WO2006027211A1 - Pyrimidines 2,4-substituees servant d'inhibiteurs de cysteine protease - Google Patents

Pyrimidines 2,4-substituees servant d'inhibiteurs de cysteine protease Download PDF

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WO2006027211A1
WO2006027211A1 PCT/EP2005/009569 EP2005009569W WO2006027211A1 WO 2006027211 A1 WO2006027211 A1 WO 2006027211A1 EP 2005009569 W EP2005009569 W EP 2005009569W WO 2006027211 A1 WO2006027211 A1 WO 2006027211A1
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cyanopyrimidin
alkyl
aryl
cyano
pyrimidinyl
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PCT/EP2005/009569
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Julia Castro Pichel
Maria Jesus Chaparro Martin
Jose-Miguel Coteron Lopez
Beatriz Diaz Hernandez
Esther Pilar Fernandez Velando
Jose Maria Fiandor Roman
Jose Luis Lavandera Diaz
Esther Porras De Francisco
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention is directed to certain substituted heteroaryl nitrile derivatives, which are protease inhibitors. More specifically, the compounds are inhibitors of cysteine proteases.
  • 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, particularly cathepsin K.
  • 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. Trap. 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.
  • Antimalarial Chemotherapy Mechanisms of Action, Resistance, and New Directions in Drug Discovery, Totowa, N.J.: Humana Press, (2001) 325-345. Plasmodial haemoglobinases are therefore potential therapeutic targets.
  • 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 P. J., (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 1 a fourth papain-family cysteine protease has been found, now known as falcipain-2 1 .
  • 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 falicipain-2' is also expected to be very similar, although probably not identical, to that of falcipain-2.
  • cysteine protease inhibition, and 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.
  • elevated levels of these enzymes in the body can result in pathological conditions leading to disease.
  • 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, tumour invasion and tumour metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, coronary disease, atherosclerosis, autoimmune diseases, respiratory diseases such as obstructive pulmonary disorder (COPD), immunologically mediated diseases (for example, transplant rejection), and other related diseases, see: International Publication Number WO 94/04172
  • 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). The expression of 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),
  • cathepsin K is an acidic lysosomal protease, strongly suggests a physiological role of cathepsin K in cartilage turnover in addition to bone resorption.
  • cathepsin K can degrade aggrecan and type Il collagen, the two major protein components of the cartilage matrix.
  • inhibition of 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). Furthermore, 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. Carcinog., 32, 84 and Brubaker, et al., (2003), J. Bone Miner. Res., 18, 222).
  • 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, 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, metastasis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Liu, et al., (2004), Arterioscler Throm Vase Biol. 24, 1359). 5.
  • 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, metastasis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Lang, et al., (2000), J. Rheumatol.
  • 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.
  • Cat 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.
  • 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 and particularly by cathepsin K, there is a need for inhibitors of these cathepsins which can be used in the treatment of a variety of conditions.
  • EP 0604798 A1 discloses certain N-arylhydrazine derivatives useful for the control of insects or acarina.
  • 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, particularly cathepsin K, 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 a compound of Formula I:
  • R 1 represents 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 1-8 alkylene-cycloalkyl;
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents hydrogen or C 1-6 alkyl
  • X represents NR 5 and 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 -C 1-6 alkyleneR A , aryl, biaryl, -aryl-heteroaryl, -heteroaryl-aryl, -aryl-heterocyclyl, -aryl-d-aalkylene-heterocyclyl, -aryl-O-d-salkylene-heterocyclyl, aryl-C-i-salkylene-heteroaryl, -aryl-heteraoaryl-d-salkylene-heterocyclyl,
  • -heteroaryl-aryl-C ⁇ salkylene-heterocyclyl aryloxy, heteroaryl, cycloalkyl, -cycloalkyl-aryl, cycloalkyloxy, heterocyclyl, -NR H -aryl-heterocyclyl, -NR H -cycloalkyl, -NR B Ci -6 alkyleneR c , -Od-ealkyleneR D or -OC 1-6 alkenyl; -aryl-d- 3 alkylene-heterocyclyl-R J , -aryl-C 1-3 alkylene-heteroaryl-R K , C 1-3 alkyene(NH 2 )-aryl;
  • R 5 represents hydrogen, C ⁇ alkyl, C 1-6 alkenyl, -C(O)R 2a , -C- ⁇ alkylene-heterocyclyl, -C 1-8 alkyleneNR G C(O)Ci -6 alkyl, -C 1-8 alkyleneNR G C(O)OCi -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
  • X represents NR 5 and A represents -SO2- and R 2 represents Ci -6 alkyl or C 1-6 aralkyl;
  • R 5 represents hydrogen, C 1-6 alkyl, C 1-6 alkenyl, -C ⁇ salkylene-heterocyclyl, -C 1-8 alkyleneNR G C(O)C 1-6 alkyl I -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl,
  • X represents CH 2 and A represents C(O) and
  • R 2 represents -NR H -aryl, -NR H -heteroaryl, -NR H C 1-6 aralkyl,
  • 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 ⁇ 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 Ci -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, d -6 alkyl, -C L ealkyleneNHC ⁇ C ⁇ alkyl, -C 1-6 alkyleneNHC(O)OC 1-4 alkyl, or -C 1-6 alkyleneNR E R F ;
  • R J represents aryl, heteroaryl, heterocyclyl, -C 1-3 alkylene(aryl) 2 , -C ⁇ alkylene-heteroaryl, -C 1-3 aralkyl, -Ci ⁇ alkylene-oxo-heterocyclyl, -O-C(O)C 1-3 alkylene-aryl,
  • R ⁇ represents one or two aryl substituents
  • 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 and the like.
  • alkyl refers to a linear or branched optionally substituted alkyl group, containing from 1-6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, neopentyl, or hexyl.
  • Preferred alkyl moieties are C 1-4 alkyl. In one embodiment alkyl is unsubstituted or substituted at one, two or three positions.
  • Optional substituents include halogen, alkoxy, NR 7 R 8 , SOR 9 and SO 2 R 9 , wherein R 7 and R 8 independently represent hydrogen or alkyl or R 7 and R 8 together with the N-atom to which they are attached form a heteroaryl or heterocyclyl ring, and R 9 represents alkyl.
  • 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.
  • 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, bute ⁇ yl, 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.
  • alkoxy refers to a linear or branched optionally substituted alkoxy group, containing from 1-6 carbon atoms; examples of such groups include methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.
  • alkoxy moieties are C ⁇ alkoxy.
  • alkoxy is unsubstituted or substituted at one, two or three positions.
  • Optional substituents include halogen, for example fluorine.
  • 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 moieties are unsubstituted.
  • aryl moieties are monosubstituted, disubstituted or trisubstituted.
  • aryl moieties are monosubstituted or disubstituted.
  • Optional aryl substituents include d -4 alkyl, C 1-4 alkoxy, halogen, nitro, trihalomethyl, trihalomethoxy, -N(C 1-3 alkyl) 2 and -SO 2 -C 1-4 alkyl.
