WO2007025775A2 - Nouveaux inhibiteurs de la cysteine protease - Google Patents

Nouveaux inhibiteurs de la cysteine protease Download PDF

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Publication number
WO2007025775A2
WO2007025775A2 PCT/EP2006/008579 EP2006008579W WO2007025775A2 WO 2007025775 A2 WO2007025775 A2 WO 2007025775A2 EP 2006008579 W EP2006008579 W EP 2006008579W WO 2007025775 A2 WO2007025775 A2 WO 2007025775A2
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methyl
cyano
pyrimidinyl
methylpropyl
chloro
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PCT/EP2006/008579
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English (en)
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Maria Jesus Chaparro Martin
Jose Miguel Coteron Lopez
Esther Pilar Fernandez Velando
Jose Maria Fiandor Roman
Maria Marco Martin
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention is directed to certain substituted heteroaryl nitrile derivatives, which are protease inhibitors. More specifically, the compounds are inhibitors of cysteine proteases. In particular, the compounds inhibit cysteine proteases of the papain superfamily, more specifically those of the falcipain family, which are cysteine proteases found in the malaria parasite Plasmodium falciparum, and also cysteine proteases of the cathepsin family such as cathepsins K, L, S and B.
  • Malaria is one of the major disease problems of the developing world.
  • the most virulent malaria-causing parasite in humans is Plasmodium falciparum, which is the cause of hundreds of millions of cases of malaria per annum, and is thought to cause over 1 million deaths each year, Breman, J. G., et al., (2001) Am. Trop. Med. Hyg. 64, 1-11.
  • One problem encountered in the treatment of malaria is the build-up of resistance by the parasite to available drugs. Thus there is a need to develop new antimalarial drugs.
  • Plasmodium falciparum parasite One way of identifying a potential new drug with antimalarial activity is to study biological targets found in the Plasmodium falciparum parasite, in turn by investigating biological pathways in which particular targets might be identified.
  • haemoglobin In Plasmodium falciparum, haemoglobin is transported to an acidic food vacuole, where it is degraded. It appears that multiple enzymes, including food vacuole cysteine, aspartic, and metalloproteases, and a cytosolic aminopeptidase, contribute to haemoglobin hydrolysis, Francis S. E. et al., (1997) Annu. Rev. Microbiol. 51 , 97-123; Rosenthal PJ. Protease inhibitors. In: Rosenthal P.J., ed. Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery, Totowa, NJ. : Humana Press, (2001) 325-345. Plas
  • Cysteine protease inhibitors were shown some years ago to block haemoglobin degradation by erythrocytic parasites, causing a characteristic morphological abnormality in which the food vacuole fills with undegraded haemoglobin and parasite development is blocked, ⁇ Rosenthal P. J., et al., (1998) J. Clin. Invest. 82, 1560-6; Gamboa de Dominguez N. D. and Rosenthal PJ., (1996) Blood 87, 4448-54. Efforts to identify enzymes responsible for haemoglobin degradation led to the characterization of "falcipain" as a trophozoite food vacuole cysteine protease, Rosenthal PJ.
  • Falcipain-2 is the principal cysteine protease of Plasmodium falciparum trophozoites, Shenai B.R. et.
  • falcipain-2 is a key target enzyme, but it is likely that the other two falcipains are also appropriate targets and that, in many cases, they are inhibited by the same compounds that are active against falcipain-2.
  • falcipain-3 readily hydrolyzes native haemoglobin under mildly reducing conditions that are similar to those found in physiological systems, Shenai B.R. et al., (2000) J. Biol. Chem. 275, 29000-10; Sijwali P.S.
  • Falcipain-2 and falcipain-3 are similar in structure but falcipain-1 is a more distant relative; it is thought that this enzyme plays a key role in the invasion of erythrocytes by Plasmodium falciparum merozoites but that it is not essential for normal development during the erythrocytic stage, Sijwali, P. S., et al., Proceedings of the National Academy of Sciences of the United States of America 101 , 8721-8726.
  • falcipain-2 a fourth papain-family cysteine protease has been found, now known as falcipain-2'.
  • Falcipain-2' is nearly identical in sequence to falcipain-2, differing by only 3 amino acids, none of which are located at the active site.
  • the structure of falcipain-2' is not known, but is likely to be very similar to that of falcipain-2.
  • the biological role of falcipain-2' is also expected to be very similar, although probably not identical, to that of falcipain-2.
  • cysteine protease inhibition in particular the inhibition of falcipain-2, blocks parasite development. Falcipain- 2 and related plasmodial cysteine proteases are thus logical targets for antimalarial chemotherapy and therefore there is a need for compounds which are inhibitors of these targets.
  • P. vivax is the second most important human malaria parasite, after P. falciparum. Although less virulent than P. falciparum, P. vivax is the most widely distributed human malaria parasite, and it causes extensive morbidity (Mendis, K., Sina, B. J., Marchesini, P. and Carter, R. (2001 ) "The neglected burden of Plasmodium vivax malaria" Am. J. Trop. Med. Hyg. 64, 97-106). These two parasites are responsible for more than 90% of episodes of human malaria, totalling several hundred million cases annually. However, comprehensive studies of P. vivax have been limited due to technical shortcomings. Notably, unlike the case with P. falciparum, routine in vitro culture of P.
  • vivax is not available, and animal models are limited to primates.
  • Very recently Na, B. K., Shenai, B. R., Sijwali, P. S., Choe, Y., Pandey, K. C, Singh, A., Craik, C. S., Rosenthal, P. J. (2004) identification and biochemical characterization of vivapains, cysteine proteases of the malaria parasite Plasmodium vivax. Biochem. J. 378, 529-538), two cysteine protease genes (vivapain-2 and vivapain-3) from P. vivax have been identified and cloned and the heterologously expressed gene products have been characterized biochemically.
  • cysteine proteases are apparent orthologues of falcipain-2 and falcipain- 3, but key differences in the biochemical properties of the plasmodial proteases warrant attention to the inhibition of each enzyme in the evaluation of antimalarial protease inhibitors.
  • Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Certain cathepsins, for example cathepsins K, B, L, and S have been described in the literature. Cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501 ,969. Cathepsin K has also been variously denoted as cathepsin O or cathepsin 02 in the literature. The designation cathepsin K is considered to be the most appropriate and is used herein. Cathepsin K has been expressed, purified, and characterised, Bossard, M. J., et al., (1996) J. Biol.
  • Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g. in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by Pneumocystis Carinii, Trypsanoma cruzi, Trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, cancer, for example pancreatic cancer (see Joyce J. A.
  • gingipains Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis, Potempa, J., et al., (1994) Perspectives in Drug Discovery and Design 2, 445- 458.
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated.
  • Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of haematopoietic lineage.
  • osteoclasts which are multinuclear cells of haematopoietic lineage.
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle of resorption and formation.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, thus indicating an essential role for cysteine proteases in bone resorption. For example, Delaisse, et al., (1980) Biochem.
  • cystatin an endogenous cysteine protease inhibitor
  • cystatin an endogenous cysteine protease inhibitor
  • Other studies report a correlation between inhibition of cysteine protease activity and bone resorption.
  • cathepsin K The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption.
  • inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
  • Cathepsin K is also expressed in synovial giant cells taken from osteoarthritic patients (Dodds, et al., (1999) Arthritis & Rheumatism, 42, 1588, and Hou, et al., (2002), American Journal of Pathology 159, 2167). Cathepsin K staining is observed in osteoarthritic as well as rheumatoid arthritic samples (Hou, et al., (2002), American Journal of Pathology 159, 2167).
  • cathepsin K has also been localized to cartilage tissue and a decrease in pH in cartilage correlated with severity of damage (Konttinen, et al., (2002), Arthritis & Rheumatism, 46, 953). This observation, combined with the fact that cathepsin K is an acidic lysosomal protease, strongly suggests a physiological role of cathepsin K in cartilage turnover in addition to bone resorption. These researchers also demonstrated that cathepsin K can degrade aggrecan and type Il collagen, the two major protein components of the cartilage matrix.
  • cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis.
  • Cathepsin K has been shown to be abnormally or overexpressed in numerous tumors and in prostate cancer (Littlewood-Evans, et al., (1997), Cancer Res., 57, 5386 and Brubaker, et al., (2003), J. Bone Miner. Res., 18, 222).
  • increased levels of bone resorption marker have been detected in bone metastases of prostate cancer suggesting that cathepsin K inhibitor may have utility in preventing metastasis of tumors to bone (Ishikawa, et al., (2001), MoI.
  • Metastatic neoplastic cells also typically express high levels of other proteolytic enzymes such as cathepsin B, S and L that degrade the surrounding matrix. Thus, inhibition of cathepsin K may also be useful for treating certain tumors and neoplastic diseases.
  • Cathepsin L has been implicated in several diseases including osteoporosis, osteoarthritis, rheumatoid arthritis, lymphoproliferative diseases, cancer, for example pancreatic cancer, metastasis, atherosclerosis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Liu, et al., (2004), Arterioscler Throm Vase Biol. 24, 1359). Cathepsin L-deficient mice have also been shown to have increased resistance to osteoporosis following ovariectomy suggesting its potential for osteoporosis (Potts, et al., (2004) Int. J. Exp. Path. 85, 85).
  • Cathepsin L is required for endothelial progenitor cell-induced neovascularization (Urbich, et al., (2005) Nat. Med. 11 , 206). Similarly, targeting cathepsin L by specific ribozymes decreases cathepsin L protein synthesis and cartilage destruction in rheumatoid arthritis (Schedel, et al., (2004) Gene Ther. 11 , 1040) suggesting its potential role in rheumatoid arthritis.
  • Cathepsin S has been implicated in several diseases including immune and auto-immune disorders, rheumatoid arthritis, inflammation, inflammatory bowel disease, myesthania gravis, atherosclerosis, lymphoproliferative diseases, cancer, for example pancreatic cancer, metastasis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Liu, et al., (2004), Arterioscler Throm Vase Biol. 24, 1359).
  • Cathepsin S is thought to play a role in invariant chain degradation and antigen presentation and cathepsin S null mice have been shown to have a diminished collagen-induced arthritis (Nakagawa, et al., (1999) Immunity, 10, 207) suggesting its potential role in rheumatoid arthritis.
