WO2001012188A1 - 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents - Google Patents

3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents Download PDF

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Publication number
WO2001012188A1
WO2001012188A1 PCT/US2000/017878 US0017878W WO0112188A1 WO 2001012188 A1 WO2001012188 A1 WO 2001012188A1 US 0017878 W US0017878 W US 0017878W WO 0112188 A1 WO0112188 A1 WO 0112188A1
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Prior art keywords
pyrazol
cyclopropyl
urea
amino
phenethyl
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PCT/US2000/017878
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English (en)
French (fr)
Inventor
Paolo Pevarello
Paolo Orsini
Gabriella Traquandi
Mario Varasi
Edward L. Fritzen
Martha A. Warpehoski
Betsy S. Pierce
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Pharmacia & Upjohn S.P.A.
Pharmacia & Upjohn Company
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Priority to MXPA02001497A priority Critical patent/MXPA02001497A/es
Priority to KR1020027001815A priority patent/KR20020060158A/ko
Application filed by Pharmacia & Upjohn S.P.A., Pharmacia & Upjohn Company filed Critical Pharmacia & Upjohn S.P.A.
Priority to CA002380786A priority patent/CA2380786A1/en
Priority to EP00955241A priority patent/EP1202734B1/en
Priority to IL14792500A priority patent/IL147925A0/xx
Priority to NZ517238A priority patent/NZ517238A/en
Priority to EA200200249A priority patent/EA200200249A1/ru
Priority to SK208-2002A priority patent/SK2082002A3/sk
Priority to AU67470/00A priority patent/AU6747000A/en
Priority to HU0301857A priority patent/HUP0301857A2/hu
Priority to DE60034683T priority patent/DE60034683T2/de
Priority to BR0013277-2A priority patent/BR0013277A/pt
Priority to JP2001516534A priority patent/JP2003507328A/ja
Publication of WO2001012188A1 publication Critical patent/WO2001012188A1/en
Priority to NO20020687A priority patent/NO20020687L/no
Priority to HK03101874.6A priority patent/HK1049790A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to 3(5)-ureido-pyrazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, particularly in the treatment of cancer and proliferative disorders.
  • cytotoxic drugs such as, e.g. fluorouracil (5-FU), doxorubicin and camptothecins, cause damage to DNA or to affect cellular metabolic pathways and thus cause, in many cases, an indirect block of the cell cycle. Therefore, by producing an irreversible damage to both normal and tumor cells, these agents result in a significant toxicity and side-effects.
  • restriction points a family of enzymes known as the cyclin-dependent kinases (cdk).
  • cdk cyclin-dependent kinases
  • Checkpoint controls are defective in tumor cells due, in part, to disregulation of cdk activity. For example, altered expression of cyclin E and cdk's has been observed in tumor cells, and deletion of the cdk inhibitor p27 KIP gene in mice has been shown to result in a higher incidence of cancer.
  • cdks are rate-limiting enzymes in cell cycle progression and, as such, represent molecular targets for therapeutic intervention.
  • the direct inhibition of cdk/cyclin kinase activity should be helpful in restricting the unregulated proliferation of a tumor cell.
  • 3-ureido-pyrazoles have cdk/cyclin kinase inhibitory activity and are thus useful in therapy as antitumor agents and lack, in terms of both toxicity and side effects, the aforementioned drawbacks of known antitumor drugs.
  • the compounds of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosar
  • these 3-ureido- pyrazole derivatives are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
  • the compounds of the invention may be useful in the treatment of Alzheimer's disease, as suggested by the fact that cdk5 is involved in the phosphorylation of tau protein (J. Biochem., 117, 741-749, 1995).
  • the compounds of this invention may also useful in the treatment of cancer, viral infections, prevention of AIDS development in HIV-infected individuals, autoimmune diseases and neurodegenerative disorders.
  • the compounds of this invention may also be useful in inhibiting tumor angiogenesis and metastasis.
  • the compounds of this invention may also act as inhibitors of other protein kineses, e.g. protein kinase C, her2, rafl, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abl and thus be effective in the treatment of diseases associated with other protein kineses.
  • the present invention provides a method for the treatment of cell proliferative disorders associated with an altered cell dependent kinase activity, comprising administering to a mammal in need thereof an effective amount of a compound represented by formula (I):
  • R is a C,-C 6 alkyl, aryl or arylalkyl group, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N-carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsulphonyl, arylamino,
  • R is -(CH 2 ) n -R 3 ; n is 0 or an integer from 1 to 4;
  • R 3 is hydrogen, hydroxy, amino, or it is selected from the group consisting of cycloalkyl, aryl and heterocyclyl, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N- carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsul
  • R 2 is hydrogen, or
  • R 2 and R together with the nitrogen atom to which they are bonded, form a heterocyclyl or heteroaryl group, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N- carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsulphonyl, ary
  • the cell proliferative disorder is selected from the group consisting of cancer, Alzheimer's disease, viral infections, autoimmune diseases and neurodegenerative disorders.
  • Examples of types of cancer that may be treated include carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, and post- surgical stenosis and restenosis.
  • inventive method provides tumor angiogenesis and metastasis inhibition.
  • inventive method may also provide cell cycle inhibition or cdk/cyclin dependent inhibition.
  • the present invention also provides a 3-ureido-pyrazole derivative represented by formula (I):
  • R is a C,-C 6 alkyl, aryl or arylalkyl group, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N-carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsulphonyl, arylamino,
  • R is -(CH 2 ) n -R 3 ; n is 0 or an integer from 1 to 4;
  • R 3 is hydrogen, hydroxy, amino, or it is selected from the group consisting of cycloalkyl, aryl and heterocyclyl, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N- carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsul
  • R 2 is hydrogen, or
  • R 2 and R together with the nitrogen atom to which they are bonded, form a heterocyclyl or heteroaryl group, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N- carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsulphonyl, ary
  • the present invention also provides a process for preparing the 3-ureido-pyrazole derivative, or a pharmaceutically acceptable salt thereof, by:
  • the present invention also provides a process for preparing the 3-ureido-pyrazole derivative, or a pharmaceutically acceptable salt thereof, by:
  • R, R, and R 2 are as defined above;
  • the present invention also provides a pharmaceutical composition, comprising the 3- ureido-pyrazole derivative and at least one pharmaceutically acceptable carrier and/or diluent.