  • aryl refers to an optionally substituted aromatic group containing one, two or three conjugated or fused rings with at least one ring having a conjugated pi-electron system.
  • aryl moieties are C 6-14 aryl.
  • aryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • Optional aryl substituents include aryl, heteroaryl, heterocyclyl, cycloalkyl, halogen, alkoxy and 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,
  • 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.
  • 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 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 ⁇ alkyl, C 1-4 alkoxy and halogen. In another embodiment optionally substituted heteroaryl moieties are benzofuranyl, pyridyl, dibenzofuranyl, imidazolyl and isoxazolyl.
  • heteroaryl is unsubstituted, monosubstituted, disubstituted or trisubstituted; in one aspect heteroaryl is unsubstituted or monosubstituted.
  • Optional heteroaryl substituents include aryl, heteroaryl, heterocyclyl, cycloalkyl, halogen, alkoxy and alkyl.
  • 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • cycloalkyl is unsubstituted or substituted at one, two or three positions.
  • Optional cycloalkyl substituents include aryl, heteroaryl, heterocyclyl, cycloalkyl, halogen, alkoxy and alkyl.
  • cycloalkyloxy as a group or a part of a group refers to an -O-cycloalkyl group wherein cycloalkyl is as herein defined.
  • heterocyclyl as a group or a part of a group refers to an optionally substituted, 3- to 7-membered, saturated or partially saturated cyclic hydrocarbon group containing one to four heteroatoms selected from N, O and S.
  • Examples of such 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, aze
  • heterocyclyl is an optionally substituted 5- or 6-membered group.
  • heterocyclyl moieties are optionally substituted pyrrolidnyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • heterocyclyl moieties are optionally substituted piperazinyl.
  • heterocyclyl moieties are unsubstituted.
  • heterocyclyl moieties are monosubstituted, disubstituted or trisubstituted.
  • heterocyclyl moieties are monosubstituted.
  • Optional heterocyclyl substituents include C 1-4 alkyl, -C(O)C- M aIkVl, -C(O)OCi- 4 alkyl and oxo.
  • heterocyclyl substituents include aryl, heteroaryl, heterocyclyl, cycloalkyl, halogen, alkoxy and alkyl.
  • Preferred heterocyclyl groups include piperidinyl, more preferably 1 -piperidinyl.
  • halogen refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) atom. In one embodiment halogen substituents are fluorine or chlorine atoms.
  • 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.
  • R 1 represents d. 8 alkyl, -C 1-8 alkyleneNR E R F ,
  • R 1 represents C 1-8 alkyl, Ci -8 alkyleneNR E R F , or C 1-8 alkyleneNR G C(O)C 1-6 alkyl.
  • R 1 represents C 1-8 alkyleneNH 2 .
  • R 1 represents C 1-8 alkyleneNR G C(O)Oterf-butyl.
  • R 1 represents C 1-8 alkyleneNR G C(O)methyl.
  • R 1 represents C 1-8 alkyl; In another embodiment R 1 represents Ci -6 alkyl; in a further embodiment R 1 represents isobutyl or neopentyl; in one embodiment R 1 represents isobutyl; in another embodiment R 1 represents neopentyl.
  • R 3 represents hydrogen or C 1-3 alkyl and R 4 represents hydrogen or Ci -3 alkyl; in another embodiment one of R 3 and R 4 represents or C 1-3 alkyl and the other represents hydrogen; in a further embodiment R 3 and R 4 both represent hydrogen.
  • X represents NR 5 and A represents C(O) and 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 -C 1-6 alkyleneR A , aryl, biaryl, -aryl-heteroaryl, -heteroaryl-aryl, -aryl-heterocyclyl, -aryl-Ci-aalkylene-heterocyclyl, -aryl-O-C-i ⁇ alkylene-heterocyclyl, aryl-C ⁇ alkylene-heteroaryl, -aryl-heteraoaryl-C-i.aalkylene-heterocyclyl, -heteroaryl-aryl-C-i-aalkylene-heterocyclyl, aryloxy, heteroaryl, cycloalkyl, -cycloalkyl- aryl, cycloalkyloxy, heterocyclyl, -NR H -aryl-heterocyclyl, -NR H -cycloalkyl, -NR 6 C 1- 6 alkyleneR c
  • R 5 represents hydrogen, C 1-6 alkyl, C 1-6 alkenyl, -C(O)R 2a , -C L salkylene-heterocyclyl, - C 1-8 alkyleneNR G C(O)C 1-6 alkyl, -C 1-8 alkyleneNR G C(O)OCi -6 alkyl, -C 1-8 alkyleneNR E R F , N-phthalidimido-Ci -8 alkylene- or -C(O)Ci_ 6 alkyl.
  • X represents NR 5 and A represents C(O) and R 2 represents -Ci -6 alkyleneR A , aryl, -aryl-heteroaryl, -aryl-heterocyclyl,
  • X represents NR 5 and A represents C(O) and R 2 represents aryl, -aryl-heteroaryl, -aryl-heterocyclyl, -aryl-C-i-aalkylene-heterocyclyl, heteroaryl, -NR H -aryl or -NR H -heteroaryl.
  • X represents NR 5 and A represents C(O) and where R 2 contains a heterocyclyl moiety
  • heterocyclyl is selected from optionally substituted pyrrolidnyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • X represents NR 5 and A represents C(O) and where R 2 contains a heterocyclyl moiety
  • heterocyclyl is selected from optionally substituted pyrrolidinyl, piperidinyl or piperazinyl.
  • X represents NR 5 and A represents C(O) wherein R 5 represents hydrogen, C 1-6 alkyl, -C(O)R 2a , -C ⁇ alkylene-heterocyclyl, -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl, -C 1-8 alkyleneNR E R F , N-phthalidimido-C ⁇ salkylene- or -C(O)Ci -6 alkyl.
  • X represents NR 5 and A represents C(O) wherein R 5 represents hydrogen, C 1-3 alkyl, -C(O)R 2a , -C 1-6 alkylene-piperidyl, -d-ealkyleneNC-i.
  • X represents NR 5
  • A represents C(O) and R 2 and R 5 together with the carbon and nitrogen atoms to which they are respectively attached form a group selected from
  • X represents NR 5
  • A represents -S02-
  • R 2 represents C 1-6 alkyl or C 1-6 aralkyl
  • R 5 represents hydrogen, C 1-6 alkyl, C 1-6 alkenyl, -C 1-8 alkylene- heterocyclyl, -Ci -8 alkyleneNR G C(O)Ci -6 alkyl, -C 1-8 alkyleneNR G C(O)OC 1 . 6 alkyl
  • X represents NR 5
  • A represents -S02-
  • R 2 represents Ci -6 alkyl or C 1-6 aralkyl
  • R 5 represents hydrogen
  • X represents CH 2
  • A represents C(O) and R 2 represents -NR H -aryl, -NR H -heteroaryl, -NR H C 1-6 aralkyl, -NR H C 1-6 alkylene-heteroaryl, -NR H -aryl-heteroaryl, -NR H -aryl-heterocyclyl or -OCi -6 aralkyl.
