WO2007025776A2 - Nouveaux inhibiteurs de la cysteine protease - Google Patents

Nouveaux inhibiteurs de la cysteine protease Download PDF

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WO2007025776A2
WO2007025776A2 PCT/EP2006/008580 EP2006008580W WO2007025776A2 WO 2007025776 A2 WO2007025776 A2 WO 2007025776A2 EP 2006008580 W EP2006008580 W EP 2006008580W WO 2007025776 A2 WO2007025776 A2 WO 2007025776A2
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mmol
aldrich
nmr
mhz
stirred
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WO2007025776A3 (fr
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Jose Miguel Coteron Lopez
Esther Pilar Fernandez Velando
Jose Maria Fiandor Roman
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • 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.
  • Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g. in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by Pneumocystis Carinii, Trypsanoma cruzi, Trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, cancer, for example pancreatic cancer (see Joyce J. A.
  • gingipains Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis, Potempa, J., et al., (1994) Perspectives in Drug Discovery and Design 2, 445- 458.
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated.
  • Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of haematopoietic lineage.
  • osteoclasts which are multinuclear cells of haematopoietic lineage.
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle of resorption and formation.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, thus indicating an essential role for cysteine proteases in bone resorption. For example, Delaisse, et al., (1980) Biochem.
  • cystatin an endogenous cysteine protease inhibitor
  • cystatin an endogenous cysteine protease inhibitor
  • Other studies report a correlation between inhibition of cysteine protease activity and bone resorption.
  • cathepsin K The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption.
  • inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
  • Cathepsin K is also expressed in synovial giant cells taken from osteoarthritic patients (Dodds, et al., (1999) Arthritis & Rheumatism, 42, 1588, and Hou, et al., (2002), American Journal of Pathology 159, 2167). Cathepsin K staining is observed in osteoarthritic as well as rheumatoid arthritic samples (Hou, et al., (2002), American Journal of Pathology 159, 2167).
  • cathepsin K has also been localized to cartilage tissue and a decrease in pH in cartilage correlated with severity of damage (Konttinen, et al., (2002), Arthritis & Rheumatism, 46, 953). This observation, combined with the fact that cathepsin K is an acidic lysosomal protease, strongly suggests a physiological role of cathepsin K in cartilage turnover in addition to bone resorption. These researchers also demonstrated that cathepsin K can degrade aggrecan and type Il collagen, the two major protein components of the cartilage matrix.
  • cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis.
  • Cathepsin K has been shown to be abnormally or overexpressed in numerous tumors and in prostate cancer (Littlewood-Evans, et al., (1997), Cancer Res., 57, 5386 and Brubaker, et al., (2003), J. Bone Miner. Res., 18, 222).
  • increased levels of bone resorption marker have been detected in bone metastases of prostate cancer suggesting that cathepsin K inhibitor may have utility in preventing metastasis of tumors to bone (Ishikawa, et al., (2001 ), MoI.
  • Cathepsin L has been implicated in several diseases including osteoporosis, osteoarthritis, rheumatoid arthritis, lymphoproliferative diseases, cancer, for example pancreatic cancer, metastasis, atherosclerosis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Liu, et al., (2004), Arterioscler Throm Vase Biol. 24, 1359). Cathepsin L-deficient mice have also been shown to have increased resistance to osteoporosis following ovariectomy suggesting its potential for osteoporosis (Potts, et al., (2004) Int. J. Exp. Path. 85, 85).
  • Cathepsin S has been implicated in several diseases including immune and auto-immune disorders, rheumatoid arthritis, inflammation, inflammatory bowel disease, myesthania gravis, atherosclerosis, lymphoproliferative diseases, cancer, for example pancreatic cancer, metastasis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Liu, et al., (2004), Arterioscler Throm Vase Biol. 24, 1359).
  • Cathepsin B has been implicated in immune and auto-immune disorders, rheumatoid arthritis, inflammation, inflammatory bowel disease, myesthania gravis, osteoarthritis, lymphoproliferative diseases, cancer, for example pancreatic cancer, metastasis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Lang, et al., (2000), J. Rheumatol. 27, 1970). Cathepsin B has been implicated in the processing of invariant chain (Zhang, et al., (2000) Immunology, 100, 13) suggesting its role in immune disorders such as those listed above.
  • Cathepsin B is one of the most highly expressed cysteine protease in cartilage and inhibitors of cathepsin B has been shown to inhibit cartilage degradation. Cathepsin B may contribute to matrix degradation through cleavage of aggrecan and collagen, two components of cartilage matrix (Mort et al., (1998), Biochem. J., 335, 491 ). Additionally, cathepsin B could contribute to the mechanical loading component of osteoarthritis by cleaving lubricin, an abundant lubricating protein in synovial fluid. Cleavage of lubricin by cathepsin B has been shown to increase the coefficient of friction in synovial fluid and intact joints (Elsaid, K.A. et al. (2005), Transactions of the Orthopedic Research Society, 51 st Annual Meeting, Abstract 924). These data suggest potential for cathepsin B inhibitors in osteoarthritis.
  • cathepsins K, L, S and B In view of the number of pathological responses and conditions that are mediated by cathepsins K, L, S and B, there is a need for inhibitors of these cathepsins which can be used in the treatment of a variety of conditions.