  • Cathepsin B has been implicated in immune and auto-immune disorders, rheumatoid arthritis, inflammation, inflammatory bowel disease, myesthania gravis, osteoarthritis, lymphoproliferative diseases, cancer, for example pancreatic cancer, metastasis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Lang, et al., (2000), J. Rheumatol. 27, 1970). Cathepsin B has been implicated in the processing of invariant chain (Zhang, et al., (2000) Immunology, 100, 13) suggesting its role in immune disorders such as those listed above.
  • Cathepsin B is one of the most highly expressed cysteine protease in cartilage and inhibitors of cathepsin B has been shown to inhibit cartilage degradation. Cathepsin B may contribute to matrix degradation through cleavage of aggrecan and collagen, two components of cartilage matrix (Mort et al., (1998), Biochem. J., 335, 491 ). Additionally, cathepsin B could contribute to the mechanical loading component of osteoarthritis by cleaving lubricin, an abundant lubricating protein in synovial fluid. Cleavage of lubricin by cathepsin B has been shown to increase the coefficient of friction in synovial fluid and intact joints (Elsaid, K.A. et al. (2005), Transactions of the Orthopedic Research Society, 51 st Annual Meeting, Abstract 924). These data suggest potential for cathepsin B inhibitors in osteoarthritis.
  • cathepsins K, L, S and B In view of the number of pathological responses and conditions that are mediated by cathepsins K, L, S and B, there is a need for inhibitors of these cathepsins which can be used in the treatment of a variety of conditions.
  • WO 2005/085210 A1 discloses certain fused bicyclic pyrimidine compounds as inhibitors of cathepsin K, useful in the treatment of bone diseases such as osteoporosis and the like.
  • WO 2005/103012 A1 discloses certain hydrazine-heterocyclic nitrile compounds as inhibitors of cathepsin K, useful in the treatment of bone diseases such as osteoporosis and the like.
  • the invention is directed to novel heteroaryl nitrile derivatives and their use as protease inhibitors, more specifically inhibitors of cysteine protease, even more specifically inhibitors of cysteine proteases of the papain superfamily.
  • the cysteine proteases are those of the falcipain family, for example falcipain-2 and falcipain-3, which are examples of cysteine proteases indicated in malaria.
  • cysteine proteases are those of the cathepsin family for example cathepsins K, L, S and B, which is a cysteine protease indicated for example in conditions characterised by excessive bone loss such as osteoporosis and bone metastasis, and other bone and joint diseases such as osteoarthritis.
  • the compounds of the invention may also have utility as serine protease inhibitors.
  • the invention involves the compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds as protease inhibitors.
  • the present invention provides at least one chemical entity selected from compounds of Formula I:
  • R 4 represents halogen
  • R 2 represents
  • phenyl-C 1-3 alkylene-X i) -phenyl-C 1-3 alkylene-X, -pyridyl-phenyl-C 1-3 alkylene-X or -phenyl-C 1-3 alkylene-X-R J , wherein phenyl is optionally substituted with one group selected from halogen or CF 3 ; or
  • Y represents an aromatic group comprising a 5-membered ring having one to four heteroatoms selected from N, O and S, the ring being optionally fused to a phenyl ring;
  • R J represents Z, -C 1-4 alkylene-Z or -C(O)Z
  • X and Z independently represent:
  • X and Z are independently optionally substituted with a) one group selected from: C 1-4 alkyl, C 1-4 alkylOH, -C 1-4 alkylOC 1-4 alkylOH, OH, -C 1-4 alkylC(O)OC 1-4 alkyl, -C(O)OC 1- 4 alkyl, NR E R F , -C 1-4 alkylNR E R F , -NC(O)C 1-3 alkyl, -NC(O)OCi -4 alkyl and -C(O)NR E R F and b) optionally an additional group which is C 1-4 alkyl;
  • R E and R F independently represent hydrogen or C 1-4 alkyl or C 1-4 alkenyl
  • R 4 represents chlorine, bromine or iodine. In another embodiment, R 4 represents chlorine or bromine. In a further embodiment, R 4 represents bromine.
  • R 2 represents -phenyl-C 1-3 alkylene-X, -pyridyl- phenyl-C 1-3 alkylene-X or -phenyl-Ci -3 alkylene-X-R J , wherein phenyl is optionally substituted with one group selected from halogen or CF 3 .
  • R 2 represents -pyridyl-phenyl-d-salkylene-X or -phenyl-C 1-3 alkylene-X-R J , wherein phenyl is optionally substituted with one group selected from halogen or CF 3 .
  • R 2 represents -phenyl-d-salkylene-X-R" 1 , wherein phenyl is optionally substituted with one group selected from halogen or CF 3 .
  • R 2 represents -pyridyl-phenyl-C 1-3 alkylene-X, wherein phenyl is optionally substituted with one group selected from halogen or CF 3 .
  • R 2 represents - phenyl-C 1-3 alkylene-X, wherein phenyl is optionally substituted with one group selected from halogen or CF 3 .
  • the optional substituent is fluorine.
  • the phenyl group in R 2 is unsubstituted.
  • the groups directly bonded to the phenyl group in R 2 are in para orientation relative to one another.
  • the groups directly bonded to the phenyl group in R 2 are in meta orientation relative to one another.
  • R 2 contains a pyridyl group the groups directly bonded to the pyridyl group (excluding optional substituents) are in para orientation relative to one another.
  • R 2 contains a pyridyl group
  • the groups directly bonded to the pyridyl group (excluding optional substituents) are in meta orientation relative to one another.
  • R 2 represents -Y-C 1-3 alkylene-X or -Y-C 1-3 alkylene-X-R J . In another embodiment, R 2 represents -Y-C 1-3 alkylene-X. In a further embodiment, R 2 represents -Y-C 1 . 3 alkylene-X-R J . In one embodiment, the alkylene group or groups in R 2 is methylene.
  • Y represents furan, thiophene, isoxazole or benzofuran.
  • R J represents Z.
  • R J represents -C 1-3 alkylene-Z.
  • R J represents -C(O)Z.
  • X and Z independently represent an optionally substituted monocyclic 4-membered, saturated hydrocarbon group containing one nitrogen atom.
  • X and Z independently represent an optionally substituted monocyclic 5-membered, saturated or partially saturated hydrocarbon group containing one nitrogen atom.
  • X and Z independently represent an optionally substituted monocyclic 6-membered, saturated, partially saturated or aromatic hydrocarbon group containing one or two nitrogen atoms and optionally an oxygen atom.
  • X represents piperidine, piperazine or morpholine, each of which is optionally substituted.
  • X represents piperidine or piperazine, each of which is optionally substituted.
  • X represents piperidine which is optionally substituted. In one embodiment, X represents pyrrolidine or pyrroline, each of which is optionally substituted. In another embodiment, X respresents pyrrolidine which is optionally substituted. In one embodiment X is unsubstituted.
  • Z represents piperidine, piperazine or morpholine, each of which is optionally substituted.
  • Z represents piperidine or piperazine, each of which is optionally substituted.
  • Z represents piperazine which is optionally substituted.
  • Z represents pyrrolidine which is optionally substituted. In one embodiment Z is unsubstituted.
  • X is optionally substituted with a) one group selected from: C ⁇ alkyl, C 1-4 alkylOH, -C ⁇ alkylOC ⁇ alkylOH, OH, -C 1- 4 alkylC(O)OC 1-4 alkyl, -C(O)OC 1-4 alkyl, NR E R F , -C 1-4 alkylNR E R F , -NC(O)C 1-3 alkyl, -NC(O)OC 1-4 alkyl and -C(O)NR E R F and b) optionally an additional group which is C 1-4 alkyl.
  • X is optionally substituted with a) one group selected from: C 1-4 alkyl, C 1-4 alkylOH, -C ⁇ alkylOC ⁇ alkylOH, OH, -C 1-4 alkylC(O)OC 1-4 alkyl, -C(O)OC 1 . 4 alkyl, NR E R F , -NC(O)C 1-3 alkyl, -NC(O)OC ⁇ alkyl and -C(O)NR E R F and b) optionally an additional group which is C 1-4 alkyl.
  • the C ⁇ alkyl substituent group is selected from methyl and propyl.
  • the C 1-4 alkyl substituent group is methyl.
  • X is substituted with two methyl groups.
  • Z is optionally substituted with C 1-4 alkyl. In another embodiment, Z is optionally substituted with methyl.
  • R E and R F represent C 1-4 alkyl. In another embodiment, R E and R F independently represent methyl, ethyl or propyl. In a further embodiment, R E and R F represent methyl. In one embodiment of the invention, R E and R F represent In another embodiment, R E and R F represent propenyl.
  • R 1 represents C 1-8 alkyl, -C 1 ⁇ alkyleneNR E R F , -C ⁇ alkyleneNR ⁇ COJOC ⁇ alkyl, -C 1-8 alkyleneNR G C(O)Ci -6 alkyl or -d-salkylene-cycloalkyl;
  • R 3 represents hydrogen, C 1-3 alkyl, alkoxy, or -C(O)Oalkyl
  • R 4 represents hydrogen, halogen, alkoxy, -C ⁇ C-aryl, -NHCi -3 alkylene-aryl, NO 2 , CF 3 , or OCF 3 ;
  • R 3 and R 4 are not both hydrogen, and when R 3 is Ci -3 alkyl then R 4 is other than hydrogen;
  • A represents C(O) and i) R 2 represents R 2a or R 2b wherein
  • R 2a represents -NR H -aryl, -NR H -heteroaryl, -NR H -aryl-heteroaryl or -NR H -heteroaryl-aryl;
  • R 2b represents aryl, biaryl, -aryl-heteroaryl, -heteroaryl-aryl, -aryl-heterocyclyl, -aryl-C ⁇ alkylene-heterocyclyl, -aryl-O-Ci.