  • X represents CH 2
  • A represents C(O) and R 2 represents -NH-aryl, -NH-heteroaryl, -NHC 1 .
  • heterocyclyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • X represents CH 2
  • A represents C(O) and where R 2 contains a heterocyclyl moiety
  • heterocyclyl is selected from optionally substituted pyrrolidinyl, piperidinyl or piperazinyl.
  • R A represents hydrogen, halogen, -NR E R F , C 1-3 alkyl, cycloalkyl, aryl, -aryl-d ⁇ alkylene-heterocyclyl or -aryl-O-C ⁇ salkylene-heterocyclyl.
  • R A represents hydrogen.
  • R A contains a heterocyclyl moiety heterocyclyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • R A contains a heterocyclyl moiety, heterocyclyl is selected from optionally substituted pyrrolidinyl, piperidinyl or piperazinyl.
  • R B represents hydrogen. In another embodiment R B represents C 1-8 alkyl. In another embodiment R B represents C 1-6 alkyl.
  • R c represents hydrogen, halogen, -NR E R F , cycloalkyl, aryl, -aryl-C- ⁇ alkylene-heterocyclyl, C 1-3 alkenylaryl, -NHC(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl or -NHC(O)OC 1-6 aralkyl.
  • R c represents hydrogen.
  • R c contains a heterocyclyl moiety
  • heterocyclyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • R c contains a heterocyclyl moiety
  • heterocyclyl is selected from optionally substituted pyrrolidinyl, piperidinyl or piperazinyl.
  • R D represents hydrogen, cyano, CCI 3 , C 1-3 alkyl, cycloalkyl, heterocyclyl, aryl, -NHC(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl or -NR E R F .
  • R D represents hydrogen.
  • heterocyclyl is selected from optionally substituted pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • R D contains a heterocyclyl moiety
  • heterocyclyl is selected from optionally substituted pyrrolidinyl, piperidinyl or piperazinyl.
  • R E represents hydrogen or Ci -3 alkyl. In another embodiment R E represents hydrogen. In a further embodiment R E represents C 1-3 alkyl.
  • R F represents hydrogen or Ci -3 alkyl. In another embodiment R F represents hydrogen. In a further embodiment R F represents C 1-3 alkyl.
  • R G represents hydrogen or C 1-3 alkyl. In another embodiment R G represents hydrogen. In a further embodiment R G represents C 1-3 alkyl.
  • R H represents hydrogen, Ci -6 alkyl, -C 1-6 alkyleneNHC(O)OC 1-4 alkyl or -C 1-6 alkyleneNR E R F .
  • R H represents hydrogen or C 1-6 alkyl.
  • R H represents C 1-6 alkyl.
  • R H represents hydrogen.
  • the meaning of any functional group or substituent thereon at any one occurrence in Formula I, or any subformula thereof, is independent of its meaning, or any other functional group's or substituenfs meaning, at any other occurrence, unless stated otherwise. It is to be understood that the present invention covers all combinations of groups and embodiments described herein.
  • X represents NR a or CHR 6 b .
  • R 1 represents alkyl
  • R and R independently represent hydrogen or alkyl
  • R represents hydrogen, C 1-3 alkyl or -C(O)R 2. ;
  • R 6 represents hydrogen
  • R 2 represents aryl, heteroaryl, -NH-aryl, -NH-heteroaryl, alkoxy, -Oalkylaryl or -Oalkylheteroaryl;
  • R 2 represents -NH-aryl or -NH heteroaryl
  • X represents NR 5 . In another aspect of the invention, X represents CHR 6 wherein R 6 represents hydrogen.
  • R 1 represents C 1-4 alkyl, for example isobutyl or neopentyl; in one embodiment R 1 represents isobutyl.
  • R 2 represents aryl, heteroaryl, -NH-aryl, -NH-heteroaryl, alkoxy or -Oalkylaryl, in another aspect R 2 represents aryl, heteroaryl, -NH-aryl or -NH-heteroaryl, in a further aspect R 2 represents aryl, (substituted with alkoxy or halogen), heteroaryl (substituted with alkoxy), -NH-aryl (substituted with alkoxy, alkyl, halogen, imidazolyl or piperidinyl), or -NH-heteroaryl (substituted with halogen, alkoxy, alkyl).
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents hydrogen or -C(O)R 2 , in another embodiment R 5 represents hydrogen.
  • chemical entities useful in the present invention may be at least one chemical entity selected from:
  • Ex 49 1-methylpropyl 2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)hydrazine carboxylate trifluoroacetate;
  • Ex 50 1 -methyl-2-phenylethyl 2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyl) hydrazinecarboxylate trifluoroacetate;
  • Ex 51 1 ,3-dimethylbutyl 2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)hydrazine carboxylate;
  • Ex 63 1 ,1-dimethylethyl 2-(2-cyano-4-pyrimidinyl)-1-methyl-2-(2-methylpropyl) hydrazinecarboxylate; Ex 64: 1 ,1-dimethylethyl 2-(2-cyano-4-pyrimidinyl)-1-[3-(dimethylamino)propyl]-2-(2- methylpropyl)hydrazinecarboxylate;
  • Ex 70 1,1-dimethylethyl 2-(2-cyano-6-methyl-4-pyrimidinyl)-2-(2,2-dimethylpropyl) hydrazinecarboxylate;
  • Ex 71 N'-(2-cyanopyrimidin-4-yl)-N I -(2,2-dimethylpropyl)-4-methoxybenzohydrazide;
  • Ex 138 2-(2-cyanopyrimidin-4-yl)-N-ethyl-2-isobutylhydrazinecarboxamide trifluoroacetate
  • Ex 139 N-(2-chloroethyl)-2-(2-cyanopyrimidin-4-yl)-2-isobutylhydrazinecarboxamide trifluoroacetate
  • Ex 206 : ⁇ /-(3-aminopropyl)-2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyl) hydrazinecarboxamide trifluoroacetate;
  • Ex 207 ⁇ /-(2-aminoethyl)-2-(2-cyanopyrimidin-4-yl)-2-isobutylhydrazinecarboxamide;
  • Ex 210 A/-(5-aminopentyl)- ⁇ /-butyl-2-(2-cyanopyrimidin-4-yl)-2- isobutylhydrazinecarboxamide; Ex 211 : ⁇ /-(4-aminobutyl)-2-(2-cyanopyrimidin-4-yl)-2-isobutylhydrazinecarboxamide trifluoroacetate;
  • Ex 215 ⁇ /-(6-aminohexyl)- ⁇ /-butyl-2-(2-cyanopyrimidin-4-yl)-2- isobutylhydrazinecarboxamide trifluoroacetate;
  • Ex 216 /V-(3-aminopropyl)-2-(2-cyanopyrimidin-4-yl)-/V-(4-fluorophenyl)-2- isobutylhydrazinecarboxamide trifluoroacetate;
  • Ex 220 /V-(6-aminohexyl)-2-(2-cyanopyrimidin-4-yl)- ⁇ /-(4-fluorophenyl)-2- isobutylhydrazinecarboxamide trifluoroacetate;
  • Ex 221 Methyl [5-( ⁇ [2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)hydrazino] carbonyl ⁇ amino)pentyl]carbamate;
  • Ex 225 ⁇ /-[5-(acetylamino)pentyl]-/V-butyl-2-(2-cyanopyrimidin-4-yl)-2- isobutylhydrazinecarboxamide; Ex 226: ⁇ /- ⁇ 5-[1-(2-cyanopyrimidin-4-yl)-2-(4-fluorobenzoyl)riydrazino]-4,4- dimethylpentyl ⁇ acetamide; Ex 227: ⁇ /- ⁇ 5-[1 -(2-cyanopyrimidin-4-yl)-2-(cyclohexylcarbonyl)hydrazino]-4,4- dimethylpentyl ⁇ acetamide;
  • Ex 236 ⁇ /'-(2-cyano-4-pyrimidinyl)-A/ I -(3,3-dimethylbutyl)-4-fluorobenzo hydrazide;
  • Ex 237 4-[(2,2-dimethylpropyl)(2,4-dioxo-1-imidazolidinyl)amino]-2-pyrimidinecarbonitrile;
  • Ex 240 /V-(2-cyano-4-pyrimidinyl)-4-fluoro-/ ⁇ /'-(3-methylbutyl)benzo hydrazide; Ex 241 : 1 ,1-dimethylethyl 2-(2-cyano-5-methyl-4-pyrimidinyl)-2-(2-methyl propyl)hydrazinecarboxylate;
  • 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 may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically acceptable salts of the compounds according to Formula I.