  • 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.
  • the invention involves the compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds as protease inhibitors.
  • B represents C 1-5 alkylene
  • Y represents hydrogen, halogen, CF 3 , or Ci -3 alkyl
  • D represents a direct bond or d. 3 alkylene
  • R E and R F independently represent hydrogen or C ⁇ alkyl
  • R 4 represents chlorine, bromine or iodine. In another embodiment, R 4 represents chlorine or bromine. In a further embodiment, R 4 represents bromine.
  • X represents piperidine, piperazine or morpholine, each of which is optionally substituted.
  • X represents piperidine or piperazine, each of which is optionally substituted.
  • X represents piperidine.
  • X is unsubstituted.
  • X is optionally substituted with C ⁇ alkyl (for example, methyl).
  • Z represents piperidine, piperazine or morpholine, each of which is optionally substituted.
  • Z represents piperidine or piperazine, each of which is optionally substituted.
  • Z is unsubstituted.
  • Z is optionally substituted with d. 4 alkyl.
  • Z is optionally substituted with methyl.
  • D represents a direct bond
  • R E and R F represent C 1-4 alkyl (for example, ethyl).
  • 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 ⁇ alkylene-cycloalkyl;
  • R 3 represents hydrogen, Ci -3 alkyl, alkoxy, or -C(O)Oalkyl
  • R 4 represents hydrogen, halogen, alkoxy, -C ⁇ C-aryl, -NHCi-salkylene-aryl, NO 2 , CF 3 , or OCF 3 ;
  • R 3 and R 4 are not both hydrogen, and when R 3 is C 1-3 alkyl then R 4 is other than hydrogen;
  • A represents C(O)
  • A represents -SO 2 -
  • 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 ⁇ represents one or two aryl substituents
  • R 3 represents hydrogen, Ci -3 alkyl, alkoxy, or -C(O)Oalkyl
  • R 4 represents hydrogen, halogen, alkoxy, -C ⁇ C-aryl, -NHC 1-3 alkylene-aryl, NO 2 , CF 3 , or OCF 3 ;
  • A represents C(O)
  • R B represents hydrogen or C 1-8 alkyl
  • R G represents hydrogen or C 1-3 alkyl
  • R J represents aryl, heteroaryl, heterocyclyl, -d. 3 alkylene(aryl) 2 , -Ci-salkylene-heteroaryl, -C 1-3 aralkyl, -Ci -3 alkylene-C(O)-heterocyclyl, -O-C(O)C 1-3 alkylene-aryl, -C(O)-O-C 1- 3 alkylene-aryl or -C ⁇ alkylene-heterocyclyl
  • R 1 represents C 1-8 alkyl, or -C ⁇ alkylene-cycloalkyl. In another embodiment, R 1 represents isobutyl (2-methylpropyl). In an alternative embodiment, R 1 represents -methylene-cyclopentyl or -methylenecyclohexyl. In another embodiment, R 1 represents -methylene-cyclopentyl.
  • A represents C(O) and R 2 and R 5 together with the carbon and nitrogen atoms to which they are respectively attached form the group
  • R A , R c and R D independently represent hydrogen, aryl, -aryl- C 1-3 alkylene-heterocyclyl, -aryl-O-C ⁇ alkylene-heterocyclyl, or -NHC(O)OCi- 6 alkyl.
  • R B represents C h alky!
  • R E and R F independently represent hydrogen or C 1-3 alkyl; or R E and R F together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring;
  • R H represents hydrogen, C 1-6 alkyl, or -C 1-6 alkyleneNR E R F .
  • alkyl as a group or a part of a group refers to a linear or branched alkyl group containing the indicated number of carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl or hexyl, 3,3-dimethylbutyl and the like.
  • alkylene as a group or a part of a group refers to a linear or branched saturated hydrocarbon linker group containing the indicated number of carbon atoms. Examples of such groups include methylene, ethylene and the like. In one embodiment, alkylene is methylene.
  • alkenyl as a group or a part of a group refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and containing the indicated number of carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.
  • alkoxy as a group or a part of a group refers to an -O-alkyl group wherein alkyl is as herein defined.
  • alkyl is as herein defined. Examples of such groups include methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy, pentoxy, hexoxy and the like.
  • aralkyl as a group or a part of a group refers to an alkyl group as herein defined which contains the indicated number of carbon atoms, the alkyl group being substituted with an aryl group as herein defined.
  • aryl as a group or a part of a group refers to an optionally substituted hydrocarbon aromatic group containing one, two or three conjugated or fused rings with at least one ring having a conjugated pi-electron system.
  • groups include optionally substituted phenyl, naphthyl or tetrahydronaphthalenyl and the like.
  • aryl represents phenyl.
  • aryl represents naphthyl.
  • aryl moieties are unsubstituted.
  • aryl moieties are monosubstituted, disubstituted or trisubstituted.
  • aryl moieties are monosubstituted or disubstituted.
  • Optional aryl substituents include Ci- 4 alkyl, d. 4 alkoxy, halogen, nitro, trihalomethyl, trihalomethoxy, -C(O)CH 3 , -N(C 1 . 3 alkyl) 2 and -SO 2 -C 1-4 alkyl.
