+

WO2005002673A1 - Inhibiteurs de raf kinase - Google Patents

Inhibiteurs de raf kinase Download PDF

Info

Publication number
WO2005002673A1
WO2005002673A1 PCT/GB2004/002877 GB2004002877W WO2005002673A1 WO 2005002673 A1 WO2005002673 A1 WO 2005002673A1 GB 2004002877 W GB2004002877 W GB 2004002877W WO 2005002673 A1 WO2005002673 A1 WO 2005002673A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
yloxymethyl
fluoro
use according
optionally substituted
Prior art date
Application number
PCT/GB2004/002877
Other languages
English (en)
Inventor
Adrian Liam Gill
Steven John Woodhead
Andrew James Woodhead
Martyn Frederickson
Alessandro Padova
Robert Patrick Apaya
Original Assignee
Astex Therapeutics Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astex Therapeutics Limited filed Critical Astex Therapeutics Limited
Publication of WO2005002673A1 publication Critical patent/WO2005002673A1/fr

Links

Classifications

    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to pyridine and pyrazine derivatives which inhibit the activity of raf kinase, and the use of these compounds as pharmaceuticals .
  • Raf kinase is key downstream target for the ras GTPase and mediates the activation of the MAP kinase cascade consisting of raf-MEK-ERK.
  • Activated ERK is a kinase that subsequently targets a number of proteins responsible for mediating amongst other things the growth, survival and transcriptional functions of the pathway. These include the transcription factors ELK1, C-JUN, Ets 7 and the FOS family.
  • the ras-raf-MER-ERR signal transduction pathway is activated in response to many cell stimuli including growth factors such as EGF, PDGF, KGF etc.
  • raf-MEK-ERK has been found to be upregulated in many factor dependent tumours.
  • activating mutations in other components of the pathway also occur in human tumours. This is true for the raf kinases.
  • B-raf kinase may not necessarily activate B-raf kinase directly but do up-regulate the activity of the ras-raf-MEK-ERK pathway by mechanisms which are not fully understood but may involve cross talk with other raf isoforms, such as A-raf (Wan, P., et al . , Cell, 116, 855-867 (2004)) . In such cases inhibition of raf activity would remain a beneficial aim in cancer treatment.
  • raf kinase activity could be beneficial in the treatment of cancer and that targeting inhibition of B-raf could be particularly beneficial in those cancers containing a constitutively activated B-raf mutation.
  • the raf-MEK-ERK pathway functions downstream of many receptors and stimuli indicating a broad role in regulation of cell function. For this reason inhibitors of raf may find utility in other disease conditions which are associated with upregulation of signalling via this pathway.
  • the raf-MEK-ERK pathway is also an important component of the normal response of non-transformed cells to growth factor action. Therefore inhibitors of raf may be of use in diseases where there is inappropriate or excessive proliferation of normal tissues. These include, but are not limited to glomerulonephritis and psoriasis .
  • Bayer have disclosed series of compounds which act as raf kinase inhibitors; one such compound (WO 99/32455) has the structure:
  • pyridine and pyrazine derivatives can be used as pharmaceuticals to inhibit the activity of raf kinase.
  • the first aspect of the present invention provides the use of a compound of formula I:
  • R 2 and R 3 are independently selected from H, optionally substituted C 1 -.7 alkyl, optionally substituted C5-- 20 aryl, optionally substituted C 3 -- 20 heterocyclyl, halo, amino, amido, hydroxy, ether, thio, thioether, acyla ido, ureido and sulfonamino; R 4 an optionally substituted C 5 -. 20 carboaryl or C 5 -. 20 heteroaryl group; and
  • the above aspect may relate to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of raf kinase.
  • Particularly preferred compounds of the present invention are of formulae Ila and lib:
  • X is selected from H and halo;
  • raf kinase Diseases or conditions ameliorated by the inhibition of raf kinase are discussed herein, and include, but are not limited to cancer.
  • Proliferative diseases including cancers, may be treated or prevented by the inhibition of raf kinase.
  • the compounds of the present invention may find particular use in the treatment of diseases, for example, cancers, with:
  • a second aspect of the present invention provide the use of a compound of the first aspect of the invention for the manufacture of a medicament for use in the treatment and/or prophylaxis of cancer.
  • This aspect may also relate to the use of a compound of the first aspect of the invention for the manufacture of a medicament for use in alleviating and/or reducing the incidence of cancer.
  • the cancers treated are those with elevated level of raf kinase, particularly B-raf kinase.
  • a third aspect of the invention provides a method of inhibiting raf kinase in vi tro or in vi vo, comprising contacting a cell with an effective amount of a compound of the first aspect of the invention .
  • a fourth aspect of the invention pertains to a method for the treatment of a disease or condition ameliorated by the inhibition of raf kinase comprising administering to a subject suffering from said disease or condition ameliorated by the inhibition of raf kinase a therapeutically-effective amount of a compound of the first aspect of the invention.
  • a fifth aspect of the invention pertains to a method for the treatment of diseases, for example cancers, with: (a) activating mutants of ras or raf; (b) upregulation of ras or raf; (c) upregulated raf-MEK-ERK pathway signals; or (d) upregulation of growth factor receptors, such as ERB2 and EGFR, comprising: (i) diagnosing a subject suffering from a disease with: (a) activating mutants of ras or raf; (b) upregulation of ras or raf; (c) upregulated raf-MEK-ERK pathway signals; or (d) upregulation of growth factor receptors, such as ERB2 and EGFR;
  • the compounds of the invention selectively inhibit B-raf kinase over at least one other raf kinase (A-raf and/or C-raf-1) .
  • the treatment is related to or directed at a mutated form of raf, in particular B- raf, such as the mutations discussed in Wan, P., et al . , Cell , 116, 855-867 (2004) and WO 03/056036.
  • Tumours with, for example, activating mutations of ras, raf and EGFR or over expression of ras, raf and EGFR including any of the isoforms thereof, may be particularly sensitive to raf inhibitors .
  • the compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechnanisms discussed herein.
  • the function of inflammatory cells is controlled by many factors the effects of which are mediated by different signal trnsduction pathways. Although some key pro-inflammatory functions are mediated by p38 Map kinase (e.g. TNF release) other are mediated by other pathways.
  • the raf-MEK-ERK pathway in particular is an important activating and proloiferative signal in many inflammatory cells.
  • B and T lymphocytyes in particular require activation of the raf-mek-erk for clonal expansion and generation of effector populations (Cantrell, D.A., Immunol Rev. , 192, 122- 30 (2003); Genot, E. and Cantrell, D.A., Curr Opin Immunol .
  • the raf kinase inhibitors of formula I may be used in the treatment of inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, and other arthritic conditions; Alzheimer's disease; toxic shock syndrome, the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, Reiter's syndrome, gout, acute synovitis, sepsis, septic shock, endotoxic shock, gram negative sepsis, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury , graft vs.
  • inflammatory diseases such as rheumatoid arthritis, osteoarthritis, rheumatoid spond
  • allograft rejections fever and myalgias due to infection, such as influenza, cachexia, in particular cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS) , AIDS, ARC (AIDS related complex) , keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, chronic obstructive pulmonary disease (COPD) , acute respiratory distress syndrome (ARDS) , asthma, pulmonary fibrosis and bacterial pneumonia .
  • AIDS acquired immune deficiency syndrome
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • Preferred inflammatory disease to be treated include arthritic conditions, including rheumatoid arthritis and rheumatoid spondylitis; inflammatory bowel disease, including Crohn's disease and ulcerative colitis; and chronic obstructive pulmonary disease (COPD) .
  • arthritic conditions including rheumatoid arthritis and rheumatoid spondylitis
  • inflammatory bowel disease including Crohn's disease and ulcerative colitis
  • COPD chronic obstructive pulmonary disease
  • Upregulation of a kinase includes elevated expression or over- expression of the kinase, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation of the kinase, including activation by mutations.
  • C ⁇ - 7 alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 7 carbon atoms, which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated.
  • alkyl includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc., discussed below.