  • alkylene- heterocyclyl aryl-Ci-salkylene-heteroaryl, -aryl-heteraoaryl-C L salkylene- heterocyclyl, -heteroaryl-aryl-C L salkylene-heterocyclyl, aryloxy, heteroaryl, cycloalkyl, -cycloalkyl-aryl, cycloalkyloxy, heterocyclyl, -NR H -aryl-heterocyclyl,
  • R 5 represents hydrogen, C 1-6 alkyl, C ⁇ alkenyl, -C(O)R 2a , -C 1-8 alkylene- heterocyclyl, -C 1-8 alkyleneNR G C(O)C 1-6 alkyl, -C ⁇ alkyleneNR G C(O)OC ⁇ alkyl, -C 1-8 alkyleneNR E R F , N-phthalidimido-C 1-8 alkylene- or -C(O)C 1-6 alkyl;
  • R 2 and R 5 together with the carbon and nitrogen atoms to which they are respectively attached form a group selected from
  • A represents -SO 2 -
  • R 2 represents C 1-6 alkyl, aryl, C 1-6 aralkyl or -d-ealkyleneheterocyclyl;
  • R 5 represents hydrogen, C 1-6 alkyl, C ⁇ alkenyl, -d- ⁇ alkylene-heterocyclyl,
  • R A , R c and R D independently represent hydrogen, halogen, -NR E R F , cyano, CCI 3 , -C(O)C 1-6 alkyl, C 1-3 alkyl, cycloalkyl, heterocyclyl, aryl, biaryl, -aryl-heteroaryl, -aryl-C ! .
  • alkylene-heterocyclyl -aryl-O-Ci-salkylene-heterocyclyl, -C ⁇ salkenylaryl, heteroaryl, C 1-6 aralkyl, -NHC(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, -NHC(O)C 1-6 aralkyl or -NHC(O)OC ⁇ aralkyl;
  • R B represents hydrogen or C 1-8 alkyl
  • R E and R F independently represent hydrogen or C 1-3 alkyl; or R E represents cycloalkyl and R F represents hydrogen; or R E and R F together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring;
  • R G represents hydrogen or C 1-3 alkyl
  • R H represents hydrogen, C 1-6 alkyl, -C 1-6 alkyleneNR E R F , -C ⁇ alkyleneNHCCOJC ⁇ alkyl, or -C ⁇ alkyleneNHC(O)OC 1-4 alkyl;
  • R J represents aryl, heteroaryl, heterocyclyl, -C 1-3 alkylene(aryl) 2 , -C ⁇ alkylene-heteroaryl, -C 1-3 aralkyl, -Ci -3 alkylene-C(O)-heterocyclyl, -O-C(O)C 1-3 alkylene-aryl, or -0-C(O)Ci- 3 alkylene-aryl;
  • R ⁇ represents one or two aryl substituents
  • R 1 represents C 1- ⁇ alkyl, -C 1-8 alkyleneNR E R F , -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl, -C 1- ⁇ alkyleneNR G C(O)C 1-6 alkyl or -C ⁇ alkylene-cycloalkyl;
  • R 3 represents hydrogen, C 1-3 alkyl, alkoxy, or -C(O)Oalkyl
  • R 4 represents hydrogen, halogen, alkoxy, -C ⁇ C-aryl, -NHC L salkylene-aryl, NO 2 , CF 3 , or OCF 3 ;
  • R 3 and R 4 are not both hydrogen, and when R 3 is C 1-3 alkyl then R 4 is other than hydrogen;
  • A represents C(O)
  • R 2 represents R 2a or R 2b wherein
  • R 2a represents -NR H -aryl, -NR H -heteroaryl, -NR H -aryl-heteroaryl or
  • R 2b represents -C 1-6 alkyleneR A , aryl, biaryl, -aryl-heteroaryl, -heteroaryl-aryl,
  • alkylene-heterocyclyl -heteroaryl-aryl-C ⁇ alkylene-heterocyclyl, aryloxy, heteroaryl, cycloalkyl, -cycloalkyl-aryl, cycloalkyloxy, heterocyclyl, -NR H -aryl-heterocyclyl,
  • R 5 represents hydrogen, Ci -6 alkyl, C 1-6 alkenyl, -C(O)R 2a , -C ⁇ alkylene-heterocyclyl, - C 1-8 alkyleneNR G C(O)C 1-6 alkyl, -C 1-8 alkyleneNR G C(O)Od. 6 alkyl, -C ⁇ alkyleneNR E R F , N- phthalidimido-C 1-8 alkylene- or -C(O)d ⁇ alkyl;
  • R 2 and R 5 together with the carbon and nitrogen atoms to which they are respectively attached form a group selected from
  • A represents -SO 2 -
  • R 2 represents C 1-6 alkyl, aryl, C 1-6 aralkyl or -C ⁇ alkyleneheterocyclyl
  • R 5 represents hydrogen, C 1-6 alkyl, C ⁇ alkenyl, -d- ⁇ alkylene-heterocyclyl,
  • R A , R c and R D independently represent hydrogen, halogen, -NR E R F , cyano, CCI 3 , 3 alkylene-heterocyclyl, -aryl-O-C ⁇ alkylene-heterocyclyl, -C 1-3 alkenylaryl, heteroaryl, C 1-6 aralkyl, -NHC(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, -NHC(O)C 1-6 aralkyl or -NHC(O)OC 1-6 aralkyl;
  • R B represents hydrogen or C h alky!
  • R E and R F independently represent hydrogen or C 1-3 alkyl; or R E represents cycloalkyl and R F represents hydrogen; or R E and R F together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring;
  • R G represents hydrogen or C 1-3 alkyl
  • R H represents hydrogen, C ⁇ alkyl, -C 1-6 alkyleneNR E R F , -C ⁇ alkyleneNHCCOJC ⁇ alkyl, -C ⁇ alkyleneNHCCOJOC ⁇ alkyl, -C ⁇ alkyleneheterocyclyl, or -C ⁇ alkyleneheterocyclyl-R 1 ';
  • R J represents aryl, heteroaryl, heterocyclyl, -C 1 . 3 alkylene(aryl) 2 , -C L salkylene-heteroaryl, -C 1-3 aralkyl, -C 1-3 alkylene-C(O)-heterocyclyl, -O-C(O)Ci. 3 alkylene-aryl, -C(O)-O-C 1 . 3 alkylene-aryl or -C ⁇ alkylene-heterocyclyl
  • R ⁇ represents one or two aryl substituents
  • R 1 represents Ci. 8 alkyl, or in another embodiment, R 1 represents isobutyl (2-methylpropyl). In an alternative embodiment, R 1 represents -methylene-cyclopentyl or -methylenecyclohexyl. In another embodiment, R 1 represents -methylene-cyclopentyl.
  • R 3 represents hydrogen, C 1-3 alkyl or -C(O)Oalkyl; in another embodiment R 3 represents hydrogen.
  • R 4 represents halogen
  • A represents C(O) and R 2 represents R 2a or R 2b wherein R 2a represents -NR H -aryl; and R 2b represents -C 1-6 alkyleneR A , aryl, biaryl, -aryl-heteroaryl, - heteroaryl-aryl, -aryl-heterocyclyl, -aryl-Cvsalkylene-heterocyclyl, -aryl-O-C 1-3 alkylene- heterocyclyl, aryl-C 1-3 alkylene-heteroaryl, heteroaryl, -cycloalkyl-aryl, -NR B C 1-6 alkyleneR c , -OC ⁇ alkyleneR 0 , -aryl-C ⁇ alkylene-heterocyclyl-R 1 ', -aryl-C 1-3 alkylene-heteroaryl-
  • A represents C(O) and R 2 and R 5 together with the carbon and nitrogen atoms to which they are respectively attached form the group
  • R A , R c and R D independently represent hydrogen, aryl, -aryl- C 1-3 alkylene-heterocyclyl, -aryl-O-Ci-salkylene-heterocyclyl, or In respect of compounds of Formula IA, Formula IB and salts and solvates thereof: in one embodiment of the invention R B represents C 1-8 alkyl;
  • R E and R F independently represent hydrogen or C 1-3 alkyl; or R E and R F together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring;
  • R H represents hydrogen, C 1-6 alkyl, or -C 1-6 alkyleneNR E R F .
  • alkyl as a group or a part of a group refers to a linear or branched alkyl group containing the indicated number of carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl or hexyl, 3,3-dimethylbutyl and the like.
  • alkylene as a group or a part of a group refers to a linear or branched saturated hydrocarbon linker group containing the indicated number of carbon atoms. Examples of such groups include methylene, ethylene and the like. In one embodiment, alkylene is methylene.
  • alkenyl as a group or a part of a group refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and containing the indicated number of carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.
  • alkoxy as a group or a part of a group refers to an -O-alkyl group wherein alkyl is as herein defined. Examples of such groups include methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy, pentoxy, hexoxy and the like.
  • aralkyl as a group or a part of a group refers to an alkyl group as herein defined which contains the indicated number of carbon atoms, the alkyl group being substituted with an aryl group as herein defined.
  • aryl as a group or a part of a group refers to an optionally substituted hydrocarbon aromatic group containing one, two or three conjugated or fused rings with at least one ring having a conjugated pi-electron system.
  • groups include optionally substituted phenyl, naphthyl or tetrahydronaphthalenyl and the like.
  • aryl represents phenyl.
  • aryl represents naphthyl.
  • aryl moieties are unsubstituted.
  • aryl moieties are monosubstituted, disubstituted or trisubstituted.
  • aryl moieties are monosubstituted or disubstituted.
  • Optional aryl substituents include C 1- 4 alkyl, C 1-4 alkoxy, halogen, nitro, trihalomethyl, trihalomethoxy, -C(O)CH 3 , -N(C 1-3 alkyl) 2 and -SO 2 -Ci. 4 alkyl.
  • aryloxy as a group or a part of a group refers to an -O-aryl group wherein aryl is as herein defined.
  • biasing as a group or a part of a group refers to an aryl group which is directly substituted with a second aryl group, wherein aryl is as herein defined.
  • heteroaryl as a group or a part of a group refers to an optionally substituted aromatic group comprising one to four heteroatoms selected from N, O and S, the aromatic group containing one, two or three 5- or 6- membered conjugated or fused rings with at least one ring having a conjugated pi-electron system.
  • Examples of monocyclic heteroaryl groups include optionally substituted thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
  • fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, dibenzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzo[1 ,3]-dioxole and the like.
  • heteroaryl moieties are pyridyl, imidazolyl, oxazolyl, benzofuranyl, dibenzofuranyl, benzothiazolyl, indolyl or indazolyl.
  • heteroaryl moieties are pyridyl, imidazolyl, isoxazolyl, benzofuranyl, dibenzofuranyl, benzothiazolyl, indolyl or indazolyl.