  • 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) 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, ethane
  • 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) with a suitable inorganic or organic base (e.g. ammonia, triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic base e.g. ammonia, triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
  • 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.
  • 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.
  • non-pharmaceutically acceptable salts for example oxalates may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of Formula (I).
  • the term "compounds of the invention” means both the compounds according to Formula I and salts and solvates thereof.
  • the term "a compound of the invention” also appears herein and refers to both a compound according to Formula I and its salts and solvates.
  • 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.
  • 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, particularly cathepsin K.
  • 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, 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), Paget's disease; hypercalcemia of malignancy,
  • 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 or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate 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, particularly 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.
  • 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, particularly 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.
  • 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, particularly cathepsin K 1 for example conditions characterised by excessive bone loss such as osteoporosis and bone metastasis, and other bone and joint diseases such as osteoarthritis.
  • 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 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising at least one chemical entity selected from a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
  • 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, particularly cathepsin K,
  • 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, particularly cathepsin K, for example in the treatment of conditions characterised by excessive bone loss such as osteoporosis and bone metastasis, and other bone and joint diseases such as osteoarthritis.
  • the invention is further directed to pharmaceutical compositions comprising at least one chemical entity selected from a compound of Formula I or a pharmaceutically acceptable salt or solvate 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 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing at least one chemical entity selected from a compound of Formula I or a pharmaceutically acceptable salt or solvate 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 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 or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent. When a compound of Formula I or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone.
  • 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.
  • antifolates e.g. dapsone, proguanil, sulfadoxine, pyrimethamine, chlorcycloguanil, cycloguanil
  • antibacterial drugs such as azithromycin, doxycycline, ciprofloxacin and clindamycin.
  • 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.
  • either the compound of the present invention or the second therapeutic agent may be administered first.
  • 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. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • compositions The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect 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 recipient thereof.
  • the pharmaceutical 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. Alternatively, 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.
  • 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: Diluents, fillers, 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, hemectants, 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.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • H-D-VLR-AFC HD-Valyl-Leucyl-Arginyl-7-Amido-4-trifluoromethylcoumarin Hex hexane
  • KQKLR-AMC N-Acetyl-Lysyl-Glutaminyl-Lysyl-Leucyl-Arginyl-y-Amido ⁇ - methylcoumarin
  • the semicarbazide compounds of Formula Ia which are compounds of Formula I wherein R 1 is C 1-8 alkyl, -C 1-8 alkyleneN(C 1-3 alkyl) 2 -C 1-8 alkyleneNR G C(O)OCi -6 alkyl or -C 1 .
  • R 5 is hydrogen, C 1-6 alkyl, -C 1- 8alkyleneN(C 1-3 alkyl) 2 , -Ci -8 alkyleneNR G C(O)OC 1-6 alkyl or -C 1-8 alkyleneNR G C(O)C 1-6 alkyl, or -C(O)NR H R 10 in which R H is C ⁇ alkyl, -C 1-8 alkyleneN(C 1-3 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 and R 10 is aryl, heteroaryl, aryl-heteroaryl, cycloalkyl or -C 1-6 alkyleneR c , wherein R c is hydrogen, C 1-3 alkyl, aryl or halogen, may be prepared from
  • Procedure A Compounds of Formula Ha, which are compounds of Formula II, wherein R 5 is hydrogen, are reacted with one equivalent of the isocyanate, R 10 NCO, wherein R 10 is as defined above for 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. Under these conditions, when an excess of the isocyanate R 10 NCO is added, compounds of Formula Ia wherein R 5 is C(O)NR H R 10 (N,N-bis aminocarbonyl compounds) are obtained.
  • Procedure B A primary amine R 10 -NH 2l or a secondary amine R 10 -NH-R H , wherein R 10 and R H are as defined as above for Formula Ia, is dissolved in a suitable solvent such as dry THF and cooled to a suitable temperature, e.g. -10 0 C to 10 0 C, then reacted with triphosgene, and the resulting mixture is added to compounds of Formula Il in the presence of a suitable base such as triethylamine. This mixture may be stirred at a suitable temperature for a suitable length of time for complete reaction, for example at room temperature for 6 h, to give compounds of Formula Ia wherein R 5 , R 10 and R H are as defined above for Formula Ia.
  • acylhydrazide compounds of Formula Ib which are compounds of Formula I wherein R 1 is C 1-8 alkyl, -C 1-8 alkyleneN(C 1-3 alkyl) 2 -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl or -C 1-8 alkyleneNR G C(O)Ci -6 alkyl, A is C(O), X is NR 5 and R 5 is hydrogen C 1-8 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, and R 2 is aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-heterocyclyl, biaryl, aryl-heteroaryl, -aryl-Ci-salkylene-heterocyclyl, -aryl
  • alkoxycarbonyl hydrazine compounds of Formula Ic which are compounds of Formula I wherein R 1 is C 1-8 alkyl, -C 1-8 alkyleneN(C 1-3 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), X is NR 5 and R 5 is hydrogen, C 1-8 alkyl, -C 1-8 alkyleneN(C 1-3 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 and R 2 is OR 11 in which R 11 is aryl, cycloalkyl, C 1-6 alkenyl, biaryl, heteroaryl, -aryl-heteroaryl, or -C 1-6 alkyleneR D , wherein R D is hydrogen, C 1-3 alkyl,
  • 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 II 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 Ha which are compounds of Formula Il wherein R 5 is hydrogen, may be prepared from compounds of Formula III, wherein R 1 is wherein R 1 is C 1-8 alkyl, -C 1-8 alkyleneN(Ci -3 alkyl) 2 -C 1 . 8 alkyleneNR G C(O)OCi -6 alkyl or
  • Compounds of Formula V may be prepared from the compound of Formula VII by a reductive amination reaction with an aldehyde VIII, wherein R 13 is one carbon shorter in chain length than R 1 , wherein R 1 is C 1-a alkyl, -Ci. 8 alkyleneN(C 1-3 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, according to Scheme 7.