  • saturated alkyl groups include, but are not limited to, methyl (Ci) , ethyl (C 2 ) , propyl (C 3 ) , butyl (C 4 ) , pentyl (C 5 ) , hexyl (C 6 ) and heptyl (C 7 ) .
  • saturated linear alkyl groups include, but are not limited to, methyl (Ci) , ethyl (C 2 ) , n-propyl (C 3 ) , n-butyl (C 4 ) , n-pentyl (a yl) (C 5 ) , n-hexyl (C 6 ) , and n-heptyl (C 7 ) .
  • saturated branched alkyl groups include iso-propyl (C 3 ) , iso-butyl (C 4 ) , sec-butyl (C 4 ) , tert-butyl (C 3 ) , iso-pentyl (C 5 ) , and neo-pentyl (C 5 ) .
  • C 3 -.7 Cycloalkyl refers to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 7 ring atoms .
  • each ring has from 3 to 7 ring atoms:
  • saturated cylcoalkyl groups include, but are not limited to, those derived from: cyclopropane (C 3 ) , cyclobutane (C 4 ) , cyclopentane (C 5 ) , cyclohexane (C 6 ) and cycloheptane (C 7 ) .
  • C 2 _ 7 Alkenyl The term "C 2 - 7 alkenyl” as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds.
  • Examples of unsaturated cyclic alkenyl groups include, but are not limited to, cyclopropenyl (C) , cyclobutenyl (C 4 ) , cyclopentenyl (C 5 ) , and cyclohexenyl (C 6 ) .
  • C 2 _ 7 Alkynyl The term "C 2 _ 7 alkynyl”, as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds.
  • unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C ⁇ CH) and 2-propynyl (propargyl, - CH 2 -C ⁇ CH) .
  • C 1 _ 4 alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 4 carbon atoms, which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated.
  • C ⁇ - 4 alkyl includes the sub-classes "C 2 - 4 alkenyl", , ⁇ C 2 _ 4 alkynyl” and "C 2 _ 4 cycloalkyl”. Examples of these moieties are given above .
  • C 3 -. 20 heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms .
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms, which include N, 0 and S.
  • monocyclic heterocyclyl groups include, but are not limited to, those derived from:
  • Ni aziridine (C 3 ) , azetidine (C 4 ) , pyrrolidine (tetrahydropyrrole) (C 5 ) , pyrroline (e.g., 3-pyrroline, 2, 5-dihydro ⁇ yrrole) (C 5 ) , 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C 5 ) , piperidine (C 6 ) , dihydropyridine (C 6 ) , tetrahydropyridine (C 6 ) , azepine (C7) ;
  • Oi oxirane (C 3 ) , oxetane (C 4 ) , oxolane (tetrahydrofuran) (C 5 ) , oxole (dihydrofuran) (C 5 ) , oxane (tetrahydropyran) (C ⁇ ) , dihydropyran (C 6 ) , pyran (C 6 ) , oxepin (C 7 ) ;
  • Si thiirane (C 3 ) , thietane (C 4 ) , thiolane (tetrahydrothiophene) (C 5 ) , thiane (tetrahydrothiopyran) (C 6 ) , thiepane (C ) ;
  • dioxolane (C 5 ) dioxane (C 6 ) , and dioxepane (C 7 ) ;
  • trioxane (C 6 ) 0 3 : trioxane (C 6 ) ;
  • N 2 imidazolidine (C 5 ) , pyrazolidine (diazolidine) (C 5 ) , imidazoline (C 5 ) , pyrazoline (dihydropyrazole) (C 5 ) , piperazine (C 6 ) ;
  • N 1 O 1 tetrahydrooxazole (C s ) , dihydrooxazole (C 5 ) , tetrahydroisoxazole (C 5 ) , dihydroisoxazole (C 5 ) , morpholine (C 6 ) , tetrahydrooxazine (C 6 ) , dihydrooxazine (C 6 ) , oxazine (C 6 ) ;
  • NiSi thiazoline (C 5 ) , thiazolidine (C 5 ) , thiomorpholine (C 6 ) ;
  • Nitrogen containing C 5 - 7 heterocyclyl The term "nitrogen containing C 5 -- 7 heterocyclyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 5 to 7 ring atoms, of which a least one is a nitrogen ring atom.
  • nitrogen containing C 5 -. 7 heterocyclyl groups include, but are not limited to, those derived from:
  • Ni pyrrolidine (tetrahydropyrrole) (C 5 ) , pyrroline (e.g., 3-pyrroline, 2, 5-dihydropyrrole) (C 5 ) , 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C 5 ) , piperidine (C 5 ) , dihydropyridine (C 6 ) , tetrahydropyridine (C 6 ) , azepine (C 7 ) ;
  • N 2 imidazolidine (C 5 ) , pyrazolidine (diazolidine) (C 5 ) , imidazoline (C 5 ) , pyrazoline (dihydropyrazole) (C 5 ) , piperazine (c 6 ) ;
  • N 1 O 1 tetrahydrooxazole (C 5 ) , dihydrooxazole (C 5 ) , tetrahydroisoxazole (C 5 ) , dihydroisoxazole (C 5 ) , morpholine (C 6 ) , tetrahydrooxazine (C 6 ) , dihydrooxazine (C 6 ) , oxazine (C 6 ) ;
  • NiSi thiazoline (C 5 ) , thiazolidine (C 5 ) , thiomorpholine (C 6 ) ;
  • N 1 O 1 S 1 oxathiazine (C 6 ) .
  • C 5 -- 20 carboaryl The term "C 5 -- 2 o carboaryl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 5 to 20 carbon ring atoms. Preferably, each ring has from 5 to 7 ring atoms.
  • carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C 6 ) , naphthalene (C ⁇ 0 ) , azulene (C ⁇ 0 ) , anthracene (C ⁇ 4 ) , phenanthrene (Ci-j) , naphthacene (C 18 ) , and pyrene (C i6 ) .
  • aryl groups which comprise fused rings, at least one of which is an aromatic ring include, but are not limited to, groups derived from indene (Cg) , isoindene (C 9 ) , and fluorene (C13) •
  • C 5 -- 20 heteroaryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 5 to 20 ring atoms, which include one or more heteroatoms. Preferably, each ring has from 5 to 7 ring atoms.
  • monocyclic heteroaryl groups include, but are not limited to, those derived from:
  • Ni pyrrole (azole) (C 5 ) , pyridine (azine) (C 6 ) ; Oi : furan (oxole) (C 5 ) ;
  • Si thiophene (thiole) (C 5 ) ; 1 O 1 : oxazole (C 5 ) , isoxazole (C 5 ) , isoxazine (C 6 ) ;
  • N 3 O ⁇ oxatriazole (C 5 ) ; NxSi: thiazole (C 5 ) , isothiazole (C 5 ) ;
  • N 2 imidazole (1, 3-diazole) (C 5 ) , pyrazole (1, 2-diazole) (C 5 ) , pyridazine (1, 2-diazine) (C 6 ) , pyrimidine (1, 3-diazine) (C 6 ) (e.g., cytosine, thymine, uracil) , pyrazine (1, 4-diazine) (C 6 ) ;
  • N 3 triazole (C 5 ) , triazine (C 6 ) ; and, N 4 : tetrazole (C 5 ) .
  • heteroaryl groups which comprise fused rings include, but are not limited to: Cg heteroaryl groups (with 2 fused rings) derived from benzofuran (Oi) , isobenzofuran (Oi) , indole (Ni) , isoindole (Ni) , indolizine (Nx) , indoline (Ni) , isoindoline (Ni) , purine (N 4 ) (e.g., adenine, guanine) , benzimidazole (N 2 ) , indazole (N 2 ) , benzoxazole (N 1 O 1 ) , benzisoxazole (N 1 O 1 ) , benzodioxole (0 2 ) , benzofurazan (N 2 O ⁇ ) , benzotriazole (N 3 ) , benzothiofuran (Si) , benzothiazole (NiSn)
  • Heterocyclic groups which have a nitrogen ring atom in the form of an -NH- group may be N-substituted, that is, as -NR- .
  • pyrrole may be N- methyl substituted, to give N-methypyrrole .