  • optionally substituted heteroaryl moieties are benzofuranyl, pyridyl, dibenzofuranyl, imidazolyl and isoxazolyl.
  • heteroaryl moieties are unsubstituted. In another embodiment heteroaryl moieties are monosubstituted, disubstituted or trisubstituted. In a further embodiment heteroaryl moieties are monosubstituted or disubstituted.
  • Optional heteroaryl substituents include C 1-4 alkyl, C 1-4 alkoxy and halogen.
  • cycloalkyl as a group or a part of a group refers to a saturated cyclic hydrocarbon group of 3 to 7 carbon atoms. Examples of such groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • cycloalkyloxy as a group or a part of a group refers to an -O-cycloalkyl group wherein cycloalkyl is as herein defined.
  • heterocyclyl or “heterocyclic ring” as a group or a part of a group refer to i) an optionally substituted, monocyclic 3- to 7-membered, saturated or partially saturated hydrocarbon group containing one to four heteroatoms selected from N 1 O and S and also ii) to polycyclic groups, e.g. bicyclic and tricyclic groups, which are fused rings of optionally substituted, 3- to 7-membered, saturated or partially saturated hydrocarbon groups containing one to four heteroatoms selected from N, O and S.
  • Examples of monocyclic groups include include pyrrolidinyl, azetidinyl, imidazolidinyl, oxoimidazolidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl,
  • bicyclic groups include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5- tetrahydro-1 H-3-benzazepine, tetrahydroisoquinolinyl, hexahydropyrrolo[1 ,2-a]pyrazin- 2(1H)-yl and the like.
  • heterocyclyl is an optionally substituted 5- or 6- membered monocyclic group, or a 9-membered bicyclic group.
  • heterocyclyl is an optionally substituted 5- or 6- membered monocyclic group.
  • heterocyclyl moieties are optionally substituted pyrrolidnyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl. In a yet further embodiment heterocyclyl moieties are optionally substituted piperazinyl. In one embodiment heterocyclyl moieties are unsubstituted. In another embodiment heterocyclyl moieties are monosubstituted, disubstituted or trisubstituted or tetrasubstituted. In a further embodiment heterocyclyl moieties are monosubstituted.
  • Optional heterocyclyl substituents include C h alky!, -C(O)C 1-4 alkyl, -C(O)OC 1-4 alkyl, -NC(O)C 1-4 alkyl, -NC(O)OC ⁇ alkyl, -C(O)NR B C ⁇ alkyl, -C 1-6 alkyleneOH, -C 1-3 alkyleneC(O)OCi -3 alkyl, -Cvaalkylene-O-CvsalkyleneOH, -C 1 .
  • halogen refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) atom. In one embodiment halogen substituents are a fluorine or chlorine atom.
  • the term "pharmaceutically acceptable” used in relation to an ingredient (active ingredient such as an active ingredient, a salt thereof or an excipient) which may be included in a pharmaceutical formulation for administration to a patient refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.
  • N-phthalimido refers to a phthalimide group which is bonded through the nitrogen atom.
  • proteases are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis.
  • Proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases.
  • Protease “inhibitors” bind more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolysing natural substrates and thereby act as inhibitors.
  • At least one chemical entity selected from the list: N'-(5-bromo-2-cyano-4-pyrimidinyl)-4-[(4-methyl-1-piperazinyl)methyl]-N'-(2- methylpropyl)benzohydrazide;
  • N'-(2-methylpropyl)benzohydrazide N l -(5-chloro-2-cyano-4-pyrimidinyl)-4-( ⁇ 4-[3-(di-2-propen-1-ylamino)propyl]-1- piperazinyl ⁇ methyl)-N'-(2-methylpropyl)benzohydrazide;
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, solvate, or prodrug e.g. ester or carbamate of a compound of Formula I, IA or IB, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of Formula I, IA or IB, or an active metabolite or residue thereof.
  • pharmaceutically acceptable derivatives are salts, solvates, esters and carbamates.
  • pharmaceutically acceptable derivatives are salts, solvates and esters.
  • pharmaceutically acceptable derivatives are salts and solvates.
  • the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of the compounds according to Formula I, IA or IB, IA or IB may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form.
  • the invention is further directed to pharmaceutically acceptable salts of the compounds according to Formula I, IA or IB.
  • the term "pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects.
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula I, IA or IB with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, sulfamic, nitric, phosphoric, succinic, maleic, hydroxymaleic, acrylic, formic, acetic, hydroxyacetic, phenylacetic, butyric, isobutyric, propionic, fumaric, citric, tartaric, lactic, mandelic, benzoic, o-acetoxybenzoic, chlorobenzoic, methylbenzoic, dinitrobenzoic, hydroxybenzoic, methoxybenzoic salicylic, glutamaic, stearic, ascorbic, palmitic, oleic, pyruvic, pamoic, malonic, lauric, glutaric aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic,
  • 2-naphthalenesulfonic 2-naphthalenesulfonic
  • p- aminobenzenesulfonic i.e. sulfanilic
  • hexanoic heptanoic
  • phthalic acid optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, succinate, maleate, malate, formate, acetate, trifluoroacetate, saccharate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p- toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g.
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of Formula I, IA or IB with a suitable inorganic or organic base (e.g.
  • ammonia triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
  • a suitable solvent such as an organic solvent
  • Pharmaceutically acceptable base salts include ammonium salts and salts with organic bases, including salts of primary, secondary and tertiary amines, including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines, such as methylamine, ethylamine, isopropylamine, diethylamine, ethylenediamine, ethanolamine, trimethylamine, dicyclohexyl amine, diethanolamine, cyclohexylamine and N-methyl-D-glucamine.
  • organic bases including salts of primary, secondary and tertiary amines, including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines, such as methylamine, ethylamine, isopropylamine, diethylamine, ethylenediamine, ethanolamine, trimethylamine, dicyclohexyl amine, diethanolamine, cyclohexylamine
  • suitable pharmaceutically acceptable base salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as hydroxides, carbonates and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of Formula I, IA or IB.
  • pharmaceutically acceptable metal salts for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as hydroxides, carbonates and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc
  • pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of Formula I, IA or IB.
  • non-pharmaceutically acceptable salts for example oxalates may be used, for example in the isolation of compounds of the invention.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of Formula I, IA or IB.
  • the term "compounds of the invention” means the compounds according to Formula I, IA or IB and the pharmaceutically acceptable derivatives thereof.
  • the term “a compound of the invention” means any one of the compounds of the invention as defined above.
  • At least one chemical entity means at least one chemical substance chosen from the group of compounds consisting of compounds of Formula I, IA or IB and pharmaceutically acceptable derivatives thereof.
  • the compounds of the invention may exist as solids or liquids, both of which are included in the invention. In the solid state, the compounds of the invention may exist as either amorphous material or in crystalline form, or as a mixture thereof. It will be appreciated that solvates of the compounds of the invention may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallisation. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” The invention includes all such solvates.
  • At least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof for use in human or veterinary medical therapy.
  • the compounds of the invention are cysteine protease inhibitors, such as inhibitors of cysteine proteases of the papain superfamily, for example of the falcipain family, including falcipain-2 or falcipain-3.
  • the compounds of the invention are also inhibitors of cysteine proteases of the papain superfamily, for example those of the cathepsin family such as cathepsins K, L, S and B.
  • the compounds of the invention may be useful for treating conditions in which cysteine proteases are implicated, including infections by Plasmodium falciparum which is the most virulent malaria-causing parasite, and by Plasmodium vivax, Pneumocystis carinii, Trypsanoma cruzi, Trypsanoma brucei, and Crithidia fusiculata; as well as in treating conditions such as schistosomiasis, malaria, cancer, for example pancreatic cancer, tumour invasion and tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, chronic obstructive pulmonary disorder (COPD), atherosclerosis; and especially conditions in which cathepsin K is implicated, including diseases of excessive bone or cartilage loss and other bone and joint diseases such as osteoporosis, bone metastasis, gingival disease (including gingivitis and periodontitis), arthritis (including osteoarthritis and rheumatoid arthritis),
  • metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of the invention. Accordingly, the invention is directed to methods of treating such conditions.
  • At least one chemical entity selected from a compound of Formula I 1 IA or IB or a pharmaceutically acceptable derivative thereof, for use in the treatment of a condition mediated by inhibition of a cysteine protease, particularly inhibition of a cysteine protease of the papain superfamily such as those of the falcipain family, including falcipain-2 or falcipain-3, for example malaria.
  • At least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition mediated by inhibition of a cysteine protease, particularly inhibition of a cysteine protease of the papain superfamily, such as those of the cathepsin family for example cathepsins K, L, S and B, i) in one embodiment cathepsin K, for example conditions characterised by excessive bone loss such as osteoporosis and bone metastasis, and other bone and joint diseases such as osteoarthritis, or ii) in another embodiment cathepsin L or S, for example pancreatic cancer.
  • a cysteine protease particularly inhibition of a cysteine protease of the papain superfamily, such as those of the cathepsin family for example cathepsins K, L, S and B
  • cathepsin K for example conditions characterised by excessive bone loss such as osteoporosis and bone metasta
  • a chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of a condition mediated by inhibition of a cysteine protease, particularly inhibition of a cysteine protease of the papain superfamily such as those of the falcipain family, including falcipain-2 or falcipain-3, for example malaria.
  • a cysteine protease particularly inhibition of a cysteine protease of the papain superfamily, such as those of the cathepsin family, for example cathepsins K 1 L, S and B, i) in one embodiment cathepsin K, for example conditions characterised by excessive bone loss such as osteoporosis and bone metastasis, and other bone and joint diseases such as osteoarthritis, or ii) in another embodiment cathepsin L or S, for example pancreatic cancer.
  • a cysteine protease particularly inhibition of a cysteine protease of the papain superfamily, such as those of the cathepsin family, for example cathepsins K 1 L, S and B, i) in one embodiment cathepsin K, for example conditions characterised by excessive bone loss such as osteoporosis and bone metastasis, and other bone and joint diseases such as osteoarthritis, or ii) in another embodiment cathepsin L or S, for
  • a method for the treatment of a human or animal subject suffering from a condition mediated by inhibition of a cysteine protease, particularly inhibition of a cysteine protease of the papain superfamily such as those of the falcipain family, including falcipain-2 or falcipain-3, for example malaria which method comprises administering an effective amount of at least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof or a pharmaceutical composition comprising at least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof.
