together represents a 4-[1,2,4]triazolo[1,5-a] and wherein B is optionally substituted with 4-methylplperazin-1-yl. In a further aspect, A and B together represents a 4-[1,2,4]triazolo[1,5-a] and wherein B is optionally substituted with -S(0) ₂ (4-methyl-plperazin-1-yl). In a further aspect, X represents a single bond _*

In a further aspect, A represent phenyl and X is a bond.

Compounds of formula (1) are capable of existing in stereolsomeric forms. It will be understood that the invention encompasses the use of all geometric and optical Isomers (Including atropisomers) of the compounds of formula (1) and mixtures thereof Including racemates. The use of tautomers and mixtures thereof also form an aspect of the present Invention. Enantiomerical!y pure forms are particularly desired. In a aspect, the compound(s) disclosed herein is in the form of a pure stereoisomer thereof. In a further aspect, the compound(s) disclosed herein is in the form of a pure SRR Isomer.

In one aspect the substltuent -A-X-B Is selected from the group of:

In a further aspect the substituent A-X-B Is selected from the group of: Specific embodiments of the Invention

In one aspect, a herein disciosed compound is selected from the group consisting afi.

wherein

R ¹ represents hydrogen; halogen; hydroxy!; nitro; cyano or mercapto; or R ¹ represents -O - CH ₃ ; -O-C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ or -Cj, ₃ -a!kyl; which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S -C _Z H ₅ or - C _1- 3-alkyl is optfonaiiy substituted with at ieast one substituent selected from halogen, hydroxyl, nitro, cyano and mercapto;

R ² represents hydrogen; halogen; hydroxyl; nitro; cyano or mercapto; or R ² represents -O-CH ₃ ; -0--C ₂ H ₅ ; -S-CH ₃ ; -S-C ₂ H ₅ ; cyciopropy!, C _{1 -3} -alkyl; C _2-3 -alkenyl; or C _2-3 -alkynyl; which -O-CH ₃ , -O-QjHs, -S-CH ₃ , -S-C ₂ H ₅ , cycioprapy!, Ci _-3 -aikyl, C _2-3 -alkenyl or C _2-3 -alkynyl Is optionally substituted with at Ieast one substituent selected from halogen, hydroxyl, nitro, cyano and mercapto; or R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring optionally comprises at Ieast 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 Ieast one substituent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, - NR ³ R ⁴ , and mercapto; or R ² represents a phenyl ring, which phenyl ring Is optionally substituted with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, cyano, -NR ³ R ⁴ , and mercapto; or R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen atom(s), and which aromatic ring Is optionally substituted with at Ieast one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ - ₆ ~cycioa!kyi or C ₃ .. ₆ -heterocycioalkyl, which C ₃ . _e -cycloalkyl or C ₃ ^-heterocycloalkyl Is optionally substituted with at Ieast one substituent selected from halogen, hydroxyl, nitro, cyano and mercapto; D represents an oxygen atom or a sulphur atom;

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 selected from halogen, C÷. _-3 -a!kyl optionally substituted with halogen, Ci. 6-alkoxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxyl, nitre, cyano, mercapto and

trifluoromethyl;

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 halogen; carboxyl; oxo; hydroxyl; amino; nitro; cyano; mercapto; C _3-6 -cycioaikyi; C ₂ . ₆ -alkenyl; trifluoromethyl; trifluoromethoxy; Ci^-alkoxy; C _1-6 - thioalkyl; d. ₆ -alkylcarbonyl; C aikylcarbonyloxy; Ci. ₆ -alkoxycarbonyi; -NR ³ R ⁴ ; -C(0)NR ⁵ R ⁶ ; -N(R ⁷ )C(0)R ^e ; -S-C _1- 3-alkyi; -S(0) ₂ NR ⁹ R ¹⁰ ; -N(R ^il )S(0) ₂ R ¹² ; -S(0).R ¹³ wherein a Is 0, 1 or 2; -NHC(=NH)NH ₂ ; -C(=NH)NH ₂ ; benzyloxy; -S(0) ₂ -(4- R ¹⁹ -plperazin-1 -yl) optionally

substituted at a carbon atom with at least one substituent selected from R ²⁰ ; ~(C ₁ . ₂ -alkyl)-4~ R ¹⁹ -piperazin-1 -yl in which the C _1-2 -alkyl is optionally substituted with one or more -R ¹⁷ and in which the piperazlne ring Is optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; -N(R ¹⁸ )-4-R ¹⁹ -plperazln- 1 -yl ; -O-4- R ¹⁹ -piperazin-1 -yl; -C(=0)- 4-R ¹⁹ -piperazln-1 -yl; -S(0) ₂ (-C _1- e-alkyldlazepanyl) which is optionally substituted at a carbon atom with at least one substituent selected from halogen, Q-ralkyi optionally substituted with halogen, C _1- e-alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and

trifluoromethyl; 4-(C _1-6 - alkyl)piperazin-1 -yl which is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, d^-alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifluoromethyl; piperidinyl which is optionally substituted with -NR ¹⁴ R ¹⁵ or C _{1 -6} -alkyl optionally substituted with halogen, hydroxyl, Ci. ₆ -alkoxy, -NR ¹⁴ R ^,J , phenyl, piperidinyl, morphoi!nyl or 4- R ¹⁹ - piperazin-1 -yl; -C _1-3 -alkyl-plperidlnyl optionally substituted with -NR ¹⁴ R ¹⁵ or C _1-6 -alkyl optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ¹⁵ , phenyl, piperidinyl, morphollnyl or 4- R ¹⁹ -piperazln-1 -yl; C ₃₄ -cydoalkyl optionally substituted with -NR ¹ R ^ls or C _1- g-alkyl optionally substituted with halogen, hydroxyl, -NR ¹⁴ R ¹⁵ , phenyl, piperidinyl, morphollnyl or 4- R ¹⁹ - plperazin-1 -yl; and Q^-alkyl, which Ci. ₅ -alkyS is optionally substituted with one or more of halogen, amino, cyano, hydroxy, Ci^-alkoxy, -NR ¹ R ¹⁵ , phenyl, morphoiinyl or C _3-6 cydoalkyl, which C _3-6 cydoalkyl is optionally substituted with -NR ¹⁴ R ¹⁵ , phenyl, piperidinyl, morphoiinyl or 4-R ¹⁹ -piperazin-1 -yl; with the proviso that when B is phenyl, then B is substituted with at least one substituent; X represents a single bond, an oxygen atom or a sulphur atom, -S(O)-, -S(0 _? )-, -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;

R ³ and R ⁴ each independently represent hydrogen, C _1- e-alkyl or C _3-6 -cycloaikyl, 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 ^e each Independently represent hydrogen, C _1- «-alkyl or C ₃ .6-cycloaikyl, or R ^s 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 _1HS -alkyl or C _3-6 -cydoalkyl, or R* 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 _1- e-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 ^e , R ¹¹ , R ¹² and R ¹³ each independently represent a hydrogen atom or a Cus-alkyl or C _3-6 - cydoalkyl;

R ¹⁸ represents a hydrogen atom or Ci. ₆ -a!kyl;

R ¹⁷ represents halogen, cyano, cyciopropyl or C _1-3 -alkyl optionally substituted with halogen, cyano, or cydopropyl optionally substituted with methyl or halogen; or two R ¹⁷ together with the carbon atom(s) to which they are attached form a cydopropyl;

R ¹⁸ represents a hydrogen atom, or Ci _-3 -alkyl optionally substituted with halogen or methyl cydopropyl, wherein methyl cydopropyl is optionally substituted with methyl or halogen;

R ¹⁹ represents C _3-5 -cydoalkyl, -C _1-3 ~aikyl-C ₃ - _s -cycioalkyi or C _{1 -6} -alkyl; and R ²⁰ each independently represent halogen, hydroxyl, cyano, mercapto, amino or C _1- e-alkyl optionally substituted with halogen, hydroxyl, cyano, amino or mercapto; as well as stereoisomers, pharmaceutically acceptable salts, solvates, and hydrates thereof.. Embodiment 2. The compound according embodiment 1, wherein ¹ represents hydrogen.

Embodiment 3. The compound according to any one of embodiments 1-2, wherein

R ² represents hydrogen, halogen, hydroxyl, nitro, cyano, or mercapto, or R ² represents cydopropyl or C _t-3 -alkyl _f which Ci _-3 -aikyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, nitro, cyano and mercapto or R ² represents a 5- membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring comprises at least one ring heteroatom selected from a sulphur atom, nitrogen atom and an oxygen atom, and which aromatic ring or non-aromatic ring Is optionally substituted with at least one substituent selected from halogen. C _1-3 alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto.

Embodiment 4. The compound according to any one of embodiments 1-3, wherein

R ² represents cydopropyl or C _1-3 -alkyl such as methyl or ethyl.

Embodiment 5. The compound according to any one of embodiments 1-2, wherein R ² represents a phenyl ring, which phenyl ring is optionally substituted with at least one substituent selected from halogen, C^-aikyl optionally substituted with halogen, carboxyl, hydroxyl, cyano, -NR ³ R ⁴ , and mercapto.

Embodiment 6. The compound according to any one of embodiments 1-3, wherein

R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non- aromatic ring comprises at least one oxygen atom or sulfur atom, and which aromatic ring or non-aromatic ring is optionally substituted with at least one substituent selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, - NR ³ R ⁴ , and mercapto.

Embodiment 7. The compound according to any one of embodiments 1-3 and 6, wherein R ² represents furanyl, thiophenyl, or thiazolyl, wherein furanyl, thlophenyl, or thiazolyl is optionally substituted with at feast one substituent selected from halogen, C _1-3 - alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto.

Embodiment 8. The compound according to any one of embodiments 1-7, wherein

X Is a single bond.

Embodiment 9. The compound according to any one of embodiments 1-8, wherein

D represents an oxygen atom. Embodiment 10. The compound according to any one of embodiments 1-9, wherein

A represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises one, two or three ring nitrogen, oxygen, sulphur atom(s), and which aromatic ring system is optionally substituted with at least one substituent selected from halogen, C _1-3 - alkyl, which C _1-3 -alkyl Is optionally substituted with halogen, C^e-alkoxy, trifluoromethoxy, - NR ³ R ⁴ , carboxyl, hydroxyl, nitro, cyano, mercapto and trlfiuoromethyl,

Embodiment 11. The compound according to any one of embodiments 1-10, wherein A represents furanylene, benzothlazolene, naphthylene, thienylene, benzotriazolene, triazolopyridlnylene, indolylene, or phenylene. Embodiment 12, The compound according to any one of embodiments 1-11, wherein A represents phenylene.

Embodiment 13. The compound according to any one of embodiments 1-12, wherein B represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises at least one, two or three ring heteroatom(s) selected from nitrogen and sulphur, and which aromatic ring system is optionally substituted with at least one substituent Q as defined in embodiment l.

Embodiment 14. The compound according to any one of embodiments 1-13, wherein B represents optionally substituted benzothiazolyl, pyrrolyl, pyrazolyl, Indolyl, thiazolyl, py dazlnyl, phenyl, triazolopyridinyl or Imldazolyl. Embodiment 15. The compound according to any one of embodiments 1-14, wherein B represents phenyl substituted with Q as defined in embodiment 1.

Embodiment 16. The compound according to any one of embodiments 1-15, wherein Q Is at least one substituent selected from halogen; cyano; trlfiuoromethyl; -S(0) ₂ - (4- R ⁱ⁹ -piperazln-1 -yl) optionally substituted at a carbon atom with at least one substituent R ²⁰ ; -(C ₁ . ₂ -alkyl)-4-R ¹⁹ -plperazin-1 -yl In which the C^-alkyl Is optionally substituted with one or more R ¹⁷ and in which the plperazine ring is optionally substituted at a carbon atom with at least one substituent selected from R ²⁰ ; 4-(C _{1 -6} -alkyl)-plperazln-1 -yl optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, Ci^-alkoxy, trifluoromethoxy, hydroxyl, nitro, cyano, mercapto and trlfiuoromethyl; -Ci _-3 -alky1-plperldlnyl optionally substituted with -NR ¹⁴ R ¹⁵ or Ci^-alkyl; and C _1- 8-a!kyl, which C _1- e-alkyl Is optionally substituted with one or more of halogen, amino, cyano, hydroxy, Ci^-alkoxy, -NR ^l4 R ¹⁵ , phenyl, morphol!nyl or C _3-6 cycioalkyi. Embodiment 17. The compound according to embodiment 16, wherein Q is -S(Q) ₂ -

(4-(C _1< -a!kyl)-piperazin-1 -yl) optionally substituted at a carbon atom with at least one substituent R ²⁰ ,

Embodiment 18. The compound according to embodiment 16, wherein Q is -(C _a . ₂ - alkyl)-4-R ¹⁹ -plperazln-1 -yl in which the Ci. ₂ -alkyi is optionally substituted with one or more

R ¹⁷ ,

Embodiment 19, The compound according to embodiment 18, wherein C _1-2 -alkyl is methyl or ethyL

Embodiment 20. The compound according to any one of embodiments 1-19, wherein R ¹⁷ Is selected from cyano; cyclopropyl; methyl substttueret with cyclopropyl; ethyl substitueret with cyclopropyl; and ethyl substttueret with cyclopropyl which cyclopropyl Is substltueret with methyl.

Embodiment 21. The compound according to any one of embodiments 1-19, wherein two R ¹⁷ together with the carbon atom(s) to which they are attached form a cyclopropyl.

Embodiment 22. The compound according to any one of embodiments 1-21, wherein R ¹⁹ is selected from methyl; ethyl; propyl; cyclopropyl; cydobutyl cyciopentyl ;

Isopropyl; methy lcyclopropyl ; ethylcyciopropyl; and propyl cyclopropyl.

Embodiment 23. The compound of formula (I) wherein R ¹ represents hydrogen, halogen, hydroxyl, nltro, cyano, or mercapto, or R ¹ represents -O- CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ or -C _1-3 -alkyl, which -O-CH ₃ , -O-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, nltro, cyano and mercapto;

R ² represents hydrogen, halogen, hydroxyl, nltro, cyano, or mercapto, or R ² represents -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ , cyclopropyl or C _1-3 -alkyl, which -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ , cyclopropyl or C _{1 -3} -alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, nltro, cyano and mercapto, or R ² represents a 5-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 selected from halogen, Ci _-3 -alkyl optionally substituted with halogen, carboxy!, hydroxy!, nltro, cyano, -N ^{3 4} , and mercapto, or R ² represents a phenyl ring, which phenyl ring is optionally substituted with at least one substituent selected from halogen, Q _-3 - alkyl optionally substituted with halogen, carboxyl, hydroxy!, cyano, -NR ³ R ⁴ , and mercapto; or R ² represents a 6-membered aromatic ring, which aromatic ring comprises one, two or three nitrogen a om(s}, and which aromatic ring Is optionally substituted with at least one substituent selected from halogen, C _1- 3-alkyl optionally substituted with halogen, carboxyl, hydroxy!, nitro, cyano, -NR ³ R ⁴ , and mercapto; or R ¹ and R ² together form C ₃ - ₆ -cycioalkyi or C _3-6 -heterocycloa!kyi, which C _3-6 -cycioaiky! or C _3* 6-heterocydoalkyi is optionai!y substituted with at least one substituent selected from halogen, hydroxy!, nltro, cyano and mercapto;

D represents an oxygen atom or a sulphur atom;

A represents a 5- to 1.0-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 selected from halogen, d- ₃ -alkyl, which C _1-3 -alkyl Is optionally substituted with halogen, Ci.. ₆ -aikoxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxy!, nltro, cyano, mercapto and trifiuoromethy!;

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 optionaiiy substituted with at ieast one substituent selected from halogen; carboxyl; hydroxy!; amino; nitro; cyano;

mercapto; C _3-6 -cyc!oa!ky!; C ₂ . ₆ -a!kenyi; trifluoromethyl ; trifluoromethoxy; Ci^-alkoxy; <Ζ _1-6 - thloalkyl; C _1- e-alkylcarbonyl; Ci^-alkylcarbonyloxy; C _1- s-alkoxycarbonyl; -NR R ⁴ ; -C(0)NR ⁵ R ⁶ ; -N(R ⁷ )C(0)R ⁸ ; -S-C _1- 3-a!kyl; -S(0) ₂ NR ⁹ R ¹⁰ ; -N(R )S(0) ₂ R ¹² ; -S(0),R ¹³ wherein a is 0, 1 or 2; -NHC(«=NH)NH ₂ ; -C(=NH)NH ₂ ; benzyloxy; -S(0) ₂ -(4-(Ci. ₆ -alkyl)plperazln-1 -yl) which is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyi optionally substituted with halogen, C a!koxy, trifluoromethoxy, hydroxy!, nltro, cyano, mercapto and trifluoromethyl ; -(Ci. ₂ -alkyl)-4-R ¹⁹ -piperazin-1-yl in which the C _1-2 -alkyl is optionally substituted with one or more -R ¹⁷ ; -N(R ¹⁸ )-4-R ¹⁹ -plperazln-1-yl; -O-4- R ¹⁹ - plperazln-1-yl; -C(-0)-4-R ¹⁹ -plperazln-1-yl; -S(0) ₂ -(4-(C ₃ .5-cycloaikyl)p!perazin-1 -yi); - S(0) ₂ -(4-(C ₃ . ₅ -cycloalKyl-C _1-3 -alkyl)plperazin-1-yi); -S(0) ₂ (-C ₁ - ₆ -alkyldlazepanyl) which Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1- j-alkyl optional!y substituted with halogen, C _1-e -alkoxy, trifluoromethoxy, hydroxy!, n!tro, cyano, mercapto and trifluoromethyl; 4-(C _! . ₆ - alkyi)piperazin-1 -y! which is optional!y substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C^-alkoxy, trifiuoromethoxy, hydroxy!, nitro, cyano, mercapto and trifluoromethyl; plperldlnyl which Is optionally substituted with -NR ¹⁴ R ¹⁵ or C _w - alkyl and wherein Ci^-alkyl is optionally substituted with halogen, hydroxy I, C _t -e-alkoxy, - NR ¹ R ¹⁵ , phenyl or morpholinyl; with the proviso that when B Is phenyl, then B is substituted with at least one substituent;

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-a-alkylene, ethenylene or ethynylene;

R ³ and R ⁴ each independently represent hydrogen, Ci.. ₆ -a!ky! or C ₃ ^-cydoalkyl, 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 ^s and R ⁶ each Independently represent hydrogen, C _1- s-aiky! or C _3-6 -cycloaikyi, or R ^s 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 _1-5 -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, d-s-aiky! or C ₃ .. ₆ -cycSoalkyi, 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 d-e-alkyl or C _3-6 - cydoa!kyi;

R ¹⁶ represents a hydrogen atom or d^-alkyl;

R ¹⁷ represents a hydrogen atom, halogen, or d _-3 -aiky! optionally substituted with halogen or methylcyclopropyi, wherein methylcyclopropyl is optionally substituted with methyl or halogen;

R ^1S represents a hydrogen atom, or C _a-3 -alkyl optionally substituted with halogen or methyl cyciopropy!, wherein methyl cyclopropyl Is optionally substituted with methyl or halogen; and R represents -C _1-3 -alkyl-C ₃ .s-cycloall<yl or C _1- 3-alkyl; as well as stereoisomers, a pharmaceutically acceptable salts, solvates, and hydrates thereof.

Embodiment 24. The compound according to any one of embodiments 1-23, 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 optionally substituted with at least one substituent selected from halogen, carboxyl, hydroxyl, amino, nltro, cyano, mercapto, C _3-6 -cycioaikyi, C ₂ -6-alkenyl, trifiuoromethyl, trifluoromethoxy, Cj. ₆ -alkoxy, C _1-6 - thioalkyl, d^-alkylcarbonyl, C _1-6 -aikylcarbonyloxy, C _1-6 -aikoxycarbonyi, -NR ³ R ⁴ , -C(0)NR ⁵ R ⁶ , -N(R ⁷ )C(0)R ⁸ , -S-C _1-3 -alkyl, -S0 ₂ NR ⁹ R ¹ °, -N(R")S0 ₂ R", -S(0).R ¹³ wherein a Is 0, 1 or 2, - NHC(=NH)NH ₂ , -C(=NH)NH ₂ , benzyloxy, -SCOfcCd-e-N-alkylpiperazlnyl), which -S(0) ₂ (C _1-6 -N- alkylplperazlnyl) is optionally substituted at a carbon atom with at feast one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, Q^-a!koxy,

trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and trifiuoromethyl, -S(0) ₂ (Ci^-N- alkyldiazepanyl), which -S(0) ₂ (Ci. ₆ -N- alkyldiazepanyl) Is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C _1-5 -a!koxy, trifluoromethoxy, hydroxyl, nltro, cyano, mercapto and

trifiuoromethyl, C _1-6 -N- alkylpiperazinyl, which C _1-6 -N- alkylpiperazlnyl 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, nltro, cyano, mercapto and trifiuoromethyl, piperidinyl, which piperidlnyl is optionally substituted with - NR ^W R ^1S or C _1- e-a!ky!, and C _1-6 -alkyl, which C _1-6 ~aikyi is optionally substituted with halogen, hydroxyl, Q^-alkoxy, -NR ¹⁴ R ^1S , phenyl or morpholinyi; with the proviso that when B Is phenyl, then B Is substituted with at least one substituent. Embodiment 25. The compound according to any one of embodiments 1-24, wherein R ² represents hydrogen, halogen, hydroxyl, nltro, cyano, or mercapto, or R ² represents -O-CH ₃ , -O-C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ , cyciopropy! or C _1-3 -alkyl, which -O-CH ₃ , -O- C ₂ H ₅ , -S-CH ₃ , -S-C ₂ H ₅ , cyciopropy! or Ci _-3 -alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, nltro, cyano and mercapto, or R ² represents a 5- 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 selected from halogen, Ci _-3 -a!kyl optionally substituted with halogen, carboxyl, hydroxyl, nltro, cyano, -NR ³ R ⁴ , and mercapto. Embodiment 26. The compound according to any one of embodiments 1-25, wherein R ¹ represents hydrogen, halogen, hydroxy!, nitro, cyano, or mercapto.