  • the compound of Formula VII, fe/f-butyl carbazate, is commercially available (ALDRICH).
  • Reductive amination of the compound of Formula VII with aldehydes of Formula VIII 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
  • -C 1-8 alkyleneNR G C(O)C 1-6 alkyl A is C(O), X is CH 2 and R 2 is -NR H R 14 , wherein R 14 is aryl, heteroaryl, -C 1-6 aralkyl, -aryl-heterocyclyl, -aryl-heteroaryl, Ci -6 alkylene-heteroaryl, and R H is hydrogen, C 1-6 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)Ci -6 alkyl, may be prepared from the corresponding compound of Formula IX, wherein R 1 is as defined for Formula Id, according to Scheme 8.
  • Compounds of Formula IX may be prepared from compounds of Formula X, wherein R 1 is as defined for Formula Id above, and R 12 is C 1-4 alkyl, according to Scheme 9.
  • the ester group of compounds of Formula X may be hydrolysed under basic conditions, for example by treatment with lithium hydroxide, in a suitable solvent such as THF, to give compounds of Formula IX.
  • Compounds of Formula X may be prepared from compounds of Formula Xl, wherein R 1 is as defined for Formula Id above and R 12 is C 1-4 alkyl according to Scheme 10, by cyanation, by displacement of the chloro substituent of compounds of Formula Xl, 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. cyanation
  • Compounds of Formula Xl may be prepared from compounds of Formula XII, wherein R 1 is as defined for Formula Id above and R 12 is C 1-4 alkyl, according to Scheme 11 , by reaction of compounds of Formula XII with 2,4-dichloropyrimidine XIII (commercially available from FLUKA or SIGMA) in a suitable solvent such as i-PrOH, for example under microwave conditions and heating to a suitable temperature, e.g. 110°C-150°C for 20 min, for example according to the literature procedure given in Guanglin L. et al., (2002) Tetrahedron Lett. 43, 5739-5742.
  • a suitable solvent such as i-PrOH
  • Procedure A compounds of Formula XIV, wherein R 12 is C 1-4 alkyl, may be reacted with a primary amine R 1 -NH 2 , wherein R 1 is as defined for Formula I above, in the presence of a suitable base such as a mixture of isobutylamine and triethylamine, and in a suitable solvent such as THF, for example according to the literature procedure given in Guerrini R. et al., (2000) J. Med. Chem. 43, 2805-2813.
  • a suitable base such as a mixture of isobutylamine and triethylamine
  • THF a suitable solvent
  • Compounds of Formula XIV are commercially available.
  • R 12 is C 1-4 alkyl, which are commercially available, by reductive amination with aldehydes of Formula VIII, wherein R 13 is one carbon shorter in chain length than R 1 .
  • the reaction may be carried out using a suitable reducing agent such as hydrogen, in the presence of a suitable catalyst such as platinum or palladium or platinum oxide, in a suitable solvent such as i-PrOH, EtOH.
  • Aldehydes of Formula VIII are either commercially available, or they may be prepared according to Scheme 13 i) from the corresponding commercially available dimethyl or diethyl acetal compound of Formula XV wherein R 13 is as defined above for compounds of
  • Formula VIII by acid hydrolysis using a suitable acid such as hydrochloric acid, or ii) by oxidation of the commercially available alcohol compound of Formula XVI, wherein R 13 is as defined above for compounds of Formula VIII, following standard procedures as the Swern oxidation or Dess-Martin oxidation.
  • Compounds of Formula Ib(ii) which are compounds of Formula I wherein R 1 is -C 1-8 alkyleneNC(O)C 1-6 alkyl, A is C(O), X is NR 5 and R 5 is hydrogen or C 1-6 alkyl and R 2 is aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-heterocyclyl, biaryl, aryl-heteroaryl, -aryl-C L salkylene-heterocyclyl, -aryl-O-C 1-3 alkylene-heterocyclyl or C 1-6 alkyleneR A , wherein R A is hydrogen, Ci -3 alkyl, halogen, -N(C 1-3 alkyl) 2 , aryl, biaryl, cycloalkyl, -aryl-C ⁇ alkylene-heterocyclyl or -aryl-O-C- ⁇ alkylene-heterocyclyl, may be prepared from
  • R 2 is -NR B C 1 . 6 alkyleneR c (wherein R B is C 1-8 alkyl and R c is aryl, -aryl-d-salkylene-heterocyclyl, Ci -3 alkenylaryl, -NHC(O)OC 1-6 alkyl, -NHC(O)C 1-6 alkyl, -NHC(O)OCi.
  • 6 alkyl, -NHC(O)C 1-6 aralkyl may be prepared from compounds of Formula Il wherein R 1 is C 1-8 alkyl and R 5 is hydrogen according to Scheme 17, by treatment with triphosgene followed by treatment with an amine R 2 H, wherein R 2 is as defined for Formula Ie, in the presence of a suitable base such as caesium carbonate or triethylamine in a suitable solvent such as THF at an appropriate temperature, e.g. -10°C to 10°C.
  • a suitable base such as caesium carbonate or triethylamine
  • -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl, -Ci -8 alkyleneN(C 1-3 alkylene), N-phthalidimido-C.,. 8 alkylene- and R 2 is Ci -6 alkyl or C 1-6 aralkyl, may be prepared from compounds of Formula Il wherein R 1 is C 1-8 alkyl, -C 1-8 alkyleneN(C 1-3 alkyl) 2 -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl or -Ci. 8 alkyleneNR G C(O)C 1-6 alkyl, and R 5 is hydrogen or C-,.
  • 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°C.
  • 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 fe/t-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or terf-butyl; or esters such as acetate.
  • alky silyl groups such as trimethylsilyl or fe/t-butyldimethylsilyl
  • alkyl ethers such as tetrahydropyranyl or terf-butyl
  • esters such as acetate.
  • 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 (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 was added to this solution containing the intermediate hydrazone 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.
  • a solution of N-methylpiperazine (ALDRICH, 1.46 ml, 13.1 mmol) in dimethylformamide (5 ml) was cooled to 0° C and, then, potassium carbonate (K 2 CO 3 , 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.
  • Triphenylphosphine (ALDRICH, 26 g, 98.6 mmol) and 4-(2-hydroxyethyl) morpholine (ALDRICH, 8.6g, 66 mmol) were added to a solution of methyl 4-hydroxybenzoate (ALDRICH, 10 g, 66 mmol) in dry THF (200 ml) under nitrogen atmosphere.