  • N- substitutents include, but are not limited to C - ⁇ alkyl, C 3 _ 20 heterocyclyl, C 5 -- 20 carboaryl, C 5 -- 2 o heteroaryl and acyl groups.
  • quinoline may be substituted to give quinoline N-oxide; pyridine to give pyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also known as benzofuroxan) .
  • Monocyclic examples of such groups include, but are not limited to, those derived from:
  • Polycyclic examples of such groups include, but are not limited to, those derived from: C 9 : indenedione; C 10 : tetralone, decalone; C 14 : anthrone, phenanthrone; Ni : oxindole (Cg) ; Oi : benzopyrone (e.g., coumarin, isocoumarin, chromone) (Cio) ; NjOi: benzoxazolinone (Cg) , benzoxazolinone (C 10 ) ; N 2 : quinazolinedione (Cio); N 4 : purinone (Cg) (e.g., guanine) .
  • C 9 indenedione
  • C 10 tetralone, decalone
  • C 14 anthrone, phenanthrone
  • Ni oxindole
  • Oi benzopyrone (e.g., coumarin, isocoumarin, chromone)
  • alkyl, heterocyclyl, carboaryl and heteroaryl groups may themselves optionally be substituted with one or more groups selected from themselves and the additional substituents listed below, unless otherwise stated.
  • Carboaryl and heteroaryl groups may also be substituted by alkoxylene groups as defined below. Halo: -F, -Cl, -Br, and -I.
  • Ether -OR, wherein R is an ether substituent, for example, a C 1 -- 7 alkyl group (also referred to as a C 1 -. 7 alkoxy group, discussed below) , a C 3 -- 20 heterocyclyl group (also referred to as a C 3 -- 2 o heterocyclyloxy group) , or a C 5 -. 20 aryl group (also referred to as a C 5 -- 20 aryloxy group), preferably a C 1 -- 7 alkyl group.
  • the term C 5 - 20 aryl group encompasses both C 5 - 20 carboaryl and C 5 _ 20 heteroaryl groups .
  • C 1 -- 7 alkoxy -OR, wherein R is a C 1 - 7 alkyl group.
  • Examples of C 1 - 7 alkoxy groups include, but are not limited to, -OMe (methoxy) , -OEt (ethoxy) , -O(nPr) (n-propoxy) , -O(iPr) (isopropoxy) , -O(nBu) (n-butoxy) , -O(sBu) (sec-butoxy) , -O(iBu) (isobutoxy) , and -O(tBu) (tert-butoxy) .
  • Examples of acetal groups include, but are not limited to, -CH(OMe) 2 , -CH(OEt) 2 , and -CH(OMe) (OEt) .
  • Hemiacetal -CH(OH) (OR 1 ), wherein R 1 is a hemiacetal substituent, for example, a C 1 --7 alkyl group, a C 3 -- 20 heterocyclyl group, or a C5-. 20 aryl group, preferably a C 1 -. 7 alkyl group.
  • R 1 is a hemiacetal substituent, for example, a C 1 --7 alkyl group, a C 3 -- 20 heterocyclyl group, or a C5-. 20 aryl group, preferably a C 1 -. 7 alkyl group.
  • hemiacetal groups include, but are not limited to, -CH (OH) (OMe) and -CH(OH) (OEt) .
  • Ketal -CR(OR 1 ) (OR 2 ), where R 1 and R 2 are as defined for acetals, and R is a ketal substituent other than hydrogen, for example, a C 1 - 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ _ 7 alkyl group.
  • ketal groups include, but are not limited to, -C(Me) (OMe) 2 , -C (Me) (OEt) 2 , -C(Me) (OMe) (OEt), -C(Et) (OMe) 2 , -C(Et) (OEt) 2 , and -C (Et) (OMe) (OEt) .
  • hemiketal groups include, but are not limited to, -C(Me) (OH) (OMe), - C(Et) (OH) (OMe), -C (Me) (OH) (OEt), and -C(Et) (OH) (OEt).
  • Imino (imine) : NR, wherein R is an imino substituent, for example, hydrogen, C 1 -- 7 alkyl group, a C 3 _ 2 o heterocyclyl group, or a C 5 - 20 aryl group, preferably hydrogen or a C 1 -. 7 alkyl group.
  • R is an acyl substituent, for example, a C 1 - 7 alkyl group (also referred to as C 1 - 7 alkylacyl or C 1 - alkanoyl) , a C 3 - 2 oheterocyclyl group (also referred to as C 3 -. 20 heterocyclylacyl) , or a C 5 -- 20 aryl group (also referred to as C 5 -. 2 o arylacyl) , preferably a C ⁇ _ 7 alkyl group.
  • R is an acyl substituent, for example, a C 1 - 7 alkyl group (also referred to as C 1 - 7 alkylacyl or C 1 - alkanoyl) , a C 3 - 2 oheterocyclyl group (also referred to as C 3 -. 20 heterocyclylacyl) , or a C 5 -- 20 aryl group (also referred to as C 5 -. 2 o aryl
  • Carboxy (carboxylic acid): -C( 0)0H.
  • Thionocarboxy (thionocarboxylic acid): -C( S)0H.
  • Imidic acid : -C ( NH) OH .
  • R is an ester substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 -. 20 aryl group, preferably a C ⁇ _ 7 alkyl group.
  • R is an acyloxy substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 - 2 o heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ - 7 alkyl group.
  • acyloxy groups include, but are not limited to,
  • Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide) : -C( 0)NR 1 R 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 and R 2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl : succinimidyl maleimidyl phthalimidyl
  • R 1 is a ureido substituent, for example, hydrogen, a C ⁇ _ 7 alkyl group, a C 3 - 2 o heterocyclyl group, or a Cs- 2 o aryl group, preferably hydrogen or a Ci- 7 alkyl group.
  • ureido groups include, but are not limited to, -NHC0NH 2 , -NHCONHMe, -NHCONHEt, -NHCONMe 2 , -NHC0NEt 2 , -NMeCONH 2 , -NMeCONHMe, -NMeCONHEt, -NMeCONMe 2 , and -NMeCONEt 2 .
  • Tetrazolyl a five membered aromatic ring having four nitrogen atoms and one carbon atom
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a C ⁇ _ 7 alkyl group (also referred to as C ⁇ - alkylamino or di-C ⁇ _ 7 alkylamino) , a C3_ 20 heterocyclyl group, or a C 5 -- 20 aryl group, preferably H or a C ⁇ -- 7 alkyl group, or, in the case of a "cyclic" amino group, R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms.
  • R 1 and R 2 are independently amino substituents, for example, hydrogen, a C ⁇ _ 7 alkyl group (also referred to as C ⁇ - alkylamino or di-C ⁇ _ 7 alkylamino) , a C3_ 20 heterocyclyl group, or a C 5 -- 20 aryl group, preferably H or a C ⁇ -- 7 alkyl group, or, in the case of
  • Amino groups may be primary (-NH 2 ) , secondary (-NHR 1 ) , or tertiary (- NHR 1 R 2 ) , and in cationic form, may be quaternary (- + NR 1 R 2 R 3 ) .
  • amino groups include, but are not limited to, -NH 2 , -NHCH 3 , -NHC(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , and -NHPh .
  • Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino .
  • Imino: NR, wherein R is an imino substituent, for example, for example, hydrogen, a C ⁇ -- 7 alkyl group, a C 3 -- 20 heterocyclyl group, or a C 5 -- 2 o aryl group, preferably H or a C 1 -. 7 alkyl group.
  • Thioether (sulfide) -SR, wherein R is a thioether substituent, for example, a C ⁇ _ 7 alkyl group (also referred to as a C ⁇ - 7 alkylthio group) , a C 3 _ 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • R is a thioether substituent, for example, a C ⁇ _ 7 alkyl group (also referred to as a C ⁇ - 7 alkylthio group) , a C 3 _ 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • Examples of C 1 . ⁇ alkylthio groups include, but are not limited to, -SCH 3 and -SCH 2 CH 3 .
  • Sulfine (sulfinyl, sulfoxide): -S ( 0) R, wherein R is a sulfine substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 - 2 o heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ -alkyl group.