Embodiment 27, The compound according to any one of embodiments 1-26, wherein R ¹ represents hydrogen or halogen. Embodiment 28. The compound according to any one of embodiments 1-27, wherein R ¹ represents hydrogen.

Embodiment 29. The compound according to any one of embodiments 1-28, wherein R ² represents hydrogen, halogen, hydroxyl, nitro, cyano, or mercapto, or R ² represents cyclopropyl or d _-3 -alkyl, which Q _-3 -aikyi is optionally substituted with at least one substltuent selected from halogen, hydroxy!, nitro, cyano and mercapto or R ² represents a 5- membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring comprises at least one ring heteroatom selected from a sulphur atom, nitrogen atom and an oxygen atom, and which aromatic ring or non-aromatic ring Is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto.

Embodiment 30. The compound according to any one of embodiments 1-29, wherein R ² represents C _1-3 -alkyl.

Embodiment 31. The compound according to any one of embodiments 1-30, wherein R ² represents methyl or ethyl. Embodiment 32. The compound according to any one of embodiments 1-31, wherein R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring comprises at least one ring heteroatom selected from a sulphur atom, nitrogen atom and an oxygen atom, and which aromatic ring or non-aromatic ring Is optionally substituted with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto.

Embodiment 33. The compound according to any one of embodiments 1-32, wherein R ² represents a 5-membered aromatic ring or non-aromatic ring, which aromatic ring or non-aromatic ring comprises at least one oxygen atom, and which aromatic ring or non- aromatic ring Is optionally substituted with at least one substltuent selected from halogen, C .. 3-alkyi optionally substituted with halogen, carboxyl, hydroxyl, nitro, cyano, -NR ³ R ⁴ , and mercapto. Embodiment 34. The compound according to any one of embodiments 1-33, wherein ² represents furan-2-yl, thlophen-2-yl, or thlazol-2-yi, wherein furan-2-yl, thiophen- 2-yl, or thiazol-2-yl is optionally substituted with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, carboxyl, hydroxy!, nitro, cyano, - NR ³ R ⁴ , and mercapto.

Embodiment 35. The compound according to any one of embodiments 1-34, wherein R ² represents furan-2-yl, which is optionally substituted with halogen such as fluoro.

Embodiment 36. The compound according to any one of embodiments 1-35, wherein X Is a single bond. Embodiment 37. The compound according to any one of embodiments 1-36, wherein D represents an oxygen atom.

Embodiment 38. The compound according to any one of embodiments 1-37, wherein D represents a sulphur atom.

Embodiment 39. The compound according to any one of embodiments 1-38, 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 selected from halogen, C _1-3 -alkyl, which C _1-3 -alkyl Is optionally substituted with halogen, C _1-6 -alkoxy, Cj.- ₅ -aikoxy, trifluoromethoxy, -NR ³ R ⁴ , carboxyl, hydroxyl, nitro, cyano, mercapto and trifiuoromethyl.

Embodiment 40. The compound according to any one of embodiments 1-39, 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 selected from halogen, C _1-3 -alkyl, which Q _-3 -a!kyi Is optionally substituted with halogen, C _1-e - alkoxy, Ci. ₆ -alkoxy, trifluoromethoxy, -NR*R ⁴ , carboxyl, hydroxyl, nitro, cyano, mercapto and trifiuoromethyl.

Embodiment 41. The compound according to any one of embodiments 1-40, wherein A represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises one, two or three ring nitrogen, oxygen, sulphur atom(s), and which aromatic ring system is optionally substituted with at least one substituent selected from halogen, Ci _-3 -alkyl, which C _1-3 -alkyl is optionally substituted with halogen, C -alkoxy, C _1-6 - alkoxy, trifiuoromethoxy, -NR ³ R ⁴ , carboxyi, hydroxy!, nltro, cyano, mercapto and

trifiuoromethyl .

Embodiment 42. The compound according to any one of embodiments 1-41, wherein A represents furanylene, benzothlazolene, naphthylene, thlenylene, benzotriazoi, triazolopyridinylene, indoiylene, or phenyiene.

Embodiment 43. The compound according to any one of embodiments 1-42, wherein A represents indoiylene, or phenyiene.

Embodiment 44. The compound according to any one of embodiments 1-43, wherein A represents phenyiene. Embodiment 45. The compound according to any one of embodiments 1-44, wherein B represents a 5- to 10-membered aromatic ring system, which aromatic ring system comprises at least one, two or three ring heteroatom(s) selected from nitrogen and sulphur, and which aromatic ring system Is optionally substituted with at least one

substltuent selected from halogen, carboxyi, hydroxy!, amino, nitro, cyano, mercapto, C _3-6 - cyc!oalkyl, C _2-6 -a!kenyi, trifiuoromethyl, trifiuoromethoxy, Q-e-alkoxy, C _{1 -6} -thioalkyl, C _1-e - alkylcarbonyl, C _1-e -alkylcarbonyloxy, C _1-6 -alkoxycarbonyl, -NR ³ R ⁴ , -C(0)NR ⁵ R ⁶ , -N(R ⁷ )C(0)R ^e , -S-C _1- 3-aikyl, -S(0) ₂ NR ⁹ R ¹⁰ , -N(R )S(0) ₂ R ¹² , -S(0),R ¹³ wherein a is 0, 1 or 2, - NHC(=NH)NH ₂ , -C(=NH)NH ₂ , benzyloxy, -S(0) ₂ (C _1-e -N-alkylpiperazinyl), which -S(0) _z (C _1-6 -N- alkylplperazlnyl) is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1-? -aikyi optionally substituted with haiogen, C _{1 -6} -alkoxy,

trifiuoromethoxy, hydroxy!, nltro, cyano, mercapto and trifiuoromethyl, -S(0) ₂ {C _1-6 -N- alkyidlazepanyl), which -S(0) ₂ (Ci<-N- alkyldiazepanyl) is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, Ci. _B -aikoxy, trifiuoromethoxy, hydroxyl, nitro, cyano, mercapto and

trifiuoromethyl, Ci. ₆ -N- aikyipiperazinyl, which C _1-6 -N- alkyip!perazinyl is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1-3 -aikyi optionally substituted with halogen, Ci^-alkoxy, trifiuoromethoxy, hydroxyl, nltro, cyano, mercapto and trifiuoromethyl, pEperidinyi, which plpertdlnyl is optionally substituted with - NR ¹ R ¹⁵ or C _1- s-alkyl, and Q. ₆ -a!kyl, which C _1-e -alkyl Is optionally substituted with halogen, hydroxyl, C _1-6 -alkoxy, -NR ¹⁴ R ¹⁵ , phenyl or morpholiny!.

Embodiment 46. The compound according to any one of embodiments 1-45, wherein B represents benzothiazolyl, pyrro!yl, pyrazolyl, Indolyi, thiazolyl, pyrldazinyl, phenyl, triazolopyridinyl or imidazolyl. Embodiment 47. The compound according to any one of embodiments 1-46, wherein B represents thiazolyl.

Embodiment 48. The compound according to any one of embodiments 1-46, wherein B represents imidazolyi. Embodiment 49, The compound according to any one of embodiments 1-46, wherein B represents phenyl.

Embodiment 50. The compound according to any one of embodiments 1-46, wherein B represents benzothiazolyl.

Embodiment 51. The compound according to any one of embodiments 1-46, wherein B represents pyrazolyl.

Embodiment 52. The compound according to any one of embodiments 1-46, wherein B represents pyrrolyl.

Embodiment 53. The compound according to any one of embodiments 1-46, wherein B represents indolyi. Embodiment 54. The compound according to any one of embodiments 1-46, wherein B represents triazolopyridinyl.

Embodiment 55. The compound according to any one of embodiments 1-54, wherein B represents a 5- to 10-membered aromatic ring system, which aromatic ring system is substituted with at least one substttuent selected from halogen, cyano,

trffluoromethyl, C^-thioalkyl, -S(0) ₂ {Ci. ₆ -aikylpiperazlnyl}, which -S(0) ₂ (Ci. ₆ -N- alkylpiperazlnyl) is optionally substituted at a carbon atom with at least one substttuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C alkoxy, trtfluoromethoxy, hydroxyl, nitro, cyano, mercapto and trifluoromethyl, Ci^-alkylplperazinyl, which Q.-6- - alkylplperazinyl is optionally substituted at a carbon atom with at least one substituent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, Q-e-alkoxy, trifluoromethoxy, hydroxy!, nitro, cyano, mercapto and trifluoromethyl, and piperidinyl, which piperidlnyl Is optionally substituted with -NR ¹⁴ R ¹⁵ or C _1- j-alkyl.

Embodiment 56. The compound according to any one of embodiments 1-55, wherein 3 represents a 5- to 10-membered aromatic ring system, which aromatic ring system Is substituted with at least one 4-C _1- 6-alkylplperazln-1 -yl, which 4-Ci- ₆ -a!kylpiperazln- 1-yl Is optionally substituted at a carbon atom with at least one substltuent selected from halogen, Q _-3 -aikyl optionally substituted with halogen, C _1- e-alkoxy, trffluoromethoxy, hydroxyl, nltro, cyano, mercapto and trlfluoromethyl. Embodiment 57. The compound according to any one of embodiments 1-56, wherein B represents phenyl substituted with at least one substltuent selected from halogen, cyano, trlfluoromethyl, -S(0) ₂ (4-C _{1 -6} -alkylpiperazln-1 -yl), which -S(0) ₂ (4-C ₁ . ₆ -aikyipiperazin- 1-yl) Is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C _1- e-alkoxy, trtfluoromethoxy, hydroxyl, nltro, cyano, mercapto and trlfluoromethyl, 4-Ci^-alkylplperazln-1 -yl, which 4-C _1- e- alkylpiperazin-1 -yl is optionally substituted at a carbon atom with at least one substltuent selected from halogen, C _1-3 -alkyl optionally substituted with halogen, C _1-6 -alkoxy,

trtfluoromethoxy, hydroxyl, nltro, cyano, mercapto and trlfluoromethyl, and plperidlnyl, which piperidinyl Is optionally substituted with -NR ^{14 15} or C _1- e-alkyl. Embodiment 58. The compound according to any one of embodiments 1-57, wherein B represents phenyl substituted with -S(0) ₂ (4-C _1-6 -alkyl-plperazln-1 -yl), which - S(0) ₂ (4-Ci^-alkyl-piperazln-1 -yl) Is optionally substituted at a carbon atom with at least one substltuent selected from halogen, Q.j-alkyi optionally substituted with halogen, C _1- e-alkox , trtfluoromethoxy, hydroxyl, nltro, cyano, mercapto and trlfluoromethyl. Embodiment 59. The compound according to any one of embodiments 1-58, wherein A and B together represents 4,4'-biphenyi, 4-(thlazol-4-yl)phenyl, 4-(thiazol-5- yl)phenyl or 4-([1 ,2,4]triazolo[1 ,5-a]pyridlne-6-yl)phenyl, wherein B Is optionally substituted as defined above.

Embodiment 60. The compound according to any one of embodiments 1-59, wherein A and B together represents an 4,4'-biphenyl, and wherein B is optionally substituted with -S(0) ₂ (4-C ₁ ^-alkyl-plperazin-1 -yl), which - S(0)i(4-Ci.e-alkyl-plperazln-1 -yl) is optionally substituted at a carbon atom with at least one substltuent selected from halogen, Cx-3-alkyl optionally substituted with halogen, C _1- e-alkoxy, trtfluoromethoxy, hydroxyl, nltro, cyano, mercapto and trifluoromethyl. Embodiment 61. The compound according to any one of embodiments 1-59, wherein A and B together represents an 4,4'-blphenyl, and wherein B is substituted with - S(0) ₂ (4-methyl-plperazln-1 -yi). Embodiment 62. The compound according to any one of embodiments 1-59, wherein A and B together represents an 4,4'-blphenyl, and wherein B Is substituted with 4- methyl-plperazln-1 -yl.

Embodiment 63. The compound according to any one of embodiments 1-59, wherein A and B together represents 4-(thiazol-4-yi)phenyi, and wherein B Is optionally substituted with -S(0) ₂ (4-methyl-plperazln-1 -yl).

Embodiment 64. The compound according to any one of embodiments 1-59, wherein A and B together represents 4-(thlazol-5-yl)phenyl, and wherein B Is optionally substituted with 4-methyl-piperazln-1 -yl. Embodiment 65. The compound according to any one of embodiments 1-59, wherein A and B together represents 4-(thlazol-5-yl)phenyl, and wherein B Is optionally substituted with -S(0) ₂ (4-methyl-plperazin-1 -yl).

Embodiment 66. The compound according to any one of embodiments 1-59, wherein A and B together represents 4-(thlazol-4-yl)phenyl, and wherein B is optionally substituted with 4-methyl-plperazln-1 -yl.

Embodiment 67. The compound according to any one of embodiments 1-59, wherein A and B together represents an optionally substituted 4-([1 ,2,4]triazolo[1 ,5- a]pyrldlne-6-yl)phenyl.

Embodiment 68. The compound according to any one of embodiments 1-59, wherein A and B together represents a 4-[1 ,2,4]triazolo[1 ,5-a] and wherein B is optionally substituted with 4-C _1- e-alkyl-piperazin-1 -yl.

Embodiment 69. The compound according to any one of embodiments 1-59, wherein A and B together represents a 4-[1 ,2,4]triazolo[1 ,5-a] and wherein B is optionally substituted with 4-methylplperazin-1 -yl. Embodiment 70. The compound according to any one of embodiments 1-59, wherein A and B together represents a 4-[1 ,2,4]triazolo[1 ,5-a] and wherein B Is optionally substituted with -S(0) ₂ (4-methyl-plperazln-1 -yl).

Embodiment 71. The compound according to any one of embodiments 1-70, wherein X represents a single bond. Embodiment 72. The compound according to to any one of embodiments 1-49, in the form of a pure stereoisomer thereof.

Embodiment 73. The compound according to any one of embodiments 1-71, in the form of a pure S Isomer. Embodiment 74. The compound according to any one of embodiments 1-73, in the form of a pharmaceuticaiiy acceptable sait thereof.

Embodiment 75. The compound according to any of the preceding embodiments for use in medicine.

Embodiment 76. The compound according to embodiment 1-75 for use as a cysteine peptidase inhibitor.

Embodiment 77. The compound according to embodiment 1-75 for use as a dipeptidy! peptidase I (DPPI) Inhibitor.

Embodiment 78. The compound according to any of embodiments 1-77 for use in treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, acute myocardial Infarction, stroke, respiratory syncytial virus Infection, CDS T cell Inhibition, inflammatory bowel diseases, psoriasis, non-melanoma skin cancer, atopic dermatitis, periodontitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application In target cell apoptosis.

Embodiment 79. The compound according to any of embodiments 1-77 for use in treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe Influenza, respiratory syncytial virus infection, CDS 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. Embodiment 80. The compound according to any of embodiments 1-77 for use in treating asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, Inflammatory bowel diseases, cystic fibrosis, sepsis or allergic rhinitis. Embodiment 81. A pharmaceutical composition comprising, as an active substance, a compound as defined in any of embodiments 1-77 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable adjuvant, carrier or diluent.

Embodiment 82. The pharmaceutical composition according to embodiment 81 in unit dosage form, comprising from about 1 vg to about 1000 rng such as, e.g., from about 10 ug 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.

Embodiment 83. The pharmaceutical composition according to embodiment 81 or

82 for oral, nasai, transdermai, pulmonal or parenteral administration. Embodiment 84. 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) as disclosed In any one of embodiments 1 to 77 or a pharmaceutically acceptable salt thereof.

Embodiment 85. 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 of embodiments 1-77 or of a composition as defined In any of embodiments 81-83.

Embodiment 86. The method according to embodiment 84, wherein the effective amount of the compound is in a range of from about 1 ς 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.

Embodiment 87. Use of a compound as defined in any of embodiments 1-77 for the preparation of a medicament.

Embodiment 88. Use of a compound as defined In any of embodiments 1-77 for the preparation of a medicament for treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, acute myocardial infarction, stroke, respiratory syncytial virus infection, CD8 T cell Inhibition, Inflammatory bowel diseases, psoriasis, non-melanoma skin cancer, atopic dermatitis, periodontitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application In target cell apoptosis. Embodiment 89. Use of a compound as defined in any of embodiments 1-77 for the preparation of a medicament for treating inflammation, asthma, chronic obstructive pulmonary disease, cystic fibrosis, allergic rhinitis, severe influenza, respiratory syncytial virus Infection, CDS 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 apoptosls.

Embodiment 90. Use of a compound of formula (I) as disclosed in any one of embodiments 1 to 77 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.

Embodiment 91. 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 of embodiments 1-77 or a composition as defined in any of embodiments 81-83 In an amount effective to modulate said DPPI levels In said subject. Embodiment 92. A method according to embodiment 91, wherein said DPPI Is

Inhibited.

Embodiment 93. The compound according to any of embodiments 1-77, which has a ICso(Cathepsln B)/ IC _S0 (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. Embodiment 94. The compound according to any of embodiments 1-77, 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.

Embodiment 95. The compound according to any of embodiments 1-77, which has a ICso(Cathepsin L)/ IC _S0 (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.

Embodiment 96. The compound according to any of embodiments 1-77, which has a IC ₅₀ (Cathepsin K)/ IC _5Q (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.

Embodiment 97. The compound according to any of embodiments 1-77, which has a IC _5g (Cathepsin S)/ ICso(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. Embodiment 98. A combination of a compound of formula (I) as disclosed in anyone of embodiments 1 to 77 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.

Embodiment 99. The compound according to any of embodiments 1-77, which has a IC ₅₀ (DPPI assay)/ IC ₅₀ (neutrophil ceil based DPPI inhibitor assay) of 0.2S 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.

Embodiment 100. The compound according to any of embodiments 1-77, which has a ICso (neutrophil cell based DPPI inhibitor assay) of 50 nM or lower, such as e.g. 25 n 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.

Embodiment 101. The compound according to any of embodiments 1-77, 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.

Embodiment 102. The compound according to any of embodiments 1-77, 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 or 3000 nM or more.

Embodiment 103. The compound according to any of embodiments 1-77, which have an apparent Hill-coeffldent 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.

Moreover, in all of the above embodiments 1-103, the compound of formula (I) may more specifically be a compound of formula (II) or (III).

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 Eungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginai, 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, inciuding 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 dally 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 soiubiilty 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 enzymatical!y cleaved In vivo. Such modifications, which Include the preparation of phosphates, amides, esters, thloesters, carbonates, and carbamates, are well known to those skilled In the art. In both drug discovery and drug development, prodrugs have become an established too! for Improving physicochemlcal, 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 dl- (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. dlpeptldyl peptidase IV (DPPIV/CD26), d!peptidy! peptidase I (DDPI/cathepsln C), amlnopeptldase N (APN/CD13), pyroglutamyl aminopeptidase (PGAP), aminopeptldase 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 add or a dl- (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 disdosed herein or a pharmaceutically acceptable salt thereof together with a

pharmaceutically acceptable adjuvant, carrier or diluent, is provided. The pharmaceutical compositions disdosed 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 disdosed 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 of the invention. However, in certain embodiments, the pharmaceutical compositions disdosed herein contain more than one compound of the invention. For example, In certain

embodiments the pharmaceutical compositions disdosed herein contain two compounds of the Invention. In addition, the pharmaceutical compositions disdosed herein may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions disclosed herein typically contain more than one

pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions disclosed herein contain one pharmaceutically-acceptable exdpient. As used herein, "pharmaceutlcally-acceptable exclplent" means a pharmaceutically acceptable material, composition or vehicle Involved In giving form or consistency to the pharmaceutical composition. Each exclplent 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 exdpient must of course be of sufficiently high purity to render it pharmaceutlcally-acceptable. The compound of the Invention and the pharmaceutlcally-acceptabie exceplent or excepients 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, capiets, pills, troches, powders, syrups, ellxers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconsOtution; (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 pharmaceutlcally-acceptable exdplents will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutica!ly-acceptab!e excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutJcally-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 pharmaceutlcally-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 pharmaceutlcally-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutlcally-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, emuisifiers, 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 pharmaceutlcally-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the exdpient 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 pharmaceutlcally-acoeptable exdplents 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 pharmaceutlcally-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Pubiishing 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-geiat!n!zsd starch), cellulose and Its derivatives (e.g. mlcrocrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders Include starch (e.g. com starch, potato starch, and pre-gelatinlzed starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalllne cellulose). The oral solid dosage form may further comprise a dlslntegrant. Suitable disintegrants Include crospovidone, sodium starch glycolate, croscarmeiose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants Include stearic a id, 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 pharmaceutlcally- 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-, dl-, 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 avaiiabie to the patient for inhaiation, Aiternativeiy, the dry powder may be presented in capsules (e.g. gelatin or piastic), cartridges, or biister 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 pro pedants Include halocarbons, hydrocarbons, and other liquified gases. Representative propellants include: trichlorofluoromethane (propellant 11 ), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1 ,1-dlfluoroethane (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 pharmaceutlcally-acceptable exclpients typically used with MDIs such as surfactants, lubricants, cosolvents and other exdplents 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 nebuilzatlon may be any pharmaceuticalry-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 adds, e.g., ascorbic acid, citric acid, acetic add, tartaric add, etc. may be used for this purpose.

Other pharmaceutlcally-acceptable exclpients may be added to the suspension or solution. The compound of the invention may be stabilized by the addition of an inorganic add, e.g., hydrochloric add, nitric add, sulphuric add and/or phosphoric add; an organic add, e.g., ascorbic add, dtric add, acetic add, and tartaric add, 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 aione or together to stabilize the compound of the invention. Preservatives may be added such as benzalkonlum chloride or benzoic add and salts thereof. Surfactant may be added particularly to Improve the physical stability of suspensions. These include lecithin, dlsodlum dloctylsulphosucdnate, oleic acid and sorbltan esters.