  • a cysteine protease particularly inhibition of a cysteine protease of the papain superfamily, such
  • the compounds of the invention are cysteine protease inhibitors and can be useful in the treatment of a condition mediated by inhibition of a cysteine protease, particularly inhibition of a cysteine protease of the papain superfamily such as those of the falcipain family, including falcipain-2 or falcipain-3, for example in the treatment of malaria, or those of the cathepsin family for example cathepsins K, L, S and B, i) in one embodiment cathepsin K, for example conditions characterised by excessive bone loss such as osteoporosis and bone metastasis, and other bone and joint diseases such as osteoarthritis, or ii) in another embodiment cathepsin L or S, for example pancreatic cancer. Accordingly, the invention is further directed to pharmaceutical compositions comprising at least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof.
  • excessive bone loss is a disease state in which the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
  • Diseases which are characterised by excessive bone loss include, but are not limited to, osteoporosis and gingival diseases, excessive cartilage or matrix degradation including osteoarthritis and rheumatoid arthritis.
  • the methods of treatment of the invention comprise administering a safe and effective amount of at least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof, or a pharmaceutical composition containing at least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof, to a patient in need thereof.
  • treatment means: (1) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount means an amount of the compound sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound of the invention will vary with the particular compound chosen (e.g. depending on the potency, efficacy, and half- life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, optic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the 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 desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from about 0.01 to about 25 mg/kg, in one embodiment from about 0.1 to about 14 mg/kg. Typical daily dosages for parenteral administration range from about 0.001 to about 10 mg/kg; in one embodiment from about 0.01 to about 6 mg/kg.
  • the compounds of Formula I 1 IA or IB may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
  • each compound may differ from that when the compound is used alone.
  • Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • the compounds of the present invention may be used alone or in combination with one or more additional active agents, such as other inhibitors of cysteine and serine proteases, antimalarial drugs or drugs to treat excessive bone loss.
  • additional active agents such as other inhibitors of cysteine and serine proteases, antimalarial drugs or drugs to treat excessive bone loss.
  • Such other active agents include inhibitors of bone resorption or other bone diseases, for example bisphosphonates (i.e., alendronate, risedronate, etidronate, and ibandronate), hormone replacement therapy, anti-estrogens, calcitonin, and anabolic agents such as bone morphogenic protein, iproflavone, and PTH.
  • bisphosphonates i.e., alendronate, risedronate, etidronate, and ibandronate
  • hormone replacement therapy i.e., alendronate, risedronate, etidronate, and ibandronate
  • anti-estrogens calcitonin
  • anabolic agents such as bone morphogenic protein, iproflavone, and PTH.
  • antimalarial drugs such as folates (e.g.
  • such other active agents include anti-cancer agents.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • administration either the compound of the present invention or the second therapeutic agent may be administered first.
  • administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
  • they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient.
  • the invention is directed to pharmaceutical compositions comprising a compound of the invention.
  • the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier and/or excipient.
  • the carrier and/or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the receipient thereof.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from about 0.5 mg to about 1750 mg, e.g. from about 5 mg to about 1000 mg for oral dosage forms and from about 0.05 mg to about 700 mg, e.g. from about 0.5 mg to about 500 mg for parenteral dosage forms.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically acceptable excipient. As used herein, the term "pharmaceutically acceptable" means suitable for pharmaceutical use.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid or liquid oral dosage form such as a liquid, tablet, lozenge or a capsule, comprising a safe and effective amount of a compound of the invention and a carrier.
  • the carrier may be in the form of a diluent or filler.
  • Suitable diluents and fillers in general include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • a liquid dosage form will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • any routine encapsulation is suitable, for example using the aforementioned carriers or a semi solid e.g.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums or oils, and may be incorporated in a soft capsule shell.
  • An oral solid dosage form may further comprise an excipient in the form of a binder.
  • Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose).
  • the oral solid dosage form may further comprise an excipient in the form of a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise an excipient in the form of a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • a process of preparing a pharmaceutical composition comprises mixing at least one compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable carrier and/or excipient.
  • Preparations for oral administration may be suitably formulated to give controlled/extended release of the active compound.
  • KQKLR-AMC N-Acetyl-Lysyl-Glutaminyl-Lysyl-Leucyl-Arginyl-Z-Amido- ⁇ methylcoumarin
  • the semicarbazide compounds of Formula Ia which are compounds of Formula IA wherein, R 3 and R 4 are as defined above for Formula IA, R 1 is C ⁇ alkyl, -C 1-8 alkyleneN(Ci. 3 alkyl) 2 , -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl or -C 1-8 alkyleneNR G C(O)C 1-6 alkyl, A is C(O), R 5 is hydrogen, d-ealkyl, C 1-6 alkenyl, -C 1-8 alkyleneN(C 1-3 alkyl)2,
  • R 2 is -NR H -aryl- heterocyclyl, -NR H -cycloalkyl, -NH-N(C 1-3 alkyl)-heteroaryl, -NR H -aryl, -NR H -heteroaryl, -NR H -aryl-heteroaryl or -NR H -heteroaryl-aryl; in which R H is as defined above for Formula IA, may be prepared from the corresponding hydrazine compounds of Formula II, wherein R 3 and R 4 are as defined above for Formula IA, R 1 is C 1-8 alkyl, -Ci- 8 alkyleneN(C 1-3 alkyl) 2 , -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl or and R 5 is hydrogen, C 1-6 alkyl, C
  • Procedure A Compounds of Formula Na, which are compounds of Formula II, wherein R 5 is hydrogen, are reacted with one equivalent of the isocyanate, R ⁇ NCO, wherein R 2x N is as defined above for R 2 in Formula Ia, in the presence of a suitable base such as triethylamine in a suitable solvent such as DCM to give compounds of Formula Ia wherein R 5 is hydrogen and R H is hydrogen.
  • Procedure B A primary amine R 10 -NH 2 , or a secondary amine R 10 -NH-R H , wherein and R H is as defined as above for Formula Ia, and R 10 is aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, aryl-heterocyclyl, N(Ci -3 alkyl)-heteroaryl, cycloalkyl or -C 1-6 alkyleneR c , wherein R c is hydrogen, C 1-3 alkyl, aryl or halogen is dissolved in a suitable solvent such as dry THF and cooled to a suitable temperature, e.g.
  • acylhydrazide compounds of Formula Ib which are compounds of Formula IA wherein R 1 , R 3 , R 4 are as hereinbefore defined for Formula IA (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, R 3 represents hydrogen and R 4 represents halogen), A is C(O), R 5 is hydrogen, C 1-6 alkyl, -Ci- ⁇ alkylene-heterocyclyl, -C 1-8 alkyleneN(C 1 .
  • R 5 is hydrogen
  • R 2 is aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-heterocyclyl, biaryl, aryl-heteroaryl, -heteroaryl-aryl, -aryl-C 1-3 alkylene-heterocyclyl, 3 alkylene-heterocyclyl or C 1-6 alkyleneR A , wherein R A is hydrogen, Ci -3 alkyl, halogen, - N(Ci -3 alkyl) 2 , aryl, biaryl, cycloalkyl, -aryl-C 1-3 alkylene-heterocyclyl or -aryl-O-C 1-3 alkylene- heterocyclyl; (for example, R 2 is
  • R 3 represents hydrogen and R 4 represents halogen
  • R 5 is hydrogen, C 1-8 alkyl, -C ⁇ alkylene-heterocyclyl, -C 1 . 8 alkyleneN(C 1- 3 alkyl) 2 , -C ⁇ alkyleneNR ⁇ COOC ⁇ alkyl or -C 1-8 alkyleneNR G C(O)C 1-6 alkyl; (for example, R 5 is hydrogen); according to Scheme 3.
  • Compounds of Formula Il are reacted with an acid chloride R 2 COHaI, wherein R 2 is as defined above for Formula Ib 1 and Hal is Cl or Br, in a suitable solvent such as pyridine to give compounds of Formula Ib.
  • acylhydrazide compounds of Formula Ibi which are compounds of Formula Ib (and therefore of Formula IA) wherein R 1 , R 3 , R 4 are as hereinbefore defined for Formula IA, (for example, R 1 represents C 1-8 alkyl, e.g.
  • R 3 represents hydrogen and R 4 represents halogen
  • A is C(O)
  • R 5 is hydrogen, C 1-6 alkyl, -C 1-8 alkyleneN(C 1-3 alkyl) 2 , - C 1-8 alkyleneNR G C(O)OCi -6 alkyl, or -C 1-8 alkyleneNR G C(O)Ci- 6 alkyl, (for example, R 5 is hydrogen); and
  • R 2 is -aryl-C ⁇ alkylene-heterocyclyl, -aryl-C L salkylene-heterocyclyl-R 1 ', -heteroaryl-aryl-C ⁇ alkylene-heterocyclyl, (for example, R 2 is -phenyl-C 1-3 alkylene-X, - pyridyl-phenyl-Ci -3 alkylene-X or -phenyl-d-salkylene-X-R 1 ', wherein phenyl is optionally substituted
  • R 3 represents hydrogen and R 4 represents halogen
  • R 5 is hydrogen, C 1-8 alkyl, -C 1 . 8 alkyleneN(C 1-3 alkyl)2, -Ci -8 alkyleneNR G C(O)OC 1-6 alkyl or (for example, R 5 is hydrogen)
  • R x is -arylhaloC 1-3 alkylene or -heteroaryl- arylhaloCi -3 alkylene, by reaction with compounds of Formula XIII, which compounds are heterocyclyl or heterocyclyl-R J , for example compounds XIII are 11 X" or "X-R J ", wherein "X" and “R J " are as defined hereinabove for Formula I, in the presence of a base, for example an inorganic base such as potassium carbonate, or an organic base such as an amine, e.g. DIPEA, and optionally in the presence of iodide, for example by addition of NaI, according to Scheme 4.
  • a base for
  • Compounds of Formula XII may be prepared using an analogous procedure to that described for Scheme 3, by a reaction between compounds of Formula Il and R x CHal, wherein R x is R x is -arylhaloC 1-3 alkylene or -heteroaryl-arylhaloC 1-3 alkylene, and Hal is Cl or Br, in the presence of a base, for example an inorganic base such as potassium carbonate, or an organic base such as an amine, e.g. DIPEA.