  • 3-ureido-pyrazole derivatives are known in the art as pesticides, herbicides or even as therapeutic agents. Among them are, as an example, heteroaryl-pyrazoles active as p38 kinase inhibitors (WO 9852941, G.D. Searle and Co.). Aryl-ureido-pyrazoles such as, for instance, phenyl-ureidopyrazoles are also known in the art as p38 kinase inhibitors (WO 99/32111, Bayer Co.). Several 5-aryl-(lH-pyrazol-5-yl)-urea derivatives are known in the art as neuropeptide Y antagonists useful as hypolipemic agents (WO 98//24768, Banyu pharmaceutical Co.).
  • halogen atom includes a fluorine, chlorine, bromine or iodine atom.
  • alkyl and alkoxy include C,- C 6 alkyl and C,-C 6 alkoxy groups.
  • the term straight or branched C,-C 6 alkyl or C,-C 6 alkoxy group includes a group selected from, methyl, ethyl, npropyl. isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, n-pentyl, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.
  • alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, alkylcarbonyl, alkylsulphonyl, alkoxycarbonyl, N-alkylpiperazinyl and the like we intend any of the aforementioned groups wherein the alkyl and alkoxy moieties stand for C,-C 6 alkyl or alkoxy groups.
  • cycloalkyl includes a C 3 -C 6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl as well as cycloalkyl and bridged cycloalkyl groups with up to 10 carbon atoms.
  • aryl stands for mono-, bi- or poly- carbocyclic or heterocyclic hydrocarbons with from 1 to 4 ring moieties, wherein at least one of the rings is aromatic, either fused or linked to each other by single bonds. These groups may have from 5 to 20 carbon atoms, preferably from 6 to 20 carbon atoms.
  • aryl also include aromatic heterocycles otherwise referred to as heteroaryl groups.
  • heterocycle refers to a 5 or 6 membered saturated or unsaturated carbocycle wherein one or more carbon atoms are replaced by one or more atoms selected from nitrogen, oxygen and sulphur.
  • the number of heteroatoms is not limited and may be, for example, one, two, three, or more.
  • aryl groups include phenyl, 1-naphtyl, 2-naphthyl, indanyl, indenyl, biphenyl, benzocycloalkyl, e.g. bicyclo[4.2.0]octa-l,3,5,-triene, benzoheterocyclyl, e.g.
  • Example of heterocycles are pyrrolidine, piperidine, piperazine, morpholine and the like.
  • C 2 -C 4 alkenyl or alkynyl includes a group selected from vinyl, allyl, 1- propenyl, isopropenyl, 1-butenyl, 2-butenyl. 3-butenyl, ethynyl. propynyl, butynyl and the like.
  • perfluorinated alkyl group includes a C,-C 4 alkyl group further substituted by more than one fluorine atom such as, for instance, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl and the like.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts with inorganic or organic, e.g., nitric, hydrochloric, hydrobromic, sulphuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, isethionic and salicylic acid, as well as the salts with inorganic or organic bases, e.g., alkali or alkaline-earth metals, especially sodium, potassium, calcium or magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine or piperidine.
  • inorganic or organic bases e.g., alkali or alkaline-earth
  • the compounds of formula (I) may have asymmetric carbon atoms and may therefore exist either as racemic admixtures or as individual optical isomers.
  • Preferred compounds of the invention of formula (I), are those where R is a C 3 -C 6 cycloalkyl or an optionally substituted straight or branched C r C 4 alkyl group, a cycloalkyl or an aryl or arylalkyl group, and R, is a C,-C 4 alkyl group or a phenyl, phenylalkyl, heteroaryl, heteroarylalkyl or heterocyclyl group, each being optionally substituted as defined above.
  • R is a C 3 -C 6 cycloalkyl and R, is a C,-C 4 alkyl group substituted by hydroxy or amino, or is an aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the aryl or heterocyclyl moiety is selected from the group consisting of phenyl or optionally benzocondensed pyiridine, indole, thiophene, thiazole, isoxazole, furan, piperidine, morpholine, each optionally further substituted.
  • Another class of preferred compounds of formula (I) are those where R, and R 2 form an optionally substituted heterocyclyl ring such as piperidino, piperazino or morpholino.
  • the number of substituents is not particularly limited.
  • the groups described above may be substituted with, for example, one, two, three, or more of the substituents.
  • the substituents may be the same or different, i.e., they are indepedently selected.
  • Examples of preferred compounds of the invention which may be in the form of a pharmaceutically acceptable salt, e.g., hydrobromide or hydrochloride salt, include the following:
  • N-cyclobutyl-N'-(3 -cyclopenthyl-lH-pyrazol-5-yl)urea N-(3-cyclopenthyl lH-pyrazol-5-yl)-l-pyrrolidinecarboxamide
  • N-(3-cyclopropyl-lH-pyrazol-5-yl)-N'-(3-aminophenyl)urea N-(3 -cyclopropyl- 1 H-pyrazol-5-yl)-N'-( 1 H-imidazol-6yl)urea; N-(3-cyclopropyl-lH-pyrazol-5-yl)-N'-(3-hydroxyphenyl)urea; N-(3-cyclopropyl- 1 H-pyrazol-5-yl)-N'-(4-hydroxyphenyl)urea.