The compounds according to Formula I, II or ΙΠ are prepared using conventional organic syntheses. Suitable synthetic routes are shown in the examples. Starting materials and reagents 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). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. In one aspect, ² , B or Q may be in a deuterated form. A person of ordinary skill In the art will know how to synthesize deuterated forms of the compounds of Formula (I). 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. Perkln Trans. I, 1996,6, 537-40). a-amino adds in which deuterium atoms have been Incorporated into the side-chains are commerelally available or may be prepared by conventional techniques. Examples of compounds are Cpd. 1091, 1092, 1093 and 1094. The skilled artisan will appredate 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 disdosed herein may be converted to a pharmaceutically acceptable salt thereof, preferably an add addition salt such as a hydrochloride, hydro bromide,

trifluoroacetate, sulphate, phosphate, acetate, fu ma rate, 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 soivated, for example hydrated, as well as unsolvated forms, and the present Invention encompasses all such soivated 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-neoplastlc therapy and chronic Infection, including tuberculosis and aspergillosis and other fungal Infections; complications of lung transplantation; vascuiitic 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, coronavlrus (including SARS) and adenovirus; skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitls; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma

gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angloedema, vasculitldes, toxic erythemas, cutaneous eoslnophllias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective;

pannlculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-Induced disorders Including fixed drug eruptions; eyes: blepharitis; conjunctivitis, Including perennial and vemal 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; vu!vo-vaginitls; 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, antiphosphollpld 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 lymphoprollferatlve systems, such as Hodgkln'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, coronavlrus, influenza, para-Influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other Infectious diseases, such as malaria, fungal diseases, chlamydia, Candida, asperglllus, cryptococcal meningitis, Pneumocystis camil, cryptosporidiosls, 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 card!omegaly.

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, acute myocardial Infarction, stroke, respiratory syncytial virus Infection, CDS T cell Inhibition, inflammatory bowel diseases, psoriasis, non-melanoma skin cancer, atopic dermatitis, periodontitis, rheumatoid arthritis, Huntington's disease, malaria, Chagas' disease, Alzheimer's disease, sepsis or for application In target cell apoptosls.

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, CDS 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 apoptosls.

In a further aspect, the compound(s) disclosed herein Is for use in treating asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel diseases, cystic fibrosis, sepsis, malaria 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 jig 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 mol/kg, has a concentration In bone marrow of 250 n or more, such as 500 n or, 750 n or more or 1000 n 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) or a pharmaceutically acceptable salt thereof, is provided herein.

In one aspect, a method for the treatment of aliments, 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 μς 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, CDS 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 poptosis, 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 IC _S0 (Cathepsin B)/ IC _se (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 mors, is provided.

In one aspect, a compound, which has a IC _S0 (Cathepsin H)/ IC _5Q (DPPI assay) of 25 or more such as, e.g., 50 or more, 5 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 IC ₅₀ (Cathepsin L)/ IC _M (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 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, is provided.

In one aspect, a compound, which has a IC ₅₀ (Catheps!n S)/ IC _S0 (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 IC ₅₀ (DPPI assay)/ IC _5G (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 IC _S0 (neutrophil ceil based DPPI Inhibitor assay) of 50 nM or lower, such as e.g. 25 nM or lower, 10 n or lower, 5 nM or lower, 2 nM or lower, 1 nM or Eower, 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 phosphod (esterase Inhibitor; a peptidase Inhibitor; a glucocorticoid; an anticholinergic agent; a moduiator of chemoklne receptor function; and an Inhibitor of kinase function, is provided. In one aspect, the herein disclosed compounds have an apparent Hiii-coefficient in the DPPI assay or in the neutrophil ceii 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 cathepsln 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 ICgg or IC99.5 values.

In the present context, the Hill coefficient n (also called the cooperatlvity factor) provides a quantitative method for characterizing DPPI inhibition. The macromolecule (P) Is assumed to bind to n ligands (I) simultaneously (where n is to be determined)

to form the complex C. Hence the dissociation constant equals

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

Taking the logarithm yields an equation linear in n

Hence, the slope of this line yields n, whereas its intercept is determined by log K<< .

More generally, plotting iog [Θ/1-Θ] versus log [L] and taking the slope gives the effective number of !igands 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 cooperatlvlty 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 cooperatlvlty 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 non- linear curve fitting routine, using the curve formula Y=A-D/(l+(X C) ^A n)+D.

MATERIALS AND METHODS

Human DPPI assay

Using this assay, the IC _∞ value of a compound of the Invention may be determined using Gly-Phe-paranitroanlllde as a DPPI specific substrate. Assay buffer:

20 mM citric acid (2.1 g citric acid), 150 mM NaCl (4.4 g NaCl) and 2 mM EDTA (370 mg EDTA) was dissolved in 500 mL H20, and pH was adjusted to 4.5 with HCl.

Substrate:

Gly-Phe-paranitroanillde (Sigma Aldrich; Cat. No G0142) was used as the substrate for determination of IC _SC values. Km was 2.2 mM. The substrate was solublllzed in

dlmethyrrormamid 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 H0rsholm, Denmark) was stored at -20 °C in a buffer containing 2.5 m Na-phosphate, 150 m NaCi, 2 mM cysteamlne, 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 n .

Assay conditions:

The assay was performed In 96-well plates. Dllluted 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 absorbtion was measured at 405 nm at 37 °C for every 90 sec for 12 minutes or every 20 sec for 4 mln. Each measurement was made In duplicate. IC _S0 was determined using a 4-parameter logistic equation In a non-linear curve fitting routine.

Using this assay 20 of the exemplified compounds were found to have an IC ₅₀ of 150 nM or lower and nine of the exemplified compounds were found to have an IC _S0 of 20 nM or lower.

Call 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 M£thot N; Rubin J; Guay D; Beaulieu C; Ethler D; Reddy TJ; Rlendeau D and Percivai MD (2007) J Biol Chem, 282, 20836-20846.

U937 cei!s were propagated in culture media (RP I 1640, supplemented with 10% FBS, 10 mM Hepes, 1 m sodium pyruvate, 100 units/ml of each of penicillin and streptomycin). Cells were seeded in 2-well plates at 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 0.1 nM to 50 μΜ Inhibitor were tested. After 24 hours cells were harvested, washed twice with PBS and lysed In 20 mM Tris-HCl, pH 7.5, 100 mM NaCi, 0.2% Triton X-100.

Debris was removed by centrifugation and supematants 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-nltroaniline 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 μί. 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 more than 5 of the exemplified compounds were found to have an IC ₅₀ of 500 nM or lower. More than one of the exemplified compounds were found to have an IC ₅₀ of 5 nM or lower using this cell based assay.

Test for metabolic stability

The test for metabolic stability was performed by Absorption System, Exton, PA 19341, USA. The test compound (DPPI Inhibitor) was d (solved in 100 % DMSO at a concentration of 10 mM. The reaction mixture, consisted of Mouse Microsomes (1.0 mg/mL), 1 mM NADPH, 100 mM Potassium Phosphate, pH 7.4, 10 mM Magnesium Chloride and test compound at a concemtratlon 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 MADPH to 1 mM (not Into the negative controls) and then incubated in a shaking water bath at 37°C. Allquots (100 μΙ_) 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) were 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 40 mln.

Synthesis of methyl 2-(tert-butoxycarbonylamlno)acrylate (compound 1) At 0 °C, methylsulfonyl chloride (81.1 g, 0.71 mo!) was added to a solution of Boc-Ser-O e (77.5 g, 0.35 mol) and TEA (141.4 g, 1.4 mol) In dichloromethane (1 L). The reaction was stirred for 3 h at ambient temperature, then quenched with 5% NaHC0 ₃ solution (300 ml). The organic phase was collected, dried over anhydrous Na ₂ 50 ₄ , and concentrated under vacuum. The residue was purified by HPFC (PE: EA » 10: 1) to afford methyl 2-(tert- butoxycarbonylamlno)acrylate (63.5 g, 90.3%). LC- S: 202.3 (M+l).

vl)cvclopropyl)butanamlde

Synthesis Scheme

4'-fluoroblpheny{-4-carbaldehyde (Compound 20)

Pd(PPh ₃ ) ₄ (3 g) was added to a mixture of 4-formylphenylboronic acid pinacol cyclic ester (26.5 g, 0.11 moi), 4-bromofiuorobenzene(20 g, 0.1.1 moi), and potassium carbonate (31.5 g, 0.23 moi) in toluene (1 L) under nitrogen protection. The mixture was refluxed overnight. After cooling to room temperature, the solvent was removed under vacuum. To the residue were added water (500 ml) and ethyl acetate (500 ml). The organic phase was collected, and the water phase was extracted with ethyl acetate (500 ml x2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPFC (PE: EA «= 50: 1) to afford 4'-fiuorobiphenyl-4-carbaldehyde (19.3 g, 87,7%). LC-MS: 201.2 ( +l).

N'-((4 ^, -fluoroblphenyl-4-yl)methyl)sutfonlc hydrazlde (Compound 21)

To a solution of 4 ^! -fiuorobiphenyi-4-carbaidehyde (19.3 g, 96.5 mmol) In MeOH (600 ml), was added TsNHNH ₂ , (Sulfonyl hydrazine) (20.9 g, 0.11 moi) at ambient temperature. The reaction was stirred for 30 mln, then cooled to 0 °C. The resulting solid was collected by filtration and washed with cooled MeOH (50 ml x2). The solid was dried to afford the title compound (32 g, 90.1%). LC-MS: 369.3 (M+l). (lR,2R)-methyl l-amino-2-(4'-fluoroblpheny!-4~yi)cyciopropanecarboxyiate (Compound 22)

At -78 °C, BuLi (34.8 ml, 87 mmol) was added dropwlse to a solution of N'-((4'- fluoroblphenyl-4-yl)methyl)sulfonic hydrazJde (32 g, 87 mmol) In THF. The reaction was stirred for 1 h at -78 °C and the solvent was removed under vacuum. Then to the flask, was added a mixture of toluene, methyl 2-(tert-butoxycarbonylamlno)acrylate (17.5 g, 87 mmol), benzy!triethylammonlum chloride (0.5 g, 2.2 mmol), and catalyst CIFeTPP (0.31 g, 0.22 mmol). The reaction was stirred for 4 days at 50 °C under N ₂ protection. The solvent was removed under vacuum and the residue was partitioned between dlchloromethane and water. The organic phase was collected, and the water phase was extracted with dlchloromethane for two more times. The organic phases were combined, dried over anhydrous Na ₂ 50 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA = 10: 1) to afford Boc protected (lR,2R)-methyl l-amlno-2-(4'-fluorobiphenyl-4-yl)cyclopropanecarboxylate which was treated with 6 M HCl/EA solution (10 ml) for 30 mln at ambient temperature to give the title compound (2.7 g, 10.9%). LC- S: 286.1 (M+l). (lR,2R)-methyl l-((S)-2-(tert-butoxycarbonylamino)butanamldo)-2-(4 ^I -fluorobiphenyl-4- yl)cydopropanecarboxylate (Compound 23)

To a solution of Boc-Abu-QH (1.6 g, 6.4 mmol) and NM (1.07 g, 10.6 mmol) In

dlchloromethane (50 ml) at 0 °C, was added ethyl chloroformate (0.7 g, 6.4 mmol). The reaction was stirred for 30 mln at 0 °C, and a solution of (lR,2R)-methy! l-amlno-2-(4'- fluoroblphenyI-4-yl)cydopropanecarboxylate (1.5 g, 5.3 mmol) In dlchloromethane (10 ml) was added In. The cooling system was removed and the reaction was stirred for 2 h at ambient temperature. After washing with 5% HCl, the organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (PE: EA = 4: 1) to afford the title compound (1.8 g, 73%). LC-MS: 471.2 (M+l), 493.1 (M+Na). Tert-butyl (S)-1 -((lR,2R)-1 -carbamoyl-2-(4'-fiuorOblphenyl-4-yl)cyclopropylamino)-1 - oxobuta n -2-ylca rba mate (Compound 24)

UOH.HjO (0.87 g, 19.5 mmol) was added to a solution of (lR,2R)-methyl l-((S)-2-(tert- butoxycarbonyiam!no)butanam!do)-2-(4 -fiuorobiphenyl-4-yl)cycSopropanecarboxylate (1.8 g, 3.9 mmol) in THF (20 ml) and water (20 ml). The reaction was stirred for 3 h at ambient temperature. After removal of THF under vacuum, the water phase was extracted with dlchloromethane (20 ml). The dlchloromethane phase was discarded, and EA (30 ml) was added to the water phase. The mixture was triturated with 10% HCl to pH 2-3. The organic layer was collected, dried over anhydrous Na ₂ SO_., and concentrated. The residue was dissolved in dlchloromethane (50 mi), and NMM (0.77 g, 7.8 mmol) was added. After cooling the solution to 0 °C, ethyl chloroformate (0.51 g, 4.7 mmol) was injected. The reaction was stirred for 30 min at 0 °C, then the mixture was poured into a flask with 200 mi of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mi x3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (PE: EA - 1: 1) to afford the titie compound (1.0 g, 57%). LC-MS: 478.1 (M+Na).

(S)-2-amino-N-((l ,2R)-1 -cyano-2-(4'-fluoroblphenyl-4-yl)cyclopropyl)butanamide and (S)- 2-amlno-N-((lS,2S)-1 -cyano-2-(4'-fluorobiphenyl-4-yl)cyclopropyl)butanamide Step 1.

Tert-butyl (S)-1 -((lR,2R)-1 -carbamoyl-2-(4 ^, -fluoroblphenyl-4-yl)cydopropylamino)-1 - oxobutan-2-ylcarbamate (SRR-24) end tert-butyl (S)-1 -((lS,2S)-1 -carbamoyl-2-(4'- fluoroblphenyl-4-yl)cyclopropylamino)-1 -oxobutan-2-ylcarbamate (SSS-24) were separated by chirai column. To a solution of a (SRR-24) or (SSS-24) (400 mg, 0.88 mmol) In DMF (10 ml), was added cyanuric chloride (0.32 g, 1.76 mmol). The reaction was stirred for 3 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA = 2: 1) to afford tert-butyl (S)-1 -((lR,2R)-1 -cyano-2-(4'-fluoroblphenyl-4-yl)cyclopropylamlno)-1 -oxobutan- 2-ylcarbamate or tert-butyl (S)-1 -((lS,2S)-1 -cyano-2-(4'-fluorobiphenyl-4- yl)cyclopropylamlno)-1 -oxobutan-2-ylcarbamate.

Tert-butyl (S)-1 -((iR,2R)-1 -cyano-2-(4'-fluorobiphenyl-4-yl)cydopropylamlno)-1 -oxobutan- 2-ylcarbamate 187 mg, 49%) LC-MS: 460.1 (M+Na). *H NMR (CDCI ₃ , 300 MHz) δ: 7.12-7.57 (m, 8H, Ph), 6.42 (br, 1H, NH), 4.68 (br, 1H, NH), 3.80 (m, 1H, COCH), 3.05 (t, J = 9.0 Hz, 1H, PhCH), 1.98 (dd, J = 6.9 Hz, 9.6 Hz, 1H, cydopropane-CH ₂ ), 1.79 (t, 3 = 7.8 Hz, 1H, cydopropane-CH ₂ ), 1.30 (s, 9H, Boc), 1.24 (br, 2H, CH ₂ ), 0.77 (br, 3H, CH ₃ ).

Tert-butyl (S)-1 -((lS,2S)-1 -cyano-2-(4'-fiuoroblphenyl-4-yl)cyclopropylamino)-1 -oxobutan- 2-ylcarbamate (180 mg, 47%) LC-MS: 460.1 (M+Na). *H NMR (CDCI ₃ , 300 MHz) δ 7.12- 7.54 (m, 8H, Ph), 6.45 (br, 1H, NH), 4.90 (br, 1H, NH), 3.80 (dd, J = 6.9 Hz, 14.1 Hz, 1H, COCH), 3.05 (t, J = 9.0 Hz, 1H, PhCH), 2.10 (m, 1H, cyclopropane-CH ₂ ), 1.83 (t, J - 7.6 Hz, 1H, cydopropane-CH ₂ ), 1.42 (s, 9H, Boc), 1.32 (br, 2H, CH ₂ ), 0.63 (br, 3H, CH ₃ ). Step 2,

Tert-butyl (S)-1-((l ,2R)-l^ano-2-(4'-fluorobiphenyl-4-yl)cydopropylamlno)-1-oxob irtan- 2-y!carbamate or tert-butyl (S)-1-((lS,2S)-1-cyano-2-(4'-fIuoroblphenyl-4- yl)cydopropytamlno)-1-oxobutan-2-ylcarbamate (120 mg, 0.27 mmol) was treated with excess HCOOH (10 ml) for 3 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 ml x3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield (S)-2-amlno-N-((lR,2R)-1-cyano-2-(4'- fluorobiphenyl-4-yl)cyclopropyl)butanamlde or (S)-2-amino-N-((lS,2S)-1-cyano-2-(4'- fluorobipheny!~4~yl)cyclopropyl)butanamlde.

(S)-2-amino-N-((lR,2R)-1-cyano-2-(4'-fiuoroblphenyl-4-yl) cyclopropyl)butanamide (62 mg, 68%). LC-MS: 338.1 (M+l). *H NMR (DMSO-</6, 300 MHz) δ: 7.25-7.68 (m, 8H, Ph), 3.08 (m, 1H, COCH), 3.05 (t, J = 6.4 Hz, 1H, PhCH), 1.97 (d, J = 9.0 Hz, 2H, cydopropane-CH ₂ ), 1.10 (m, 2H, CH ₂ ), 0.57 (t, J = 7.8 Hz, 3H, CH ₃ ). (S)-2-amlno-N-((lS,2S)-1-cyano-2-(4'-fluorobiphenyl-4-yl)cyd opropyl)butanamlde (68 mg, 75%). LC-MS: 338.1 (M+l). *H NMR (DMSO-d6, 300 MHz) <5: 7.25-7.68 (m, 8H, Ph), 3.80 (t, J = 9.1 Hz, 1H, COCH), 3.05 (t, J = 6.0 Hz, 1H, PhCH), 1.95 (m, 2H, cydopropane-CH ₂ ), 0.95-1.19 (m, 2H, CH ₂ ), 0.36 (m, J - 7.4 Hz, 3H, CH ₃ ).

(S)-2-amlno-jV-((lfi.2f¾)-1-cyano-2-(4'-(trifiuorOmethyl )biphenyl-4- yl)cyclopropy|)bUtanajiilde and (g)-2-amlno-N-((lS,2g)-1-cyanQ-2-(4'- (tTifluorpmethyl)blphenyl-4-yl)cydopropyl)butanamlde

Synthesis Scheme

4'-trifiuoromethy!biphenyi-4-carbaldehyde (Compound 25}

Pd(PPh ₃ ) ₄ (6 g) was added to a mixture of 4-fbrmyiphenylboronic acid plnacoS cyclic ester (53 g, 0,22 mol), 4-trifluoromethylbromobenzene(50 g, 0.22 mol), and potassium carbonate (63 g, 0.46 mol) In toluene (2 L) under nitrogen protection. The mixture was refiuxed overnight. After cooling to room temperature, the solvent was removed under vacuum. To the residue were added water (l L) and ethyl acetate (1 L), The organic phase was collected, and the water phase was extracted with ethyl acetate (1 L x2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPFC (PE: EA = 50: 1) to afford the title compound (50.2 g, 90.1%). LC- S: 251.2 (M+l).

N'-((4 ^, -trifluoromethylblphenyl-4-yl)methyl)sulfonlc hydrazlde (Compound 26)

To a solution of 4 ^, -trifluoromethylblphenyl-4-carbaldehyde (50 g, 0.20 mol) In MeOH (1 L), was added TsNHNH ₂ (75.5 g, 0.4 mol) at ambient temperature. The reaction was stirred for 30 min, then cooled to 0 °C. The resulting solid was collected by filtration and washed with cooled MeOH (50 ml x2). The solid was dried to afford the title compound (72.7 g, 87%). LC- MS: 419.2 (M+l). (iR,2R)- methyl l-amino-2-(4'- trifiuoromethyl blphenyl-4-yl)cyclopropane-carboxylate

(Compound 27)

At -78 0C, n-butylllthium (69 ml, 0.17 mo!) was added dropwise to a solution of N'-((4'- tr1fluoromethyl-4-y1)methyl)sulfonic hydrazlde (72 g, 0.17 mol) In THF (1 L). The reaction was stirred for 1 h at -78 OC and the solvent was removed under vacuum. Then to the flask, was added a mixture of toluene, methyl 2-(tert-butoxycarbonylamlno)acrylate (34.7 g, 0.17 mol), benzyltriethylammonium chloride (0.98 g, 4.3 mmol), and catalyst CIFeTPP (0.61 g, 0.43 mmol). The reaction was stirred for 4 days at 50 °C under N ₂ protection. The solvent was removed under vacuum and the residue was partitioned between dlchloromethane and water. The organic phase was collected, and the water phase was extracted with

dichloromethane for two more times. The organic phases were combined, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA » 10: 1) to afford (lR,2R)-methyl l-(tert-butoxycartx3nylamino)-2-(4*-(trifluoromethyl)bipheny l-4- yl)cyclopropanecarboxylate, which was treated with 6 HCl/EA solution (50 ml) for 30 min at ambient temperature to give the title compound (5.9 g, 10.3%). LC-MS: 336.1 ( +i),

(1R,2R)- methyl l-((S)-2-(tert-butoxycarbonylamlno)butanamldo)-2-(4'- trifiuoromethyl biphenyl-4-yl)cyclopropanecarboxylate (Compound 28)

To a solution of Boc-Abu-OH (1.1 g, 5.4 mmol) and NMM (0.91 g, 9.0 mmol) In

dichloromethane (30 ml) at 0 °C, was added ethyl chloroformate (0.59 g, 5.4 mmol). The reaction was stirred for 30 min at 0 °C, and a solution of (lR,2R)-methyl l-amlno-2-(4 ^* - trifluoromethyl biphenyl-4-yl)cyclopropane-carboxylate (1.5 g, 4.5 mmol) In dlchloromethane (10 ml) was added in. The cooling system was removed and the reaction was stirred for 2 h at ambient temperature. After washing with 5% HCl, the organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (PE: EA « 4: 1) to afford the title compound (1.9 g, 81%). LC-MS: 543.1 (M+Na).