  • a base for example an inorganic base such as potassium carbonate, or an organic base such as an amine, e.g. DIPEA.
  • Compounds of Formula IA may be prepared from compounds of Formula III, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above for Formula IA, according to Scheme 5 by cyanation, by displacement of the chloro substituent of compounds of Formula III using a variety of conditions, for example by treatment with potassium or sodium cyanide in the presence of a suitable base such as DABCO in a suitable solvent such as DMSO.
  • alkoxycarbonyl hydrazine compounds of Formula Ic which are compounds of Formula IA wherein R 1 , R 3 and R 4 are as defined above for Formula IA, A is C(O), and R 5 is hydrogen, C 1-6 alkyl, d-ealkenyl, -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl or -C 1-8 alkyleneNR G C(O)C ⁇ alkyl and R 2 is OR 11 in which R 11 is C 1-6 alkenyl, or -C 1-6 alkyleneR D , wherein R D is hydrogen, C 1-3 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclyl, CCI 3 , cyano, -NHC(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, or -C(O)C 1-6 alkyl, may be prepared from the corresponding hydrazine compounds of Formula II, wherein R
  • Chloroformates R 11 OCOCI are either commercially available, or they may be obtained by reaction between the corresponding commercially available alcohol R 11 OH, wherein R 11 is as defined above for Formula Ic, and triphosgene in a suitable solvent such as THF, which may be directly reacted with compounds of Formula Il in the presence of a suitable base such as triethylamine in a suitable solvent, for example pyridine, to give compounds of Formula Ic.
  • Compounds of Formula Na which are compounds of Formula Il wherein R 5 is hydrogen, may be prepared from compounds of Formula IV, wherein R 1 , R 3 and R 4 are as defined above for Formula Il (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, R 3 represents hydrogen and R 4 represents halogen), according to Scheme 7 by deprotection in the presence of a suitable acid such as trifluoroacetic acid.
  • Compounds of Formula IV may be prepared from compounds of Formula V, wherein R 1 , R 3 and R 4 are as defined above for Formula IV (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, e.g. cycloalkylmethyl, R 3 represents hydrogen and R 4 represents halogen), according to Scheme 8 by cyanation, by displacement of the chloro substituent of compounds of Formula V using a variety of conditions, for example by treatment with potassium or sodium cyanide in the presence of a suitable base such as DABCO in a suitable solvent such as DMSO.
  • R 1 , R 3 and R 4 are as defined above for Formula IV (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, e.g. cycloalkylmethyl, R 3 represents hydrogen and R 4 represents halogen)
  • Scheme 8 by cyanation, by displacement of the chloro substituent of compounds of Formula V using a variety of conditions, for example by treatment with potassium or sodium cyan
  • Compounds of Formula V may be prepared from compounds of Formula Vl, wherein R 1 is as defined above for Formula V (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, e.g. cycloalkylmethyl), according to Scheme 9 by reaction of compounds of Formula Vl with a compound of Formula VII 1 wherein R 3 and R 4 are as described for Formula V, (for example, R 3 represents hydrogen and R 4 represents halogen), (commercially available from FLUKA or SIGMA) in a suitable solvent such as EtOH, for example at room temperature for 3-4 days, for example according to the literature procedure given in Bagley J. R. et al., (1989) J. Med. Chem. 32, 663-671.
  • R 1 is as defined above for Formula V
  • R 1 represents C 1-8 alkyl, e.g. isobutyl, e.g. cycloalkylmethyl
  • Scheme 9 by reaction of compounds of Formula Vl with a compound of Formula VII 1 wherein
  • Compounds of Formula Vl may be prepared from the compound of Formula VIII by a reductive amination reaction with an aldehyde IX, wherein R 13 is one carbon shorter in chain length than R 1 , wherein R 1 is C 1-8 alkyl, -C 1-8 alkyleneNR E R F , -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl, -C 1 . 8 alkyleneNR G C(O)C 1-6 alkyl or -C ⁇ alkylene- cycloalkyl, (for example, R 1 represents C ⁇ alkyl, e.g. isobutyl), according to Scheme 10.
  • the compound of Formula VIII, terf-butyl carbazate is commercially available (ALDRICH).
  • Reductive amination of the compound of Formula VIII with aldehydes of Formula IX is carried out in the presence of a suitable reducing agent such as hydrogen, and a suitable catalyst such as platinum or palladium or platinum oxide, in a suitable solvent such as i- PrOH, EtOH or a mixture thereof, for example according to the literature procedures given in Hilpert, H. (2001 ) Tetrahedron, 57, 7675-7683 or Dyker, H. et al, (2001) J. Org. Chem. 66, 3760-3766).
  • a suitable reducing agent such as hydrogen
  • a suitable catalyst such as platinum or palladium or platinum oxide
  • Aldehydes of Formula IX are either commercially available, e.g. isobutylaldehyde, or they may be prepared according to Scheme 11 i) from the corresponding commercially available dimethyl or diethyl acetal compound of Formula X wherein R 13 is as defined above for compounds of Formula IX, by acid hydrolysis using a suitable acid such as hydrochloric acid, or ii) by oxidation of the commercially available alcohol compound of Formula Xl, wherein R 13 is as defined above for compounds of Formula IX, following standard procedures as the Swern oxidation or Dess-Martin oxidation.
  • Compounds of Formula Ib(iii), which are compounds of Formula IA which are compounds of Formula IA wherein R 2 , R 3 , R 4 and R 5 are as defined above for Formula IA, R 1 is Ci. 8 alkyleneNH 2 , and A is C(O), may be prepared from a compound of Formula Ib wherein R 2 , R 3 , R 4 and R 5 are as defined for Formula Ib(iii), and R 1 is -C ⁇ alkyleneNCCOJOCv 6 alkyl, by a deprotection reaction in the presence of a suitable acid such as trifluoroacetic acid, in a suitable solvent such as dichloromethane, or alternatively hydrobromic acid in a suitable solvent such as acetic acid according to Scheme 12.
  • a suitable acid such as trifluoroacetic acid
  • a suitable solvent such as dichloromethane
  • hydrobromic acid in a suitable solvent such as acetic acid according to Scheme 12.
  • Compounds of Formula Ib(iv) which are compounds of Formula IA wherein R 2 , R 3 , R 4 and R 5 are as defined for Formula Ib(iii), R 1 is -C ⁇ alkyleneNCCOJC ⁇ alkyl, and A is C(O), may be prepared from compounds of Formula Ib(iii) as defined above, according to Scheme 13, by treatment of lb(i) with an anhydride of Formula O[C(O)Ci -6 alkyl] 2 in a suitable solvent such as dichloromethane, at a suitable temperature, e.g. -10 0 C to 1O 0 C.
  • R G is as defined for Formula IA, or N-phthalidimido-CI- ⁇ alkylene-
  • R 2 is OR 11 in which R 11 is C 1-6 alkenyl or -C ⁇ alkyleneR 0 , wherein R D is hydrogen, C 1-3 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclyl, CCI 3 , cyano, -NHCCOJC L ⁇ alkyl, -NHC(O)OCi. 6 alkyl, or -C(O)Ci.
  • 6 alkyl may be prepared from compounds of Formula IHa wherein R 3 and R 4 are as defined above for Formula IA, R 1 is C ⁇ alkyl, and R 5 is hydrogen and R 2 is OR 11 in which R 11 is as defined for lc(i), according to Scheme 14 by treatment of Ilia with an alkylating agent of Formula R 5 -CI, R 5 -Br or R 5 OSO 2 Y, wherein R 5 is as defined for Formula lc(i) and Y is methyl or p-tolyl, in the presence of a suitable catalyst such as tetrabutylammonium hydrogensulfate and optionally sodium iodide in the presence of a base such as a mixture of potassium carbonate and sodium hydroxide, in a suitable solvent such as toluene, optionally at elevated temperature, e.g. 90-170 0 C.
  • a suitable catalyst such as tetrabutylammonium hydrogensulfate and optionally sodium iodide
  • Compounds of Formula Id which are compounds of Formula IA wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above for Formula IA, A is -SO 2 -, may be prepared from compounds of Formula Il wherein R 1 , R 3 , R 4 and R 5 are as defined above for Formula IA according to Scheme 15, by treatment of compounds Il with a sulfonyl chloride R 2 SO 2 CI, wherein R 2 is as defined above for Formula I; in a suitable solvent such as pyridine.
  • Sulfonyl chlorides R 2 SO 2 CI may be commercially available or they may be prepared from the corresponding sulfonic acids R 2 SO 2 OH by treatment of the sulfonic acids with thionyl chloride in a suitable solvent such as toluene at elevated temperatures such as 90-170 0 C.
  • R 3 and R 4 groups in compounds of Formula IA may be converted into other R 3 and R 4 groups in order to provide further compounds of Formula IA.
  • R 4 when R 4 is bromo, it may be converted to R 4 is -C ⁇ C-aryl by reaction with H-C ⁇ C-aryl in the presence of copper (I) iodide and bis(triphenylphosphine)palladium(ll) chloride.
  • R 4 when R 4 is bromo, it may be converted to R 4 is NHCi -3 alkylene-aryl by reaction with a suitable amine H-NHCi -3 alkylene-aryl in the presence of palladium acetate and a suitable base, for example a mixture of BINAP and potassium carbonate.
  • a suitable base for example a mixture of BINAP and potassium carbonate.
  • R 4 when R 4 is bromo, it may be converted to R 4 is CF 3 by reaction with 2,2-difluoro-2-(fluorosulfonyl)acetate, hexamethylphosphoramide and copper (I) iodide, optionally heating at a suitable temperature, for example 80 0 C.
  • conversions may be carried out on compounds of Formula III, for example when R 3 is chloro, it may be converted to R 3 is methoxy by reaction with sodium methoxide in a suitable solvent, for example methanol.
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis” by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups” by PJ. Kocienski (Georg Thieme Verlag 1994).
  • suitable amino protecting groups include acyl type protecting groups (e.g.
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
  • aliphatic urethane protecting groups e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl or aralkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).
  • oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or terf-butyl; or esters such as acetate.
  • alky silyl groups such as trimethylsilyl or tert-butyldimethylsilyl
  • alkyl ethers such as tetrahydropyranyl or terf-butyl
  • esters such as acetate.