  • aryloxy as a group or a part of a group refers to an -O-aryl group wherein aryl is as herein defined.
  • biasing as a group or a part of a group refers to an aryl group which is directly substituted with a second aryl group, wherein aryl is as herein defined.
  • heteroaryl as a group or a part of a group refers to an optionally substituted aromatic group comprising one to four heteroatoms selected from N, O and S, the aromatic group containing one, two or three 5- or 6- membered conjugated or fused rings with at least one ring having a conjugated pi-electron system.
  • Examples of monocyclic heteroaryl groups include optionally substituted thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
  • 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.
  • cycloalkyl as a group or a part of a group refers to a saturated cyclic hydrocarbon group of 3 to 7 carbon atoms. Examples of such groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • cycloalkyloxy as a group or a part of a group refers to an -O-cycloalkyl group wherein cycloalkyl is as herein defined.
  • Examples of monocyclic groups include include pyrrolidinyl, azetidinyl, imidazolidinyl, oxoimidazolidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl,
  • halogen refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) atom.
  • halogen substituents are a fluorine or chlorine atom.
  • N-phthalimido refers to a phthalimide group which is bonded through the nitrogen atom.
  • At least one chemical entity selected from the list: 2-(5-bromo-2-cyano-4-pyrimidinyl)-N-(4-fluorophenyl)-N- ⁇ 3-[4-(4-methyl-1-piperazinyl)-1- piperidinyl]propyl ⁇ -2-(2-methylpropyl)hydrazine carboxamide bis(trifluoroacetate); ⁇ /-[3-(1,4 l -bipiperidin-1'-yl)propyl]-2-(5-bromo-2-cyano-4-pyrimidinyl)- ⁇ /-(4-fluorophenyl)-2- (2-methylpropyl)hydrazinecarboxamide bis(trifluoroacetate); and pharmaceutically acceptable derivatives thereof.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula I, IA or IB with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, sulfamic, nitric, phosphoric, succinic, maleic, hydroxymaleic, acrylic, formic, acetic, hydroxyacetic, phenylacetic, butyric, isobutyric, propionic, fumaric, citric, tartaric, lactic, mandelic, benzoic, o-acetoxybenzoic, chlorobenzoic, methylbenzoic, dinitrobenzoic, hydroxybenzoic, methoxybenzoic salicylic, glutamaic, stearic, ascorbic, palmitic, oleic, pyruvic, pamoic, malonic, lauric, glutaric aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic,
  • non-pharmaceutically acceptable salts for example oxalates may be used, for example in the isolation of compounds of the invention.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of Formula I, IA or IB.
  • the term "compounds of the invention” means the compounds according to Formula I, IA or IB and the pharmaceutically acceptable derivatives thereof.
  • the term “a compound of the invention” means any one of the compounds of the invention as defined above.
  • At least one chemical entity selected from a compound of Formula I, IA or IB or a pharmaceutically acceptable derivative thereof for use in human or veterinary medical therapy.
  • the compounds of the invention 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.
  • such other active agents include anti-cancer agents.
  • KQKLR-AMC N-Acetyl-Lysyl-Glutaminyl-Lysyl-Leucyl-Arginyl-y-Amido ⁇ - methylcoumarin
  • the semicarbazide compounds of Formula Ia which are compounds of Formula IA wherein, R 3 and R 4 are as defined above for Formula IA (for example R 3 is hydrogen and R 4 is halogen), R 1 is C 1-8 alkyl, -Ci -8 alkyleneN(C 1-3 alkyl) 2 , -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl or -Ci. 8 alkyleneNR G C(O)C 1 . 6 alkyl, A is C(O), (for example R 1 is C ⁇ alkyl, e.g. isobutyl), R 5 is hydrogen, C 1-6 alkyl, Ci -6 alkenyl, -Ci-8alkyleneN(Ci -3 alkyl) 2 ,
  • R 5 is hydrogen
  • R 2 is -NR H -aryl-heterocyclyl, -NR H -cycloalkyl, -NR B C 1 .
  • R H is as defined above for Formula IA; (for example R 2 is -NR H - aryl, e.g.
  • Procedure A Compounds of Formula Ma, which are compounds of Formula II, wherein R 5 is hydrogen, are reacted with one equivalent of the isocyanate, R 2x NCO, wherein R 2x N is as defined above for R 2 in Formula Ia, in the presence of a suitable base such as triethylamine in a suitable solvent such as DCM to give compounds of Formula Ia wherein R 5 is hydrogen and R H is hydrogen.
  • Procedure B A primary amine R 10 -NH 2 , or a secondary amine R 10 -NH-R H , wherein R H is as defined for Formula Ia (which are compounds of Formula IA), (for example R H is -Ci.
  • R E and R F together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, which is substituted with R E and R F in the form of a further heterocyclic ring
  • R 10 is aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, aryl-heterocyclyl, N(C 1-3 alkyl)-heteroaryl, cycloalkyl or -Ci -6 alkyleneR c , wherein R c is hydrogen, C 1-3 alkyl, aryl or halogen, (for example R 10 is aryl), is dissolved in a suitable solvent such as dry THF and cooled to a suitable temperature, e.g.