Tert-butyl (S)-1 -((lR,2R)-1 -carbamoyl-2-(4'-(tr1fluoromethyl)blphenyl-4- yi)cydopropylamino)-1 -oxobutan-2-ylcarbamate (Compound 29)

UOH.HjO (0.9 g, 18.5 mmol) was added to a solution of (lR,2R)-methyl l-((S)-2-(tert- butoxycarbonylamino)butanamido)-2-(4'- trifiuoromethyl blphenyl-4- yl)cyclopropanecarboxylate 1.9 g, 3.7 mmol) In THF (20 ml) and water (20 ml). The reaction was stirred for 3 h at ambient temperature. After removal of THF under vacuum, the water phase was extracted with dlchloromethane (20 ml). The dlchloromethane phase was discarded, and EA (30 ml) was added to the water phase. The mixture was triturated with 10% HCl to pH 2-3. The organic layer was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated.

The residue was dissolved in dichloromethane (50 ml), and NMM (0.87 g, 8.8 mmol) was added. After cooling the solution to 0 °C, ethyl chloroformate (0.49 g, 4.4 mmol) was Injected. The reaction was stirred for 30 mln at 0 °C, then the mixture was poured Into a flask with 200 ml of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 ml x3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (PE: EA - 1: 1) to afford the title compound (1.1 g, 58%). LC-MS: 528.1 (M+Na). (S)-2-amlno-N-((l«,2«)-1 -cyano-2-(4'-(trifiuoromethyl)biphenyi -4- yl)cydopropyl)butanamlde and (S)-2-amlno-/v-((lS,2S)-1 -cyano-2-(4'- (trifluoromethyl)biphenyl-4-yl)cyclopropyl)butanamlde

Step 1.

Tert-butyl (S)-1 -((lR,2 )-1 -carbamoyi-2-(4'- trlfluoromethylblphenyl-4- yl)cydopropylamlno)-1 -oxobutan-2-ylcarbamate (SRR-29) and tert-butyl (S)-1-((1S,2S)-1- carbamoyl-2-(4'- trifiuoromethylbiphenyi-4-yl)cydopropylamino)-1 -oxobutan-2-yicarbamate (SSS-29).

To a solution of (SRR-29) or (SSS-29) (400 mg, 0.79 mmol) In D F (10 ml), was added cyanuric chloride (0.29 g, 1.58 mmol). The reaction was stirred for 3 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 _4> and concentrated. The crude product was purified by HPFC (PE: EA ^» 3: 1) to afford Boc-protected (S)-2-amlno-N-((l«,2/?)-1 -cyano-2-(4 ^, -(trifluoromethyl)blphenyl-4- yl)cyclopropyl)butanamide or Boc-protected (S)-2-amlno-N-((lS,2S)-1 -cyano-2-(4'- (trlfluoromethyl)blphenyl-4-yl)cydopropyl)butanamide .

Boc-protected (S)-2-amino- v-((l/?,2«)-1 -cyano-2-(4'-(trifluoromethyl)blphenyl-4- yi)cydopropy!)butanamide (165 mg, 43%) LC-MS: 510.1 (M+Na). *H NMR (CDCI ₃ , 300 MHz) δ: 7.30-7.73 (m, 8H, Ph), 6.47 (br, 1H, NH), 4.89 (br, 1H, NH), 3.71 (dd, J = 6.9 Hz, 14.1 Hz, 1H, COCH), 3.09 (t, J « 9.0 Hz, 1H, PhCH), 2.11 (dd, J = 6.9 Hz, 9.6 Hz, 1H, cydopropane-CHj), 1.84 (t, J = 7.7 Hz, 1H, cydopropane-CH ₂ ), 1.42 (s, 9H, Boc), 1.33-1.62 (m, 2H, CH ₂ ), 0.64 (br, 3H, CH ₃ ). Boc-protected (S)-2-amlno-N-((lS,2S)-1 -cyano-2-(4'-(trtfluorometJiyl)blphenyl-4- yl)cydopropy!)butanamide (160 mg, 42%) LC- S: 510.1 (M+Na). H NMR (CDCI ₃ , 300 MHz) δ: 7.28-7.70 (m, 8H, Ph), 6.41 (br, 1H, NH), 4.78 (br, 1H, NH), 3.69 (m, 1H, COCH), 3.11 (t, J = 9.0 Hz, 1H, PhCH), 2.08 (m, 2H, cydopropane-CH ₂ ), 1.43 (s, 9H, Boc), 1.26-1.47 (m, 2H, CH ₂ ), 0.66 (br, 3H, CH ₃ ),

Step 2.

Boc-protected (S)-2-amino-Ai-C(l/?,2/¾)-1 -cyano-2-(4'-(trifluoromethyl)biphenyi-4- yl)cydopropyl)butanamlde or Boc-protected (S)-2-amlno-N-((lS,2S)-1 -cyano-2-(4'- (trtfluoromethyl)blphenyl-4-yl)cyclopropyl)butanamlde (120 mg, 0.25 mmol) was treated with excess HCOOH (10 ml) for 3 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 ml x3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield (S)-2-amlno-N-((lR,2R)-1 -cyano-2-(4'- (trifluoromethyl)blphenyl-4-yl)cyclopropyl)butanamlde or (S)-2-amlno-N-((lS,2S)-1 -cyano- 2-(4'-(trifiuoromethyl)blphenyl-4-yl)cydopropyl)butanamlde

(S)-2-amIno-N-((l/?,2R)-1 -cyano-2-(4'-(trlfiuoromethyl)biphenyi-4- yl)cyclopropyl)butanamide (70 mg, 74%). LC-MS: 388.1 (M+l). H NMR (DMSO-d6, 300 MHz) δ-: 7.33-7.88 (m, 8H, Ph), 3.09 (t, J = 9.3 Hz, 1H, COCH), 2.92 (t, J = 6.5 Hz, 1H, PhCH), 1.97 (d, J = 9.0 Hz, 2H, cydopropane-CH ₂ ), 1.10 (m, 2H, CH ₂ ), 0.47 (t, J = 7.5 Hz, S)-2-amino-W--((lS,2S)-1 -cyano-2-(4 ¹ -(trif!uoromethyl)biphenyl-4-yl)cyciopropyS)butanamlde (72 mg, 75%). LC-MS: 388.1 (M + l). *H NMR (DMSO-o¾, 300 MHz) δ: 7.33-7.88 (m, 8H, Ph), 3.10 (t, J » 9.0 Hz, 1H, COCH), 2.86 (t, J » 6.3 Hz, 1H, PhCH), 1.98 (m, 2H, cydopropane-CH ₂ ), 0.93-1.18 (m, 2H, CH ₂ ), 0.38 (m, J = 7.6 Hz, 3H, CH ₃ ).

yl)cyc|ppropyl)-3-(furan-2-yl)propanamlde

The title compound was prepared by a process analogous to the process described for example 2 using Boc-Fura-OH instead of Boc-Abu-OH.

(S)-2-amino-W-((lR _f 2fl)-1-cyano-2-(4'-(Wfluorom

2-yl)propanamide {60 mg, 62%). LC- S: 440.1 (M+l). *H NMR (DMSO-d6, 300 MHz) δ: 8.96 (s, 1H, CONH), 7.33-7.87 (m, 9H, Ph+Fura), 6.26 (m, 1H, Fura), 5.93 (m, 1H, Fura), 3.24 (dd, J ^« 4.2 Hz, 8.7 Hz, 1H, COCH), 3.14 (t, J - 9.0 Hz, 1H, PhCH), 2.25 (m, 2H, cyciopropane-CHj), 1.99 (m, 2H, CH ₂ ).

(S)-2-amino-W-((lS,2S)-1-cyano-2-(4 ^! -(trifluoromethyl)blphenyi-4-yl)cyclopropyi)-3-(fura 2-yl)propanamide (53 mg, 55%). LC-MS: 440.2 (M+l). *H NMR (DMSO-t/6, 300 MHz) 6\ 7.33-7.88 (m, 9H, Ph+Fura), 6.28 (m, 1H, Fura), 5.96 (d, J = 3.0 Hz, 1H, Fura), 3.25 (m, 1H, COCH), 3.11 (t, J = 9.1 Hz, 1H, PhCH), 2.23 (m, 2H, cydopropane-CH ₂ ), 2.03 (m, 2H, CH ₂ ).

fS)-2-amino-N-ffl«.2/¾)-1 -cvano-2-f4'-ftrif]uoromethvnblDhenvi-4- vncvclopropyl¾hexanamlde and fSV2-amlno-N-(flS.2S -cvano-2-(4'-

The title compound was prepared by a process analogous to the process described In example 2 using Boc-NorLeu-OH instead of Boc-Abu-OH.

(S)-2-amlno-N-((l«,2/?)-1-cyano-2-(4'-(trlfluoromethyl)biph enyl-4- yl)cydopropyi)hexanamlde (58 mg, 61%). LJC- S: 416-1 ( +l). *H NM (DMSO-d6, 300 MHz) δ: 7.33-7.90 (m, 8H, Ph), 3.09 (t, J = 9.0 Hz, 1H, COCH), 2.84 (m, 1H, PhCH), 1.98 (m, 2H, cydoprapane-CH ₂ ), 0.85 (m, 6H, CH ₂ ), 0.59 (t, J - 6.9 Hz, 3H, CH ₃ ). (S)-2-amlno-N-((lS,2S)-1-cyano-2-(4'-(trffluoromethyl)biphen yl-4- yl)cyclopropyl)hexanamlde (73 mg, 77%). LC-MS: 416.0 (M+l). ^a H NMR (DMSO-cftS, 300 MHz) 6: 7.34-7.90 (m, 8H, Ph), 3.09 (t, J - 9.2 Hz, 1H, COCH), 2.84 (t, J = 6.3 Hz, 1H, PhCH), 2.01 (d, J » 9.6 Hz, 2H, cyciopropane-CH ₂ ), 0.91 (m, 6H, CH ₂ ), 0.60 (t, J = 6.9 Hz, 3H, CH ₃ ). .BXAMP.UB..5 j,

N'~(4-Bromebenzy!idene)~4~methyEbenzenesulfQnQhydr3zEde (2) To a solution of 4-bramobenzaldehyde (85.1 g, 0.46 mol) In MeOH (1 L) was added p~ toluenesutfbnyi hydrazide (98,6 g, 0.53 mpi) at ambient temperature. The reaction was stirred for 30 mln, then cooled to 0 °C. The precipitate was collected by filtration and washed with cooled MeOH (50 ml x2). The solid was dried In an oven to afford N'-(4- bromobenzylldene)-4-methylbenzenesulfonohydrazlde 2 (150.3 g, yield 92%). LC-MS: 354.1 (M+l).

(1R, 2R plus IS, 2S)-Methyl-2-(4-bromophenyl)-1-(tert-butoxycarbonyl- amino)cydopropanecarboxylate (3)

A solution of N ^, -(4-bromobenzylidene)-4- methyl benzenesulfono-hydrazide (2, 56.4 g, 0.16 mol) In THF (1 L) was kept at -78 °C. n-Butyllithlum (64 ml, 0.16 mol) was added dropwlse to the solution. The reaction was stirred for 1 h at -78 °C, and the solvent was removed under vacuum. To the residue was added a mixture of methyl 2-(tert- butoxycarbonylamino)acryiate (1, 32.2 g, 0.16 mol), benzyltriethylammonlum chloride (0.91 g, 4 mmol), and catalyst CIFeTPP (0.56 g, 0.4 mmol) in toluene (1 L). The reaction was stirred for 4 days at 50 °C under N ₂ protection. The solvent was removed under vacuum and the residue was partitioned between dichloromethane (500 ml) and water (500 ml). The organic layer was collected, and the water layer was extracted with dichloromethane (500 ml x 2). The organic phases were combined, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA = 10: 1) to afford a mixture of (1R, 2R)- and (IS, 2S)- 3 (29.1 g, yield 49%). LC-MS: 371.2 (M+l). l-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p henylsulfonyl]plperazlne (955-

2)

Pd(PPh ₃ )* (3 g) was added to a mixture of l-(4-bromophenyl sulfonyl)-4-methylpiperazine (20 g, 62.6 mmol), plnacolatodlboron (11 g, 62.6 mmol), and potassium carbonate (17.8 g, 0.13 mol) In toluene (1 L) under nitrogen protection. The mixture was heated under reflux overnight. After cooling to room temperature, the solvent was removed under vacuum. To the residue were added water (500 ml) and ethyl acetate (500 ml). The organic phase was collected, and the water phase was extracted with ethyl acetate (500 ml x2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 1- methyl-4-[4- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl]piperazln e (955-2, 15.1 g, yield 65%). LC-MS: 367.2 (M+l).

(1R, 2R)- (IS, 2S)-Methyl l-(tert-butoxycart>onylamlno)-2-[4 ^, -(4-methyl-piperazln-1-yl- suffonyl)blphenyl-4-yl]cydopropanecarboxylate (955-3)

PdCI ₂ (dppf) ₂ (2 g) was added to a mixture of 955-2 (15 g, 40.9 mol), compound 3 (15.1 g, 40.9 mmol), and sodium carbonate aqueous solution (8.67 g, 2 M) In 1,4-dioxane (1 L) under nitrogen protection. The mixture was refluxed overnight. After cooling to room temperature, the solvent was removed under vacuum. To the residue were added water (500 ml) and ethyl acetate (500 ml). The organic phase was collected, and the water phase was extracted with ethyl acetate (500 ml x2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPFC (ethyl acetate/petroleum ether as eluent) to afford the (1R, 2R)- and (IS, 2S)- mixture 955-3 (12.9 g, yield 60%). LC- MS: 530.2 ( +l).

(1R, 2R)- & (IS, 2S)-Methyl l-amino-2-[4'-(4-methylpiperazin-l yl -sul fony!)-b!phenyl-4- yljcyclopropanecarboxylate (955-4)

To a solution of 955-3 (2.5 g, 4.7 mmol) in THF (30 ml) was added 100 ml of aqueous 6 N HCl. The mixture was stirred for 4 h at 40 °C, then adjusted to pH 8 with sat. NaHC0 ₃ . The mixture was extracted with ethyl acetate (200 ml x3). The organic layer were separated, dried over anhydrous sodium sulfate, and concentrated to afford 955-4 quantitatively.

(1R, 2R)-Methyl-(S)-2-(tert-butoxycarbonylamino)butanamido)-2-(4' -(4-methylpiperazin-1 - ylsulfonyl)blphenyl-4-yl)cydopropanecarboxylate (955-5), (IS, 2S)-methyl l-((S)-2-(tert- butoxycarbonylamlno)butanamldo)-2-(4 ^, -(4-methyl-pi perazin-1 -ylsulfonyl)blphenyl-4- yl)cyclopropanecarboxyiate (956-5)

To a solution of Boc-Abu-OH (2.35 g, 9.4 mmol) and NMM (1.77 g, 18.8 mmol) in

dichloromethane (50 ml) at 0 °C was added ethyl chloroformate (1.03 g, 9.4 mmol). The reaction was stirred for 1 h at 0 °C, and a solution of 955-4 (2.03 g, 4.7 mmo!) In

dichloromethane (10 ml) was added. The reaction was allowed to warm to ambient temperature and stirred overnight. It was poured into 100 ml of water and extracted with dichloromethane (100 ml). The dichloromethane layer was separated, and the aqueous phase was extracted with dichloromethane (100 ml x2) and ethyl acetate (100 ml x 2). The combined organic extract was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum. The residue was purified by HPFC (ethyl acetate petroleum ether as eluent) to yield a mixture of stereomers, which was separated by chira!-HPLC to afford 955-5 (700 mg) and 956-5 (650 mg). LC-MS: 615.3 (M+l).

Tert-butyl (S)-1-((1R, 2R)-1 -carbamoyl-2-(4'-(4-methylplperazln-1 -yl-sul fonyl)blphenyl-4- yl)cydopropylamlno)-1 -oxobutan-2-ylcarbamate (955-6) UOH.HzO (0.25 g, 5.5 mmol) was added to a solution of 955-5 (0.7 g, 1.1 mmol) In THF (20 ml) and water (20 mi). The reaction was stirred for 3 h at ambient temperature. It was adjusted to pH3 with aqueous 1 N HCf and extracted with ethyl acetate (100 ml x 3). The combined extract was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum. The residue was dissolved in dichloromethane (SO ml), and NMM (0.33 g, 3.3 mmol) was added. After cooling the solution to 0 °C, ethyl chloroformate (0.24 g, 2.2 mmol) was injected into the reaction mixture. The reaction was stirred for l h at 0 °C, and the mixture was poured Into a flask with 200 ml of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 ml x 3) and ethyl acetate (200 ml x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford 955-6 (550 mg, 81%). LC-MS: 600.2 (M+H).

Tert-butyl (S)-1-((1S, 2S)-1 -carbamoyl-2-(4 ^, -(4-methylpiperazin-1 -yl-sulfo nyl)blphenyl-4- yl)cydopropylamino)-1 -oxobutan-2-ylcarbamate (956-6) UOH.H ₂ 0 (0.25 g, 5.5 mmol) was added to a solution of 956-5 (0.65 g, 1.0 mmol) in THF (20 ml) and water (20 ml). The reaction was stirred for 3 h at ambient temperature. It was adjusted to pH3 with aqueous 1 N HCl and extracted with ethyl acetate (100 ml x 3). The combined extract was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum.

The residue was dissolved In dichloromethane (50 ml), and NMM (0.33 g, 3.3 mmol) was added. After cooling the solution to 0 °C, ethyl chloroformate (0.24 g, 2.2 mmol) was injected Into the reaction mixture. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 ml of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 ml x 3) and ethyl acetate (200 ml x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford 956-6 (520 mg, 82%). LC-MS: 600.3 (M+H).

(S)-2-amlno-N-((lR, 2R)-1 -cyano-2-(4'-(4-methylpiperazln-1 -ylsulfonyl)blphenyl-4- yl)cydopropyl)butanamlde (PZ955)

To a solution of 955-6 (550 mg, 0.92 mmol) In DMF (10 ml) was added cyanuric chloride (0.50 g, 2.75 mmol). The reaction was stirred for 4 h at ambient temperature. Solvent was removed under vacuum, and the residue was partitioned between water (30 mL) and ethyl acetate (60 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum. The crude product was purified by HPFC (EA) to afford Boc-(S)-2-amino-N-((lR, 2R)-1 -cyano-2-(4'-(4~methylp!perazln

-1-ylsulfonyl) blphenyl-4-yl)cyclopropyl)butanamide (Boc-PZ955) (150 mg), Boc-PZ955 (150 mg, 0.26 mmol) was treated with excess HCOOH (10 ml) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHCO _* In water and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 ml x 3) and dlchloromethane (200 ml x 3). The combined organic extract was dried over anhydrous NajSOi, and concentrated to yield (S)-2-Am!no-N-((lR, 2R)-1 -cyano-2-(4'- (4-metbyl- piperazln-1 -ylsulfonyl}bi phenyl-4-yl)cydopropy1)-3-(furan-2-yl) propanamlde (PZ955) (60 mg). LC- S: 482.1 (M+H). *H NMR (CDCI ₃ , 300 MHz) δ: 7.81 (d, J - 8.4 Hz, 2H, Ph), 7.68 (d, J - 8.4 Hz, 2H, Ph), 7.54 (d+s, J = 8.1 Hz, 3H, Ph+CONH), 7.34 (d, J = 8.1 Hz, 2H, Ph), 3.19 (m, 1H, COCH), 3.07 (m, 5H, NCH ₂ +PhCH), 2.51 (m, 4H, NCH ₂₎ , 2.28 (s, 3H, NCH ₃ ), 2.09 (m, 1H, cydopropane-CHz), 1.84 (m, 1H, cydopropane-CH ₂ ), 1.48 (m, 2H, CH ₂ ), 0.63 (t, J - 7.2 Hz, 3H, CH ₃ ).

(S)-2-amlno-N-((lS, 2S)-1 -cyano-2-(4'-(4-methylplperazln-1 -ylsurfbnyl)blphenyl-4- yl)cyclopropyl)butanamide (PZ956)

To a solution of 956-6 (520 mg, 0.87 mmol) In DMF (10 ml) was added cyanurlc chloride (0.50 g, 2.75 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water (30 mL) and ethyl acetate (60 mL). The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum. The crude product was purified by HPFC (EA) to afford Boc-(S)-2-amlno-N- ((1S, 2S)-1 -cyano-2-(4'-(4-methyl-plperazln-1 -ylsulfonyl) biphenyl-4- yl)cyclopropyl)butanamide (Boc-PZ956) (120 mg).

Boc-PZ956 (120 mg, 0.21 mmol) was treated with excess HCOOH (10 ml) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 ml x 3) and dlchloromethane (200 ml x 3). The combined organic extract was dried over anhydrous Na ₂ S0 , and concentrated to yield (S)-2-amino-N-((lS, 2S)-1 -cyano-2-(4'-(4-methyl- piperazin-1 -ylsulfonyl) biphenyl-4-yl)cydopropyl)butanamlde (PZ956) (98 mg). LC-MS: 482.1 (M+H). ^l H NMR (DMSO-cな, 300 MHz) δ: 7.90 (d, J = 8.4 Hz, 2H, Ph), 7.78 (d, J - 8.4 Hz, 2H, Ph), 7.66 (d, J - 8.1 Hz, 2H, Ph), 7.34 (d, J = 8.4 Hz, 2H, Ph), 3.10 (t, J = 9.0 Hz, 1H, COCH), 2.91 (m, 4H, NCH ₂ ), 2.84 (m, 1H, PhCH), 2.36 (m, 4H, NCH ₂₎ , 2.13 (s, 3H, NCH ₃ ), 1.99 (m, 2H, cydopropane-CH ₂ ), 1.09 (m, 1H, CH ₂ ), 0.97 (m, 1H, CH ₂ ), 0.37 (t, J = 8.0 Hz, 3H, CH ₃ ). fPZ966)

Synthesis Scheme

Procedure

(1R, 2R)- ethyl l-((S)-2-(tert-butoxycarbonylamino)-3-(furan-2-y1) propanamldo)-2-(4'-(4- methy!piperazln-1 -yisuifony!)biphenyl-4-yi)cyciopropanecarboxylate (965-1), and (IS, 2S)~ methyl l-((S)-2-(tert-butoxycarbonylamlno)-3-(fu ran-2-yl)propanamido)-2-(4'-(4- methylplperazln-1 -ylsulf nyl)blphenyl-4-yl)cydopropanecarboxylate (966-1)

To a solution of Boc-FUA-GH (2.40 g, 9.4 mmol) and NMM (1.77 g, 18.8 mmol) in

dlchloromethane (50 ml) at 0 °C was added ethyl chloroformate (1.03 g, 9.4 mmol). The reaction was stirred for 1 h at 0 °C, and a solution of (1R, 2R)- & (IS, 2S)-Methyl l-amlno-2- [4'-(4-methylplperazln-1 -yl-sul fonyl)-blphenyl-4-yl]cyclopropanecarboxylate (955-4; see examp^^

was allowed to warm to ambient temperature and stirred overnight. It was poured into 100 ml of water and extracted with dlchloromethane (100 ml). The organic layer was separated, and the aqueous phase was extracted with dlchloromethane (100 ml x 2) and ethyl acetate (100 ml x 2). The combined organic extract was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum. The residue was purified by HPFC (EA) to yield a mixture of stereomers, which was then separated on chlral prep-HPLC to afford 965-1 (500 mg) and 966-1 (510 mg). LC-MS: 667.3 (M+l).