  • a solution of N-methylpiperazine (ALDRICH 1 1.46 ml, 13.1 mmol) in dimethylformamide (5 ml) was cooled to 0° C and, then, potassium carbonate (1.81 g, 13.1 mmol) was added. This mixture was stirred at 0° C for 30 min. Then, methyl 4-(bromomethyl) benzoate (ALDRICH, 3 g, 13.1 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 17 h. The mixture was concentrated under reduce pressure. The residue was dissolved in DCM and washed with water, the aqueous layer was extracted with DCM.
  • a solution of 1 ,1-dimethylethyl hydrazinecarboxylate (ALDRICH, 9.2 g, 70 mmol) in i-PrOH (50 ml) was treated at O 0 C with /-butylaldehyde (ALDRICH; 6.4 ml, 70 mmol) over 15 min and stirring at O 0 C for 2 h, then the mixture was stirred 5 h at room temperature.
  • PtO 2 PtO 2 and the suspension was hydrogenated at room temperature and 2.6 bar for 48 h. The suspension was filtered and the solvent was removed under reduced pressure to give the title compound.
  • ADRICH 4-fluoro-3-methylbenzoic acid
  • carbon tetrachloride 25 mL
  • N-bromosuccinimide ADRICH, 2.54 g, 14.27 mmol
  • benzoyl peroxide ADRICH, 11 1 mg
  • the reaction mixture was refluxed for two hours and stirred at room temperature overnight.
  • the mixture was filtered and the solvent was evaporated under reduced pressure.
  • the residue obtained was purified by preparative HPLC (LUNA 50x250 mm, ACN:H 2 O, 0.1%TFA, gradient 30- 80%) to give the title compound.
  • AVOCADO Ethyl 5-methylisoxazole-3-carboxylate
  • CCI 4 60 mL
  • N-bromosuccinimide ALDRICH, 1.717 g, 9.67 mmol
  • ADRICH benzoyl peroxide
  • the reaction mixture was filtered, evaporated and the residue was purified by preparative-HPLC (LUNA column 50x250 mm, gradient: 30%ACN; 0.1%TFA to 80%ACN, 0.1%TFA) to obtain the title compound.
  • 6-chloronicotinic acid (ALDRICH, 300 mg, 1.90 mmol) was dissolved in 1 ,2- dimethoxyethane (15 mL) under nitrogen. Palladium tetrakistriphenylphosphine (ALDRICH, 440 mg, 0.38 mmol) was added, the resulting reaction mixture was stirred for 15 min. Sodium carbonate (161 mg, 1.52 mmol), water (4 mL) and 3- (Hydroxymethyl)benzeneboronic acid (LANCASTER, 404 mg, 2.66 mmol) were added subsequently. The resulting reaction mixture was refluxed at 95 0 C for 16 h and then cooled to r.t.
  • 6-chloronicotinic acid (ALDRICH, 500 mg, 2.5 mmol) was dissolved in 1 ,2- dimethoxyethane (20 mL) under nitrogen. Palladium tetrakistriphenylphosphine (ALDRICH, 733 mg, 0.64 mmol) was added, the resulting reaction mixture was stirred for 15 min. Sodium carbonate (2.7 g, 25.4 mmol), water (20 mL) and 4-(hydroxymethyl) benzene boronic acid (LANCASTER, 674 mg, 4.44 mmol) were added subsequently. The resulting reaction mixture was refluxed at 95 0 C for 16 h and then cooled to r.t. After filtration over celite, the reaction mixture was acidified and was concentrated under reduced pressure. The crude was used in next step without purification. Synthesis (2003), 551-554
  • Examples 2-5 were prepared by methods analogous to that described for Example 1 replacing Intermediate 6 and 4-[(4-methyl-1-piperazinyl) methyljbenzoyl chloride with the intermediates and acid/acid chlorides indicated in Table 1.
  • Example 6 yV-(5-bromo-2-cyano-4-pyrimidinyl)-4-fluoro-W-(2-methylpropyl)-3-[(4- propyl-1 -piperazinyl)methyl]benzohydrazide trifluoroacetate.
  • Example 8 4-(1,4 l -bipiperidin-1 l -ylmethyl)-/V-(5-chloro-2-cyano-4-pyrimidinyl) - ⁇ f-(2- methylpropyl)benzohydrazide trifluoroacetate.
  • Example 38 ⁇ T-tS-chloro-Z-cyano-A-pyrimidinyO ⁇ -KA-hydroxy-i-piperidinyl) methyl]- ⁇ f-(2-methylpropyl i)/boeennzzoohnyydarraazziiduee t udiifiliuuo ⁇ rrouadcueetiacute.
  • Example 39 ⁇ / l -(5-chloro-2-cyano-4-pyrimidinyl)-4- ⁇ [4-(2-hydroxyethyl)-1 - piperidinyl]methyl ⁇ -/ ⁇ r-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 40 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-4- ⁇ [4-(2-hydroxyethyl)-1 - piperazinyllmethy ⁇ - ⁇ T ⁇ -methylpropyObenzohydrazide trifluoroacetate.
  • Example 41 /V-(5-chloro-2-cyano-4-pyrimidinyl)-4- ⁇ [4-(hydroxymethyl)-1- piperidinyl]methyl ⁇ -W-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 42 1 -[(4- ⁇ [2-(5-chloro-2-cyano-4-pyrimidinyl)-2-(2-methylpropyl) hydrazino]carbonyl ⁇ phenyl)methyl]- ⁇ /, ⁇ /-dimethyl-L-prolinamide trifluoroacetate.
  • Example 43 4-(1 -azetidinylmethyl)-/V-(5-bromo-2-cyano-4-pyrimidinyl)-/ ⁇ / 1 -(2- methylpropyl)benzohydrazide trifluoroacetate.
  • Example 44 /V-(5-chloro-2-cyano-4-pyrimidinyl)-AT-(2-methylpropyl)-4- ⁇ [(2S)-2-(1 - pyrrolidinylcarbonyl)-1-pyrrolidinyl]methyl ⁇ benzohydrazide trifluoroacetate.
  • Example 45 N'-(5-chloro-2-cyano-4-pyrimidinyl)-N I -(2-methylpropyl)-4- ⁇ [4-(4- morpholinyl)-1 -piperidinyl]methyl ⁇ benzohydrazide trifluoroacetate.
  • Example 46 AT-(5-chloro-2-cyano-4-pyrimidinyl)-A/ l -(2-methylpropyl)-4-( ⁇ 4-[2-(1 - piperidinyl)ethyl]-1-piperazinyl ⁇ methyl)benzohydrazide trifluoroacetate.
  • Example 47 /V-(5-chloro-2-cyano-4-pyrimidinyl)-4-( ⁇ 4-[(1 -methyl-3- piperidinyl)methyl]-1-piperazinyl ⁇ methyl)-A/"-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 48 W-(5-chloro-2-cyano-4-pyrimidinyl)-W-(2-methylpropyl)-4-( ⁇ 4-[3-(1- piperidinyl)propyl]-1-piperazinyl ⁇ methyl)benzohydrazide trifluoroacetate.
  • Example 50 W-(5-chloro-2-cyano-4-pyrimidinyl)-4- ⁇ [4-(4-methyl-1 -piperazinyl)-1 - piperidinyl]methyl ⁇ -/V-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 51 N'-(5-chloro-2-cyano-4-pyrimidinyl)-N'-(2-methylpropyl)-4- ⁇ [4-(4- pyridinyl)-1-piperazinyl]methyl ⁇ benzohydrazide trifluoroacetate.
  • Example 52 ⁇ r-(5-chloro-2-cyano-4-pyrimidinyl)- ⁇ T-(2-methylpropyl)-4-( ⁇ 4-[2-(1 - pyrrolidinyl)ethyl]-1-piperazinyl ⁇ methyl)benzohydrazide trifluoroacetate.
  • Example 53 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-4-( ⁇ 4-[2-(dimethylamino) ethyl]-1- piperazinyl ⁇ methyl)- ⁇ / 1 -(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 54 ⁇ r-fS ⁇ hloro ⁇ -cyano ⁇ -pyrimidinyO- ⁇ f- ⁇ -methylpropyO-S-O- pyrrolidinylmethyl)benzohydrazide trifluoroacetate.
  • Example 55 /ST-(5-chloro-2-cyano-4-pyrimidinyl)-W-(2-methylpropyl)-3- ⁇ [4-(4- morpholinyl)-1-piperidinyl]methyl ⁇ benzohydrazide trifluoroacetate.
  • Example 56 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-3- ⁇ [4-(2-hydroxyethyl)-1 - piperazinyl]methyl ⁇ - ⁇ f-(2-methylpropyi)benzohydrazide trifluoroacetate.
  • Example 57 /V-(5-chloro-2-cyano-4-pyrimidinyl)-3- ⁇ [4-(hydroxymethyl)-1 - piperidinyl]methyl ⁇ - ⁇ f-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 58 ⁇ f-fS-chloro ⁇ -cyano ⁇ yrimidinyO- ⁇ r- ⁇ -methylpropyO-S- ⁇ - ⁇ -fi- piperidinyl)propyl]-1-piperazinyl ⁇ methyl)benzohydrazide trifluoroacetate.
  • Example 59 /V-(5-chloro-2-cyano-4-pyrimidinyl)-3- ⁇ [4-(4-methyl-1 -piperazinyl)-1 - piperidinyl]methyl ⁇ -W-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 60 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-3- ⁇ [4-(diethylamino)-1 - piperidinyl]methyl ⁇ -/V-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 61 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-3-( ⁇ 4-[2-(diethylamino)ethyl]-1- piperazinyl ⁇ methyl)- ⁇ T-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 62 ⁇ / * -(5-chloro-2-cyano-4-pyrimidinyl)-3- ⁇ [4-(1 -methyl-4-piperidinyl)-1 - piperazinyl]methyl ⁇ -AT-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 63 /V-(5-chloro-2-cyano-4-pyrimidinyl)-AT-(2-methylpropyl)-3-( ⁇ 4-[3-(4- morpholinyl)propyl]-1-piperazinyl ⁇ methyl)benzohydrazide trifluoroacetate.