  • the compounds of formula (I) object of the present invention and the salts thereof can be obtained, for instance, by a process comprising: (a) reacting a compound of formula (II):
  • R is defined as above;
  • the compounds of formula (V) may be obtained by a process comprising:
  • the compounds of formula (I) may alternatively be obtained by a process comprising:
  • the compounds of formula (I) can alternatively be obtained by a process comprising: (a) reacting a compound of formula (V):
  • the compounds of formula (I) can alternatively be obtained by a process comprising:
  • the compounds of formula (I) can alternatively be obtained by a process comprising: (a) reacting the oxime resin (XVI) with triphosgene to give a polystyrene supported agent (XVII):
  • reaction between a compound of formula (II) or formula (V) and a compound of formula (III) can be carried out in the presence of sodium hydrogen carbonate or a tertiary base, such as triethylamine, N-methylmo ⁇ holine, N,N-diisopropylethylamine or pyridine, in a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide, at a temperature ranging from about 10°C to reflux.
  • sodium hydrogen carbonate or a tertiary base such as triethylamine, N-methylmo ⁇ holine, N,N-diisopropylethylamine or pyridine
  • a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydrofuran,
  • reaction of a compound of formula (IV) to give a compound of formula (I) can be carried out with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate in a suitable solvent such as a mixture of methanol or ethanol and water at room temperature.
  • a base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate
  • a suitable solvent such as a mixture of methanol or ethanol and water at room temperature.
  • reaction of the compounds of formula (II) and the compounds of formula (III) to give the compounds of formula (XIII) can be carried out with a base such as sodium hydrogencarbonate or sodium hydrate in suitable solvent such as ethanol or methanol at room temperature.
  • the reaction of the compounds of formula (XIII) to give the compounds of formula (I) can be carried out by heating at a temperature ranging from 60 to 80°C in presence of an excess of compounds of formula (III) in presence of a base such as sodium hydrate in a suitable solvent such as methanol or ethanol.
  • reaction of a compound of formula (XIV) to give a compound of formula (I) can be carried out with an acid such as trifluoroacetic acid, hydrochloric acid, formic acid, in a suitable solvent such as methylene chloride at a temperature ranging from -10°C to room temperature.
  • an acid such as trifluoroacetic acid, hydrochloric acid, formic acid
  • a suitable solvent such as methylene chloride
  • reaction of a compound of formula (IX) to give a compound of formula (X) may be carried out with acetonitrile and a base such as sodium hydride in a suitable solvent such as diethylether, tetrahydrofuran, dioxane at a temperature ranging from room temperature to 120°C.
  • a base such as sodium hydride
  • a suitable solvent such as diethylether, tetrahydrofuran, dioxane
  • reaction of a compound of formula (X) to give a compound of formula (II) may be carried out with hydrazine hydrate, in a solvent such as methanol or ethanol at a temperature ranging from room temperature to 80°C.
  • reaction of a compound of formula (II) to give a compound of formula (XI) may be carried out with oxone® (potassium peroxymonosulfate) or another oxidizing agent such as hydrogen peroxide in a suitable solvent such as a mixture of water-acetone at a temperature ranging from 0°C to room temperature.
  • oxone® potassium peroxymonosulfate
  • another oxidizing agent such as hydrogen peroxide
  • reaction of a compound of formula (XI) to give a compound of formula (XII) may be carried out with terbutoxycarbonyl anhydride in a suitable solvent such as a mixture of methylene chloride-water at room temperature, in the presence of sodium hydrogen carbonate.
  • reaction of a compound of formula (XII) to give a compound of formula (V) may be carried out directly with hydrogen in presence of a catalyst such as palladium on charcoal in a suitable solvent such as methanol or ethanol at room temperature.
  • a catalyst such as palladium on charcoal in a suitable solvent such as methanol or ethanol at room temperature.
  • the reaction of a compound of formula (V) to give a compound of formula (VI) may be carried out with 4-nitrophenyl chloroformate or a polymer supported form of it in the presence of a tertiary base such as triethylamine, N-methylmo ⁇ holine, N,N- diisopropylethylamine or pyridine, in a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide, at a temperature ranging from about -10°C to room temperature.
  • a tertiary base such as triethylamine, N-methylmo ⁇ holine, N,N- diisopropylethylamine or pyridine
  • a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydro
  • reaction between a compound of formula (VI) or (XV) and a compound of formula (VII) to give a compound of formula (VIII) can be carried out in a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide, at a temperature ranging from about room temperature to reflux.
  • a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide
  • reaction of a compound of formula (VIII) to give a compound of formula (I) can be carried out with an acid such as trifluoroacetic acid, hydrochloric acid, formic acid, in a suitable solvent such as methylene chloride at a temperature ranging from -10°C to room temperature.
  • an acid such as trifluoroacetic acid, hydrochloric acid, formic acid
  • a suitable solvent such as methylene chloride
  • reaction of a compound of formula (V) to give a compound of formula (XV) can be carried out with 1,1 '-carbonyldiimidazole, bis(trichloromethyl)carbonate or trichloromethyl chloroformate in the presence, if necessary, of a tertiary base such as tri ethyl amine, N,N-diisopropylethylamine or pyridine, in a suitable solvent such as dichioromethane, chloroform, toluene, dioxane or tetrahydrofuran at a temperature ranging from 0°C to reflux.
  • a tertiary base such as tri ethyl amine, N,N-diisopropylethylamine or pyridine
  • the reaction of the oxime resin (XVI) with triphosgene to give the compound of formula (XVII) can be carried out in a suitable solvent such as dichioromethane at room temperature.
  • reaction of the compound of formula (XVII) with the compound of formula (II) to give a compound of formula (XVIII) can be carried out in a suitable solvent such as dichioromethane at room temperature.
  • reaction of the compounds of formula (XVIII) with the compounds of formula (VII) to give the compounds of formula (I) can be carried out in a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide at a temperature ranging from room temperature to reflux.
  • a suitable solvent such as toluene, dichioromethane, chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide
  • the compounds of formula (I) are active as cdk/cyclin inhibitors as they gave positive results when tested according to the following procedure.