Tert-butyl (S)-1-((1R, 2 )-1 -carbamoyl-2-(4 ^, -(4-methylplperazin-1 -ylsulfonyl)blphenyl-4- yl)cyclopropylamlno)-3-(furan-2-yl)-1 -oxopropan-2-ylcarbamate (965-2)

LiOH.HjO (0.16 g, 3.5 mmol) was added to a solution of 965-1 (0.5 g, 0.7 mmol) In THF (20 ml) and water (20 ml). The reaction was stirred for 3 h at ambient temperature. It was adjusted to pH 3 and extracted with ethyl acetate (100 mix 3). The combined extract was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum.

The residue was dissolved in dlchloromethane (50 ml), and N M (0.28 g, 2.8 mmol) was added. After cooling the solution to 0 °C, ethyl chloroformate (0.15 g, 1.4 mmol) was Injected through a syringe. The reaction was stirred for 1 h at 0 °C, and the mixture was poured into a flask with 200 ml of ammonia in water. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 ml x 3) and ethyl acetate ((200 ml x 3). The combined extract was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum to afford 965-2 (400 mg, yield 82%). LC-MS: 652.3 (M+H). Tert-butyl (S)-1-((1S, 2S)-1 -carbamoyl-2-(4'-(4-methylplperazln-1 -ylsulfonyl)blphenyl-4- yl)cyclopropylamino)-3-(furan-2-yl)-1 -oxopropan-2-ylcarbamate (966-2)

LiOH.H ₂ 0 (0.16 g, 3.5 mmol) was added to a solution of 966-2 (0,51 g, 0.71 mmol) in THF (20 ml) and water (20 ml). The reaction was stirred for 3 h at ambient temperature. It was adjusted to pH 3 and extracted with ethyl acetate (100 mix 3). The combined extract was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum.

The residue was dissolved in dlchloromethane (50 ml), and NMM (0.28 g, 2.8 mmol) was added. After cooling the solution to 0 °C, ethyl chloroformate (0.15 g, 1.4 mmol) was Injected through a syringe. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 ml of ammonia In water. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 ml x 3) and ethyl . acetate ((200

concentrated under vacuum to afford 966-2 (395 mg, yield 81%). LC-MS: 652.2 (M+H). (S)-2-Amino-N-((lR, 2R)-1 -cyano-2-(4'-(4-methylplperazin-1 -ylsulfonyl)bi phenyl -4- yl)cyciopropyl}-3-(furan-2-yl)propanamlde (PZ965)

To a solution of 965-2 (400 mg, 0.61 mmol) In DMF (10 ml) was added cyanuric chloride (0.33 g, 1.83 mmol). The reaction was stirred for 4 h at ambient temperature. Solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum. The crude product was purified by HPFC (ethyl acetate as eluent) to afford Boc-(S)-2-Amino-N- ((1R, 2R)-1 -cyano-2-(4 ^, -(4-methyl-plperazln-1 -ylsulfonyl)bi phenyl-4-yl)cyclopropyl)-3- (furan-2-yl)propanamlde (Boc-PZ965) (120 mg). BOC-PZ965 (120 mg, 0.19 mmol) was treated with excess HCOOH (10 ml) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 ml x3) and dichloromethane (200 ml x3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield (S)-2-Amino-N-((lR, 2R)-1 -cyano-2-(4'-(4- methylpiperazin-1 -ylsulfonyl)bi phenyl-4-yl)cyclopropyl)-3-(furan-2-yl)propanamide (PZ965) (63 mg). LC-MSi 534.1 (M+H). *H NMR (CDCIj, 300 MHz) δ: 7.80 (d, J - 8.4 Hz, 2H, Ph), 7.68 (d, J = 8.1 Hz, 2H, Ph), 7.55 (d+s, J - 8.1 Hz, 3H, Ph+Fura), 7.33 (d, J = 8.1 Hz, 2H, Ph), 6.23 (m, 1H, Fura), 5.98 (d, J = 3 Hz, 1H, Fura), 3.51 (m, 1H, COCH), 3.08 (m, 5H, NCH ₂ +PhCH+FuraCH ₂ ), 2.51 (m, 4H, NCH ₂₎ , 2.38 (m, 1H, FuraCH ₂ ), 2.28 (s, 3H, NCH ₃ ), 2.13 (m, 1H, cyclopropane-CH ₂ ), 1.86 (m, 1H, cydopropane-CH ₂ ) .

(S)-2-Amino-N-((lS, 2S)-1 -cyano-2-(4 ^, -(4-methylpiperazin-1 -ylsulfbnyl)biphenyl-4- yl)cyclopropyl)-3-(furan-2-yl)propanamlde (PZ966): To a solution of 966-2 (395 mg, 0.60 mmol) In DMF (10 ml) was added cyanuric chloride (0.33 g, 1.83 mmol). The reaction was stirred for 4 h at ambient temperature. Solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (ethyl acetate as eluent) to afford Boc-(S)-2-Amlno-N-((lS, 2S)-1 -cyano-2-(4'-(4-methylpiperazln-1 - ylsulfonyl) blphenyl-4-yl)cydopropyl)-3-(furan-2-yl)propanamlde (Boc-PZ966) (110 mg).

BOC-PZ966 (110 mg, 0.18 mmol) was treated with excess HCOOH (10 ml) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0 ₃ in water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 ml x3) and dichloromethane (200 mi x3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield (S)-2-Amlno-N-((lS, 2S)-1 -cyano-2-(4 ^, -(4- methylp!perazin-1 -ylsulfonyl) blphenyl-4-yl)cyclopropy1)-3-(furan-2-yl) propanamide (PZ966) (55 mg). LC-MS: 534.1 (M+H). *H NMR (CDCI ₃ , 300 MHz) δ 7.82 (d, J = 8.4 Hz, 2H, Ph), 7.70 (d, J = 8.4 Hz, 2H, Ph), 7.58 (br, 1H, CONH), 7.52 (d, J = 8.1 Hz, 2H, Ph), 7.34 (S, 1H, Fura), 7.20 (d, J - 8.1 Hz, 2H, Ph), 6.33 (s, 1H, Fura), 6.09 (d, J - 2.7 Hz, 1H, Fura), 3.48 (m, 1H, COCH), 3.07 (m, 7H, PhCHNCH ₂ +FuraCH ₂ ), 2.53 (s, 4H, NCH¾, 2.29 (s, 3H, NCH ₃ ), 2.18 (m, 1H, cydopropane-CH ₂ ), 1.77 (rn, 1H, cydopropane-CH ₂ ). .EXAMPLE..

cvano-2-f4-f2-f4-me hvlplDerazin-1 -vlVri.2.41triazolori.5-a1ovridln-6- vnphenvncvclopropvnbutanamlde fPZ9_73

N-(5-bromo-2-pyridlnyl)-N'-carboethoxy-thlourea (PZ972-1): To a solution of 5-bromo-2- aminopyridine (1.5 g, 8.67 mmol) In 1,4-dloxane (20 mL), was added dropwlse a solution of ethoxycarbonyl Isothlocyanate (1.25 g, 9.54 mmol) In 1,4-dioxane (10 mL). The reaction was stirred at rt for 2 h. The solvent was removed, and the residue was purified by HPFC (PE: EA - 5: 1) to afford PZ972-1 (2.34 g, 89%). LC-MS: 304.1, 306.2 ( +l).

6-Bromo-[1 ,2,4]triazolo[1 ,5-a]pyridln-2-amine (PZ972-2): DMAP (2.82 g, 23.1 mmol) was added to a mixture of PZ972-1 (2.34 g, 7.7 mmol), hydroxylamine HCl salt (2.67 g, 38.5 mmol) in methanol/ethanol (20 mL 20 mL). The reaction was stirred at rt for 1.5 h, then at 60 °C for 3 h. The solvent was removed under vacuum, and the resulting residue was partitioned between dichloromethane (30 mL) and water (30 mL). The water phase was extracted with dichloromthane (30 mLx2). The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated. The crude product was washed with petroleum ether to get PZ972-2 (1 g, 60.9%). LC-MS: 213.2, 215.2 (M+l).

6-Bromo-2-(4-methylplperazin-1 -yl)-[1 ,2,4]triazolot1 ,5-a]pyridine (PZ972-3): At 15-20 °C, sodium nitrite (1.17 g, 16.98 mmol) and cone. H ₂ S0 ₄ (6 mL) were added to a mixture of

PZ972-2 (3 g, 14.2 mmol) In glacial acetic acid (30 mL). The mixture was stirred at rt for 1 h, and added to a mixture of CuBr (2 g, 14.15 mmol) in HBr (10 mL, 40%) at 0 °C. The reaction was stirred at rt for 2 h. pH was adjusted to 8 by 20% sodium carbonate and extracted with ethyl acetate (50 mLx2) and dichloromethane (50 mLx2). The organic phasese were collected, dried over anhydrous sodium sulfate and concentrated. The residue was purified by HPFC (PE: EA = 5 : l) to afford 2,6-dlbromo-[1 ,2,4]triazolo[1 ,5-a]pyridine (2.7 g, 70%). LC- MS: 276.1, 278.2, 280.1 (M+l).

A solution of 2,6-dlbromo-[1 ,2,4]trlazolo[i,5-a]pyrldlne (2.7 g, 9.7 mmol), triethylamlne (2.94 g, 29.1 mmol), and N-methylpiperazlne (1.94 g, 19.4 mmol) in toluene was refluxed overnight. The solvent was removed under vacuum, and the residue was purified by HPFC (PE: EA -1 : 1) to yield PZ972-3 (1.82 g, 63%). LC-MS: 296.1, 298.1 (M+l).

(1 , 2R plus IS, 2S)-Methyl l-(tert-butoxycarbonylamino)-2-(4-(2-(4-methyl-piperazin-1 - yl)-[1 ,2,4]triazolo[1 ,5-a]pyrldin-6-yl)phenyl)-cycloprOpane-carboxylate (PZ972-4): Under N ₂ protection, a mixture of PZ957-6 (1.83 g, 4.39 mmol; a mixture of (lR,2R)-methyl l-(tert- butoxycarbonylamino)-2- (4-(4,4,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)

phenyl)cyclopropanecarboxylate and (lS,2S)-methyl l-(tert-butoxycarbonylamino)-2- (4- (4,4,5-tf1methyl-1 ,3,2-dioxaborolan-2-yl) phenyl)cyclopropanecarboxylate), PZ972-3 (1 g, 3.38 mmol), 2 M sodium carbonate aqueous solution (1.1 g, 10.14 mmol) and trace of dCl ₂ (dppf) ₂ /Pd(PPh3)4 in DMF (20 mL) was heated at 85-95 °C overnight. The mlxtrue was poured Into a mixture of ethyl acetate (100 mL) and water (100 mL). The water phase was separated and extracted with ethyl acetate (100 mLx2), The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by HPFC (PE: EA =1 :1) to afford PZ972-4 (1.2 g, 70.2%). LC-MS: 507.2 (M+l).

(lR,2R)-methyl l-((S)-2-(tert-butoxycarbonylamlno)butanamido)-2-(4-(2- (4- methy!piperazin-1-yi)-t1,2,43triazoSo[1,5-a3pyridin-6-yi)phe nyl)cyciopropanec3rboxyiate (PZ972-5), (lS,2S)-methyl l-((S)-2-(tert-butoxycarbonylamino) butanamido)-2-(4-(2-(4-metiiylpiperazIn-1-yl)-[1,2,4]tria2ol o[1,5-a]pyridin-6-yl)- phenyl)cydopropanecarboxylate (PZ973-5): A solution of PZ972-4 (3.1 g, 6.13 mmol) in 100 mL of 20% MCI was stirred for 1 h, pH was adjusted to 8 by sat. NaHC0 ₃ and extracted with dichloromethane (200 mLx3). The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated to dryness. The reslude was mixed with a solution of Boc- Abu-OH (1.62 g, 7.96 mmol) and DMTMM (2.2 g, 7.96 mmol) In dichloromethane (50 mL) at 0 °C. The reaction was stirred for 2 h at 0 °C, and quenched with a mixture of

water/dichloromethane (100 m 17100 mL). The DCM phase was separated, and the aqueous phase was extracted with dichloromethane (100 mLx2). The organic phases were collected, dried over anhydrous Na ₂ S0 , and concentrated. The crude product was purified by HPFC (EA) to yield a mixture of stereomers (3.5 g), which was separated by chiral-HPLC to afford PZ973-5 (0.7 g) (LC-MS: 592.1 (M+l)) and PZ973-5 (1.3 g) (LC-MS: 592.1 (M+l)).

Tert-butyl (S)-1-((lR,2R)-1-carbamoyl-2-(4-(2-(4-methylplperazin-1-yl)- [1,2,4]tria2olo[1,5- a]pyridin-6-yl)phenyl)cyclopropylamino)-1-oxobutan-2-ylcarba mate (PZ972-6): UOH.H ₂ 0 (0.25 g, 5,9 mmol) was added to a solution of PZ972-5 (0.7 g, 1.18 mmol) in THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHS0 ₄ and then to 8 by triethylamine, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness.

The residue was dissolved in dichloromethane (30 mL), and triethylamine (0.36 g, 3.5 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.13 g, 1.18 mmol) was injected in. The reaction was stirred for 1 h at 0 °C, and the mixture was poured into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mLx3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ972-6 (0.6 g, 88%). LC-MS: 577.1 (M+l).

Tert-butyl (S)-1-((lS,2S)-1-carbamoyl-2-(4-(2-(4-methylpiperazin-1-yl)- i1 ,2,4]triazoloi1 ,5-a3pyridin~6-y!)phenyi)cyciopropyiamino)-l~oxobutan-2-yica rbamate (PZ973-6): LiOH.H ₂ 0 (0,28 g, 6,6 mmol) was added to a solution of PZ973-5 (1.3 g, 2.2 mmol) in THF (20 ml) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHS0 ₄ and then to 8 by triethylamlne, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 , and concentrated to dryness.

The residue was dissolved in dlchloromethane (30 mL), and triethylamlne (0.67 g, 6.6 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.24 g, 2.2 mmol) was injected in. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mLx3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ973-6 (1.1 g, 87%). LC-MS: 577.1 (M+l).

Tert-butyl (S)-1 -((l ,2R)-1 -cyano-2-(4-(2-(4-methylplperazln-1 -yl)-[1 ,2,4]triazolo[1 ,5- a]pyridin-6-yl)phenyl)cyclopropylamlno)-1 -oxobutan-2-yl-carbamate (PZ972-7): To a solution of PZ972-6 (600 mg, 1.04 mmol) in DMF (10 mL), was added cyanurlc chloride (0.42 g, 2.28 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (EA) to afford PZ972-7 (400 mg, 69%). LC-MS: 559.2 (M+l).

Tert-butyl (S)-1 -((lS,2S)-1 -cyano-2-(4-(2-(4-methylplperazln-1 -yl) -[1 ,2,4]triazolo[1 ,5- a]pyridln-6-yl)phenyl)cyclopropylamlno)-1 -oxobutan-2-yl-carbamate (PZ973-7): To a solution of PZ973-6 (800 mg, 1.39 mmol) in DMF (10 mL), was added cyanuric chloride (0.51 g, 2.78 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (EA) to afford PZ973-7 (280 mg, 36%). LC-MS: 559.3 (M+ l).

(S)-2-amino-N-((lR,2R)-1 -cyano-2-(4-(2-(4-methylplperazln-1 -yl)-[1 ,2,4]triazolo[1 ,5- a]pyridin-6-yl)phenyi)cyclopropyl)butanamide (PZ972): PZ972-7 (400 mg, 0.72 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ972 (150 mg, 46%). LC-MS: 459.36 (M+H). H NMR (CDC! _3> 300 MHz) 5: 8.53 (s, 1H, NH), 7.62-7.46 (m, 5H, Ph+CH), 7.34 (d, J - 8.1 Hz, 2H, Ph), 3.70 (t, J = 4.8 Hz, 4H, NCH ₂ ), 3.21 (m, 1H, CH), 3.10 (m, 1H, CH), 2.58 (t, J = 5.0 Hz, 4H, NCH ₂ ) 2.39 (s, 3H, NCH ₃ ), 2.10 (m, 1H, cyciopropane-CHz), 1.84 (m, 1H, cydopropane-CHJ, 1.27 (m, 2H, CH ₂ ), 0.70 (t, J = 7.6

HZ, 3H _f Ch^) _*

(S)-2-amlno-N-((lS,2S)-1-<^ano-2-(4-(2-(4-methylplpera zln-1-yl)-[1,2,4]tr1azolo[1,5- a]pyrtdin-6-yl)pheny!)cydopropyl)butanamlde (PZ973): PZ973-7 (280 mg, 0.50 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ973 (80 mg, 35%). LC-MS: 459.29 (M+H). H NMR (CDCI ₃ , 300 MHz) δ: ^X H NMR (CDCIj,

300 MHz) δ: 8.55 (s, 1H, NH), 7.63 (d, J = 9.0 Hz, 1H, CH), 7.55-7.47 (m, 4H, Ph+CH), 7.31 (d, J - 8.1 Hz, 2H, Ph), 3.70 (t, J - 5.0 Hz, 4H, NCH _? ), 3.16 (m, 1H, CH), 3.05 (m, 1H, CH), 2.59 (t, J - 4.8 Hz, 4H, NCH ₂ ) 2.39 (s, 3H, NCH ₃ ), 2.15 (m, 1H, cydopropane-CH ₂ ), 1.85 (m, 1H, cyclopropane-CHz), 1.75-1.38 (m, 2H, CH ₂ ), 0.84 (t, J = 7.5 Hz, 3H, CH ₃ ). S¾AB¾EI»EJ¾l

Synthesis Scheme

Procedure (lR,2R)-methyl l-((S)-2-(tert-butoxy<artonylamlno)-3-CYdopropyl-propanam ldo)-2-(4'-(4- methylpiperazin-1 -ylsuifonyl)biphenyi-4-yi)cyclopropanecarboxylate (PZ988-1), (1S,2S)- methyl l-((S)-2-(tert-butoxycari3onylamlno)-3-cyclopropylpropanamid o)-2-(4 ^, -(4- methylplperazln-1 -ylsuifonyl)biphenyi-4-yi)cyc!opropanecarboxylate (PZ989-1): A so!ution of PZ955-4 (See example 5; 2 g, 4.67 mmol) In dlchloromethane (20 mL) was mixed with a solution of Boc-CPA-OH (1.28 g, 5.60 mmol) and D TMM (1.55 g, 5.60 mmol) In

dlchloromethane mL) at 0 °C. The reaction was stirred for 2 h at 0 °C, and quenched with a mixture of water/dichloromethane (100 mL/100 mL). The DC phase was separated, and the aqueous phase was extracted with dichloromethane (100 mLx2), The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (EA) to yield a mixture of stereomers (2.6 g), which was separated by chlrai-HPLC to afford PZ988-1 (1.0 g) (LC- S: 641.2 ( +l)) and PZ989-1 (1.3 g) (LC-MS; 641.1 (M+l)). Tert-butyl (S)-1 -((l ,2R)-1 -carbamoyl-2-(4'-(4-metfiylplperazln-1 -yl^ulfbnyl)biphenyl-4- yl)cyclopropylamlno)-3-cyclopropyl-1 -oxopropan-2-ylcarbamate (PZ988-2): UOH.H ₂ 0 (0.34 g, 8.0 mmol) was added to a solution of PZ988-1 (1.0 g, 1.60 mmol) In THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHS0 ₄ and then to 8 by triethylamine, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness.

The residue was dissolved In dlchloromethane (30 mL), and triethylamine (0.48 g, 4.8 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofbmate (0.18 g, 1.60 mmol) was injected in. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mLx3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ988-2 (0.7 g, 71%). LC-MS: 626.1 (M+l).

Tert-butyl (S)-1 -((lS,2S)-1 -carbamoyl-2-(4 ^, -(4-methylplperazln-1 -yl-sulfonyl)blphenyl-4- yl)cyclopropylamino)-3-cydopropyl-1 -oxopropan-2-ylcarbamate (PZ989-2): UOH.H ₂ 0 (0.44 g, 10.8 mmol) was added to a solution of PZ989-1 (1,3 g, 2.08 mmol) In THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHSO ₄ and then to 8 by triethylamine, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness.

The residue was dissolved In dlchloromethane (30 mL), and triethylamine (0.63 g, 6.2 mmol) was added. After cooling the solution to 0 °C, ethyl chlorof ornate (0.24 g, 2.1 mmol) was Injected in. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mL x3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ989-2 (0.84 g, 66%). LC-MS: 626.1 (M+l).

Tert-butyl(S)-1 -((lR,2R)-1 -cyano-2-(4'-(4-methylpiperazin-1 -ylsulfonyl) blphenyl-4- yl)cydopiOpylamlno)-3-cyclopropyl-1 -oxopropan-2-ylcarbamate (PZ988-3): To a solution of PZ988-2 (700 mg, 1.12 mmol) in DMF (10 rnL), was added cyanuric chloride (0.62 g, 3.36 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (EA) to afford PZ988-3 (210 mg, 31%). LC- S: 608.2 ( +l).