  • the amines R 10 -NH 2 and R 10 -NH-R H are either commerically available, or they may be prepared using standard procedures. For example, when the amine is R 10 -NH-R H , wherein R H is -C 1 .
  • the amine may be prepared by an alkylation reaction between a primary amine arylNH 2 and BrC 1- 6 alkyleneBr, followed by reaction of the resulting product arylNHCi -6 alkyleneBr with an amine HNR E R F .
  • acylhydrazide compounds of Formula Ib which are compounds of Formula IA wherein R 1 , R 3 , R 4 are as hereinbefore defined for Formula IA (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, R 3 represents hydrogen and R 4 represents halogen),
  • A is C(O)
  • R 5 is hydrogen, C 1-6 alkyl, -C 1-8 alkylene-heterocyclyl, -C 1-8 alkyleneN(C 1-3 alkyl) 2 , -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl, -C 1-8 alkyleneNR G C(O)C 1-6 alkyl; (for example, R 5 is hydrogen); and
  • R 2 is aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-heterocyclyl, biaryl, aryl-heteroaryl, -heteroaryl-aryl, -aryl
  • -heteroaryl-aryl-C L salkylene-heterocyclyl, -aryl-C 1-3 alkylene-heterocyclyl-R J , -aryl-O-Ci. 3 alkylene-heterocyclyl or C 1-6 alkyleneR A , wherein R A is hydrogen, C 1-3 alkyl, halogen, - N(Ci.
  • R 2 is -phenyl-C 1-3 alkylene-X, -pyridyl-phenyl-C 1-3 alkylene-X or - phenyl-C 1-3 alkylene-X-R J , wherein phenyl is optionally substituted with one group selected from halogen or CF 3 ); may be prepared from the corresponding hydrazine compounds of Formula II, wherein R 1 , R 3 and R 4 are as hereinbefore defined for Formula IA, (for example, R 1 represents C 1-8 alkyl, e.g.
  • R 3 represents hydrogen and R 4 represents halogen
  • R 5 is hydrogen, C 1-8 alkyl, -C 1-8 alkylene-heterocyclyl, -Ci -8 alkyleneN(Ci. 3 alkyl) 2 , -C 1-8 alkyleneNR G C(O)OC 1-6 alkyl or -C 1-8 alkyleneNR G C(O)C 1-6 alkyl; (for example, R 5 is hydrogen); according to Scheme 3.
  • Compounds of Formula Il are reacted with an acid chloride R 2 COHaI, wherein R 2 is as defined above for Formula Ib, and Hal is Cl or Br, in a suitable solvent such as py ds of Formula Ib.
  • acylhydrazide compounds of Formula Ibi which are compounds of Formula Ib (and therefore of Formula IA) wherein R 1 , R 3 , R 4 are as hereinbefore defined for Formula IA, (for example, R 1 represents d- ⁇ alkyl, e.g. isobutyl, R 3 represents hydrogen and R 4 represents halogen), A is C(O), R 5 is hydrogen, C 1-6 alkyl, -C 1-8 alkyleneN(C 1 .
  • R 5 is hydrogen
  • R 2 is -aryl-Ci-salkylene-heterocyclyl, -aryl-C ⁇ alkylene-heterocyclyl-R'', -heteroaryl-aryl-Ci-salkylene-heterocyclyl, (for example, R 2 is -phenyl-C 1-3 alkylene-X, - pyridyl-phenyl-C 1-3 alkylene-X or -phenyl-Ci -3 alkylene-X-R J , wherein phenyl is optionally substituted with one group selected from halogen or CF 3 ); may be prepared from the corresponding acylhydrazide compounds of Formula XII, wherein R 1 , R 3 and R 4 are as hereinbefore defined for Formula IA, (for example, R 1 represents C 1-8 alkyl, e.g.
  • R 3 represents hydrogen and R 4 represents halogen
  • 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; (for example, R 5 is hydrogen); and R x is -arylhaloC 1-3 alkylene or -heteroaryl- arylhaloC L salkylene, by reaction with compounds of Formula XIII, which compounds are heterocyclyl or heterocyclyl-R J , for example compounds XIII are "X" or "X-R J ", wherein "X" and “R J " are as defined hereinabove for Formula I, in the presence of a base, for example an inorganic base such as potassium carbonate, or an organic base such as an amine, e.g. DIPEA, and optionally in the presence of i
  • Scheme 4 Compounds of Formula XII may be prepared using an analogous procedure to that described for Scheme 3, by a reaction between compounds of Formula Il and R x CHal, wherein R x is R x is -arylhaloC 1-3 alkylene or -heteroaryl-arylhaloC 1-3 alkylene, and Hal is Cl or Br, in the presence of a base, for example an inorganic base such as potassium carbonate, or an organic base such as an amine, e.g. DIPEA.
  • a base for example an inorganic base such as potassium carbonate, or an organic base such as an amine, e.g. DIPEA.