  • R is a sulfine substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 - 2 o heterocyclyl group, or a C 5 - 20 aryl group, preferably a C ⁇ -alkyl group.
  • R is a sulfone substituent, for example, a C ⁇ - 7 alkyl group, a C 3 _ 20 heterocyclyl group, or a C 5 -- 20 aryl group, preferably a C ⁇ - 7 alkyl group, including, for example, a fluorinated or perfluorinated C ⁇ _ 7 alkyl group.
  • R is a sulfonate substituent, for example, a C ⁇ - 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 -. 20 aryl group, preferably a C ⁇ -- 7 alkyl group.
  • R is a sulfinyloxy substituent, for example, a C ⁇ - 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 _ 20 aryl group, preferably a C ⁇ _ 7 alkyl group.
  • R is a sulfonyloxy substituent, for example, a C ⁇ - 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a C ⁇ - 7 alkyl group.
  • R is a sulfate substituent, for example, a C 1 -- 7 alkyl group, a C 3 -. 20 heterocyclyl group, or a C 5 -- 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 and R 2 are independently amino substituents, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfonamino substituent, for example, a Ci- 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 _ 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • R 1 is an amino substituent, as defined for amino groups
  • R is a sulfinamino substituent, for example, a C ⁇ _ 7 alkyl group, a C 3 - 20 heterocyclyl group, or a C 5 - 2 o aryl group, preferably a C ⁇ _ 7 alkyl group.
  • Alkoxylene refers to a bidentate group which may be a substituent of an aryl group. It bonds to adjacent atoms of the aryl group, and may one or two carbon atoms in the chain between the oxygen atoms, as thus has the structure -0(CH 2 ) n O-, where n is either 1 or 2. The carbon atoms may bear any of the substituents listed above.
  • a reference to carboxylic acid also includes the anionic (carboxylate) form (-C00-) , a salt or solvate thereof, as well as conventional protected forms .
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ) , a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 " ) , a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
  • Isomers, Salts, Solvates, Protected Forms, and Prodrugs Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L- forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal- forms; a- and ⁇ -forms; axial and
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space) .
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl .
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C ⁇ _ 7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl) .
  • C ⁇ _ 7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto enol enolate Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D) , and 3 H (T) ;
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • 0 may be in any isotopic form, including 16 0 and 18 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
  • Isomeric forms substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1%, of the other isomeric form are also envisaged.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below.
  • a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
  • a pharmaceutically-acceptable salt examples are discussed in Berge et al . , 1977,
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ) .
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CE 3 ) .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono- hydrate, a di-hydrate, a tri-hydrate, etc.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like) .
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group) .
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRC0-0R) , for example, as: a methyl amide (-NHCO-CH 3 ) ; a benzyloxy amide (-NHC0-0CH 2 C 6 H 5 , -NH- Cbz) ; as a t-butoxy amide (-NHCO-OC (CH 3 ) 3 , -NH-Boc) ; a 2-biphenyl- 2-propoxy amide (-NHCO-OC (CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc) , as a 9- fluorenylmethoxy amide (-NH-Fmoc) , as a 6-nitroveratryloxy amide (-NH-Nvoc) , as a 2-trimethylsilylethyloxy amide (-NH-Teoc) , as a 2, 2, 2-trichlor
  • a carboxylic acid group may be protected as an ester for example, as: an C ⁇ _ 7 alkyl ester (e.g., a methyl ester; a t- butyl ester); a C ⁇ _ 7 haloalkyl ester (e.g., a C ⁇ _ 7 trihaloalkyl ester) ; a triC ⁇ -- alkylsilyl-C ⁇ _ 7 alkyl ester; or a C 5 -- 2 o aryl-C ⁇ -- 7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an C ⁇ _ 7 alkyl ester e.g., a methyl ester; a t- butyl ester
  • a C ⁇ _ 7 haloalkyl ester e.g., a C ⁇ _ 7 trihaloalkyl ester
  • prodrug it may be convenient or desirable to prepare, purify, and/or handle the active compound in the form of a prodrug.
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • Ci- T alkyl e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu
  • acyloxy-C ⁇ - 7 alkyl e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl ;
  • some prodrugs are N-oxides of the active compound (where the active compound contains an amine group) .
  • the active compound contains an amine group
  • one or more than one nitrogen atom may be oxidised to from an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen containing heterocycle .
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 tn Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady ( Syn . Comm . 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloroperoxybenzoic acid
  • N-oxides may be reduced in vivo to the active compound.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.) .
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • the molecular weight of the compound is less than 1000, and more preferably less than 750, although the molecular weight may be less than 700, 650, 600, 550, 525 or even 500.
  • R 5 is preferably selected from R 5 ' , halo, NHR 5 ', OR 5 ', SR 5 ' , wherein R 5' is H or C ⁇ - 3 alkyl (optionally substituted by halo, NH 2 , OH, SH) .
  • R 5' is H or C ⁇ - 3 alkyl (optionally substituted by halo, NH 2 , OH, SH) .
  • H, NHR 5' (more preferably NH 2 ) , OH, SH and halo (more preferably F or Cl) are more preferred, with H and NH 2 being the most preferred.
  • R 5 is a pyridine then preferably R 5 is NH 2
  • R 1 if the compound is a pyrazine preferably R 5 is H.
  • R 1 is most preferably H.
  • R 2 and R 3 are preferably independently selected from H, halo, amino, hydroxy and thio, and more preferably from H and halo. If only one of R 2 and R 3 is a substituent, then R 2 is the preferred substituent.
  • R 4 is preferably an optionally substituted C 5 _ ⁇ o aryl group, more preferably either a C 5 _ ⁇ 0 carboaryl group or a C 5 -- 10 heteroaryl group having one or two nitrogen ring atoms, for example, naphthyl, phenyl, indole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, pyridine, phthalazine, tetrahydrophthalazine, quinazoline and tetrahydroquinazoline .
  • R 4 is an optionally substituted C 5 -- 10 carboaryl group, and more preferably an optionally substituted phenyl or napthyl group .
  • R 4 is a napthyl group it is preferably unsubstituted, and may be in any configuration, with napth-1-yl being preferred.
  • R 4 is a phenyl group, then it is preferably substituted, more preferably with one or two substituents.
  • halo more preferably F and CI
  • ether more preferably C ⁇ - 7 alkoxy, and in particular -OMe, and arylalkoxy, and in particular benzyloxy
  • C 1 -7 alkyl more preferably C ⁇ _ 4 alkyl, and in particular -Me, and -CF 3
  • C 5 -- 20 aryl groups more preferably C s _ ⁇ o carboaryl or heteroaryl groups
  • Alkoxylene groups linked to adjacent atoms are also preferred.
  • amido, acylamido, ureido, carbamate and reverse carbamate groups are preferred, optionally in combination with a halo group, which is preferably para to the former groups.
  • the former groups are preferably in the 3-position.
  • the ortho and meta positions are preferred, with the meta position being the most preferred. If two substituents are present, it may be preferred that neither is in the para position, unless one is F, when this is preferred to be in the para position.
  • R 4 is preferably a bicyclic aryl group, where the second ring can be aromatic or non-aromatic (partially or fully saturated) .
  • Such groups include napthyl, indole, oxindole, quinoline, isoquinoline, tetrahydroquinoline and tetrahydroisoquinoline .
  • R 4 is preferably a 2, 6-dichlorophenyl group.
  • preferred compounds of the present invention are of formulae Ila and lib:
  • R' 1 is preferably selected from H and NR C1 R C2 , and more preferably from H and NHR C1 . If R' 1 is NHR C1 , then R cl is preferably C ⁇ _ 4 alkyl (more preferably C ⁇ _ 2 alkyl) which may be, and is more preferably, substituted by OH, NH 2 , C 5 _ 20 carboaryl (more preferably C 5 -. ⁇ 0 carboaryl, e.g. phenyl), and C 5 _ 20 heteroaryl (more preferably C5--10 heteroaryl, e.g. pyridyl) . Examples of preferred R' 1 groups include, but are not limited to, -NH-C 2 H-OH and -NH-CH 2 -C 6 H 5 .