Tert-butyl (S)-1-((lS,2S)-1-cyano-2-(4'-(4-methylpiperazln-1-ylsulfonyl ) blphenyl-4- yl)cyclopropylamino)-3-cyclopropyl-1-oxopropan-2-ylcarbamate (PZ989-3): To a solution of PZ989-2 (840 mg, 1.34 mmol) In DMF (10 ml_), was added cyanuric chloride (0.74 g, 4.03 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 _4> and concentrated. The crude product was purified by HPFC (EA) to afford PZ989-3 (350 mg, 43%). LC-MS: 608.2 (M+l).

(S)-2-amlno-N-((l ,2R)-1-cyano-2-(4'-(4-methylplperazln-1-ylsulfonyl)biphenyl- 4- yl)cydopropyl)-3-cyclopropylpropanamlde (PZ988): PZ988-3 (210 mg, 0.35 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ988 (80 mg, 46%). LC-MS: 508.1 (M-!-H). ¹ H NMR (DMSO-c 6, 300 MHz) 5: 7.91 (d, J = 8.1 Hz, 2H, Ph), 7.79 (d, J = 8.1 Hz, 2H, Ph), 7.67 (d, J = 8.1 Hz, 2H, Ph), 7.34 (d, J = 7.8 Hz, 2H, Ph), 3.11 (m, 1H, CH), 3.03 (m, 1H, CH), 2.89 (br, 4H, NCH ₂ ), 2.37 (m, 4H, NCH ₂ ), 2.13 (s, 3H, NCH ₃ ), 2.05 (m, 2H, cydopropane-CH ₂ ), 1.19 (m, 2H, CH ₂ ), 0.99-0.14 (m, 5H, cycopropyi).

(S)-2-amlno-N-((lS,2S)-1-cyano-2-(4 ^, -(4-methylpiperazin-1-ylsulfonyl)biphenyl-4- yl)cyclopropyl)-3-cyclopropylpropanamlde (PZ989): PZ988-3 (350 mg, 0.58 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0 ₃ In water and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ989 (163 mg, 58%). LC-MS: 508.3 (M+H), H NMR (DMSO-i 6, 300 MHz) fl: 7.92 (d, J - 8.4 Hz, 2H, Ph), 7.79 (d, J = 8.4 Hz, 2H, Ph), 7.67 (d, J = 8.1 Hz, 2H, Ph), 7.33 (d, J - 8.4 Hz, 2H, Ph), 3.13 (m, 1H, CH), 2.92 (br, 5H, CH+NCH ₂ ), 2.36 (m, 4H, NCH ₂ ), 2.13 (s, 3H, NCH ₃ ), 1.98 (m, 2H, cyclopropane-CH ₂ ), 1.27-0.04 (m, 7H, CH ₂ +cycopropyl).

Synthesis Scheme

Procedure

(l ,2R)-methyl l-((S)-2-(tert-butoxycarbonylamlno)pent-4-ynamido)-2-(4 ^, -(4- methylpiperazin~l-ylsuifonyl)biphenyi-4~y[}cyc!opropanecarbo xyi3te (P2996-1), (15,2S)~ methyl l-((S)-2-(tert-butoxycarbonylamlno)pent-4-ynamido)- 2-(4'-(4-methylplperazln-1- ylsulfonyl) blphenyl-4-yl) cyclo-propanecarboxyiate (PZ997-1): A solution of PZ955-4 (See example 5; 2 g, 4.67 mmol) In dlchloromethane (20 mL) was mixed with a solution of (S)-2- (tert-butoxycarbonylamino)pent-4-ynolc acid (1.19 g, 5.60 mmol) and DMTMM (1.55 g, 5.60 mmol) in dlchloromethane (50 mL) at 0 °C. The reaction was stirred for 2 h at 0 °C, and quenched with a mixture of water/dlchloromethane (100 mL/100 mL). The DC phase was separated, and the aqueous phase was extracted with dlchloromethane (100 mLx2), The brganic phased

product was purified by HPFC (EA) to yield a mixture of stereomers (2.53 g), which was separated by chiral-HPLC to afford PZ996-1 (1.02 g) (LC-MS: 625.3 ( +l)) and PZ997-1 (1.27 g) (LC-MS: 625.3 (M+l)).

Tert-butyl (S)-1 -((l ,2R)-1 -carbamoyi-2-(4'-(4-methylpiperazin-1 -y!suifonyl)biphenyi-4- yl)cyclopropylamlno)-1 -oxopent-4-yn-2-ylcarbamate (PZ996-2): LiOH.H ₂ 0 (0.34 g, 8.0 mmol) was added to a solution of PZ996-1 (1.02 g, 1.63 mmol) in THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHSO ₄ and then to 8 by trlethylamine, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness. The residue was dissolved In dichloromethane (30 mL), and trlethylamine (0.48 g, 4.8 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.19 g, 1.7 mmol) was Injected in. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mLx3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ996-2 (0.8 g, 80%). LC-MS: 610.1 (M+l).

Tert-butyl (S)-1 -((lR,2R)-1 -carbamoyl-2-(4 ^, -(4-methylpipera2in-1 -ylsulfonyl)biphenyl-4- yl)cycloprOpylamino)-1 -oxopent-4-yn-2-ylcarbamate (PZ997-2): UOH.H ₂ 0 (0.44 g, 10.8 mmol) was added to a solution of PZ996-1 (1.27 g, 2.04 mmol) In THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHSO4 and then to 8 by triethyfamine, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness.

The residue was dissolved in dichloromethane (30 mL), and trlethylamine (0.63 g, 6.2 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.24 g, 2.1 mmol) was Injected In. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mL x3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ997-2 (0.91 g, 73%). LC-MS: 610.2 (M+l).

Tert-butyl (S)-1 -((lR,2R)-1 -cyano-2-(4'-(4-methylpiperazin-1 -ylsulfonyl)blphenyl-4- yl)cydopra (PZ996-3): To a solution of PZ996-2

(800 mg, 1.31 mmol) in DMF (10 mL), was added cyanuric chloride (0.73 g, 3.94 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (EA) to afford PZ988-3 (310 mg, 40%). LC-MS: 592.2 (M+l).

Tert-butyl (S)-1 -((lS,2S)-1 -cyano-2-(4 ^, -(4-methylplperazln-1 -ylsulfonyl)blphenyl-4- yl)cyclopropylamino)-1 -oxopent-4-yn-2-ylcarbamate (PZ997-3): To a solution of PZ997-2 (910 mg, 1,49 mmol) In DMF (10 mL), was added cyanuric chloride (0.83 g, 4.48mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ SQ ₄ , and concentrated. The crude product was purified by HPFC (EA) to afford PZ997-3 (410 mg, 47%). LC-MS: 592.1 (M+l).

(S)~2-amino-N-((lR,2 )-1 -cyano-2-(4'-(4-methylplperazln-1 -ySsulfony!)biphenyi-4- yl)cyclopropyl)pent-4-ynamide (PZ996): PZ996-3 (310 mg, 0.52 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHC0 ₃ in water and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dichloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ996 (120 mg, 47%). LC-MS: 492.15 (M+H). *H NMR (CDCI ₃ , 300 MHz) δ 7.83 (d, J = 8.4 Hz, 2H, Ph), 7.71 (d, J = 8.4 Hz, 2H, Ph), 7.57 (d, J « 7.5 Hz, 2H, Ph), 7.35 (d, J = 8.1 Hz, 2H, Ph), 3.38 (m, 1H, CH), 3.12. (br, 5H, CH÷NCH ₂ ), 2.53 (br, 4H, NCH ₂ ), 2.30 (s, 3H, NCH ₃ ), 2.14 (m, 3H, CH+cydopropane-CHa), 1.88 (m, 2H, CH ₂ ).

(S)-2-amino-N-((lS,2S)-1 -cyano-2-(4 ^, -(4-methylpiperazin-1 -ylsulfonyl)biphenyl-4- yl)cydopropyl)pent-4-ynamlde (PZ997): PZ997-3 (410 mg, 0.69 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHCO _? In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dichSoromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ997 (240 mg, 70%). LC-MS: 492.2 (M+H). ^X H NMR (CDCI ₃ , 300 MHz) δ 7.84 (d, J = 8.4 Hz, 2H, Ph), 7.73 (d, J = 8.4 Hz, 2H, Ph), 7.58 (d, J - 8.4 Hz, 2H, Ph), 7.34 (d, J - 8.1 Hz, 2H, Ph), 3.34 (m, 1H, CH), 3.06 (br, 5H, CH+NCH ₂ ), 2.60 (br, 2H, CH ₂ ), 2.53 (br, 4H, NCH ₂ ), 2.30 (s, 3H, NCH ₃ ), 2.17 (m, 1H, CH ₂ ), 2.02 (m, 1H, CH), 1.86 (m, 1H, CH ₂ ).

Procedure

(lR _< 2R)-methyl-1 -((S)-2-(tert-butoxycartx>nylamino)-3-phenyl-propanamldo) -2-(4'-(4- methyl-piperazin-1 -yisuifonyi)biphenyI-4-yi)cyc!opropanecarboxylate (PZ10Q4-1), and (lS,2S)-methyl l-((S)-2-(tert-butoxycarbonylamlno)- 3-pheny!propanam!do}-2-(4'-(4- methylplperazln-1 -ylsulfonyl)blphenyl-4-yl)cyciopropanecarboxylate (PZ1005-1):

A solution of PZ955-4 (See example 5; 2.5 g, 5.83 mmol) In d!chloromethane (30 mL) was mixed with a solution of Boc-Phe-OH (1.85 g, 7.0 mmol) and DMTM (1.94 g, 7.0 mmol) In dichloromethane (50 mL) at 0 °C. The reaction was stirred for 2 h at 0 °C, and quenched with a mixture of water/dichloromethane (100 mL 100 mL). The DCM phase was separated, and the aqueous phase was extracted with dichloromethane (100 mLx2), The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA = 1 : 3) to yield a mixture of stereomers (3.0 g), which was separated by chlral-HPLC to afford PZ1004-1 (1.4 g) (LC- S: 677.2 (M+l)) and PZ1005-1 (1.4 g) (LC-MS: 677.3 (M+l)). Tert-butyl (S)-1 -((lR,2R)-1 -carbamoyl-2-(4 ^, -(4-methylplperazln-1 -ylsulfonyl)blphenyl-4- yi)cyclopropylamino)-1 -oxo-3 -phenyipropan-2~ylcarbamate (PZ1004-2): LiOH.H ₂ 0 (0.43 g, 10.35 mmol) was added to a solution of PZ1004-1 (1.4 g, 2.07 mmol) in THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to A by 5% KHS0 and then to 8 by triethylamine, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness. LC-MS: 663.3 (M+l).

The residue was dissolved In dichloromethane (30 mL), and triethylamine (0.42 g, 4.14 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.25 g, 2.28 mmol) was injected In. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mLx3) and ethyl acetate (200 mLx3) _» The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ1004-2 (1.2 g, 88%). LC-MS: 662.1 (M+l).

Tert-butyl (S)-1 -((lS,2S)-1 -art«moyl-2-(4'-(4-methylplperazln-1 -ylsulfonyl)biphenyl-4- yl)cydopropylamino)-1 -oxo-3-phenylpropan-2-ylcarbamate (PZ1005-2): UOH.H ₂ 0 (0.43 g, 10.35 mmol) was added to a solution of PZ1005-1 (1.4 g, 2.07 mmol) In THF (20 mL) and water (20 m After pH adjustment to 4 by 5% KHSO ₄ and then to 8 by triethylamine, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness. LC- S: 663.0 (M+l).

The residue was dissolved In dlchloromethane (30 mL), and triethylamlne (0.42 g, 4.14 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.25 g, 2.28 mmol) was injected In. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mL 3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ1005-2 (1.2 g, 88%). LC-MS: 662.1 (M+l). Tert-butyl (S)-1 -((l ,2 )-1 -cyano-2-(4 ^, -(4-methylplperazln-1 -ylsulfonyl)blphenyl-4- yl)cyclopropylamlno)-1 -oxo-3-phenyipropan-2-ylcarbamate (PZ1004-3): To a solution of PZ1004-2 (1.2 g, 1.82 mmol) in DMF (15 mL), was added cyanuric chloride (1.0 g, 5.45 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₇ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA = 1: 1) to afford PZ 1004-3 (0.8 g, 68%). LC-MS: 644.1 (M+l).

Tert-butyl (S)-1 -((lS,2S)-1 -cyano-2-(4'-(4-methylplperazin-1 -ylsulfonyl)biphenyl-4- yl)cyclopropylamlno)-1 -oxo-3-phenylpropan-2-yl carbamate (PZ1005-3): To a solution of PZ1005-2 (1.2 g, 1.82 mmol) In DMF (15 mL), was added cyanuric chloride (1.0 g, 5.45 mmoi). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S ₄ , and concentrated. The crude product was purified by HPFC (PE: EA «= 1: 1) to afford PZ1005-3 (0.9 g, 80%). LC-MS: 644.2 (M+l).

(S)-2-amino-N-((lR,2R)-1 -cyano-2-(4'-(4-methylplperazin-1 -ylsulfonyl)blphenyl-4- yl)cyclopropyf)-3-phenylpropanamide (PZ1004): PZ1004-3 (0.8 g, 1.24 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ in water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ1004 (90 mg, 13%). LC-MS: 544.16 (M+H). *H NMR (CDCI ₃ , 300 MHz) δ: 7.56 (d, J = 8.1 Hz, 2H, Ph), 7.68 (d, J - 8.1 Hz, 2H, Ph), 7.57 (d, J = 8.1 Hz, 2H, Ph), 7.49 (s, 1H, NH), 7.33 (d, J = 8.1 Hz, 2H, Ph), 7.25 (m, 3H, Ph), 7.08 (m, 2H, Ph), 3.48 (m, 1H, CH), 3.10 (m, 6H,

CH+Bn+NCH ₂ ), 2.52

CH ₂ ), 1.87 (m, 1H, cydopropane-CH ₂ ) . (S)-2-amino-N-((lS,2S)-1 -CYano-2-(4'-(4-methylplperazln-1 -ylsulfbnyl)blphenyl-4- yl)cyclopropyl)-3-phenylpropanam!de (PZ1005): PZ1005-3 (Q.9 g, 1.4 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ In water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dichloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ1005 (0.51 g, 67%). LC-MS: 544.19 ( +H). *H NMR (CDCI ₃ , 300 MHz) 6: 7.85 (d, J - 8.1 Hz, 2H, Ph), 7.72 (d, .7 = 8.1 Hz, 2H, Ph), 7.46 (m, 3H, Ph+NH), 7.31 (m, 3H, Ph), 7.11 (m, 4H, Ph), 3.51 (m, 1H, CH), 3.07 (m, 7H, CH+Bn+NCH ₂ ), 2.54 (m, 4H, NCH ₂ ), 2.30 (s, 3H, NCH ₃ ), 2.14 (m, 1H, cydopropane-CH ₂ ), 1.74 (m, 1H, cydopropane-CH ₂ ).

vDpropanamide (PZ1012)

Synthesis Scheme

Procedure

(l ,2R)-methyl l-((S)-2-(tert-butoxycarbonyiamSno)-3-(thlophen-2-yi)-propan amido)-2-(4'- (4-methylplperazln-1 -ylsuifonyl)blphenyl-4-yl)cyclopropanecarboxylate (PZlOll-1), (1S,2S)- methyl l-((S)-2-(tert-butoxycarbonylamino)-3-(thlophen-2-yl)propana mldo)-2-(4'-(4- methylplperazin-1 -ylsulfonyl)blphenyl-4-yl)cyciopropanecarboxylate (PZ1012-1): A solution of PZ955-4 (Example 5; 4.72 g, 11 mmol) In dichloromethane (50 mi.) was mixed with a solution of Boc-THI-OH (3.0 g, 11 mmol) and DMT M (6.1 g, 22 mmol) in dichloormethane (50 mi.) at 0 °C. The reaction was stirred for 2 h at 0 °C, and quenched with a mixture of water/dichloromethane (200 mL/200 mL). The DCM phase was separated, and the aqueous phase was extracted with dichloromethane (200 mLx2). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA « 1: 1) to yield a mixture of stereomers (6.8 g), which was separated by chlral-HPLC to afford PZlOll-1 (3.1 g) (LC-MS: 683.1 (M+H)) and PZ1012-1 (3.0 g) (LC-MS; 683.1 (M+H)). Tert-butyl (S}-1 -((l ,2 )-1 -carbamoyi-2-(4'-(4-methylpiperazln-i~ylsulfony!)blpheny! -4~ yl)cyclopropylamlno)-1 -oxo-3-(thlophen-2-yl)propan-2-ylcarbamate (PZ1011-2): LiOH,H ₂ 0 (0.96 g, 22.8 mmol) was added to a solution of P21011-1 (3.1 g, 4.6 mmol) In THF (20 ml.) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHS0 ₄ and then to 8 by triethylamlne, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness. LC-MS: 669.1 ( +H).

The residue was dissolved In dlch!oromethane (30 mL), and triethylamlne (0.91 g, 9.0 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.59 g, 5.4 mmol) was injected In. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mLx3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ1011-2 (2.6 g, 86%). LC-MS: 668.1 (M+H). Tert-butyl (S)-1 -((lS,2S)-1 -carbamoyl-2-(4'-(4-methylpiperazln-1 -ylsulfonyl)blphenyl-4- yl)cyclopropylamlno)-1 -oxo-3-(thlophen-2-yl)propan-2-ylcarbamate (PZ1012-2): LIOH.H ₂ Q (0.96 g, 22.8 mmol) was added to a solution of PZ1012-1 (3.0 g, 4.5 mmol) In THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% KHS0 ₄ and then to 8 by triethylamlne, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous ajSa,, and concentrated to dryness. LC-MS: 669.1 (M+H).

The residue was dissolved in dlchloromethane (30 mL), and triethylamlne (0.91 g, 9.0 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.59 g, 5.4 mmol) was injected In. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mLx3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ1012-2 (2.8 g, 92%). LC-MS: 668.1 (M+H).

Tert-butyl (S)-1 -((lR,2R)-1 -cyano-2-(4 ^, -(4-methylpiperazin-1 -ylsulfonyl)blphenyl-4- yl)cydopropylamlno)-1 -oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (PZ1011-3): To a solution of PZ1011-2 (1.3 g, 2.0 mmol) In DMF (15 mL), was added cyanuric chloride (1.1 g, 5.9 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 , and concentrated. The crude product was purified by HPFC (PE: EA = 1: 1) to afford PZ1011-3 (0.8 g, 63%). LC-MS? 650.1 (M+H).

Tert-butyl (S)-1 -((lS,2S)-1 -cyano-2-(4'-(4-methylpiperazin-1 -ylsulfonyl)biphenyl-4- yl)cydopropylamlno)-l^xo-3-(thiophen-2-yl)propan-2-ylcarbama te (PZ1012-3): To a solution of PZ1012-2 (1.4 g, 2.1 mmol) In DMF (15 mL), was added cyanurlc chloride (1.2 g, 6.1 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA « 1: 1) to afford PZ1011-3 (0.6 g, 44%). LC-MS:

650.1 (M+H).

(S)-2-amino-N-((l ,2R)-1 -cyano-2-(4'-(4-methylpiperazln-1 -ylsulfonyl)b(phenyl-4- yl)cydopropyl)-3-(thlophen-2-yl)propanamide (PZ1011): PZlOil-3 (0.8 g, 1.23 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ in water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ SO„, and concentrated to yield PZ1011 (250 mg, 37%). LC-MS: 550.1 (M+H). 'H NMR (CDCI ₃ , 300 MHz) δ: 7.82 (d, J = 8.4 Hz, 2H, Ph), 7.57 (d, J = 8.4 Hz, 2H, Ph), 7.48-7.53 (m, 3H, Ph+thiophene), 7.34 (d, J - 8.1 Hz, 2H, Ph), 7.14 (d, J = 5.1 Hz, 1H, thiophene), 6.89 (dd, J - 3.6 Hz, 5.1 Hz, 1H, thiophene), 6.72 (br, 1H, NH), 3.45-3.50 (m, 1H, CH), 3.06-3.18 (m, 6H, thlophene-

CH ₂ +NCH ₂ ), 2.55-2.64 (m, 1H, CH), 2.53 (m, 4H, NCH ₂ ), 2.89 (s, 3H, NCH ₃ ), 2.06-2.17 (m, 1H, cyclopropane-CH ₂ ), 1.84-1.90 (m, 1H, cyclopropane-CH ₂ ).