  • Compounds of Formula IA may be prepared from compounds of Formula III, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above for Formula IA, according to Scheme 5 by cyanation, by displacement of the chloro substituent of compounds of Formula III using a variety of conditions, for example by treatment with potassium or sodium cyanide in the presence of a suitable base such as DABCO in a suitable solvent such as DMSO.
  • alkoxycarbonyl hydrazine compounds of Formula Ic which are compounds of Formula IA wherein R 1 , R 3 and R 4 are as defined above for Formula IA, A is C(O), and R 5 is hydrogen, C 1-6 alkyl, C 1-6 alkenyl, -C 1-8 alkyleneN(C 1-3 alkyl)2,
  • R 11 is C 1-6 alkenyl, or -C 1-6 alkyleneR D , wherein R D is hydrogen, Ci -3 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclyl, CCI 3 , cyano, -NHC(O)C 1-6 alkyl, -NHC(O)OC 1-6 alkyl, or -C(O)Ci.
  • 6 alkyl may be prepared from the corresponding hydrazine compounds of Formula II, wherein R 5 is hydrogen, C 1-8 alkyl, C 1-6 alkenyl, -C 1-8 alkyleneN(Ci -3 alkyl) 2 , -C 1-8 alkyleneNR G C(O)OC 1 . 6 alkyl or -C 1-8 alkyleneNR G C(O)C 1-6 alkyl and R 1 , R 3 and R 4 are as defined above for Formula IA, according to Scheme 6.
  • Chloroformates R 11 OCOCI are either commercially available, or they may be obtained by reaction between the corresponding commercially available alcohol R 11 OH, wherein R 11 is as defined above for Formula Ic, and triphosgene in a suitable solvent such as THF, which may be directly reacted with compounds of Formula Il in the presence of a suitable base such as triethylamine in a suitable solvent, for example pyridine, to give compounds of Formula Ic.
  • Compounds of Formula Na which are compounds of Formula Il wherein R 5 is hydrogen, may be prepared from compounds of Formula IV, wherein R 1 , R 3 and R 4 are as defined above for Formula Il (for example, R 1 represents Ci -8 alkyl, e.g. isobutyl, R 3 represents hydrogen and R 4 represents halogen), according to Scheme 7 by deprotection in the presence of a suitable acid such as trifluoroacetic acid.
  • Compounds of Formula IV may be prepared from compounds of Formula V, wherein R 1 , R 3 and R 4 are as defined above for Formula IV (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, e.g. cycloalkylmethyl, R 3 represents hydrogen and R 4 represents halogen), according to Scheme 8 by cyanation, by displacement of the chloro substituent of compounds of Formula V using a variety of conditions, for example by treatment with potassium or sodium cyanide in the presence of a suitable base such as DABCO in a suitable solvent such as DMSO.
  • R 1 , R 3 and R 4 are as defined above for Formula IV (for example, R 1 represents C 1-8 alkyl, e.g. isobutyl, e.g. cycloalkylmethyl, R 3 represents hydrogen and R 4 represents halogen)
  • Scheme 8 by cyanation, by displacement of the chloro substituent of compounds of Formula V using a variety of conditions, for example by treatment with potassium or sodium cyan
  • Compounds of Formula V may be prepared from compounds of Formula Vl, wherein R 1 is as defined above for Formula V (for example, R 1 represents d ⁇ alkyl, e.g. isobutyl, e.g. cycloalkylmethyl), according to Scheme 9 by reaction of compounds of Formula Vl with a compound of Formula VII, wherein R 3 and R 4 are as described for Formula V, (for example, R 3 represents hydrogen and R 4 represents halogen), (commercially available from FLUKA or SIGMA) in a suitable solvent such as EtOH, for example at room temperature for 3-4 days, for example according to the literature procedure given in Bagley J. R. et al., (1989) J. Med. Chem. 32, 663-671.
  • R 1 is as defined above for Formula V
  • R 1 represents d ⁇ alkyl, e.g. isobutyl, e.g. cycloalkylmethyl
  • Scheme 9 by reaction of compounds of Formula Vl with a compound of Formula VII, wherein
  • Compounds of Formula Vl may be prepared from the compound of Formula VIII by a reductive amination reaction with an aldehyde IX, wherein R 13 is one carbon shorter in chain length than R 1 , wherein R 1 is C 1-8 alkyl, -C 1-8 alkyleneNR E R F , -Ci ⁇ alkyleneNR G C(O)OC 1-6 alkyl, -C 1-8 alkyleneNR G C(O)Ci. 6 alkyl or -C ⁇ alkylene- cycloalkyl, (for example, R 1 represents C h alky!, e.g. isobutyl), according to Scheme 10.
  • the compound of Formula VIII, te/t-butyl carbazate, is commercially available (ALDRICH).
  • Aldehydes of Formula IX are either commercially available, e.g. isobutylaldehyde, or they may be prepared according to Scheme 11 i) from the corresponding commercially available dimethyl or diethyl acetal compound of Formula X wherein R 13 is as defined above for compounds of Formula IX, by acid hydrolysis using a suitable acid such as hydrochloric acid, or ii) by oxidation of the commercially available alcohol compound of Formula Xl, wherein R 13 is as defined above for compounds of Formula IX, following standard procedures as the Swern oxidation or Dess-Martin oxidation.