  • the inhibiting activity of putative cdk/cyclin inhibitors and the potency of selected compounds was determined through a method of assay based on the use of the MultiScreen- PH 96 well plate (Millipore), in which a phosphocellulose filter paper was placed at each well bottom allowing binding of positive charged substrate after a washing/filtration step.
  • Detection filters were allowed to dry at 37°C, then 100 -1/well scintillant were added and 33P labeled histone HI was detected by radioactivity counting in the Top-Count instrument.
  • ATP and substrate concentrations were varied: 4, 8,12, 24, 48 -M for ATP (containing proportionally diluted P33g-ATP) and 0.4, 0.8, 1.2, 2.4, 4.8 -M for histone were used in absence and presence of two different, properly chosen inhibitor concentrations.
  • the inhibiting activity of putative cdk/cyclin inhibitors and the potency of selected compounds was determined through a method of assay based on the use of a SPA (Scintillation Proximity Assay) 96 well plate assay.
  • the assay is based on the ability of streptavidin coated SPA beads to capture a biotinylated peptide derived from a phosphorylation site of histone.
  • IC50 values were calculated using a variation of the four parameter logistics equation:
  • the compounds of formula (I) are therefore useful to restrict the unregulated proliferation of tumor cells, hence in therapy in the treatment of various tumors such as, for instance, carcinomas, e.g., mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors, sarcomas, e.g. soft tissue and bone sarcomas, and the hematological malignancies such as, e.g., leukemias.
  • carcinomas e.g., mammary carcinoma, lung carcinoma, bladder carcinoma, colon carcinoma, ovary and endometrial tumors
  • sarcomas e.g. soft tissue and bone sarcomas
  • hematological malignancies such as, e.g., leukemias.
  • the compounds of formula (I) are also useful in the treatment of other cell proliferative disorders such as psoriasis, vascular smooth cell proliferation associated with atherosclerosis and post-surgical stenosis and restenosis and in the treatment of Alzheimer's disease.
  • the compounds of formula (I) of the present invention suitable for administration to a mammal, e.g., to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, conditions of the patient and the administration route.
  • a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.
  • the compounds of the present invention can be administered either as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g.
  • COX-2 inhibitors COX-2 inhibitors
  • metallomatrixprotease inhibitors telomerase inhibitors
  • tyrosine kinase inhibitors anti- growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents, farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
  • the compounds of the invention can be administered in combination with one or more chemotherapeutic agents such as, for instance, taxane, taxane derivatives, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g., doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, Sugen SU-5416, Sugen SU-6668, Herceptin, and the like, optionally within liposomal formulations thereof.
  • chemotherapeutic agents such as, for instance, taxane, taxane derivatives, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g., doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine,
  • such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within the approved dosage range.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • the present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent).
  • a pharmaceutically acceptable excipient which can be a carrier or a diluent.
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arable gum, gelatins, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arable gum, gelatins, methylcellulose, carboxymethylcellulose or poly
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar-coating, or film-coating processes.
  • liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions or they may contain as a carrier propylene glycol.
  • carrier for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions or they may contain as a carrier propylene glycol.
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • the resin was then resuspended in 10 ml of dichioromethane and 232 mg (1.88 mmol) of 3-cyclopropyl-5-aminopyrazole were added. After 12 hours under stirring the resin was collected by filtration and washed with methanol. After drying in the vacuum oven, 1.097 g of resin were obtained. Analysis by FT-IR showed a strong carbonyl stretch at 1761 cm "1 .
  • oxime-carbamate resin (XVIII) was suspended in 1 ml of DMSO and 11 mg (0.08 mmol) of 3-methoxybenzylamine in 0.2 M DMSO solution were added. The reaction was heated at 80°C for three hours, then the resin was separated by filtration, washed with 150 ⁇ l of dichioromethane and 150 ⁇ l of MeOH. The filtrate was concentrated to give, after trituration with diethylether 11.4 mg (50% yield) of the title compound.
  • N-(3-cyclopropyl-lH-pyrazol-5-ylVN'-(1.3-benzodioxol-5-yl-methyl)urea To a solution of 1.5 g (6.7 mmol) of tert-butyl-3-amino-5-cyclopropyl-lH-pyrazole-l- carboxylate in 15 ml of dichioromethane under nitrogen 1.41 g (7 mmol) of p- nitrophenylchloro formate in a mixture of 7 ml of dichioromethane and 1 ml of pyridine were added dropwise at 0°C.

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PCT/US2000/017878 1999-08-12 2000-08-11 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents WO2001012188A1 (en)

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AU67470/00A AU6747000A (en) 1999-08-12 2000-08-11 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents
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CA002380786A CA2380786A1 (en) 1999-08-12 2000-08-11 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents
KR1020027001815A KR20020060158A (ko) 1999-08-12 2000-08-11 3(5)-우레이도-피라졸 유도체, 이의 제조 방법 및항종양제로서의 이의 용도
IL14792500A IL147925A0 (en) 1999-08-12 2000-08-11 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents
NZ517238A NZ517238A (en) 1999-08-12 2000-08-11 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents
HU0301857A HUP0301857A2 (hu) 1999-08-12 2000-08-11 3(5)-Ureido-pirazol-származékok, eljárás elżállításukra alkalmazásuk és ezeket tartalmazó gyógyszerkészítmények
MXPA02001497A MXPA02001497A (es) 1999-08-12 2000-08-11 Derivados de 3-(5)-ureido-pirazol, procedimiento para su preparacion y sus uso como agentes antitumorales.