(S)-2-amlno-N-((lS,2S)-1 -cyano-2-(4 ^, -(4-methylplperazin-1 -ylsulfonyl)biphenyl-4- yl)cyclopropyl)-3-(thlophen-2-yl)propanamide (PZ1012): PZ1012-3 (0.6 g, 0.92 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ in water and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ1012 (180 mg, 35%). LC-MS: 550.1 (M+H). H NMR (CDCI ₃ , 300 MHz) δ 7.83 (d, J = 8.4 Hz, 2H, Ph), 7.70 (d, J = 8.4 Hz, 2H, Ph), 7.48 (d, J - 8.4 Hz, 2H, Ph), 7.24 (m, 1H, thiophene), 7.12 (d, J = 8.4 Hz, 1H, thiophene), 7.02 (dd, J - 3.3 Hz, 5.1 Hz, 1H, thiophene), 6.84 (br, 1H, NH), 3.46-3.51 (m, 1H, CH), 3.27-3.35 (m, 1H, CH), 2.99-3.14 (m, 6H, thiophene-CH ₂ +NCH ₂ ), 2.52-2.54 (m, 4H, NCH ₂ ), 2.30 (s, 3H, NCH ₃ ), 2.12-2.18 (m, 1H, cydopropane-CH ₂ ), 1.80 (t, J = 7.7 Hz, 1H, cydopropane-CH ₂ ). (S 2-amlno-N-((lR.2R^l-cyano-2-(4'-(4-methylDiperazln-1 -vnblphenvl-4- methylplp^rgzln-1 -y|)blphenyl-4-yl)CYClopr9pyl)butanam|cl9 (PZ96Q)

Synthesis Scheme

Procedure l-(4-Bromophenyl)-4-methylplperazine (PZ959-2): A solution of 4-bromoanlllne PZ959-1 (22 g, 0.13 mol), 2-chloro-N-(2-ch!oroethyl)-W- methylethanamine (25.9 g, 0.17 mol) and triethylamine (353.5 mL, 0.38 moi) in ethanol (300 mL) was refluxed for 80 h. The solvent was removed in vacuo and the resulting residue was purified by HPFC (DCM:EtOH « 10: 1) to yield PZ959-2 (20.3 g, 61% yield). LC- S: 255.1 [M+H] ⁺ . l-Methyl-4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyi)piperazine (PZ959-3): Pd(PPh ₃ )*. (3.0 g) was added to a mixture of PZ959-2 (20 g, 78.4 mmol), pinacolatodiboron (13.8 g, 78.4 mmol) and potassium carbonate (21.9 g, 0.16 moi) in toluene (1.0 L) under nitrogen protection. The reaction mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (500 mL) and ethyl acetate (500 mL). The organic phase was collected and the aqueous phase was extracted with ethyl acetate (500 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford PZ959-3 (15.9 g, 67% yield). race/77/c- ethyl l-(te/t-butoxycarbonylamlno)-2-(4 ^, -(4-methylplperazln- l-yl)biphenyl-4- yl)cyclopropanecarboxylate (PZ959-4): PdCi ₂ (PPh) ₂ . (0.2 g) was added to a mixture of PZ959- 3 (1.6 g, 5.4 mmol), racemic methyl-2-(4- bromophenyl)-1 -(tert- butoxycarbonylamlno)cyclopropanecarboxyiate (3) (2.0 g, 5.4 mmol) and aqueous sodium carbonate solution (2.7 mL, 2 M) In 1,4-dloxane (50 mL) under nitrogen protection. The mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (100 mL) and ethyl acetate (100 mL). The organic phase was collected and aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by HPFC (EA) to afford racemic PZ959-4 (1.8 g, 72% yield). LC-MS: 466.2 [M+H] ⁺ . rscem/c-Methyl l-amino-2-(4'-(4-methylplperazln-1 -yl)blphenyl-4- yljcyclopropanecarboxyiate (PZ959-5): Concentrated HCi/water solution (20 mL, 2/1, v/v) was added to a solution of racemic PZ959-4 (1.8 g, 3.9 mmol) In THF (30 mL). The reaction mixture was stirred for 4 h at 40°C followed by pH adjustment to 8 with saturated aqueous NaMC0 ₃ solution. Then the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated to afford ^ce ^" m^c 9S9-5 ^' (i.3 ^" gV ^' 9i% ^' yfeld) ^'' (J!/?,2R)-Methyl l-((S)-2-(tert-butoxycartx>nylamlno)butanamtdo)-2-(4 ^, -(4-metiiylpipera2ln- l-yi)biphenyl-4-yl)cyclopropanecarboxylate (PZ959-6) and (IS, 2S)-methyl l-((S)-2-(tert- butoxycarbonyiamino)butanam!do}-2-(4'-(4-methylpiperazin- l -yi)blphenyl-4- yl)cycioprapanecarboxyiate (PZ960-6): To a solution of Boc-Abu-OH (1.4 g, 5.4 mmol) and N M (0.7 g, 7.2 mmol} in dichloromethane (50 mL) at 0°C was added ethyl chlorofomate (0.6 g, 5.4 mmol). The mixture was stirred for 1 h at 0°C and a solution of PZ959-5 (1.3 g, 3.6 mmol) In dichloromethane (10 mL) was added. The cooling system was removed and the reaction mixture was stirred overnight at ambient temperature. The solution was poured Into a mixture of 100 mL of water and 100 mL of dichloromethane. The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL x 2) and ethyl acetate (100 mL x 2). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (EA) to yield a mixture of stereomers, which was further purified by chiral-HPLC to yield PZ959-6 (710 mg), PZ960-6 (730 mg). LC- S: 551.2 [M+H] ⁺ . iert-Butyl (S)-1 -((-lR,2«)-1 -carbamoyl-2-(4'-(4-methylpiperazin-1 - y!)b!phenyl-4- yl)cyciopropylamino)-1 -oxobutan-2-ylcarbamate (PZ959-7): UOH-H ₂ 0 (0.3 g, 6.5 mmol) was added to a solution of PZ959-6 (0.7 g, 1.3 mmol) in THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 3, the mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated.

The residue was dissolved In dichloromethane (50 mL) and NMM (0.3 g, 2.6 mmol) was added. After the solution was cooled to 0°C, ethyl chlorofomate (0.2 g, 2.0 mmol) was added. The mixture was stirred for 1 h at 0°C and poured Into a flask with 200 mL of ammonia. The reaction mixture was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mL x 3) and ethyl acetate (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ 50 ₄ , and concentrated to afford PZ959-7 (560 mg, 82% yield). LC-MS: 536.1 [M+H] ⁺ . fert-Butyl (S)-1 -((lS,2S)-1 -carbamoyl-2-(4'-(4-methylpiperazln-1 - yl)biphenyl-4- yl)cyclopropylamlno)-1 -oxobutan-2-ylcarbamate (PZ960-7): UOH-H ₂ 0 (0.3 g, 6.5 mmol) was added to a solution of PZ960-6 (0.7 g, 1.3 mmol) in THF (20 mL) and water (20 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 3, the mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated.

The residue was dissolved In dichloromethane (50 mL) and NMM (0.3 g, 2.6 mmol) was added. After the solution was cooled to 0°C, ethyl chlorofomate (0.2 g, 2.0 mmol) was added. The mixture was stirred for 1 h at 0°C and poured into a flask with 200 mL of ammonia. The reaction mixture was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mL x 3) and ethyl acetate ((200 mL x 3). The organic phases were coilected, dried over anhydrous Na ₂ S0 , and concentrated to afford PZ960-7 (530 mg, 78% yield). LC- S: 536.1 [M+H]\

Cert-Butyl (S)-1-((-f/?,2R)-1-cyano-2-(4 ^, -(4-methylplperazin-1-yl)blphenyl-4- yl)cyclopropylamino)-1-oxobutan-2-ylcarbamate (PZ959-8): To a solution of PZ959-7 (550 mg, 1.0 mmol) in D F (10 mL) was added cyanuric chloride (554 mg, 3.1 mmol). The reaction mixture was stirred for 4 h at ambient temperature. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 _4f and concentrated. The residue was purified by HPFC (EA) to afford PZ959-8 (150 mg, 28% yield). LC-MS: 518.1 [M+H] ⁺ . ferr-Butyl (S)-l-((iS,2S)-1-cyano-2-(4 ^, -(4-methylplperazln-1-yl)blphenyl-4- yl)cydopropylamlno)-1-oxobutan-2-ylcarbamate (PZ960-8): To a solution of PZ960-7 (520 mg, 1.0 mmol) In DMF (10 mL) was added cyanuric chloride (564 mg, 3.1 mmol). The reaction mixture was stirred for 4 h at ambient temperature. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 _r and concentrated. The residue was purified by HPFC (EA) to afford PZ960-8 (130 mg, 26% yield). LC-MS: 518.1 [M+H] ⁺ . (S)-2-Amino-N-((iR,2«)-1-cyano-2-(4'-(4-methyIplperazln-1-y l)biphenyl-4- yl)cyclopropyl)butanamlde (PZ959): PZ959-8 (150 mg, 0.29 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of aqueous NaHC0 ₃ solution and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dichloromethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield

PZ959 (88 mg, 73% yield). LC-MS: 418.2 [M+H] ⁺ . *H NMR (DMSO-i , 300 MHz): 6 7.49 (d, J = 8.1 Hz, 4H, Ph), 7.22 (d, J = 8.4 Hz, 2H, Ph), 7.00 (d, J = 8.7 Hz, 2H, Ph), 3.17 (br, 4H, NCH ₂ ), 3.03 (m, 1H, COCH), 2.95 (m, 1H, PhCH), 2.46 (br, 4H, NCH ₂ ), 2.22 (s, 3H, NCH ₃ ), 1.96 (m, 2H, cyclopropane-CH ₂ ), 1.19 (m, 2H, CH ₂ ), 0.62 (t, J - 7.1 Hz, 3H, CH ₃ ). (S)-2-Amino-«-((lS,2S)-1-cyano-2-(4 ^, -(4-methylplperazln-1-yl)blphenyl-4- yl)cyclopropyl)butanamlde (PZ960): PZ960-8 (130 mg, 0.25 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of aqueous NaHC0 ₃ solution and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dichloromethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ960 (32 mg, 31% yield). LC-MS: 418.1 [M+H] ⁺ . *H NM (DMSO-d _e , 300 MHz): δ 7.48 (d, J - 8.4 Hz, 4H, Ph), 7.22 (d, J = 8.1 Hz, 2H, Ph), 7.00 (d, J = 8.7 Hz, 2H, Ph), 3.17 (br, 4H, NCHi), 3.08 (m, 1H, COCH), 2.93 (m, 1H, PhCH), 2.47 (br, 4H, NCH ₂ ), 2.22 (s, 3H, NCH ₃ ), 1.99 (m, 1H, cydopropane-CHa), 1.87 (m, 1H, cydopropane-CH ₂ ), 1.15 (m, 2H, CH ₂ ), 0.36 (t, J = 7.2 Hz, 3H, CH ₃ ).

Synthesis Scheme

Procedure

4-iJromo-2-(4-methylplperazln-1 -ylsuifonyl)thiazole (PZ984-2): At -78°C, a solution of 2,4- dibromothiazole PZ984-1 (10 g, 41.3 mmol) In THF (150 mL) was treated with isopropyl magnesium bromide (41.3 mmol) for l h followed by a pass-through of S0 ₂ gently for another 1 h. Then sulfuryl chloride (17 g, 0.12 moi) was added and the mixture was stirred for 2 h at 0°C. Triethylamine (28.9 mL, 0.2 mo!) and N-methylpiperldine (12 g, 0.12 moi) were added. The reaction mixture was stirred overnight at ambient temperature and then quenched with 10% aqueous ammonium chloride solution (100 mL). The solvent was removed under vacuum and the residue was treated with water (20Q mL) and ethyl acetate (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by HPFC (DCM:EtOH = 10:1) to yield PZ984-2 (7.2 g, 53% yield). LC-MS: 326.1 [M+H] ⁺ .

2-(4- ethylplperazln-1-ylsuSfonyS)-4-(4 _f 4,5 _r 5-tetramethyl -1,3,2-dioxaboroSan-2-yS)thiazoie (PZ984-3): Pd(PPh ₃ ) ₄ (1.0 g) was added to a mixture of P2984-2 (7 g, 21.5 mmol), plnacolatodlboron (3.8 g, 21.5 mmol) and potassium carbonate (5.9 g, 43.1 moi) in toluene (500 mL) under nitrogen protection. The reaction mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (500 mL) and ethyl acetate (500 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (500 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford PZ984-3 (5.7 g, 71% yield). racem/c-Methyl l-(iert-butoxycarbonylamino)-2-(4-(2-(4-methylplperazln-1- ylsulfonyl)thlazol-4-yl)phenyl)cyclopropanecarboxylate (PZ984-4): PdCI ₂ (PPh) ₂ (0.5 g) was added to a mixture of PZ984-3 (3.0 g, 8.1 mmol), racemic methyl-2- (4-bromophenyl)-1- (ie/t-butoxycarbonyiamino)cyciopropanecarboxyiate (3) (3.0 g, 8.1 mmol) and aqueous sodium carbonate solution (4.1 mL, 2 M) in 1,4-dioxane (50 mL) under nitrogen protection. The reaction mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (100 mL) and ethyl acetate (100 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by HPFC (EA) to afford racemic PZ984-4 (3.4 g, 79% yield). LC-MS: 537.2 [M+H] ⁺ . racem/c-Methyl l-amlno-2-(4-(2-(4-methylplperazln-1-ylsulfonyl)thiazol-4- yl)phenyl)cyclopropanecarboxylate (PZ984-5): Concentrated HCl/water solution (50 mL, 2/1, v/v) was added to a solution of PZ984-4 (3.4 g, 6.3 mmol) In THF (50 mL). The mixture was stirred for 4 h at 40°C followed by pH adjustment to 8 with saturated aqueous NaHC0 ₃ solution. Then the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated to afford racemic PZ984-5 (2.4 g, 87% yield).

(1R,2R)-Methy\ l-((S)-2-(iert-butoxycarbonylamino)butanamldo)-2-(4-(2-(4- methylplperazln-1-ylsulfonyl)thiazol-4-yl)phenyl)cydopropane carboxylate (PZ984-6) and (-fS,2S)-methyl l-^S)-2-(ie/t-butoxycarbonylamino)butanamido)- 2-(4-(2-(4- methylplperazln-1-ylsulfonyl)thlazol-4-yl)phenyl)cyclopropan ecarboxylate (PZ985-6),: To a solution of Boc-Abu-OH (1.7 g, 6.6 mmol) and NMM (1.1 g, 11.0 mmol) In dichloromethane (50 mL) at 0°C was added ethyl chlorofbmate (0.7 g, 6.6 mmol). The mixture was stirred for 1 h at 0°C and a solution of PZ984-5 (2.4 g, 5.5 mmol) in dlchloromethane (10 mL) was added. The cooling system was removed and the reaction mixture was stirred overnight at ambient temperature. The solution was poured into a mixture of 100 mL of water and 100 mL of dlchloromethane. The organic phase was separated and the aqueous phase was extracted with dlchloromethane (100 mL x 2) and ethyl acetate (100 mL x 2), The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (EA) to yield a mixture of stereomers, which was further purified by chiral- HPLC to yield PZ984-6 (1.4 g), PZ960-6 (1.3 g). LC-MS: 622.1 [M+H] ⁺ fert-Butyl (S)-1 -((2R,2 ?)-1 -carbamoyl-2-(4-(2-(4-methylplperazlnylsulfonyl) thlazol-4- yl)phenyl)cyclopropylamlno)-1 -oxobutan-2-ylcarbamate (PZ984-7): LiOH-H ₂ 0 (0.5 g, 10.5 mmol) was added to a solution of PZ984-6 (1.3 g, 2.1 mmol) In THF (20 mL) and water (20 mL). The reaction mixture was stirred for 3 h at ambient temperature. After pH adjustment to 3, the mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated.

The residue was dissolved in dichloromethane (50 mL) and NMM (0.4 g, 4.2 mmol) was added. After the solution was cooled to 0°C, ethyl chlorofbmate (0.32 g, 3.2 mmol) was added. The mixture was stirred for 1 h at 0°C and poured Into a flask with 200 mL of ammonia. The reaction mixture was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mL x 3) and ethyl acetate (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ984-7 (1.1 g, 87% yield). LC-MS: 607.2 [M+H] ⁺ . tert-Butyl (S)-1 -((2S,2S)-1 -carbamoyl-2-(4-(2-(4-methylpiperazlnylsulfonyl) thlazol-4- yl)phenyl)cyclopropylamlno)-1 -oxobutan-2-ylcarbamate (PZ985-7): UOH-H ₂ 0 (0.5 g, 10.5 mmol) was added to a solution of PZ985-6 (1.3 g, 2.1 mmol) in THF (20 mL) and water (20 mL). The reaction mixture was stirred for 3 h at ambient temperature. After pH adjustment to 3, the mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated.

The residue was dissolved in dichloromethane (50 mL) and NMM (0.4 g, 4.2 mmol) was added. After the solution was cooled to 0°C, ethyl chlorofomate (0.32 g, 3.2 mmol) was added. The mixture was stirred for 1 h at 0°C and poured Into a flask with 200 mL of ammonia. The reaction mixture was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mL x 3) and ethyl acetate (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ985-7 (1.1 g, 87% yield). LC-MS: 607.2 [M+H] ⁺ . tert-Butyl (S)-1 -((I ¾,2«)-1 -cyano-2-(4-(2-(4-methylpiperazln-1 -ylsulfbnyl) thlazol-4- yl)phenyl)cyclopropylamlno)-1 -oxobutan-2-ylcar amate (PZ984-8): To a solution of PZ984-7 (1,1 g, 1.8 mmol) in D F (10 mL) was added cyanurlc chloride (982 mg, 5.4 mmol). The reaction mixture was stirred for 4 h at ambient temperature. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was separated, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (EA) to afford PZ959-8 (560 mg, 54% yield). LC-MS: 589.1 [M+H]\ iert-Butyl (S l-((i/?,2«)-1 -cyano-2-(4-(2-(4-methylpiperazln-1 -ylsulfonyl)thlazol-4- yl)phenyl)cyclopropylamino)-1 -oxobutan-2-ylcarbamate (PZ985-8): To a solution of PZ985-7 (1.1 g, 1.8 mmol) in DMF (10 mL) was added cyanuric chloride (982 mg, 5.4 mmol). The reaction mixture was stirred for 4 h at ambient temperature. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was separated, dried over anhydrous Na ₂ S0 , and concentrated. The residue was purified by HPFC (EA) to afford PZ959-8 (630 mg, 59% yield). LC-MS: 589.1 [M+H]\ (S)-2-Amino-A/-((if^2«)-1 -cyano-2-(4-(2-(4-met^ylpiperazln-1 -ylsurrbnyl)thlazol-4- yf)phenyl)cyciopropyl)butanamide (PZ984): PZ984-8 (400 mg, 0.68 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of aqueous NaHC0 ₃ solution and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dlchloromethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield

PZ984 (165 mg, 50% yield). LC-MS: 489.1 [M+H] ⁺ . H NM (CDCI ₃ , 300 MHz): δ 7.88 (d, J = 8.4 Hz, 2H, Ph), 7.75 (s, 1H, thtazole-CH), 7.55 (br, 1H, NH), 7.31 (d, J = 8.4 Hz, 2H, Ph), 3.44 (br, 4H, NCH ₂ ), 3.17 (m, 1H, COCH), 3.06 (m, 1H, PhCH), 2.56 (m, 4H, NCH ₂ >, 2.33 (s, 3H, NCH ₃ ), 2.11 (m, 1H, cyclopropane-CH ₂ ), 1.86 (m, 1H, cyciopropane-CH ₂ ), 1.27 (m, 2H, CH ₂ ), 0.75 (t, J = 7.2 Hz, 3H, CH ₃ ).

(S)-2-Amino-N-((iS,2S)-1 -cyano-2-(4-(2-(4-methylpiperazin-1-ylsu!fonyl)thiazoi-4- yl)phenyl)cyclopropyl)butanamlde (PZ985): PZ985-8 (400 mg, 0.68 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of aqueous NaHC0 ₃ solution and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dlchloromethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ985 (197 mg, 60% yield). LC-MS: 489.2 [M+H] ⁺ . H NMR (DMSO-cfe, 300 MHz): δ 8.56 (s, 1H, thlazole-CH), 7.88 (d, J - 8.1 Hz, 2H, Ph), 7.313 (d, J = 8.1 Hz, 2H, Ph), 3.25 (br, 4H, NCH ₂ ), 3.09 (m, 1H, COCH), 2.82 (m, 1H, PhCH), 2.39 (m, 4H, NCH ₂ ), 2.15 (s, 3H, NCH ₃ ), 2.10 (m, 1H, cyclopnopane-CH ₂ ), 1.95 (m, 1H, cyclopropane-CH ₂ ), 0.96-1.19 (m, 2H, CH ₂ ), 0.43 (t, J = 7.5 Hz, 3H, CH ₃ ).

Procedure

(lR,2 )-methyl 2-{4-bromophenyl)- l-((S)-2-(tert- butoxycarbonylamino)butanamldo)cydopropanecartx>xylate (PZ1015-2): A solution of PZ1015-1 (2.9 g, 10.7 mmol) In dichloromethane (20 mL) was mixed with a solution of Boc- Abu-OH (2.18 g, 10.7 mmol) and DMT M (4.5 g, 16.1 mmol) In dichloromethane (20 mL) at 0 °C. The reaction was stirred obemight at ambient temperature, and quenched with a mixture of water/dichloromethane (200 mL 200 mL). The DCM phase was separated, and the aqueous phase was extracted with dichloromethane (200 mLx2). The organic phases were collected, dried over anhydrous Na _? S0 , and concentrated. The crude product was purified by HPFC (PE: EA « 2: 1) to yield a mixture of stereomers (4.2 g), which was separated by chlral-HPLC to afford PZ1015-2 (1.6 g) (LC-MS: 476.9, 478.9 (M+Na)) and PZ1015-2-lsomer (1.7 g) (LC-MS: 477.0, 479.0 (M+Na)).

Tert-butyl (S)-1 -((lR,2R)-2-(4-bromophenyl)-1 -carbamoylcydopropylamino)-1 -oxobutan-2- ylcarbamate (PZ1015-3): LIOH.H ₂ 0 (0.8 g, 17.6 mmol) was added to a solution of PZ1015-2 (1.6 g, 3.5 mmol) In THF (30 mL) and water (30 mL). The reaction was stirred for 3 h at ambient temperature. After pH adjustment to 4 by 5% HSO* and then to 8 by triethylamlne, the mixture was extracted with ethyl acetate (100 mLx3). The organic layers were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to dryness. LC-MS: 441.0, 443.0 (M+H). The residue was dissolved in dichloromethane (30 mL), and triethylamlne (0.74 g, 7.0 mmol) was added. After cooling the solution to 0 °C, ethyl chlorofomate (0.46 g, 4.0 mmol) was Injected In. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dichloromethane (200 mLx3) and ethyl acetate (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 , and concentrated to afford PZ1015-3 (1.4 g, 90%). LC-MS: 439.9, 441.9 (M+H).

Tert-butyl (S)-1 -((lR,2R)-2-(4-bromophenyl)-1 -cyanocyclopropylamlno)-1 -oxobutan-2- y!carbamate (PZ1015-4): To a solution of PZ1015-3 (1.4 g, 3.18 mmol) in DMF (15 mL), was added cyanurlc chloride (1.74 g, 9.54 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE: EA = 3: 1) to afford PZ1015-4 (1.1 g, 82%). LC-MS: 444.0, 446.0 (M+Na). Tert-butyl (S)-1 -((lR,2R)-1 -cyano-2-(4 ^I -((4-me hylpiperazln-1 -yl)methyl)blphenyl-4- yl)cyclopropylamino)-1 -oxobutan -2-yicarbarnate (Boc-PZ1015): A mixture of PZ1015-4 (1 g, 2,37 mmol), PZ1015-5 (0.9 g, 2.84 mmol), and 2M sodium carbonate aqueous solution (0.75 g, 7.07 mmol) in DMF (20 mL) was purged with nitrogen three times. Catalyst PdCI ₂ (dppf) ₂ (0.2 g) was added in. The reaction was stirred at 90 °C for 5 h. After cooling to room temperature, water (150 mL) and ethyl acetate (150 mL) were added In. The organic phase was collected, and the water phase was extracted with ethyl acetate (150 mL x2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPFC (DC /MeOH = 20: 1) to afford Boc-PZIQIS (0.8 g, 63%). LC-MS: 532.2 (M+H).