  • Compounds of Formula Ib(iv) which are compounds of Formula IA wherein R 2 , R 3 , R 4 and R 5 are as defined for Formula Ib(iii), R 1 is -C ⁇ alkyleneNCCOJC ⁇ alkyl, and A is C(O), may be prepared from compounds of Formula Ib(iii) as defined above, according to Scheme 13, by treatment of lb(i) with an anhydride of Formula O[C(O)C 1-6 alkyl] 2 in a suitable to 10 0 C.
  • R G is as defined for Formula IA, or N-phthalidimido-CI- ⁇ alkylene-, and R 2 is OR 11 in which R 11 is
  • Ci -6 alkenyl or -C ⁇ alkyleneR 0 wherein R D is hydrogen, Ci -3 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclyl, CCI 3 , cyano, -NHC(O)C 1-6 alkyl, -NHC(O)OC ⁇ alkyl, or -C(O)C 1-6 alkyl, may be prepared from compounds of Formula Ilia wherein R 3 and R 4 are as defined above for Formula IA, R 1 is C ⁇ alkyl, and R 5 is hydrogen and R 2 is OR 11 in which R 11 is as defined for lc(i), according to Scheme 14 by treatment of IMa with an alkylating agent of Formula R 5 -CI, R 5 -Br or R 5 OSO 2 Y, wherein R 5 is as defined for Formula lc(i) and Y is methyl or p-tolyl, in the presence of a suitable catalyst such as tetrabutyl
  • Compounds of Formula Id which are compounds of Formula IA wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above for Formula IA, A is -SO 2 -, may be prepared from compounds of Formula Il wherein R 1 , R 3 , R 4 and R 5 are as defined above for Formula IA according to Scheme 15, by treatment of compounds Il with a sulfonyl chloride R 2 SO 2 CI, wherein R 2 is as defined above for Formula I; in a suitable solvent such as pyridine.
  • Sulfonyl chlorides R 2 SO 2 CI may be commercially available or they may be prepared from the corresponding sulfonic acids R 2 SO 2 OH by treatment of the sulfonic acids with thionyl chloride in a suitable solvent such as toluene at elevated temperatures such as 90-170 0 C.
  • R 3 and R 4 groups in compounds of Formula IA may be converted into other R 3 and R 4 groups in order to provide further compounds of Formula IA.
  • R 4 when R 4 is bromo, it may be converted to R 4 is -C ⁇ C-aryl by reaction with H-C ⁇ C-aryl in the presence of copper (I) iodide and bis(triphenylphosphine)palladium(ll) chloride.
  • R 4 when R 4 is bromo, it may be converted to R 4 is NHC 1-3 alkylene-aryl by reaction with a suitable amine H-NHC 1 .
  • R 4 is bromo
  • R 4 may be converted to R 4 is CF 3 by reaction with 2,2-difluoro-2-(fluorosulfonyl)acetate, hexamethylphosphoramide and copper (I) iodide, optionally heating at a suitable temperature, for example 80 0 C.
  • conversions may be carried out on compounds of Formula III, for example when R 3 is chloro, it may be converted to R 3 is methoxy by reaction with sodium methoxide in a suitable solvent, for example methanol.
  • suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), 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).
  • acyl type protecting groups e.g. formyl, trifluoroacetyl, acetyl
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
  • aliphatic urethane protecting groups e
  • oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl or fert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
  • alky silyl groups such as trimethylsilyl or fert-butyldimethylsilyl
  • alkyl ethers such as tetrahydropyranyl or tert-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 (ALDRICH; 6.4 ml, 70 mmol) over 15 min and stirring at O 0 C for 2 h, then the mixture was stirred 5 h at room temperature.
  • PtO 2 PtO 2 and the suspension was hydrogenated at room temperature and 2.6 bar for 48 h. The suspension was filtered and the solvent was removed under reduced pressure to give the title compound.
  • 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 (1.81 g, 13.1 mmol) was added. This mixture was stirred at 0° C for 30 min. Then, methyl 4-(bromomethyl) benzoate (ALDRICH, 3 g, 13.1 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 17 h. The mixture was concentrated under reduce pressure. The residue was dissolved in DCM and washed with water, the aqueous layer was extracted with DCM.
  • a solution of methyl 4-hydroxyphenylacetate (ALDRICH, 1.2 g, 7.22 mmol) in THF (75 mL) was treated at O 0 C under nitrogen with triphenylphosphine (ALDRICH, 2.85 g 10.83 mmol) and 4-(2-hydroxyethyl)-morpholine (ALDRICH, 0.947 g, 7.22 mmol),
  • ADRICH diisopropylazodicarboxylate
  • the solution mixture was stirred at O 0 C for 30 minutes, then, it was stirred at room temperature for 8 hours.
  • 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 dropwise.
  • the reaction mixture was stirred a room temperature overnight.
  • Residue was immediately dissolved in 17 mL of anhydrous acetonitrile and sodium bicarbonate (PANREAC, 784 mg, 9.3 mmol) and n- butylamine (ALDRICH, 0.768 mL, 7.75 mmol) were added. The suspension was heated at 50-55 0 C for 2 hours and more sodium bicarbonate (PANREAC, 784 mg, 9.3 mmol) and n- butylamine (ALDRICH, 0.768 mL, 7.75 mmol) were added. Reaction was heated at 50- 55 0 C overnight, then was cooled, filtered over Celite and solvent was evaporated to dryness. Residue was dissolved in AcOEt and was washed with sat.