EP00955241A EP1202734B1 (en) 1999-08-12 2000-08-11 3(5)-ureido-pyrazole derivatives, process for their preparation and their use as antitumor agents
EA200200249A EA200200249A1 (ru) 1999-08-12 2000-08-11 Производные 3(5)-уреидопиразола, способ их получения и их применение в качестве противоопухолевых агентов
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Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001057034A1 (en) * 2000-02-07 2001-08-09 Bristol-Myers Squibb Co. 3-aminopyrazole inhibitors of cyclin dependent kinases
WO2002018346A1 (en) * 2000-08-31 2002-03-07 Pfizer Products Inc. Pyrazole derivatives and their use as protein kinase inhibitors
US6448264B2 (en) 2000-04-25 2002-09-10 Bristol-Myers Squibb Company Use of 5-thio-, sulfinyl- and sulfonylpyrazolo[3,4-b]-pyridines as cyclin dependent kinase inhibitors
KR20030071029A (ko) * 2002-02-27 2003-09-03 주식회사 팜제니아 항암제 및 방사선 치료 증진제로서 유용한 조성물
WO2003084539A2 (en) * 2002-04-10 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg New pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors
WO2003095429A1 (de) * 2002-05-10 2003-11-20 TransMIT Gesellschaft für Technologietransfer mbH Wirkstoffe zu therapie, diagnostik und prophylaxe von erkrankungen, bei denen abnorme proteinstrukturen auftreten
WO2003097610A1 (en) * 2002-05-17 2003-11-27 Pharmacia Italia S.P.A. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
WO2004022529A2 (en) * 2002-09-05 2004-03-18 Neurosearch A/S Diarylurea derivatives and their use as chloride channel blockers
WO2004009558A3 (en) * 2002-07-24 2004-04-15 Ptc Therapeutics Inc Ureido substituted benzoic acid compounds, their use for nonsense suppression and the treatment of diseases caused by such mutations
WO2004033434A1 (en) * 2002-10-09 2004-04-22 Pfizer Products Inc. Pyrazole compounds for treatment of neurodegenerative disorders
WO2005095348A2 (en) * 2004-04-01 2005-10-13 Pfizer Products Inc. Pyrazole-amine compounds for the treatment of neurodegenerative disorders
EP1609789A1 (en) * 2004-06-23 2005-12-28 Eli Lilly And Company Ureido-pyrazole derivatives and their use as kinase inhibitors
US7141568B2 (en) 2003-07-09 2006-11-28 Pfizer Italia S.R.L. Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
WO2007009898A1 (en) 2005-07-19 2007-01-25 Nerviano Medical Sciences S.R.L. 1h-thieno[2,3-c]pyrazole compounds useful as kinase inhibitors
WO2007129052A1 (en) * 2006-05-03 2007-11-15 Astrazeneca Ab Pyrazole derivatives and their use as pi3k inhibitors
EP1769795A3 (en) * 2001-12-03 2008-03-12 Bayer Pharmaceuticals Corporation Aryl urea compounds in combination with other cytostatic or cytotoxic agents for treating human cancers
WO2008046919A2 (en) * 2006-10-21 2008-04-24 Abbott Gmbh & Co. Kg Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
WO2008087529A1 (en) 2007-01-16 2008-07-24 Siena Biotech S.P.A. Nicotinic acetylcholine receptor modulators
WO2008128986A1 (en) * 2007-04-18 2008-10-30 Probiodrug Ag Urea derivatives as glutaminyl cyclase inhibitors
US7482354B2 (en) 2003-05-22 2009-01-27 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
US7528150B2 (en) * 2003-03-08 2009-05-05 Glaxo Group Limited Urea derivatives having vanilloid receptor antagonist activity
EP2163541A1 (en) * 2008-09-12 2010-03-17 Bayer Schering Pharma Aktiengesellschaft Piperazine derivatives for binding and imaging amyloid plaques and their use
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
EP2266987A1 (en) 2002-12-19 2010-12-29 Pfizer Italia S.r.l. Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
WO2012022487A1 (de) * 2010-08-20 2012-02-23 Grünenthal GmbH Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8138217B2 (en) 2004-02-03 2012-03-20 Nerviano Medical Sciences S.R.L. 1H-thieno[2,3-c]pyrazole derivatives useful as kinase inhibitors
WO2012003476A3 (en) * 2010-07-02 2012-05-03 Ventana Medical Systems, Inc. Hapten conjugates for target detection
US8541576B2 (en) 2010-12-17 2013-09-24 Nerviano Medical Sciences Srl Substituted pyrazolo-quinazoline derivatives as kinase inhibitors
WO2014078331A1 (en) * 2012-11-13 2014-05-22 Array Biopharma Inc. N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US9464092B2 (en) 2013-03-15 2016-10-11 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9540370B2 (en) 2010-12-30 2017-01-10 Abbvie Deutschland Gmbh & Co., Kg. Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9616062B2 (en) 2009-05-13 2017-04-11 The University Of North Carolina At Chapel Hill Cyclin dependent kinase inhibitors and methods of use
US9717735B2 (en) 2014-04-17 2017-08-01 G1 Therapeutics, Inc. Tricyclic lactams for use in HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US9808461B2 (en) 2010-11-17 2017-11-07 The University Of North Carolina At Chapel Hill Protection of renal tissues from ischemia through inhibition of the proliferative kinases CDK4 and CDK6
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10100048B2 (en) 2010-09-27 2018-10-16 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
US10231969B2 (en) 2014-09-12 2019-03-19 GI Therapeutics, Inc. Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat RB-positive tumors
US10351575B2 (en) 2012-11-13 2019-07-16 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US10413547B2 (en) 2014-09-12 2019-09-17 G1 Therapeutics, Inc. Treatment of Rb-negative tumors using topoisomerase with cyclin dependent kinase 4/6 inhibitors
US10709711B2 (en) 2013-03-15 2020-07-14 G1 Therapeutics, Inc. Highly active anti-neoplastic and anti-proliferative agents