  • the mixture was cooled to O 0 C and a solution of diisopropyl azodicarboxylate (ALDRICH, 17.3 g, 85.8 mmol) in dry THF (80 ml) was added drop wise.
  • the reaction mixture was stirred a room temperature overnight.
  • a mixture of 4-(bromomethyl)benzoic acid (ALDRICH, 3.0Og., 13.9 mmol), 1-N- propylpiperazine dihydrobromide (ALDRICH, 4.05 g., 13.9 mmol) and anhydrous potassium carbonate (ALDRICH, 3.86 g., 27.9 mmol) in dry acetonitrile 120ml was stirred at ambient temperature for 18 hours; the solvent was removed by evaporation. Then, 2N HCI was added until pH value approximately 2 and the product was extracted with n- butanol. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The crude product was used without any further purification.
  • the reaction mixture was diluted with 7OmL of dichloromethane, washed twice with 5OmL of hydrochloric acid 1N and with 5OmL of aqueous sodium bicarbonate saturated solution, dried over sodium sulfate and evaporated to dryness.
  • Cesium hydroxide monohydrate (ALDRICH, 1.1 g, 6.8 mmol) was added to a suspension of molecular sieves 4A in anhydrous DMF under nitrogen atmosphere. The suspension was stirred 10 minutes, terf-butylamine (ALDRICH, 500 mg, 6.8 mmol) was added and the reaction was stirred 30 minutes at room temperature. Then, 2-(Boc-amino)propyl bromide (ALDRICH, 1.8 g, 8.6 mmol) was added and the suspension was stirred under nitrogen at room temperature overnight. The reaction crude was filtered, DMF was evaporated under vacuum and the residue was partitioned between AcOEt and NaOH 1 N.
  • Benzyl N-(3-hydroxypropyl)carbamate (ALDRICH, 500 mg, 2.39 mmol) was dissolved in 12 imL of dry DCM under nitrogen atmosphere and cooled at O 0 C in an ice bath. Triethylamine (FLUKA, 0.5 mL, 3.58 mmol) and toluene-4-sulfonyl chloride (ALDRICH, 528 mg, 2.77 mmol) were added and the resultant solution was stirred at room temperature overnight. Reaction was diluted with more DCM and washed with water. Organic phase was dried with MgSO 4 , filtered and evaporated.
  • Residue was immediately dissolved in 10 mL of anhydrous acetonitrile and sodium bicarbonate (PANREAC, 507 mg, 6.04 mmol) and terf-butylamine (ALDRICH, 367 mg, 5.02 mmol) were added. The suspension was heated at 50-55 0 C for 3 hours and more sodium bicarbonate (PANREAC, 507 mg, 6.04 mmol) and terf-butylamine (ALDRICH, 367 mg, 5.02 mmol) were added. Reaction was heated at 50-55 0 C overnight, then cooled down to room temperature, filtered over Celite and evaporated to dryness. The residue was purified in silica using mixtures of DCM/Methanol.
  • the tosilate was immediately dissolved in 24 mL of dry acetonitrile, sodium bicarbonate (PANREAC, 1.17 g, 13.88 mmol) and N-methylpiperazine (ALDRICH, 1.27 mL, 11.52 mmol) were added and the resultant suspension was stirred at room temperature overnight. Reaction was filtered over Celite and the solvent was evaporated to dryness. The residue was purified using preparative HPLC (LUNA column 50x250 mm, gradient: 0% ACN-water, 0.1%TFA to 60% ACN-water, 0.1%TFA).
  • a solution of 3,3-dimethylbutyraldehyde (ALDRICH, 0.78 ml_, 6.22 mmol) in MeOH (22 ml) was treated with 4-fluorobenzoic hydrazide (ALDRICH, 959 mg, 6.22 mmol) and was stirred at room temperature overnight.
  • a solution containing the intermediate hydrazone was added PtO 2 and the suspension was hydrogenated at room temperature and 35 pSi for 12 h. The suspension was filtered and the solvent was removed under reduced pressure to give the title compound.
  • Examples 3-18 were prepared by methods analogous to that described for Example 2 replacing 4-fluorophenyl isocyanate with the isocyanates indicated in Table 1.
  • Examples 20 and 21 were prepared by methods analogous to that described for Example 18, replacing 4-methoxyphenyl isocyanate with the isocyanates indicated in Table 2.
  • Example 22 ⁇ P-(2-cyano-4-pyrimidinyl)-7-(methyloxy)- ⁇ P-(2-methylpropyI)-1 ⁇ benzofuran-2-carbohydrazide trifluoroacetate
  • Examples 23-28 were prepared by methods analogous to that described for Example 22 using Intermediate 7 or 8 and replacing 7-methoxy-benzofuran-2-carbonyl chloride with the acid chlorides indicated in Table 3.
  • Examples 32-37 were prepared by methods analogous to that described for Example 31 using Intermediate 15 or 16 and replacing 4-aminopyridine with the amines indicated in Table 4.
  • Example 39 was prepared by a method analogous to that described above for Example 1 replacing Intermediate 8 with Intermediate 7. Table 5
  • Example 40 ⁇ r-(2-cyano-4-pyrimidinyl)- ⁇ T-(2,2-dimethylpropyl)-4-[(4-methyl-1 - piperazinyl)methyl]benzohydrazide trifluoroacetate
  • Examples 42-44 were prepared by methods analogous to that described for Example 29 using Intermediate 7 and replacing 2-chlorobenzyl chloroformate with the chloroformate indicated in Table 6.
  • Example 48 1 ,2,2-Trimethylpropyl 2-(2-cyano-4-pyrimidinyl)-2-(2- methylpropyl)hydrazinecarboxylate
  • Triphosgene (ALDRICH, 202 mg, 0.68 mmol) was added to a stirred solution of 3,3- dimethyl-2-butanol (0.51 mmol) in dry THF at -5° C under nitrogen for 8 hours. Then TEA (0.128 mL, 0.92mmol) was added and stirred at 0° C. After 10 minutes, a solution of intermediate 7 (65 mg, 0.34 mmol) in pyridine was added and the mixture was stirred at room temperature for 4 hours. Solvent was removed under reduced pressure and the residue was dissolved in DCM and washed with citric acid 10 % and brine.
  • Examples 49-55 were prepared by methods analogous to that described for Example 48 using Intermediate 7 and replacing 3,3-dimethyl-2-butanol with the alcohol indicated in Table 7.
  • Example 56 1 ,1 -Dimethylethyl-2-(2-cyano-4-pyrimidinyI)-2-(2-methylpropyl)- hydrazinecarboxylate
  • Example 57 1,1-dimethylpropyl 2-(2-cyano-4-pyrimidinyl)-2-(2- methylpropyl)hydrazinecarboxylate.
  • Examples 57-61 were prepared by methods analogous to that described for Example 57 using Intermediate 7 and replacing 2-methyl-2-butanol with the alcohol indicated in Table 8.
  • Example 63 1,1-Dimethylethyl 2-(2-cyano-4-pyrimidinyl)-1-tnethyl-2-(2- methylpropyl)-hydrazinecarboxylate.