  • PANREAC sodium bicarbonate
  • ADRICH n- butylamine
  • 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).
  • ADRICH 1-Fluoro-4-iodobenzene (ALDRICH, 410 mg, 1.85 mmol), butylamine (ALDRICH, 0.274 mL, 2.77 mmol), potassium carbonate (ALDRICH, 510 mg, 3.69 mmol), copper(l) iodide (ALDRICH, 35 mg, 0.185 mmol) and L-proline (ALDRICH, 43mg, 0.37 mmol) were dissolved in 4 mL of anhydrous DMSO. The resultant suspension was heated at 6O 0 C overnight. More butylamine (ALDRICH, 0.274 mL, 2.77 mmol) was added and reaction was heated at 8O 0 C for 3 days.
  • the title compound was prepared by a method analogous to that described for intermediate 65 using intermediates 5 and 63 as starting reagents.
  • the title compound was prepared by a method analogous to that described for intermediate 65, using intermediates 5 and 64 as starting reagents.
  • a mixture of 5-Bromo-6-methyluracil (ALDRICH, 1.5 g, 7.3 mmol) and phosphorous oxychloride (ALDRICH, 5mL) was refluxed for 6 h.
  • the reaction mixture was poured into iced water.
  • the brown colour solid that precipitated was filtered off and the residue was used without purification.
  • 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.
  • Example 172 To a solution of Example 172 (710 mg, 1.78 mmol) in ACN (14 mL), p-toluensulfonic acid (ALDRICH, 758 mg, 4.46 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. The mixture was washed with water and sat. sodium bicarbonate. The organic layer was treated with brine and dried over anhydrous Na 2 SO 4 to give the title compound.
  • 1 H NMR 300 MHz, d 6 -DMSO) ⁇ ppm: 8.41 (s, 1 H), 5.01 (s, 2H), 3.35 (dd, 2H), 1.53 (dd, 2H), 0.92 (s, 6H).
  • Example 177 To a solution of Example 177 (1 g, 2.6 mmol) in 20 mL of dry ACN, p-toluensulfonic acid
  • Example A 2-(5-bromo-2-cyano-4-pyrimidinyl)- ⁇ /-(4-fluorophenyl)- ⁇ /- ⁇ 3-[4-(4-methyl- 1 -piperazinyl)-1 -piperidinyl]propyl ⁇ -2-(2-methylpropyl)hydrazine carboxamide bis(trifluoroacetate).
  • Example B ⁇ /-[3-(1 ,4'-bipiperidin-1 '-yl)propyl]-2-(5-bromo-2-cyano-4-pyrimidinyl)-/V- roacetate).
  • Reference Examples 2-1 1 and 13-63 were prepared by methods analogous to that described for Reference Example 1 using Intermediate 5 or 8 and replacing Intermediate 10 or 4-[(4-methyl-1-piperazinyl) methyl]benzoyl chloride with the acids or the acid chlorides indicated in Table 1.
  • Comparative Example 12 /V-(5-bromo-2-cyano-4-pyrimidinyl)-W-(2,2-dimethylpropyl)- 4-[(4-methyl-1-piperazinyl)methyl]benzohydrazide.
  • Reference Examples 64-88 were prepared by methods analogous to that described for Reference Example 1 using Intermediates 33, 39 or 42 and replacing Intermediate 10 or 4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride with the acids or the acid chlorides indicated in Table 2 .
  • Reference Example 84 W-(5-chloro-2-cyano-4-pyrimidinyl)-W-(2,2-dimethylpropyl)-3- [(4-propyl-1 -piperazinyl)methyl]benzohydrazide.
  • Reference Examples 90-135 were prepared by methods analogous to that described for Reference Example 89 using Intermediates 43 or 44 and replacing 1 -phenyl piperazine with the amines indicated in Table 3
  • Reference Example 92 4-(1,4'-bipiperidin-1'-ylmethyl)- ⁇ r-(5-chloro-2-cyano-4- pyrimidinyl)-W-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • ADRICH 55mg, 0.162mmol
  • potassium carbonate ADRICH, 336mg, 2.43mmol
  • sodium hydroxide PANREAC, 97mg, 2.43mmol
  • sodium iodide FLUKA, 12mg, O.O ⁇ mmol
  • iodomethane ADRICH, 0.15 mL, 2.43mmol
  • Reference Examples 137-143 were prepared by methods analogous to that described for Reference Example 136 using Intermediates 4, 7, 38 or 41 and replacing methyl iodide with the alkylating reagents indicated in Table 4.
  • Reference Examples 152-154 were prepared by methods analogous to that described for Reference Example 151 replacing Intermediate 58 with the Intermediates indicated in Table 6.
  • Reference Examples 156-158 were prepared by methods analogous to that described for Reference Example 155 replacing Intermediate 65 with the Reference Example indicated in Table 7.