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
US10988479B1 (en) 2020-06-15 2021-04-27 G1 Therapeutics, Inc. Morphic forms of trilaciclib and methods of manufacture thereof

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070244120A1 (en) * 2000-08-18 2007-10-18 Jacques Dumas Inhibition of raf kinase using substituted heterocyclic ureas
EE05180B1 (et) 1999-12-24 2009-06-15 Aventis Pharma Limited Asaindooli sisaldav farmatseutiline kompositsioon raviotstarbeliseks kasutamiseks, asaindoolid ning nende kasutamine ravimite valmistamiseks, mis on ette n„htud proteiinikinaasi kataltilise toime p„rssimiseks
WO2002048114A1 (en) * 2000-11-27 2002-06-20 Pharmacia Italia S.P.A. Phenylacetamido- pyrazole derivatives and their use as antitumor agents
GB0115109D0 (en) 2001-06-21 2001-08-15 Aventis Pharma Ltd Chemical compounds
US20050113283A1 (en) * 2002-01-18 2005-05-26 David Solow-Cordero Methods of treating conditions associated with an EDG-4 receptor
US7557129B2 (en) 2003-02-28 2009-07-07 Bayer Healthcare Llc Cyanopyridine derivatives useful in the treatment of cancer and other disorders
BRPI0412219B8 (pt) 2003-07-23 2021-07-27 Bayer Healthcare Llc compostos ômega-carboxi aril difenil uréia fluoro substituídos e composições farmacêuticas compreendendo os referidos compostos
NZ552868A (en) * 2004-08-12 2009-07-31 Pfizer Triazolopyridinylsulfanyl derivatives as P38 MAP kinase inhibitors
AR055831A1 (es) 2004-12-30 2007-09-12 Janssen Pharmaceutica Nv Pepirazinilureas y piperidinilureas como moduladores de hidrolasa de amida de acidos grasos
US20060183758A1 (en) * 2005-02-17 2006-08-17 Cb Research And Development, Inc. Method for synthesis of AZA-annelated pyrroles, thiophenes, and furans
US7429800B2 (en) * 2005-06-30 2008-09-30 Sabic Innovative Plastics Ip B.V. Molding composition and method, and molded article
AR059826A1 (es) * 2006-03-13 2008-04-30 Univ California Inhibidores de urea conformacionalmente restringidos de epoxido hidrolasa soluble
US20090062294A1 (en) * 2007-05-25 2009-03-05 Richard Apodaca Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2010051127A2 (en) * 2008-10-01 2010-05-06 The University Of North Carolina At Chapel Hill Hematopoietic protection against ionizing radiation using selective cyclin-dependent kinase 4/6 inhibitors
WO2010068452A1 (en) * 2008-11-25 2010-06-17 Janssen Pharmaceutica Nv Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
US8461159B2 (en) 2008-11-25 2013-06-11 Jannsen Pharmaceutica BV Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
WO2010141817A1 (en) 2009-06-05 2010-12-09 Janssen Pharmaceutica Nv Heteroaryl-substituted spirocyclic diamine urea modulators of fatty acid amide hydrolase
US8901111B2 (en) 2009-06-05 2014-12-02 Janssen Pharmaceutica Nv Aryl-substituted heterocyclic urea modulators of fatty acid amide hydrolase
EP2528604B1 (en) 2010-01-29 2017-11-22 The Regents of the University of California Acyl piperidine inhibitors of soluble epoxide hydrolase
UA108233C2 (uk) 2010-05-03 2015-04-10 Модулятори активності гідролази амідів жирних кислот
AR087701A1 (es) * 2011-08-31 2014-04-09 Japan Tobacco Inc Derivados de pirazol con actividad inhibidora de sglt1
TW202229268A (zh) * 2020-12-22 2022-08-01 大陸商上海拓界生物醫藥科技有限公司 Ｃｄｋ２抑制劑及其製備方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043246A (en) * 1996-12-03 2000-03-28 Banyu Pharmaceutical Co., Ltd. Urea derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3646059A (en) * 1969-05-05 1972-02-29 Du Pont Plant growth regulatory ureidopyrazoles
US3754887A (en) * 1969-05-05 1973-08-28 Du Pont Ureidopyrazoles defoliants
EP0788358B1 (en) 1994-11-10 2004-03-31 Millennium Pharmaceuticals, Inc. Use of pyrazole compounds for the treatment of glomerulonephritis, cancer, atherosclerosis or restenosis
CA2288787A1 (en) 1997-05-22 1998-11-26 G.D. Searle And Co. Pyrazole derivatives as p38 kinase inhibitors
IL136738A0 (en) 1997-12-22 2001-06-14 Bayer Ag Inhibition of p38 kinase activity using substituted heterocyclic ureas

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043246A (en) * 1996-12-03 2000-03-28 Banyu Pharmaceutical Co., Ltd. Urea derivatives

Cited By (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US6610724B2 (en) 2000-02-07 2003-08-26 Bristol-Myers Squibb Company 3-Aminopyrazole inhibitors of cyclin dependent kinases
WO2001057034A1 (en) * 2000-02-07 2001-08-09 Bristol-Myers Squibb Co. 3-aminopyrazole inhibitors of cyclin dependent kinases
US6482842B2 (en) 2000-02-07 2002-11-19 Bristol-Myers Squibb Company 3-aminopyrazole inhibitors of cyclin dependent kinases
US6448264B2 (en) 2000-04-25 2002-09-10 Bristol-Myers Squibb Company Use of 5-thio-, sulfinyl- and sulfonylpyrazolo[3,4-b]-pyridines as cyclin dependent kinase inhibitors
WO2002018346A1 (en) * 2000-08-31 2002-03-07 Pfizer Products Inc. Pyrazole derivatives and their use as protein kinase inhibitors
EP1450799B2 (en) † 2001-12-03 2018-07-11 Bayer HealthCare LLC Aryl urea compounds in combination with other cytostatic or cytotoxic agents for treating human cancers
EP1769795A3 (en) * 2001-12-03 2008-03-12 Bayer Pharmaceuticals Corporation Aryl urea compounds in combination with other cytostatic or cytotoxic agents for treating human cancers
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
KR20030071029A (ko) * 2002-02-27 2003-09-03 주식회사 팜제니아 항암제 및 방사선 치료 증진제로서 유용한 조성물
WO2003084539A3 (en) * 2002-04-10 2004-09-02 Boehringer Ingelheim Pharma New pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors
WO2003084539A2 (en) * 2002-04-10 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg New pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors
WO2003095429A1 (de) * 2002-05-10 2003-11-20 TransMIT Gesellschaft für Technologietransfer mbH Wirkstoffe zu therapie, diagnostik und prophylaxe von erkrankungen, bei denen abnorme proteinstrukturen auftreten
WO2003097610A1 (en) * 2002-05-17 2003-11-27 Pharmacia Italia S.P.A. Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
US7405233B2 (en) 2002-07-24 2008-07-29 Ptc Therapeutics, Inc. Ureido substituted benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US8334313B2 (en) 2002-07-24 2012-12-18 Ptc Therapeutics, Inc. Ureido substituted benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US7902241B2 (en) 2002-07-24 2011-03-08 Ptc Therapeutics, Inc. Ureido substituted benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2004009558A3 (en) * 2002-07-24 2004-04-15 Ptc Therapeutics Inc Ureido substituted benzoic acid compounds, their use for nonsense suppression and the treatment of diseases caused by such mutations
WO2004022529A2 (en) * 2002-09-05 2004-03-18 Neurosearch A/S Diarylurea derivatives and their use as chloride channel blockers
WO2004022529A3 (en) * 2002-09-05 2004-05-13 Neurosearch As Diarylurea derivatives and their use as chloride channel blockers
CN100497302C (zh) * 2002-09-05 2009-06-10 神经研究公司 二芳基脲衍生物和它们作为氯通道阻滞剂的用途
WO2004033434A1 (en) * 2002-10-09 2004-04-22 Pfizer Products Inc. Pyrazole compounds for treatment of neurodegenerative disorders
US7238721B2 (en) 2002-10-09 2007-07-03 Pfizer Inc Pyrazole compounds for treatment of neurodegenerative disorders
US7521464B2 (en) 2002-10-09 2009-04-21 Pfizer Inc. Pyrazole compounds for treatment of neurodegenerative disorders
US8785448B2 (en) 2002-12-19 2014-07-22 Nerviano Medical Sciences S.R.L. Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
EP2266987A1 (en) 2002-12-19 2010-12-29 Pfizer Italia S.r.l. Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
US7528150B2 (en) * 2003-03-08 2009-05-05 Glaxo Group Limited Urea derivatives having vanilloid receptor antagonist activity
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8981089B2 (en) 2003-05-22 2015-03-17 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
US7482354B2 (en) 2003-05-22 2009-01-27 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
US8541429B2 (en) 2003-05-22 2013-09-24 Nerviano Medical Sciences S.R.L. Pyrazolo quinazoline derivatives, process for their preparation and their use as kinase inhibitors
US9464090B2 (en) 2003-05-22 2016-10-11 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
US9637497B2 (en) 2003-05-22 2017-05-02 Nerviano Medical Sciences, S.R.L. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
US10280176B2 (en) 2003-05-22 2019-05-07 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
US7582628B2 (en) 2003-07-09 2009-09-01 Pfizer Italia S.R.L. Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
US7141568B2 (en) 2003-07-09 2006-11-28 Pfizer Italia S.R.L. Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
US8481584B2 (en) 2004-02-03 2013-07-09 Nerviano Medical Sciences S.R.L. 1H-thieno[2,3-c]pyrazole derivatives useful as kinase inhibitors
US8138217B2 (en) 2004-02-03 2012-03-20 Nerviano Medical Sciences S.R.L. 1H-thieno[2,3-c]pyrazole derivatives useful as kinase inhibitors
EP1958939A3 (en) * 2004-04-01 2008-09-10 Pfizer Products Inc. Pyrazole-amine compounds for the treatment of neurodegenerative disorders
US7468386B2 (en) 2004-04-01 2008-12-23 Pfizer Inc. Pyrazole-amine compounds for the treatment of neurodegenerative disorders
WO2005095348A3 (en) * 2004-04-01 2006-03-23 Pfizer Prod Inc Pyrazole-amine compounds for the treatment of neurodegenerative disorders
WO2005095348A2 (en) * 2004-04-01 2005-10-13 Pfizer Products Inc. Pyrazole-amine compounds for the treatment of neurodegenerative disorders
US7244757B2 (en) 2004-04-01 2007-07-17 Pfizer Inc Pyrazole-amine compounds for the treatment of neurodegenerative disorders
EP1609789A1 (en) * 2004-06-23 2005-12-28 Eli Lilly And Company Ureido-pyrazole derivatives and their use as kinase inhibitors
WO2007009898A1 (en) 2005-07-19 2007-01-25 Nerviano Medical Sciences S.R.L. 1h-thieno[2,3-c]pyrazole compounds useful as kinase inhibitors
WO2007129052A1 (en) * 2006-05-03 2007-11-15 Astrazeneca Ab Pyrazole derivatives and their use as pi3k inhibitors
US8642598B2 (en) 2006-10-21 2014-02-04 Abbvie Inc. Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
WO2008046919A2 (en) * 2006-10-21 2008-04-24 Abbott Gmbh & Co. Kg Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
WO2008046919A3 (en) * 2006-10-21 2008-09-25 Abbott Gmbh & Co Kg Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
US9856234B2 (en) 2006-10-21 2018-01-02 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
EP2535336A1 (en) * 2006-10-21 2012-12-19 Abbott GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
US8163729B2 (en) 2007-01-16 2012-04-24 Wyeth Modulators of α7 nicotinic acetylcholine receptors and therapeutic uses thereof
WO2008087529A1 (en) 2007-01-16 2008-07-24 Siena Biotech S.P.A. Nicotinic acetylcholine receptor modulators
US9512082B2 (en) 2007-04-18 2016-12-06 Probiodrug Ag Inhibitors of glutaminyl cyclase
WO2008128986A1 (en) * 2007-04-18 2008-10-30 Probiodrug Ag Urea derivatives as glutaminyl cyclase inhibitors
WO2010028776A1 (en) * 2008-09-12 2010-03-18 Bayer Schering Pharma Aktiengesellschaft Piperazine derivatives for binding and imaging amyloid plaques and their use