  • R , 5 >. - is preferably H.
  • X is preferably halo, and more preferably F or CI, with CI being most preferred.
  • R L2 is a carboaryl group, it is preferably phenyl. If R L2 is a heteroaryl group it is preferably comprises at least one nitrogen ring atom (e.g. pyrrole, pyridine, thiazole, pyrazole, triazole) , and is more preferably pyridine, thiazole or pyrazole, with pyrazole being the most preferred.
  • Heteroaryl groups may be formed into a moeity by removing a hydrogen from a carbon or hetero ring atom, with the preference being for removal from a carbon ring atom.
  • the C 5 -. 20 carboaryl or C 5 -- 20 heteroaryl group is preferably substituted by one or more substituent groups, more preferably one or two substituents .
  • R L2 is a six membered ring
  • at least one substituent group is in the meta position (i.e. ⁇ to attachment to R L1 ) , and if there are two substituents these are both preferably in the meta positions.
  • R L2 is a five membered ring
  • at least one substituent group is either or ⁇ to attachment to R L1 , with the Y position being preferred.
  • the substituents are preferably selected from halo (more preferably F and CI) , amino (more preferably cyclic amino groups, and in particular morpholino) , C ⁇ _ alkyl (more preferably C ⁇ _ 4 alkyl, and in particular -Me, -t-Bu and -CF 3 ) , C 5 - 20 carboaryl groups (more preferably C 5 - 10 carboaryl groups, and in particular, phenyl) and C 5 . 20 heteroaryl groups (more preferably C 5 _ ⁇ 0 heteroaryl groups) .
  • R' 5 is preferably H and R' 1 is preferably selected from H and NHR.
  • X is preferably CI or F, more preferably CI.
  • R' 5 and R' 1 are preferably H.
  • X is preferably CI or F, more preferably CI.
  • Compounds of the present invention of formula Ila include N-[4- Chloro-3- (pyridin-3-yloxymethyl) -phenyl] -2-morpholin-4-yl- isonicotinamide (44), N- [4-Chloro-3- (pyridin-3-yloxymethyl) - phenyl] -3-fluoro-5-morpholin-4-yl-benzamide (49) , N- [4-Chloro-3- (pyridin-3-yloxymethyl) -phenyl] -3-fluoro-benzamide (50), N-[4- Chloro-3- (pyridin-3-yloxymethyl) -phenyl] -benzamide (52), N-[4- Chloro-3- (pyridin-3-yloxymethyl) -phenyl] -isonicotinamide (53) , N- [3- (2-Amino-pyridin-3-yloxymethyl) -4-chloro-phenyl] -benz
  • the most preferred compounds of the present invention are: N-[4- Chloro-3- (pyridin-3-yloxymethyl) -phenyl] -2-morpholin-4-yl- isonicotina ide (44), N- [4-Chloro-3- (pyridin-3-yloxymethyl) - phenyl] -3-fluoro-5-morpholin-4-yl-benzamide (49), N- ⁇ 4-Chloro-3- [6- (2-hydroxy-ethylamino) -pyridin-3-yloxymethyl] -phenyl ⁇ -3- fluoro-5-morpholin-4-yl-benzamide (76) and [4-Chloro-3- (pyridin-
  • R' 1 is preferably selected from H and NR C1 R C2 , and more preferably from H and NHR C1 . If R' 1 is NHR C1 , then R cl is preferably C ⁇ _ 4 alkyl (more preferably C ⁇ - 2 alkyl) which may be, and is more preferably, substituted by OH, NH 2 , C 5 _ 2 o carboaryl (more preferably C5-10 carboaryl, e.g. phenyl), and C 5 _ 20 heteroaryl (more preferably C 5 - 10 heteroaryl, e.g. pyridyl). Examples of preferred R' 1 groups include, but are not limited to, H, -NH-C 2 H 4 -OH and -NH-CH 2 -C 6 H 5 .
  • R' is preferably H.
  • X is preferably halo, and more preferably F or CI, with F being most preferred.
  • R L2 is a carboaryl group, it is preferably phenyl. If R L2 is a heteroaryl group it is preferably comprises at least one nitrogen ring atom (e.g. pyrrole, pyridine, isoxazole, thiazole, pyrazole, thiadiazole, oxadiazole, triazole) , and is more preferably pyridine, thiazole, thiadiazole or pyrazole, with pyrazole being the most preferred.
  • Heteroaryl groups may be formed into a moiety by removing a hydrogen from a carbon or hetero ring atom, with the preference being for removal from a carbon ring atom.
  • the C 5 . 2 o carboaryl or C 5 - 20 heteroaryl group is preferably substituted by one or more substituent groups, more preferably one or two substituents .
  • R L2 is a six membered ring
  • at least one substituent group is in the meta position (i.e. ⁇ to attachment to R L1 ) , and if there are two substituents these are both preferably in the meta positions .
  • R L2 is a five membered ring
  • R L2 is a nitrogen containing five membered heteroaryl group
  • the substituents are preferably selected from halo (more preferably F and CI) , amino (more preferably cyclic amino groups, and in particular morpholino) , C ⁇ - 7 alkyl (more preferably C ⁇ - 4 alkyl, and in particular -Me, -i-Pr, cyclopropyl, -t-Bu and -CF 3 ) , C 3 - 20 heterocyclyl groups (more preferably C 3 _ 7 heterocyclyl groups, and in particular oxolane and oxane) , C 5 - 2 o carboaryl groups (more preferably C5--10 carboaryl groups, and in particular, phenyl) , C 5 -- 2 o heteroaryl groups (more preferably C 5 - ⁇ 0 heteroaryl groups, and in particular, pyridine, pyrazine, pyrimidine, thiazole) , carboarylalkyl groups (more preferably benzyl) and carboaryloxy groups
  • the substituents are preferably selected from halo (more preferably F and CI) , amino (more preferably cyclic amino groups, and in particular morpholino) , amido (more preferably amido groups where the amino substituents form together with the nitrogen atom to which they are attached a heterocylclic structure, e.g. N-methyl piperazinyl) , sulfonyl (more preferably where the sulfone substituent is a cylic amino group, e.g.
  • C ⁇ _ 7 alkyl (more preferably C ⁇ _ 4 alkyl, and in particular -Me, -i-Pr, cyclopropyl, -t-Bu and -CF 3 )
  • C 3 -. 20 heterocyclyl groups (more preferably C 3 - 7 heterocyclyl groups, and in particular oxolane and oxane)
  • C 5 -- 20 carboaryl groups (more preferably C 5 -- 10 carboaryl groups, and in particular, phenyl and halo-phenyl, e.g.
  • C 5 _ 20 heteroaryl groups (more preferably C 5 - 10 heteroaryl groups, and in particular, pyridine, pyrazine, pyrimidine, thiazole) , carboarylalkyl groups (more preferably benzyl) and carboaryloxy groups (more preferably phenyloxy) .
  • R' 5 is preferably H and R' 1 is preferably selected from H and NHR.
  • X is preferably CI or F, more preferably CI .
  • R' 5 is preferably H and R' 1 is preferably selected from H and NHR.
  • X is preferably CI or F, more preferably CI.
  • R' 5 and R' 1 are preferably H.
  • X is preferably CI or F, more preferably CI .
  • the C5-7 aryl substituent group may be, in some embodiments, further substituted by one or more halo groups, such that the group is a, for example, 4-C1 phenyl, 4-F phenyl or 2,4-diF phenyl. These compounds may also be further substituted on the heteroaryl group by a C ⁇ _ 7 alkyl group, e.g. t- butyl.