  • Reference Example 159 /V-(5-bromo-2-cyano-4-pyrimidinyl)-4-fluoro-/V-[3-(4-methyl- 1-piperazinyl)propyl]-W-(2-methylpropyl)benzohydrazide.
  • Reference Examples 160-161 were prepared by methods analogous to that described for Reference Example 159 replacing 4-fluorobenzoyl chloride with the acid chlorides indicated in Table 8.
  • Reference Example 162 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-4-fluoro- ⁇ /-[3-(4-methyl- 1-piperazinyl)propyl]-W-(2-methylpropyl)benzohydrazide.
  • Reference Examples 163-164 were prepared by methods analogous to that described for Reference Example 162 replacing 4-fluorobenzoyl chloride with the acid chlorides indicated in Table 9. Table 9
  • Reference Example 166 1,1-dimethylethyl 2- ⁇ 2-cyano-5-[(phenylmethyl)amino]-4- pyrimidinyl ⁇ -2-(2-methylpropyl)hydrazinecarboxylate.
  • Reference Example 171 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-W-(3,3-dimethylbutyl)-4- fluoro benzohydrazide.
  • Reference Examples 174-176 were prepared by method analogous to that described for Reference Example 1 using Intermediate 80 and replacing Intermediates 10 or 4-[(4- methyl-1-piperazinyl) methyl]benzoyl chloride with the acids or the acid chlorides indicated in Table 10.
  • Reference Example 180 ⁇ f-(5-bromo-2-cyano-4-pyrimidinyl)-4-fluoro- ⁇ P-(3- methylbutyl) benzohydrazide.
  • Reference Example 181 ⁇ r-(5-chloro-2-cyano-4-pyrimidinyl)-4-fluoro- ⁇ T-(3- methylbutyl) benzohydrazide.
  • Reference Examples 187-191 were prepared by methods analogous to that described for Reference Example 186 using Intermediates 5 or 8 and replacing benzene sulfonyl chloride with the sulfonic acid chlorides indicated in Table 11.
  • Reference Example 192 methyl 2-cyano-6-[2- ⁇ [(1 ,1-dimethylethyl)oxy]carbonyl ⁇ -1-(2- methyl propyl)hydrazino]-4-pyrimidinecarboxylate.
  • Reference Example 196 ⁇ T-(5-chloro-2-cyano-4-pyrimidinyl)-4-( ⁇ 4-[(1-methyl-3- piperidinyl)methyl]-1-piperazinyl ⁇ methyl)- ⁇ f-(2-methylpropyl)benzohydrazide trifluoroacetate.
  • Reference Example 200 N'-(5-chloro-2-cyano-4-pyrimidinyl)-N'-(2-methylpropyl)-4- ⁇ [4-(4-pyridinyl)-1-pi tate.
  • Reference Example 202 W-(5-chloro-2-cyano-4-pyrimidinyl)-A/'-(2-methylpropyl)-4- ( ⁇ 4-[2-(1-pyrrolidinyl) e trifluoroacetate.
  • Reference Example 203 /V-(5-chloro-2-cyano-4-pyrimidinyl)-4-( ⁇ 4-[2- (dimethylamino)ethyl]-1-piperazinyl ⁇ methyl)-AT-(2-methylpropyl)benzohydrazide trifluoroacetate.

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Abstract

L'invention concerne des dérivés hétéroaryle nitrilés substitués de formule (I), des procédés de préparation de ces composés, des compositions pharmaceutiques les contenant, ainsi que leur utilisation en tant qu'inhibiteurs de la cystéine protéase.
PCT/EP2006/008580 2005-09-02 2006-08-31 Nouveaux inhibiteurs de la cysteine protease WO2007025776A2 (fr)

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EP2030621A1 (fr) * 2007-08-21 2009-03-04 Glaxo Group Limited Nouveaux pyrimidines comme inhibiteurs de la cystéine protéase
WO2008052934A1 (fr) * 2006-10-30 2008-05-08 Glaxo Group Limited Nouvelles pyrimidines substituées comme inhibiteurs de cystéine protéase
EP2168600A1 (fr) 2007-06-08 2010-03-31 Nippon Chemiphar Co., Ltd. Agent thérapeutique ou prophylactique contre l'anévrisme cérébral
US20100331545A1 (en) 2007-10-24 2010-12-30 Nippon Chemiphar Co., Ltd. Regulator for signaling toll-like receptor, which comprises cathepsin inhibitor as active ingredient
DE102008063561A1 (de) * 2008-12-18 2010-08-19 Bayer Cropscience Ag Hydrazide, Verfahren zu deren Herstellung und deren Verwendung als Herbizide und Insektizide
JP7271566B2 (ja) * 2018-03-28 2023-05-11 ハンリム ファーマシューティカル カンパニー リミテッド ２－シアノピリミジン－４－イル カルバメート誘導体もしくはウレア誘導体またはその塩及びそれを含む医薬組成物

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US20040249153A1 (en) * 2001-08-30 2004-12-09 Eva Altmann Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity for the treatment of inflammations and other diseases

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US20040249153A1 (en) * 2001-08-30 2004-12-09 Eva Altmann Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity for the treatment of inflammations and other diseases

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