EP2163541A1 (en) * 2008-09-12 2010-03-17 Bayer Schering Pharma Aktiengesellschaft Piperazine derivatives for binding and imaging amyloid plaques and their use
CN102149681A (zh) * 2008-09-12 2011-08-10 拜耳先灵医药股份有限公司 用于结合和成像淀粉样蛋白斑的哌嗪衍生物及其用途
US9616062B2 (en) 2009-05-13 2017-04-11 The University Of North Carolina At Chapel Hill Cyclin dependent kinase inhibitors and methods of use
WO2012003476A3 (en) * 2010-07-02 2012-05-03 Ventana Medical Systems, Inc. Hapten conjugates for target detection
WO2012022487A1 (de) * 2010-08-20 2012-02-23 Grünenthal GmbH Substituierte cyclische carboxamid- und harnstoff-derivate als liganden des vanilloid-rezeptors
US10100048B2 (en) 2010-09-27 2018-10-16 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
US9808461B2 (en) 2010-11-17 2017-11-07 The University Of North Carolina At Chapel Hill Protection of renal tissues from ischemia through inhibition of the proliferative kinases CDK4 and CDK6
US8541576B2 (en) 2010-12-17 2013-09-24 Nerviano Medical Sciences Srl Substituted pyrazolo-quinazoline derivatives as kinase inhibitors
US9540370B2 (en) 2010-12-30 2017-01-10 Abbvie Deutschland Gmbh & Co., Kg. Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
US9562055B2 (en) 2011-05-13 2017-02-07 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9878997B2 (en) 2011-05-13 2018-01-30 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US10323022B2 (en) 2011-05-13 2019-06-18 Array Biopharma Inc. Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors
US9822118B2 (en) 2012-11-13 2017-11-21 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078331A1 (en) * 2012-11-13 2014-05-22 Array Biopharma Inc. N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9790210B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. N-(monocyclic aryl),N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9828360B2 (en) 2012-11-13 2017-11-28 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10889589B2 (en) 2012-11-13 2021-01-12 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
US9896435B2 (en) 2012-11-13 2018-02-20 Array Biopharma Inc. N-pyrrolidinyl,N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10851080B2 (en) 2012-11-13 2020-12-01 Array Biopharma Inc. Methods of treatment using pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9981959B2 (en) 2012-11-13 2018-05-29 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US10351575B2 (en) 2012-11-13 2019-07-16 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
US10709711B2 (en) 2013-03-15 2020-07-14 G1 Therapeutics, Inc. Highly active anti-neoplastic and anti-proliferative agents
US10660896B2 (en) 2013-03-15 2020-05-26 GI Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US11654148B2 (en) 2013-03-15 2023-05-23 G1 Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US9464092B2 (en) 2013-03-15 2016-10-11 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US10076523B2 (en) 2013-03-15 2018-09-18 G1 Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US9527857B2 (en) 2013-03-15 2016-12-27 GI Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US10966984B2 (en) 2013-03-15 2021-04-06 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US10085992B2 (en) 2013-03-15 2018-10-02 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9931345B2 (en) 2013-03-15 2018-04-03 Presidents And Fellows Of Harvard College Transient protection of normal cells during chemotherapy
US11040042B2 (en) 2013-03-15 2021-06-22 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US11717523B2 (en) 2013-03-15 2023-08-08 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9487530B2 (en) 2013-03-15 2016-11-08 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US10434104B2 (en) 2013-03-15 2019-10-08 G1 Therapeutics, Inc. HSPC-sparing treatments for Rb-positive abnormal cellular proliferation
US10925878B2 (en) 2013-03-15 2021-02-23 G1 Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US9717735B2 (en) 2014-04-17 2017-08-01 G1 Therapeutics, Inc. Tricyclic lactams for use in HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US10376519B2 (en) 2014-04-17 2019-08-13 G1 Therapeutics, Inc. Tricyclic lactams for use in HSPC-sparing treatments for Rb-positive abnormal cellular proliferation
US10835533B2 (en) 2014-05-15 2020-11-17 Array Biopharma Inc. 1 -((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea as a TrkA kinase inhibitor
US10231969B2 (en) 2014-09-12 2019-03-19 GI Therapeutics, Inc. Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat RB-positive tumors
US11090306B2 (en) 2014-09-12 2021-08-17 G1 Therapeutics, Inc. Treatment of Rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors
US11446295B2 (en) 2014-09-12 2022-09-20 G1 Therapeutics, Inc. Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat Rb-positive tumors
US10413547B2 (en) 2014-09-12 2019-09-17 G1 Therapeutics, Inc. Treatment of Rb-negative tumors using topoisomerase with cyclin dependent kinase 4/6 inhibitors
US10988479B1 (en) 2020-06-15 2021-04-27 G1 Therapeutics, Inc. Morphic forms of trilaciclib and methods of manufacture thereof

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BR0013277A (pt) 2002-06-18
CN1379668A (zh) 2002-11-13
NO20020687L (no) 2002-04-03
PL354058A1 (en) 2003-12-15
SK2082002A3 (en) 2002-09-10
KR20020060158A (ko) 2002-07-16
AR035557A1 (es) 2004-06-16
DE60034683T2 (de) 2008-01-17
MXPA02001497A (es) 2003-07-21
JP2003507328A (ja) 2003-02-25

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