  • Compounds of the present invention of formula lib include N-[4- Chloro-3- (pyrazin-2-yloxymethyl) -phenyl] -benzamide (92), N-[4- Chloro-3- (pyrazin-2-yloxymethyl) -phenyl] -2-morpholin-4-yl- isonicotinamide (93), N- [4-Chloro-3- (pyrazin-2-yloxymethyl) - phenyl] -3-fluoro-5-morpholin-4-yl-benzamide (94), 1- (5- Cyclopropylmethyl- [1,3,4] thiadiazol-2-yl) -3- [4-fluoro-3- (pyrazin- 2-yloxymethyl) -phenyl] -urea (96), 1- [4-Fluoro-3- (pyrazin-2- yloxymethyl) -phenyl] -3- (5-isopropyl- [1,3,4] thiadiazol-2-yl)
  • Preferred compounds of formula lib include N- [4-Chloro-3- (pyrazin-2-yloxymethyl) -phenyl] -2-morpholin-4-yl-isonicotinamide (93) , N- [4-Chloro-3- (pyrazin-2-yloxymethyl) -phenyl] -3-fluoro-5- morpholin-4-yl-benzamide (94), 3-tert-Butyl-N- [4-fluoro-3- (pyrazin-2-yloxymethyl) -phenyl] -benzamide (103) , 1- (5-tert-Butyl- 2-phenyl-2H-pyrazol-3-yl) -3- [4-fluoro-3- (pyrazin-2-yloxymethyl) - phenyl] -urea (106), 1- [4-Fluoro-3- (pyrazin-2-yloxymethyl) - phenyl] -3- (5-phenyl-lH-pyrazol-3-y
  • Q 2 is preferably meta to Q 1 ,
  • the compounds of the invention selectively inhibit B-raf kinase over at least one other raf kinase (A-raf and/or C-raf-1) .
  • Selectivity of inhibition can be measured by comparing the inhibition of the other raf kinase to that for B-raf kinase.
  • the figure obtained by dividing the B-raf kinase IC 50 by the other raf kinase IC 50 is a useful measure. It is preferred that this figure is at least 10, more preferably at least 100 and most preferably at least 1000.
  • the key step in the synthesis of compounds of the present invention is the joining of the pyridine/pyrazine ring to the C 5 . 20 aryl group with the intervening -0-CH 2 - linkage. As illustrated below, with respect to the pyridine molecule, this is most conveniently achieved by reacting a 3-hydroxy pyridine (or pyrazine) with a halomethyl aryl compound, under basic conditions :
  • the 3 hydroxy starting material is generally commercially available.
  • the substituents (R 1 , R 2 , R 3 and R 5 ) may be in place in the starting material, having been already introduced using known methods, or may be introduced later in the synthesis, as appropriate. Depending on their structure, protection may be needed to carry out the above step.
  • halomethyl aryl compounds may be commercially available or readily synthesised using known techniques.
  • One particular technique for deriving these compounds starts from the corresponding aryl carboxylic acid, which is first reduced, for example, using sodium borohydride, followed by halo-de- halogention, achieved, for example, by the use of triphenyl phosphine .
  • aryl group (R 4 ) bears substituents, then these may either be in place at the beginning of the synthesis, or can be added at any appropriate stage. In particular, certain substituents on the aryl group can be modified, using known reactions.
  • a key intermediate in the synthesis of preferred compounds of the present invention is the appropriately substituted 3- (pyridin-3-yloxymethyl) -phenylamine (F) , as shown in Scheme 1.
  • Scheme 1 illustrates one method of synthesis of this intermediate, although other routes to it are also possible.
  • the 3- (pyridin-3-yloxymethyl) -phenylamine (F) is synthesised from the corresponding 3- (5-nitro-benzyloxy) pyridine (E) by reduction of the 5-nitro group, using, for example, a metal reducing agent.
  • This 3- (5-nitro-benzyloxy) pyridine (E) is itself synthesised by the base mediated addition of l-bromomethyl-3-nitro-phenyl (C) , or 6-halo equivalent, to the appropriately substituted 3-hydroxy pyridine (D) .
  • the l-bromomethyl-3-nitro-phenyl (C) can be synthesised from the corresponding 3-nitro-benzoic acid (A) , via the (3-nitro-phenyl) methanol (B) .
  • the first step is a reduction, using, for example, sodium borohydride
  • the second step is a halo-de-hydroxylation, achieved, for example, by the use of triphenyl phosphine and carbon tetrabromide .
  • Scheme 2 Another key intermediate in the synthesis of preferred compounds of the present invention (of formula Ila) is an appropriately substituted 3- (pyridin-3-yloxymentyl) phenol (J) , as shown in Scheme 2.
  • Scheme 2 illustrates one method of synthesis of this intermediate, although other routes to it are possible.
  • the 3- (pyridin-3-yloxymentyl) phenol (J) is synthesised by the base mediated addition of l-bromomethyl-3-hydroxy-phenyl (I), or 6-halo equivalent, to the appropriately substituted 3-hydroxy pyridine (D) .
  • the l-bromomethyl-3-hydroxy-phenyl (I), or 6-halo equivalent can be synthesised from the corresponding 3-hydroy-benzoic acid (G) , via the (3-hydroxy) -phenyl) methanol (H) .
  • the first step is a reduction, using, for example sodium borohydride
  • the second step is a halo-de-hydroxylation, achieved, for example, by the use of triphenyl phosphine and carbon tetrabromide.
  • a key intermediate in the synthesis of further preferred compounds of the present invention is the appropriately substituted 3- (pyrazin-3-yloxymethyl) - phenylamine (Q) , as shown in Scheme 3.
  • Scheme 3 illustrates one method of synthesis of this intermediate, although other routes to it are also possible.
  • the 3- (pyrazin-3-yloxymethyl) -phenylamine (Q) is obtained from the corresponding [3- (pyrazine-3-yloxymethyl) -phenyl] carbamic acid tert-butyl ester (P) by acid mediated deprotection, for example, with a saturate ethyl acetate/HCl solution.
  • the [3- (pyrazine-3-yloxymethyl) -phenyl] carbamic acid tert-butyl ester (P) is synthesised by the base mediated addition of (3- hydroxymethyl-phenyl) -carbamic acid tert-butyl ester (N) , or its 4-halo eauivalent, to the appropriate 3-chloropyrazine (0) .
  • the (3-hydroxymethyl-phenyl) -carbamic acid tert-butyl ester (N) is a protected version of (5-amino-phenyl) methanol (M) , or its 2-halo equivalent, the protecting step being carried out using, for example, di- (tert-butylcarbonyloxy) anhydride (BOC anhydride),
  • the (5-amino-phenyl) methanol (M) , or its 2-halo equivalent is itself obtained by reduction of the corresponding (5-nitro- phenyl) methanol (L) , for example by hydrogenation using a palladium catalyst.
  • the (5-nitro-phenyl) methanol (L) can be synthesised from the corresponding 5-nitrobenzoic acid (K) by reduction, using, for example, a boron reducing agent.
  • Another key intermediate in the synthesis of preferred compounds of the present invention is an appropriately substituted 3- (pyrazin-3-yloxymentyl) phenol (S) , as shown in Scheme 4.
  • Scheme 4 illustrates one method of synthesis of this intermediate, although other routes to it are possible.
  • the 3- (pyrazin-3-yloxymentyl) phenol (S) is synthesised by the base mediated addition of 3-hydroxy benzyl alcohol (R) , or 6-halo equivalent, to the appropriately substituted 3-chloro pyrazine (0) .
  • R 1 is -NRR'
  • the isocyanate can also be trapped using tert-butanol to yield a tert-butyl protected carbamic acid, which then undergo base mediated substitution of an appropriate halo-compound (Hal-R) , to provide an alternative route to compounds where R 1 is NHR.
  • Hal-R halo-compound
  • R 1 is -NHS0 2 R
  • the desired product can be synthesised using the methods described in J. Med. Chem. , 1991, 34(4), 1356-1362, JP 57-038777 and J. Het . Chem . , 1980, 17(1), 11-16.
  • the desired compound (V) is made by the reaction between the appropriate phenylamine (T) and the aromatic acid (U) , or formic acid (where R is H) . Due to the relative unreactivity of the phenyl amine, this reaction is usually carried out with the aid of an activator or promoter. Activation of the acid can be achieved by converting it into the corresponding acid chloride, for example, by using oxalyl chloride.
  • An alternative method employs amide bond forming promoters, 1 [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCI) and 7-aza-l-hydroxybenzotriazole (HOAt) or 1-hydroxy benzotriazole (HOBt) .