  • Example 64 ⁇ /'-(5-chloro-2-cyano-4-pyrimidinyl)- ⁇ /'-(2-methylpropyl)-3-( ⁇ 4-[2-(1 - pyrrolidinyl)ethyl]-1-piperazinyl ⁇ methyl)benzohydrazide trifluoroacetate.
  • Example 65 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-3-( ⁇ 4-[(1 -methyl-4- piperidinyl)methyl]-1-piperazinyl ⁇ methyl)- ⁇ T-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 66 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-/V-(2-methylpropyl)-3-( ⁇ 4-[2-(1 - piperidinyl)ethyl]-1-piperazinyl ⁇ methyl)benzohydrazide trifluoroacetate.
  • Example 67 ⁇ / t -(5-chloro-2-cyano-4-pyrimidinyl)-4-fluoro- ⁇ T-(2-methylpropyl)-3- ⁇ [4- (4-morpholinyl)-1 -piperidinyl]methyl ⁇ benzohydrazide trifluoroacetate.
  • Example 68 ⁇ r-(5-chloro-2-cyano-4-pyrimidinyl)-4-fluoro-3- ⁇ [4-(hydroxymethyl)-1 - piperidinyl]methyl ⁇ - ⁇ T-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 69 3-(1 ,4'-bipiperidin-1 '-ylmethyO-W ⁇ S-chloro ⁇ -cyano ⁇ -pyrimidinyl) ⁇ - fluoro- ⁇ f-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 70 ⁇ /'-(5-chloro-2-cyano-4-pyrimidinyl)-4-fluoro-3-[(4-methyl-1 - piperazinyl)methyl]-/V-(2-methylpropyl)benzohydrazide.
  • Example 71 ⁇ r-(5-bromo-2-cyano-4-pyrimidinyl)-4- ⁇ [4-(4-methyl-1-piperazinyl)-1- piperidinyl]methyl ⁇ - ⁇ /'-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Example 72 /V-(5-bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl-1-piperazinyl) methyl]- ⁇ / 1 -(2-methylpropyl)-3-isoxazolecarbohydrazide trifluoroacetate.
  • Example 73 W-(5-bromo-2-cyano-4-pyrimidinyl)-7-[(4-methyl-1-piperazinyl) methyl]- ⁇ f-(2-methylpropyl)-1-benzofuran-2-carbohydrazide trifluoroacetate.
  • N-methylpiperazine (ALDRICH, 52 uL, 0.47 mmol) and diisopropylethylamine (FLUKA, 82 uL, 0.47 mmol) were added and the reaction was stirred at room temperature for 54 hours. Solvents were evaporated to dryness and the residue was purified using preparative HPLC (XTERRA column 19 x 150 mm, gradient: 25% ACN-water, 0.1%TFA to 100% ACN-water, 0.1 %TFA) to yield the title compound.
  • Example 74 N'-(5-bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl-1-piperazinyl) methyl]- N"-(2-methylpropyl)-3-furancarbohydrazide (0.75 TFA / 0.25 pTsOH salt).
  • Example 75 W-(5-bromo-2-cyano-4-pyrimidinyl)-6- ⁇ 3-[(4-methyl-1-piperazinyl) methyl]phenyl ⁇ -AT-(2-methylpropyl)-3-pyridinecarbohydrazide trifluoroacetate.
  • N-methylpiperazine (ALDRICH, 0.007 ml_, 0.06 mmol) and N,N-diisopropylethylamine (FLUKA, 0.014 mL, 0.08 mmol) in THF (6 mL) were stirred at room temperature for 5 min.
  • Intermediate 34 (26 mg, 0.05 mmol) was added and the solution was stirred at room temperature for 4 days and, then, it was refluxed for 4 h.
  • the reaction was concentrated under reduced pressure and the residue was purified by preparative HPLC (XTERRA 19x150 mm, ACN:H2O, 0.1%TFA, gradient 20-80%) to give the title compound.
  • Example 76 ⁇ T-(5-bromo-2-cyano-4-pyrimidinyl)-6- ⁇ 4-[(4-methyl-1 -piperazinyl) methyl]phenyl ⁇ -/V-(2-methylpropyl)-3-pyridinecarbohydrazide trifluoroacetate.
  • Example 77 ⁇ T-(5-bromo-2-cyano-4-pyrimidinyl)-5- ⁇ 4-[(4-methyl-1 -piperazinyl) methyl]phenyl ⁇ -W-(2-methylpropyl)-3-pyridinecarbohydrazide trifluoroacetate.
  • Example 78 ⁇ T-(5-bromo-2-cyano-4-pyrimidinyl)-5- ⁇ 3-[(4-methyl-1 -piperazinyl) methyl]phenyl ⁇ -/V-(2-methylpropyl)-3-pyridinecarbohydrazide trifluoroacetate.
  • Example 79 ⁇ f-(5-bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl-1 -piperazinyl) methyl]- ⁇ f-(2-methylpropyl)-1-benzofuran-2-carbohydrazide.
  • Example 80 ⁇ f-(5-bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl-1 -piperazinyl) methyl]- /V-(2-methylpropyl)-2-thiophenecarbohydrazide trifluoroacetate.
  • the title compound was prepared by a method analogous to that described for Example 1 , replacing the acid chloide of Intermediate 2 with benzoyl chloride.
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
  • Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically H-D-VLR-AFC (Falcipain-2, Falcipain-3, Vivapain-2), Z-FR-AFC (Cathepsin K 1 L, B), or KQKLR-AMC (Cathepsin S) and are determined in 100 mM sodium acetate, pH 5.5, containing 10 mM DTT and 0.5 mM CHAPS (Falcipain-2, Falcipain-3, Vivapain-2), and 100 mM sodium acetate, pH 5.5, containing 5 mM L-cysteine, 1 mM CHAPS and 5mM EDTA (Cathepsin K 1 L, B), or 5OmM MES, pH 6.5, containing 0.5mM CHAPS, 1OmM L-CYS, 5mM EDTA (Cathepsin S).
  • H-D-VLR-AFC Fluorogenic peptide substrate
  • Stock substrate solutions are prepared at 20 mM in DMSO.
  • the activity assays contained 30 uM substrate (Falcipain-2, Falcipain-3, Vivapain-2), 20 uM substrate (Cathepsin K), 25uM substrate (Cathepsin B), 5uM substrate (Cathepsin L), and 3OuM substrate (Cathepsin S). All assays contained 1% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays are conducted at ambient temperature as end point assays being quenched after 60 minutes with the exception of Cathepsin S at 90 minutes, with 16.6 uM E-64 in 1% DMSO.
  • AFC or AMC Product formation is determined from fluorescence (excitation at 405nM; emission at 53OnM, AFC, or excitation at 360 nM; emission at 460 nM, AMC) monitored with a LJL Aquest (Molecular Devices) fluorescent plate reader.
  • LJL Aquest Molecular Devices
  • the reaction is not quenched but is read in the plate reader every 3 minutes for approximately 90 minutes.
  • the mechanism of action studies for Falcipain-2 utilize Z-LR-AMC as the substrate.
  • Product formation is determined from the fluorescence of AMC, measured with a LJL Acquest (Molecular Devices) fluorescent plate reader (excitation at 36OnM; emission at 46OnM).
  • K t is the apparent K 1
  • S is the concentration of substrate
  • K M is the Michaelis binding constant for substrate
  • K / is the binding constant of a competitive inhibitor for free enzyme.
  • Vm is the maximum velocity
  • S is the concentration of substrate with Michaelis constant of K M
  • [I] is the concentration of inhibitor
  • K 1 is the binding constant of inhibitor for free enzyme
  • aK is the binding constant of inhibitor for a potential enzyme-substrate complex.
  • [AMC] V 3 t + (V 0 - vss) [1 - exp (-k o bst)] / k o bs (4)
  • Equation 7 describes the apparent K
  • the initial and final velocities were fit to equation 3 to further define the binding mechanism and potency.
  • a complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas MoI. Biol., 1988, 61, 201 ).
  • Comparative Example 81 which is a trifluoroacetate salt
  • comparative Example 82 which is the free base
  • the free base of each of these compounds is disclosed in WO 2005/103012 A1 (page 124, Example 15(2) and page 130, Example 17(4) respectively).
  • the assay result obtained for the free base of a given compound is expected to be the same as that obtained when a salt of that compound is tested. This is because the buffer used in the assay determines the pH under which the compound is tested; the pH determines the relative amounts of free base to salt of the compound being tested. This has been confirmed by testing in the enzymatic assays the free base, the hydrochloride salt and the trifluoroacetate salt of certain compounds of the type exemplified herein.
  • Examples 1-32, 35-54, 57-73, 75-77, 79 and 80 were tested in the enzymatic assay for cathepsin K.
  • Examples 33, 34, 55, 56, 74 and 78 were not tested in this assay.
  • the Examples which were tested were found to have an IC 50 value of less than 11 nM in the enzymatic assay for cathepsin K.
  • the exemplified compounds of the invention exhibit an improved activity in the whole cell assay, as compared with comparative Examples 81 and 82 of the prior art.

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Abstract

L'invention concerne des dérivés hétéroaryle nitrilés substitués de formule (I), des procédés de préparation de ces composés, des compositions pharmaceutiques les contenant, ainsi que leur utilisation en tant qu'inhibiteurs de la cystéine protéase.
PCT/EP2006/008579 2005-09-02 2006-08-31 Nouveaux inhibiteurs de la cysteine protease WO2007025775A2 (fr)

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US20100009956A1 (en) * 2006-10-30 2010-01-14 Glaxo Group Limited , a corporation Novel substituted pyrimidines as cysteine protease inhibitors
EP2030621A1 (fr) * 2007-08-21 2009-03-04 Glaxo Group Limited Nouveaux pyrimidines comme inhibiteurs de la cystéine protéase
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DE102008063561A1 (de) * 2008-12-18 2010-08-19 Bayer Cropscience Ag Hydrazide, Verfahren zu deren Herstellung und deren Verwendung als Herbizide und Insektizide
CN102267964B (zh) * 2011-06-15 2014-06-18 浙江师范大学 3-羟基-2,3-二氢苯并呋喃衍生物及其合成方法和应用
CA3093546A1 (fr) * 2018-03-28 2019-10-03 Hanlim Pharmaceutical Co., Ltd. Derive de 2-cyanopyrimidin-4-yl carbamate ou d'uree ou sel de celui-ci et composition pharmaceutique le comprenant

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