  • a mixture of Intermediate 5 (200 mg, 0.68 mmmol), tetrabutylammonium hydrogen sulfate (ALDRICH, 46 mg, 0.136 mmol), potassium carbonate (ALDRICH, 282 mg, 2.04 mmol), sodium hydroxide (PANREAC, 82 mg, 2.04 mmol), sodium iodide (FLUKA, 40 mg, 0.068 mmol) and 3-dimethylaminopropyl chloride hydrochloride (ALDRICH, 322 mg, 2.04 mmol) in dry toluene (PANREAC, 5 ml) was heated at 14O 0 C for 3 hours using a microwave oven SmithCreator Personal Chemistry.
  • the reaction mixture was diluted with 20 ml of toluene, washed with 10 ml of water and 10 ml of brine, dried over sodium sulfate and evaporated to dryness.
  • the residue was purified by PLC plates 20x20 (silica gel 60 F 254 , 2mm Merck 1.05717.0001) using dichloromethane/methanol 20:1 as eluent to give the title compound.
  • Examples 66-67 were prepared by methods analogous to that described for Example 22 using Intermediate 21 or 23 and replacing 7-methoxy-benzofuran-2-carbonyl chloride with the acid chlorides indicated in Table 3a.
  • Examples 71-133 were prepared by methods analogous to that described for Example 22 using Intermediate 7, 8 or 21 as indicated in Table 3b and the corresponding acid or acid chloride replacing 7-methoxy-benzofuran-2-carboxylic acid or 7-methoxy-benzofuran-2- carbonyl chloride with the acids or the acid chlorides indicated in Table 3b.
  • Example 126 ⁇ / I -(2-cyano-4-pyrimidinyl)- ⁇ /'-(2,2-dimethylpropyl)-4-[(4-propyl-1 ⁇ piperazinyl)methyl] benzohydrazide.
  • Example 134 W-(2-cyano-4-pyrimidinyl)-W-(2,2-dimethylpropyl)-4-(1 -piperazinyl methyl) benzohydrazide.
  • Examples 135-142 were prepared by methods analogous to that described for Example 2 using Intermediates 7 or 8 and replacing 4-fluorophenyl isocyanate with the isocyanates indicated in Table 1a.
  • Examples 143-149 were prepared by methods analogous to that described for Example 29 using intermediate 7 and replacing 2-chlorobenzyl chloroformate with the chloroformates indicated in Table 6b.
  • Example 150 Cyclohexyl 2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)hydrazine carboxylate.
  • a solution of cyclohexanol (ALDRlCH, 0.063 g, 0.63 mmol) in dry THF (5 ml_) under nitrogen atmosphere was cooled at -5° C.
  • Triphosgene (ALDRICH, 0.088 g, 0.47 mmol) was added and mixture was stirred for 1,5 hours at -5° C.
  • Triethylamine (ALDRICH, 0.237 mL, 1.7 mmol) was added and the mixture was stirred for 10 minutes more.
  • Intermediate 7 (0.065 g, 0.63 mmol) in pyridine (1mL) was added. The resultant mixture was warmed up to room temperature, diluted with DCM (5mL) and concentrated under vacuum.
  • Examples 151-158 were prepared by methods analogous to that described for Example 150 using Intermediate 7 and replacing cyclohexanol with the alcohols indicated in Table 7a.
  • Examples 159-175 were prepared by methods analogous to that described for Example 31 using Intermediate 15 or 16 and replacing 4-aminopyridine with the amines indicated in Table 4a. Table 4a
  • Examples 176-182 were prepared by methods analogous to that described for Example 64 using Intermediates 5 or 6 and replacing 3-dimethylaminopropyl chloride with the alkylating reagents indicated in Table 8.
  • Examples 184-202 were prepared by methods analogous to that described for Example 183 using Intermediate 7 and replacing intermediate 40 with the amines indicated in Table
  • Example 203 4-[[3-(4-fluorophenyl)-2-oxo-1-imidazolidinyl](2-methylpropyl) amino]- 2-pyrimidinecarbonitrile.
  • Example 204 4- ⁇ (2,2-dimethylpropyl)[3-(4-f luorophenyl)-2-oxo-1 -imidazolidinyl] amino ⁇ -2-pyrimidinecarbonitrile.
  • Example 205 4-[ ⁇ 3-[4-(methyloxy)phenyl]-2-oxo-1-imidazolidinyl ⁇ (2-methylpropyl) amino]-2-pyrimidinecarbonitrile.
  • Example 206 W-(3-aminopropyl)-2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyI) hydrazinecarboxamide trifluoroacetate
  • ADRICH Trifluoroacetic acid
  • Examples 207-220 were prepared by methods analogous to that described for Example 206 replacing Example 183 with the Examples or Intermediates indicated in Table 10.
  • Example 221 Methyl [5-( ⁇ [2-(2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)hydrazino] carbonyl ⁇ amino)pentyl]carbamate.
  • Example 212 (126 mg, 0.29 mmol) was dissolved in DCM (7 mL) and DIEA (ALDRICH, 0,152 mL, 0.87 mmol) was added. The reaction was cooled to O 0 C in an ice bath and methyl chloroformate (ALDRICH, 0,027 mL, 0.35 mmol) was added dropwise. Reaction was stirred while was allowed to reach room temperature. After 5h reaction was diluted with DCM and washed with sat. NaHCO 3 and brine. Organic layer was dried with MgSO 4 , solvent was evaporated and desired product was obtained. 1 H NMR (300 MHz DMSO-Cf 6 ) ⁇ ppm: 8.66 (br.
  • Example 222 1,1-dimethylethyl ⁇ 5-[1-(2-cyano-4-pyrimidinyl)-2-(cyclohexyl carbonyl)hydrazino]-4,4-dimethylpentyl ⁇ carbamate.
  • Example 223 1,1-dimethylethyl (5- ⁇ 1-(2-cyano-4-pyrimidinyl)-2-[(4-fluoro phenyl)carbonyl]hydrazino ⁇ -4,4-dimethylpentyl)carbamate.
  • Example 235 1,1-dimethylethyl 2-(5-bromo-2-cyano-4-pyrimidinyl)-1-(3-bromo propyl)-2-(2-methylpropyI)hydrazinecarboxylate.
  • Example 236 ⁇ T-(2-cyano-4-pyrimiclinyl)- ⁇ / I -(3,3-dimethylbutyl)-4-fluorobenzo hydrazide.
  • Example 237 4-[(2,2-dimethylpropyl)(2,4-dioxo-1 -imidazolidinyl)amino]-2- pyrimidinecarbonitrile.
  • Example 238 4-[(2,4-dioxo-1 -imidazoIidinyl)(2-methylpropyl)amino]-2- pyrimidinecarbonitrile.