  • the desired compound (BB) can be synthesised by the addition of the appropriate aromatic chloroformate (AA) to the appropriate phenylamine (T) .
  • the desired compound (EE) is made by the base mediated reaction between the appropriate phenol (CC) and the aromatic isocynate (DD) , or TMS isocyanate (where R is H) .
  • An appropriate base would be triethylamine.
  • the desired compound (II) is made via the intermediae GG without isolation.
  • the appropriate phenylamine (T) is first reacted with oxalyl chloride, followed by the appropriate amine (HH) to give the desired oxalamide (II) .
  • groups sensitive to the reaction condition can be appropriately protected to avoid side products being formed.
  • R 1 to R 5 is -OH or -SH
  • alkylation with an electrophilic reagent onto HX or Q might be expected to also undesirably substitute these groups
  • protecting groups for -OH and -SH can be employed (see above discussion of protecting groups) .
  • the present invention provides active compounds, specifically, active pyrazine derivatives as defined in the first aspect.
  • active pertains to compounds which are capable of inhibiting raf kinase activity, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
  • a candidate inhibits raf kinase activity and, in particular, B-raf kinase activity.
  • an assay which may conveniently be used in order to assess the inhibition of raf kinase activity offered by a particular compound is described in the examples below.
  • the invention further provides active compounds for use in a method of treatment of the human or animal body.
  • a method may comprise administering to such a subject a therapeutically- effective amount of an active compound, preferably in the form of a pharmaceutical composition.
  • treatment as used herein in the context of treating a disease or condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications) , in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disease or condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the disease or condition, and cure of the disease or condition.
  • Treatment as a prophylactic measure i.e. prophylaxis
  • prophylaxis is also included.
  • terapéuticaally-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy) , prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; and gene therapy.
  • Active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • raf inhibitors could be useful in the treatment of diseases in which the raf-MEK-ERK pathway is upregulated by any means.
  • a patient Prior to administration of a compound of the formula (I) , a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against raf kinases. For example, a biological sample taken from a patient may be analysed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterised by elevated expression, activation of a raf kinase (e.g. Braf) or the result of an activating mutation. Thus, the patient may be subjected to a diagnostic test to detect a marker characteristic of over- expression or activation of raf kinase or a mutation thereof.
  • a condition or disease such as cancer
  • a raf kinase e.g. Braf
  • marker include genetic markers including, for example, the measurement of DNA composition to identify mutations of raf, ras, MEK, ERK or a growth factor such as ERB2 or EGFR.
  • the term “marker” also includes markers which are characteristic of up regulation of raf, ras, MEK, ERK, growth factors such as ERB2 or EGFR including enzyme activity, enzyme levels, enzyme state (e.g. phosphorylated or not) and mRNA levels of the aforementioned proteins .
  • tumours which have an up regulated raf-MEK-ERK pathway signal may also be particularly sensitive to inhibitors of raf kinases.
  • Typical methods for screening for over expression, up regulation or mutants include, but are not limited to, standard methods such as reverse-transcriptase polymerase chain reaction (RT-PCR) or in-situ hybridisation.
  • RT-PCR reverse-transcriptase polymerase chain reaction
  • telomere amplification is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR.
  • Methods of PCR amplification, the selection of primers, and conditions for amplification, are known to a person skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described for example in Ausubel, F.M. et al . , eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et-al . , eds. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego.
  • in situ hybridization comprises the following major steps: (1) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase accessibility of target nucleic acid, and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in the hybridization, and (5) detection of the hybridized nucleic acid fragments.
  • FISH fluorescence in-situ hybridisation
  • the probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters.
  • Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid(s) under stringent conditions.
  • Standard methods for carrying out FISH are described in Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine .
  • the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumour sections, solid phase immunoassay with microtiter plates, Western blotting, 2- dimensional SDS-polyacrylamide gel electrophoresis, ELISA, and other methods known in the art for detection of specific proteins. Detection methods would include the use of site specific antibodies, such as, phospho raf, phospho ERK or phospho MEK. Inaddition to tumour biopsies other samples which could be utilised include pleural fluid, peritoneal fluid, urine, stool biopsies, sputum, blood (isolation and enrichment of shed tumour cells) .
  • mutant forms of raf, EGFR or ras can be identified by direct sequencing of, for example, tumour biopsies using PCR and methods to sequence PCR products directly as hereinbefore described.
  • PCR and methods to sequence PCR products directly as hereinbefore described The skilled artisan will recognize that all such well- known techniques for detection of the over expression, activation or mutations of the aforementioned proteins could be applicable in the present case.
  • abnormal levels of proteins such as raf, ras and EGFR can be measured using standard enzyme assays, for example for raf those assays described herein.
  • the compounds of the formula (I) are inhibitors of raf kinase activity. As such, they are expected to be useful in providing a means of preventing the growth or inducing apoptosis of neoplasias . It is therefore anticipated that the compounds will prove useful in treating or preventing proliferative disorders such as cancers . In particular tumours with activating mutants of ras or overexpression of ras may be particularly sensitive to raf inhibitors . Patients with activating mutants of any of the 3 isoforms of raf may also find treatment with raf inhibitors particularly beneficial.
  • Tumours which have other abnormalities leading to an upregulated raf-MEK-ERK pathway signal may also be particularly sensitive to inhibitors of raf kinase.
  • abnormalities include but are not limited to consitutive activation of a growth factor receptor, overexpression of one or more growth factor receptors, overexpression of one or more growth factors, or other mutations or abnormalities leading to upregulation of the pathway.
  • cancers which may be treated include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma) , kidney, epidermal, liver, lung, for example adenocarcinoma, small cell lung cancer and non- small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g.
  • a carcinoma for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma)
  • kidney epidermal
  • liver lung
  • lung for example adenocarcinoma, small cell lung cancer and non- small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g.
  • exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate, or skin for example squamous cell carcinoma
  • a hematopoietic tumour of lymphoid lineage for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin' s lymphoma, hairy cell lymphoma, or Burkett's lymphoma
  • a hematopoietic tumor of myeloid lineage for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia
  • thyroid follicular cancer a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma
  • a tumor of the central or peripheral nervous system for example astrocytoma, neuroblastoma, glioma or schwannoma
  • the treatment is related to or directed at a mutated form of raf, in particular B-raf, such as the mutations discussed in Wan, P., et al . , Cell, 116, 855-867 (2004) and WO 03/056036.
  • raf inhibitors can be used in combination with other anticancer agents.
  • the compounds of formula (I) may be combined with a therapeutic agent as discussed below.
  • the present invention provides a compound of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more of the therapeutic agents mentioned below.
  • Examples of other therapeutic agents that may be administered together (whether concurrently or at different time intervals) with the compounds of the formula (I) include but are not limited to topoisomerase inhibitors, alkylating agents, antimetabolites, DNA binders and microtubule inhibitors (tubulin target ' agents) , such as cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, mitomycin C or radiotherapy.
  • topoisomerase inhibitors such as cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, mitomycin C or radiotherapy.
  • raf kinase inhibitors combined with other therapies the two or more treatments may be given in individually varying dose schedules and via different routes.
  • topoisomerase I inhibitors such as camptothecin compounds e.g. topotecan (Hycamtin) , irinotecan and CPT11 (Camptosar)
  • antimetabolites such as anti-tumour nucleosides e.g.
  • vincristine Oncovin
  • vinorelbine Navelbine
  • vinblastine Velbe
  • taxane compounds e.g. paclitaxel (Taxol) , docetaxel (Taxotere)
  • DNA binder and topoisomerase II inhibitors such as podophyllo-toxin derivatives and anthracycline derivatives e.g.
  • cyclophosphamide Endoxana
  • -melphalan Alkeran
  • chlorambucil Leukeran
  • busulphan Myleran
  • carmustine BiCNU
  • lomustine CCNU
  • ifosfamide Mitoxana
  • aziridines e.g. mitomycin (Mitomycin C Kyoma)
  • platinum compounds e.g. cisplatin, carboplatin (Paraplatin) , oxaliplatin (Eloxatin)
  • f) monoclonal antibodies such as EGF family and its receptors and VEGF family and its receptors e.g.