(S)-2-amino-N-((lR,2R)-1 -cyano-2-(4'-((4-methylplperazln-1 -yl)methyl)blphenyl-4- yl)cyclopropyl)butanamide (PZ1015): Boc-PZ1015 (500 mg, 0.94 mmol) was treated with excess HCOOH (15 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of NaHC0 ₃ in water and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mLx3) and dlchloromethane (200 mLx3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ1015 (200 mg, 49%). LC-MS: 432.1 (M+H). *H NMR (DMSO-Gfe, 300 MHz) 6: 7.55 (br, 4H, Ph), 7.28- 7.37 (m, 4H, Ph), 3.47 (br, 2H, NCH ₂ Ph), 3.72 (br, 4H, NCH ₂ ), 3.04 (br, 1H, CH), 2.91 (br, 1H, CH), 2.37 (br, 4H, NCH ₂ ), 2.14 (s, 3H, NCH ₃ ), 1.97 (br, 1H, cyc!opropane-CHj), 1.14 (br, 2H, CH ₂ ), 0.48 (br, 3H, CH ₃ ).

Procedure l-Ethyl~4-(4-(4,4,5,5-tetramethyl~1 ,3,2-dioxaborolan-2^^ (CP-2): Pd(PPh ₃ ) (1.5 g) was added to a mixture of l-(4-bromophenylsulfonyl)-4-ethylpiperazine (CP-1) (10 g, 30 mmol), plnacolatodlboron (5.3 g, 30 mmol) and potassium carbonate (8.5 g, 0.06 mol) in toluene (200 mL) under nitrogen protection. The mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (200 mL) and ethyl acetate (200 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford CP-2 (8.1 g, 71% yield). *H NM (CDCI ₃ , 300 MHz) δ: 7.95 (d, J - 8.1 Hz, 2H, Ph), 7.73 (d, J - 8.1 Hz, 2H, Ph), 3.11 (br, 4H, NCH ₂ ), 2.60 (br, 4H, NCH ₂ ), 2.46 (br, 2H, CH ₂ ), 1.37 (s, 12H, pinacol-CH ₃ ), 1.08 (m, 3H, CH ₃ ).

(IK,2/?)- Methyl l-amlno-2-(4-bromophenyl)cyclopropanecarboxylate (CP-3-(«,/?)): To a solution of Z-form of methyl l-amino-2-(4-bromophenyl)cyclopropanec3rboxylate (CP-3; compound *3" in example 5) (30 g, ill mmol) In ethyl acetate (200 mL) was added 2,3- dibenzoyl-Z. -tartaric aicd (39.8 g, 111 mmol) followed with 1 mL of methanol. The resulting solution was left standing for 2 h until a thick precipitation was formed. The precipitation was collected by filtration, washed with ethyl acetate (20 mL) and dissolved in a mixture of 0.1 M sodium carbonate (200 mL) and ethyl acetate (200 mL). The mixture was stirred for 30 min and the two phases were separated. The aqueous phase was extracted with ethyl acetate (200 mix 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford crude CP-3-(R,R) (12.3 g, 86% purity), which was treated again following the above procedure to give CP-3-(R,R) (9.1 g, 97% purity). LC-MS: 270.1 [M+ H]*>

(J/?,2/?)-2-(4-Bromophenyl)-1 -(te/t-butoxycarbonyiamino)cyciopropanecarboxy!ic acid (CP-4- («,«)): LiOH-HzO (4.0 g, 88.9 mmol) was added to a solution of CP-3-(R,R) (8.0 g, 29.6 mmol) in THF (50 mL) and water (50 mL). The reaction was stirred for 3 h at ambient temperature. The pH value of the mixture was adjusted to 8 with HC! and then di tert -butyl dicarbonate (7.7 g, 35.6 mmol) was added. The mixture was stirred overnight at ambient temperature. THF was removed under vacuum and the aqueous phase was acidified with 5% KHS0 ₄ (pH = 4) and extracted with ethyl acetate (200 mLx 3). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated to afford CP-4-(R,R) (6.8 g, 64% yield). LC- MS: 356.1 [M+H] ^÷ . iert-Butyl (ii?,2/¾)-2-(4-bromophenyi)-1 -carbamoylcyc!opropyicarbamate (CP-5-(K,/¾)): CP-4- (R,R) (5 g, 14.0 mmol) was dissolved In dlchloromethane (50 mL) and N M (2.8 g, 28.1 mmol) was added. After the solution was cooled to 0 °C, ethyl chlorofomate (2.3 g, 21.1 mmol) was added. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with 200 mL of ammonia. The reaction was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mLx 3) and ethyl acetate (200 mLx 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford CP-5-(R,R) (4.2 g, 85% yield). LC-MS: 355.1 [M+H] ⁺ . iert-Butyl (i«,2«)-2-(4-bramophenyl)-1 -cyanocyciopropylcarbamate (CP-6-(/?,K)): To a solution of CP-5-(R,R) (4.2 g, 11.8 mmol) In DMF (20 mL) was added cyanuric chloride (4.3 g, 23.7 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The crude product was purified by HPFC (PE:EA = 3: 1) to afford CP-6-(R,R) (2.8 g, 71% yield). LC-MS: 337.2 [M+H] ⁺ .

( ^2 ?)-1 -Amino-2-(4-bromophenyi)cyclopropanecarbonttr1le (CP-7-(«,«)): CP-6-(R,R) (2.8 mg, 8.3 mmol) was treated with excess HCOOH (20 ml) for 4 h at ambient temperature. The solution was slowly added into a mixture of NaHCQ ₃ in water and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and

dlchloromethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (PE:EA = 2: 1) to afford CP-7- (R,R) (0.6 g, 33% yield). LC-MS: 237.1 [M+H] ⁺ . tert- Butyl (S)-1 -((2/¾,2/?)-2-(4-bromophenyl)-1 -cyanocyclopropylamino)-1 -oxobutan-2- yicarbamate (CP-8-(5,fl,K)): To a solution of Boc-Abu-OH (0.8 g, 3 mmol) and NMM (0.5 g, 5.1 mmol) in dlchloromethane (20 mL) at 0 °C was added ethyl chlorofomate (0.3 g, 3 mmol). The reaction was stirred for 1 h at 0 °C, and a solution of CP-7-(R,R) (0.6 g, 2,5 mmol) in dlchloromethane (10 mL) was added. The cooling system was removed and the reaction was stirred overnight at ambient temperature. The solution was poured Into a mixture of water (50 mL) and dlchloromethane (50 mL). The organic phase was separated, and the aqueous phase was extracted with dlchloromethane (50 mL x 2) and ethyl acetate (50 mL x 2). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (PE:EA - 3: 1) to yield CP-8-(S,R,R) (780 mg, 73% yield). LC-MS: 422.2 [M+H] ⁺ . iert-Butyl (S)-1 -((i/?,2 ?)-1 -cyano-2-(4 ^, -(4-ethylpiperazin-1 -ylsulfonyl)blphenyl-4- yl)cyclopropylamino)-1 -oxobutan-2-ylcarbamate (CP-9-(S,R, ?)):

Pdd ₂ (PPh ₃ ) ₂ (0.1 g) was added to a mixture of CP-8-(S,R,R) (0.7 g, 1.7 mmol), CP-2 (0.8 g, 1.4 mmol) and aqueous sodium carbonate solution (1.9 mL, 2 M) In 1,4-dioxane (30 mL) under nitrogen protection. The mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (50 mL) and ethyl acetate (50 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 mLx 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPFC (EA) to afford CP-9-(S,R,R) (0.4 g, 42% yield). LC-MS: 596.1 [M+H]\

(S)-2-Amino-W-((IR,2 ?)-1 -cyano-2-(4'-(4-ethylplperazin-1 -ylsulfonyl)blphenyl-4- yl)cyclopropyl)butanamlde (PZ1029): CP-9-(S,R,R) (0.4 g, 0.7 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of aqueous NaHC0 ₃ solution and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dlchloromethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na _z S0 ₄ , and concentrated to yield PZ1029 (120 mg, 36% yield). LC- S: 496.1 [ +H] ⁺ . H NMR (CDCI ₃ , 300 MHz) 6: 7.81 (d, J = 8.4 Hz, 2H, Ph), 7.68 (d, J = 8.4 Hz, 2H, Ph), 7.59 (br, 1H, CONH), 7.54 (d, J = 8.1 Hz, 2H, Ph), 7.34 (d, J = 8.1 Hz, 2H, Ph), 3.11 (m, 6H, COCH+NCH ₂ +PhCH), 2.61 (br, 4H, NCHj), 2.47 (br, 2H, NCH ₂ ), 2.06 (m, 1H, cyciopropane-CH ₂ ), 1.85 (m, 1H, cydopropane- CH ₂ ), 1.52 (m, 2H, CH , 1.09 (m, 3H, CH ₃ ), 0.66 (t, J = 7.1 Hz, 3H, CH ₃ ).

Synthesis Scheme

Procedure

2-(4-Etiiylphenyl)-4,4,5,5-tetramethyl-1,3,2-dloxaborolan e (CP-11): Pd(PPh ₃ )4 (1.5 g) was added to a mixture of l-bromo-4-ethylbenzene (CP- 10) (1.0.0 g, 54 mmol), pinacolatodlboron (9.5 g, 54 mmol) and potassium carbonate (15.3 g, 0.11 mol) in toluene (200 mL) under nitrogen protection. The mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (200 mL) and ethyl acetate (200 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford CP-11 (9.8 g, 78% yield). H NMR (CDCi,, 300 MHz) δ: 7.69 (d, J = 8.4 Hz, 2H, Ph), 7.08 (d, J = 8.4 Hz, 2H, Ph), 2.54 (q, J = 6.1 Hz, 2H, CH ₂ ), 1.22 (s, 12H, plnacol-CH ₃ ), 1.13 (m, 3H, CH ₃ ).

(1«,2«)-Methyl 2-(4-bromophenyl)-1-((S)-2-(tert- butoxycarbonylamlno)butanamldo)cyclopropanecarboxylate (CP-12-(S,/?,/?)): To a solution of Boc-Abu-OH (1.2 g, 4.4 mmol) and NMM (0.9 g, 8.8 mmol) in dichloromethane (20 mL) at 0 °C was added ethyl chlorofomate (0.4 g, 4.4 mmol). The reaction was stirred for 1 h at 0 °C, and a solution of CP-3-(R,R) (see example 15); 1 g, 3.7 mmol) in dichloromethane (10 mL) was added. The cooling system was removed and the reaction was stirred overnight at ambient temperature. The solution was poured Into a mixture of water (50 mL) and dichloromethane (50 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2) and ethyl acetate (50 mL x 2). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (PE:EA = 3: 1) to yield CP-12-(S,R,R) (1.4 g, 83% yield). LC-MS: 455.1 [M+H] ⁺ . tert- Butyl (S)-1-((iA^2 ?)-2-(4-bromophenyl)-1-carbamoylcyclopropylamlno)-1-oxobutan -2- ylcarbamate (CP-13-(S,«,«)): UOH-H ₂ 0 (0.4 g, 9.2 mmol) was added to a solution of CP-12- (S,R,R) (1.4 g, 3.1 mmol) In THF (10 mL) and water (10 mL). The reaction was stirred for 3 h at ambient temperature. THF was removed under vacuum and the aqueous phase was acidified with 5% KHS0 ₄ (pH = 4) and extracted with ethyl acetate (200 mL x 3). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated.

The residue was dissolved In dichloromethane (20 mL) and NMM (0.4 g, 0.8 mmol) was added. After the solution was cooled to 0 °C, ethyl chlorofomate (0.5 g, 4.7 mmol) was added. The reaction was stirred for 1 h at 0 °C, and the mixture was poured Into a flask with was extracted with dichloromethane (100 mL x 3) and ethyl acetate (100 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford CP- 13-(S,R,R) (1.2 g, 88% yield). LC- S: 440.1 [M+H] ⁺ . tert- Butyl (S)-1 -((J/?,2 ?)-2-(4-bromophenyl)-1 -cyanocydopropylamlno)-1 -oxobutan-2- ylcarbamate (CP-8-(S,K,R)): To a solution of CP-13-(S,R,R) (1.2 g, 2.7 mmol) In D F (10 mL) was added cyanuiic chloride (1.0 g, 5.4 mmol). The reaction was stirred for 4 h at ambient temperature. The solvent was removed under vacuum, and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ SO«, and concentrated. The crude product was purified by HPFC (PE:EA = 3:1) to afford CP-8-(S,R,R) (0.8 g, 67% yield). LC-MS: 422.2 [M+H] ⁺ . tert-Butyl (S)-1 -((J/^2A?)-1 -cyano-2-(4'-ethylblphenyl-4-yl)cyclopropylamlno)-1 -oxobutan-2- ylcarbamate (CP-14-(S,«,/?)): PdCI ₂ (dppf) ₂ (0.1 g) was added to a mixture of CP-8-(S,R,R) (0.8 g, 1.9 mmol), CP-11 (1.9 mL, 2 ) and aqueous sodium carbonate solution (1.9 mL, 2 M) In 1,4-dioxane (30 mL) under nitrogen protection. The mixture was refluxed overnight. After the mixture was cooled to room temperature, the solvent was removed under vacuum. To the residue were added water (50 mL) and ethyl acetate (50 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPFC (PE:EA = 3:1) to afford CP-14-(S,R,R) (0.6 g, 71% yield). LC- MS: 448.1 [M+H] ⁺ .

(S)-2-Amlno-W-((l«,2«)-1 -cyano-2-(4 ^, -ethylbiphenyl-4-yl)cyclopropyl)butanamlde (PZ1038): CP-14-(S,R,R) (0.6 g, 1.3 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added into a mixture of aqueous NaHC0 ₃ solution and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dichloormethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ1038 (135 mg, 29% yield). LC-MS: 482.1 [M+H] ⁺ . H NMR (CDC! ₃ , 300 MHz) δ: 7.57 (m, 6H, Ph), 7.26 (m, 2H, Ph), 3.22 (m, 1H, COCH), 3.07 (t, J = 8.1 Hz, 1H, PhCH), 2.71 (q, J = 5.7 Hz, 2H, CH ₂ ), 2.08 (m, 1H, cydopropane-CH ₂ ), 1.80 (m, 1H, cyclopnopane-CH ₂ ), 1.26 (m, 5H, CH ₃ +CH ₂ ), 0.71 (t, J = 7.1 Hz, 3H, CH ₃ ).

methvlDlperazin-1 -vnbiDhenvi-4-vi)cycloproDvn-3-ffuran-2-yl DroDanamide

Procedure

(I8,2K)- ethyl i-((S)-2-(iert-butoxycarbonylamino)-3-(furan-2- yl)propanamldo)-2-(4'-(4- methylpiperazln-1 -yl)b!phenyl-4-yl)cyclopropanecarboxylate (PZlOOl-1) and (IS,2S)-methyl l-((S)-2-(tert-birtoxycarbonylamino)- 3-(furan-2-yl)propanamldo)-2-(4'-(4-methylpiperazln- l-yi)biphenyi-4-yi)cyciopropanecarboxyiate (PZ1002-1): To a solution of Boc-Furan-OH (1,3 g, 4.9 mmol) and NMM (0.83 g, 8.2 mmol) In dlchloromethane (50 mL) at 0°C was added ethyl chlorofomate (0.54 g, 4.9 mmol). The reaction mixture was stirred for 1 h at 0°C, and a solution of PZ959-5 (1.5 g, 4.1 mmol) In dlchloromethane (10 mL) was added. The cooling system was removed and the reaction was stirred overnight at ambient temperature. The solution was poured Into a mixture of 100 mL of water and 100 mL of dlchloromethane. The organic phase was separated and the aqueous phase was extracted with dlchloromethane (100 mL x 2) and ethyl acetate (100 mL x 2). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (EA) to yield a mixture of stereomers, which was further purified by chlral-HPLC to yield PZlOOl-1 (1.11 g), PZ1002-1 (1.03 g). LC- S: 603.1 [M+H] ⁺ . iert-Butyl (S)-1 -((IR,2/?)-1 -carbamoyl-2-(4'-(4-methylplperazin-1 - yl)blphenyl-4- yl)cyclopropylamlno)-3-(furan-2-yl)-1 -oxopropan-2-ylcarbamate (PZ1001-2): UOH-H ₂ 0 (0.42 g, 9.0 mmol) was added to a solution of PZlOOl-l (1.1 g, 1.8 mmol) in THF (20 mL) and water (20 mL). The reaction mixture was stirred for 3 h at ambient temperature. After the pH value was adjusted to 3, the mixture was extracted with ethyl acetate (100 mL x 3) The organic layer was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated.

The residue was dissolved In dlchloromethane (50 mL) and NMM (0.42 g, 3.6 mmol) was added. After the solution was cooled to 0°C, ethyl chlorofomate (0.27 g, 2.7 mmol) was added. The mixture was stirred for 1 h at 0°C and poured Into a flask with 200 mL of ammonia. The reaction mixture was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mL x 3) and ethyl acetate (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to afford PZ1001-2 (930 mg, 87% yield). LC-MS: 588.1 [M+H] ⁺ . Cert-Butyl (S)-1 -((-tS,2S)-1 -carbamoyl-2-(4'-(4-methylplperazln-1 - yl)biphenyl-4- yl)cydopropylamlno)-3-(furan-2-yl)-1 -oxopropan-2-ylcarbamate (PZ1002-2): UOH-H ₂ 0 (0.38 g, 8.3 mmol) was added to a solution of PZ1002-1 (1 g, 1.7 mmol) In THF (20 mL) and water (20 mL). The reaction mixture was stirred for 3 h at ambient temperature. After the pH value was adjusted to 3, the mixture was extracted with ethyl acetate (100 mL x 3). The organic layer was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated.

The residue was dissolved In dlchloromethane (50 mL) and NM (0.39 g, 3.4 mmol) was added. After the solution was cooled to 0°C, ethyl chlorofomate (0.26 g, 2.6 mmol) was added. The mixture was stirred for 1 h at Q°C and poured into a flask with 200 mL of ammonia. The reaction mixture was stirred overnight at ambient temperature. The mixture was extracted with dlchloromethane (200 mL x 3) and ethyl acetate (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 _4f and concentrated to afford PZ1002-2 (910 mg, 93% yield). LC-MS: 588.1 [M+H] ⁺ . iert-Butyl (S)-1 -((2/¾,2 ?)-1 -cyano-2-(4'-(4-methylplperazin-1 - yl)blphenyl-4- yl)cydopropylamlno)-3-(furan-2-yl)-1 -oxopropan-2-ylcarbamate (PZ1001-3): To a solution of PZ1001-2 (900 mg, 1.5 mmol) in DMF (10 mL) was added cyanurlc chloride (837 mg, 4.6 mmol). The reaction mixture was stirred for 4 h at ambient temperature. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (EA) to afford PZ1001-3 (273 mg, 31% yield). LC-MS: 570.1 [ +H] ⁺ . iert-Butyl (S)-1 -((i ¾,2 ?)-1 -cyano-2-(4'-(4-methylpiperazin-1 - yl)blphenyl-4- yl)cyclopropySamino)-3-(furan-2-yi)-1 -oxopropan-2-yfcarbamate (PZ1002-3): To a soiutlon of PZ1002-2 (900 mg, 1,5 mmol) in DMF (10 mL) was added cyanurlc chloride (837 mg, 4.6 mmol). The reaction mixture was stirred for 4 h at ambient temperature. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated. The residue was purified by HPFC (EA) to afford PZ1002-3 (322 mg, 37% yield). LC-MS: 570.1 [M+H] ⁺ .

(S)-2-Amlno-W-((J/<,2 ?)-1 -cyano-2-(4 ^, -(4-methylplperazln-1 -yl)blphenyl-4-yl)cyclopropyl)-3- (furan-2-yi)propanamide (PZ1001): PZ1001-3 (250 mg, 0.44 mmoi) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of aqueous NaMC0 ₃ solution and ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dichloromethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ1001 (91 mg, 44% yield). LC-MS: 470.1 [M+H] ⁺ . H NMR (CDCJ ₃ , 300 MHz): δ 7.51 (m, 5H, Furan + Ph), 7.22 (d, J - 8.1 Hz, 2H, Ph), 7.09 (d, J « 8.1 Hz, 2H, Ph), 6.31 (br, 1H, Furan), 6.09 (br, 1H, Furan), 3.49 (m, 1H, COCH), 3.29 (br, 4H, NCH ₂ ), 3,03 (m, 2H, PhCH + (S)-2-Amfno-N-((35,2S)-1-cyano-2-(4 4-m^

(furan-2-yl)propanamlde (PZ1002): PZ1002-3 (300 mg, 0,53 mmol) was treated with excess HCOOH (10 mL) for 4 h at ambient temperature. The solution was slowly added Into a mixture of aqueous NaHC0 ₃ solution and Ice with stirring. After neutralization, the mixture was extracted with ethyl acetate (200 mL x 3) and dlchloormethane (200 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ S0 ₄ , and concentrated to yield PZ1002 (57 mg, 24% yield). LC-MS: 470,1 [ +H] ⁺ . *H NM (CDC! ₃ , 300 MHz): δ 7.51 (m, 5H, Furan + Ph), 7.33 (br, 1H, NH), 7.09 (d, J - 8.4 Hz, 2H, Ph), 6.97 (d, J = 8.4 Hz, 2H, Ph), 631 (m, 1H, Furan), 6.06 (m, 1H, Furan), 3.46 (m, 1H, COCH), 3.27 (m, 4H, NCH , 2.97 (m, 3H, PhCH + Furan-CH ₂ ), 2.60 (m, 4H, NCHj), 2.37 (s, 3H, NCH ₃ ), 2.09 (m, 1H, cydopropane-CH ₂ ), 1.71 (m, 1H, cydepropane-CHs).