  • Example 155 A solution of Example 155 (148 mg, 0.39 mmol) in dry DCM (SCHARLAU, 15 ml.) at O 0 C was added trifluoroacetic acid (ALDRICH, 5 mL) dropwise. The reaction mixture was stirred at room temperature for 7 hours. Then 1-hydroxy-1 H-benzotriazol hydrate (ALDRICH, 58 mg, 0.43 mmol) and ⁇ /-(3-dimethylaminopropyl)- ⁇ /'-ethylcarbodiimide hydrochloride (EDCI) (ALDRICH, 83 mg, 0.43 mmol) were added.
  • ADRICH 1-hydroxy-1 H-benzotriazol hydrate
  • EDCI ⁇ /-(3-dimethylaminopropyl)- ⁇ /'-ethylcarbodiimide hydrochloride
  • Example 240 W-(2-cyano-4-pyrimidinyl)-4-fluoro-W-(3-methylbutyl)benzo hydrazide.
  • Example 241 1,1-dimethylethyl 2-(2-cyano-5-methyl-4-pyrimidinyl)-2-(2-methyl propyl)hydrazinecarboxylate.
  • Examples 242 and 243 were prepared by methods analogous to that described for Example 22 using Intermediate 7 and replacing 7-methoxy-benzofuran-2-carbonyl chloride with the sulfonic acid chlorides indicated in Table 3c.
  • Example 244 A/'-(2-cyano-4-pyrimidinyl)-W-[3-(dimethylamino)propyl]-W-(2-methyl propyl)-2-phenylacetohydrazide trifluoroacetate.
  • Example 97 150 mg, 0.485 mmol
  • tetrabutylammonium hydrogen sulfate ADRICH, 33 mg, 0.097 mmol
  • potassium carbonate ADRICH, 201 mg, 1.455 mmol
  • sodium hydroxide 58 mg, 1.455 mmol
  • sodium iodide 7. mg, 0.048 mmol
  • dimethylaminopropyl chloride hydrochloride 230 mg, 1.455 mmol in dry toluene (4 mL) was heated at 14O 0 C for 3.5 hours using a microwave oven SmithCreator Personal Chemistry.
  • 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, 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, 1mM CHAPS and 5mM EDTA (Cathepsin K, 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).
  • Assays are carried out in the presence of variable concentrations of test compound. Reactions are initiated by addition of enzyme and substrate to wells containing inhibitor stamped in 100% DMSO. For endpoint assays, the reaction is quenched with the addition of E64. Dose response data is fit to an IC50 curve with preset fitting tools according to equation 1 :
  • Vm is the maximum velocity
  • S is the concentration of substrate with Michaelis constant of K Ml [I] is the concentration of inhibitor
  • K is the binding constant of inhibitor for free enzyme
  • aK s is the binding constant of inhibitor for a potential enzyme-substrate complex.
  • [AMC] v s t + (v 0 - vss) [1 - exp (-k O bst)] / k o bs (4)
  • k obs k off + k on ([l]/( appK, + [l]) (6)
  • 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).

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Abstract

La présente invention concerne des dérivés de hétéroaryle nitrile substitués présentant la formule (I), des procédés pour les préparer, des compositions pharmaceutiques comprenant de tels composés, ainsi que l'utilisation de ces composés comme inhibiteurs de cystéine protéase.
PCT/EP2005/009569 2004-09-07 2005-09-05 Pyrimidines 2,4-substituees servant d'inhibiteurs de cysteine protease WO2006027211A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007149874A1 (fr) * 2006-06-20 2007-12-27 Wyeth Inhibiteurs du canal potassique kv1-5
EP1918284A1 (fr) * 2006-10-30 2008-05-07 Glaxo Group Pyrimidines d'hydrazine comme inhibiteurs de protease de cysteine
WO2008052934A1 (fr) * 2006-10-30 2008-05-08 Glaxo Group Limited Nouvelles pyrimidines substituées comme inhibiteurs de cystéine protéase
WO2008107368A1 (fr) * 2007-03-02 2008-09-12 Glaxo Group Limited Purines comme inhibiteurs de la cystéine protéase
EP1972630A1 (fr) * 2007-03-02 2008-09-24 Glaxo Group Limited Purines comme inhibiteurs de la cystéine protéase
EP2030621A1 (fr) * 2007-08-21 2009-03-04 Glaxo Group Limited Nouveaux pyrimidines comme inhibiteurs de la cystéine protéase
WO2010078906A2 (fr) * 2008-12-18 2010-07-15 Bayer Cropscience Ag Hydrazides, procédé permettant leur préparation et leur utilisation en tant qu'herbicides et insecticides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020278A1 (fr) * 2001-08-30 2003-03-13 Novartis Ag Inhibiteurs de cysteine protease ayant une structure de 2-cyano-4-amino-pyrimidine et une activite d'inhibition de cathepsine k, pour traiter les inflammations et autres troubles
WO2003101442A1 (fr) * 2002-05-31 2003-12-11 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase
WO2004020441A1 (fr) * 2002-08-30 2004-03-11 Novartis Ag Derives d'hetereoaryle nitrile

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020278A1 (fr) * 2001-08-30 2003-03-13 Novartis Ag Inhibiteurs de cysteine protease ayant une structure de 2-cyano-4-amino-pyrimidine et une activite d'inhibition de cathepsine k, pour traiter les inflammations et autres troubles
WO2003101442A1 (fr) * 2002-05-31 2003-12-11 Smithkline Beecham Corporation Inhibiteurs de peptide deformylase
WO2004020441A1 (fr) * 2002-08-30 2004-03-11 Novartis Ag Derives d'hetereoaryle nitrile

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007149874A1 (fr) * 2006-06-20 2007-12-27 Wyeth Inhibiteurs du canal potassique kv1-5
US7504517B2 (en) 2006-06-20 2009-03-17 Wyeth Kv1.5 potassium channel inhibitors
US7803827B2 (en) 2006-06-20 2010-09-28 Wyeth Llc Kv1.5 potassium channel inhibitors
EP1918284A1 (fr) * 2006-10-30 2008-05-07 Glaxo Group Pyrimidines d'hydrazine comme inhibiteurs de protease de cysteine
WO2008052934A1 (fr) * 2006-10-30 2008-05-08 Glaxo Group Limited Nouvelles pyrimidines substituées comme inhibiteurs de cystéine protéase
WO2008107368A1 (fr) * 2007-03-02 2008-09-12 Glaxo Group Limited Purines comme inhibiteurs de la cystéine protéase
EP1972630A1 (fr) * 2007-03-02 2008-09-24 Glaxo Group Limited Purines comme inhibiteurs de la cystéine protéase
EP2030621A1 (fr) * 2007-08-21 2009-03-04 Glaxo Group Limited Nouveaux pyrimidines comme inhibiteurs de la cystéine protéase
WO2010078906A2 (fr) * 2008-12-18 2010-07-15 Bayer Cropscience Ag Hydrazides, procédé permettant leur préparation et leur utilisation en tant qu'herbicides et insecticides
WO2010078906A3 (fr) * 2008-12-18 2010-10-14 Bayer Cropscience Ag Hydrazides, procédé permettant leur préparation et leur utilisation en tant qu'herbicides et insecticides

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