  • trastuzumab Herceptin
  • cetuximab Erbitux
  • rituximab Mebthera
  • tositumomab Bexxar
  • gemtuzumab ozogamicin Mylotarg
  • Bevacizumab Avastin
  • anti-hormones such as antiandrogens including antiestorgen agents e.g.
  • gefitinib Iressa
  • i atinib Gleevec
  • erlotinib Tarceva
  • celecoxob Celebrex
  • i) proteasome inhibitors e.g. bortezimib (Velcade)
  • j) DNA methyl transferases e.g. temozolomide (Temodar)
  • k) cytokines and retinoids e.g.
  • interferon alpha IntronA, Roferon -A
  • interleukin 2 Aldesleukin, Proleukin
  • All trans- retinoic acid [ATRA] or tretinoin Vesanoid
  • the compounds can be administered simultaneously or sequentially.
  • sequentially they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1, 2, 3, 4 or more hours apart, or even longer periods apart where required) , the precise dosage regimen being commensurate with the properties of the therapeutic agent (s) .
  • the compounds of the invention may also be administered in conjunction with non-chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets .
  • the compound of the formula (I) and one, two, three, four or more, preferably one or two, preferably one other therapeutic agents can be, for example, formulated together in a dosage form containing two, three, four or more, preferably one or two, preferably one therapeutic agents.
  • the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • the disease or condition comprising abnormal cell growth in one embodiment is a cancer.
  • cancers include breast cancer, ovarian cancer, colon cancer, prostate cancer, oesophageal cancer, squamous cancer and non-small cell lung carcinomas.
  • cancers may include breast cancer, ovarian cancer, colon cancer, melanoma, prostate cancer, oesophageal cancer, squamous cancer and non-small cell lung carcinomas.
  • a further subset of cancers may include leukemia, chronic myelogenous leukemia and myelodysplastic syndrome.
  • the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion) ; topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual) ; pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g.
  • vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
  • the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • a rodent e.g. a guinea pig, a hamster, a rat, a mouse
  • murine e.g. a mouse
  • canine e.g. a dog
  • feline e.g. a cat
  • the compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a pulsatile or continuous manner.
  • the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials, as described herein.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols .
  • Formulations suitable for oral administration e.g.
  • the active compound may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
  • a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate) ; lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross- linked sodium carboxymethyl cellulose) ; surface-active or dispersing or wetting agents (e.g.
  • binders e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose
  • fillers or diluents e.g. lactose, microcrystalline
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
  • a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.
  • Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the active compound.
  • Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro- tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro- tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
  • the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base.
  • the active compounds may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent) , or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent) , or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabiliser (s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required.
  • mono-isoadipate such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the
  • high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate .
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • concentration of the active compound in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
  • appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side- effects .
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 pg to about 10 mg, more preferably 10 ng to 1 mg, per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • a typical daily dose of the compound can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 10 nanograms to 10 milligrams per kilogram of bodyweight although higher or lower doses may be administered where required.
  • the quantity of compound administered will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.
  • 2-amino-3-benzyloxypyridine (1) from benzyl chloride; ⁇ H (400 MHz; CDC1 3 ) 4.70 (2H, br s), 5.07 (2H, s), 6.59 (IH, dd, J 8, 5), 6.96 (IH, dd, J 8, 1.5), 7.40 (5H, m) , 7.68 (IH, dd, J 5, 1.5).
  • 2-amino-3- (4-fluorobenzyloxy) pyridine (4) from 4-fluorobenzyl chloride; ⁇ H (400 MHz; CDC1 3 ) 4.67 (2H, br s) , 5.02 (2H, s) , 6.59 (IH, dd, J 8, 5), 6.95 (IH, dd, J 8, 1.5), 7.08 (2H, t, J 9), 7.39 (2H, dd, J 9, 5), 7.68 (IH, dd, J 5, 1.5).
  • 2-amino-3- (2-methoxybenzyloxy) pyridine (6) from 2-methoxybenzyl chloride; ⁇ H (400 MHz; CDC1 3 ) 3.87 (3H, s) , 4.70 (2H, br s) , 5.11 (2H, s), 6.59 (IH, dd, J 8, 5), 6.93 (IH, d, J 8), 6.99 (2H, m) , 7.32 (IH, m) , 7.39 (IH, d, J 7), 7.67 (IH, dd, J 5, 1.5).
  • 2-amino-3- (2-chlorobenzyloxy) pyridine (8) from 2-chlorobenzyl chloride; ⁇ H (400 MHz; CDC1 3 ) 4.70 (2H, br s) , 5.17 (2H, s) , 6.59 (IH, dd, J 7.5, 5), 6.96 (IH, dd, J 7.5, 1.5), 7.28 (2H, m) , 7.41 (IH, ) , 7.47 (IH, m) , 7.68 (IH, dd, J 5, 1.5).
  • 2-amino-3- (3-chlorobenzyloxy) pyridine (9) : from 3-chlorobenzyl chloride; ⁇ H (400 MHz; CDC1 3 ) 4.69 (2H, br s) , 5.04 (2H, s) , 6.59 (IH, dd, J 7.5, 5), 6.93 (IH, dd, J 7.5, 1.5), 7.31 (3H, m) , 7.42 (IH, m) , 7.69 (IH, dd, J 5, 1.5).
  • R 4 is phenyl-N Synthesis of N- [4-Chloro-3- (pyridin-3-yloxymethyl) -phenyl] - benzenesulfona ide - 55 and N- [4-Chloro-3- (pyridin-3- yloxymethyl) -phenyl] -bisbenzenesulfonamide - 56
  • a stirred solution of 4-chloro-3- (pyridin-3-yloxymethyl) - phenylamine (0.09 mmol) in dry DCM at room temperature was treated with triethylamine (0.18 mmol) and sulfonyl chloride (0.126 mmol).
  • the starting material 5- (2, 6-dichloro-benzyloxy) -pyrazine-2- carboxylic acid was prepared as follows: (i) Lithium-5-chloro-pyrazine-2-carboxylate
  • the starting material [5- (2, 6-dichloro-benzyloxy) -pyrazin-2- yl] carbamic acid tert-butyl ester was prepared as follows: (i) 5- (2, 6-Dichloro-benzyloxy) -pyrazine-2-carbonyl azide 5- (2, 6-Dichloro-benzyloxy) -pyrazine-2-carboxylic acid (14 mmol) was dissolved in thionyl chloride (30 ml) and heated at reflux for 2 hours. The thionyl chloride was removed under reduced pressure with toluene, the residue dissolved in acetone (60 ml), treated with sodium azide (16.9 mmol) and then stirred overnight at room temperature.
  • B-raf kinase activity was measured using a 4-tiered cascade enzyme assay similar to that described by Marais R., et al . , J. Biol . Chem . , 272, 4378-4383 (1997).
  • B-Raf containing the V599E mutation (Davies, H., et a 1 . , Na ture, 417, 949 - 954 (2002)) and an N-terminal MDRGSH6 tag was expressed in SF9 insect cells.
  • Detergent soluble extracts from these cells were diluted 1:100 into an assay mixture containing GST-MEK-H6 (6.5 ⁇ g/ml) and GST- ERK-H6 (lOO ⁇ g/ml) in a buffer containing 800 ⁇ M ATP and appropriate concentrations of inhibitor or diluent as control.
  • the mixture was incubated for up to 10 minutes at 30 °C to activate the ERK in a B-Raf dependent manner within the cascade.
  • the reaction was then stopped by addition of 20mM EDTA.
  • the extent of activation of the GST-ERK was then determined by adding a portion of this quenched reaction mixture to a further reaction containing MBP and lOOuM ATP/gamma [ 32 P]ATP.
  • Compounds 94 and 120 have an IC 50 of less than 0.01 ⁇ M and compounds 147 and 165 have an IC 50 of less than 0.5 ⁇ M.
  • B-raf kinase activity was measured using an alternative 4-tiered cascade enzyme assay.
  • B-Raf containing the V599E mutation (Davies, H., et al . , Na ture, 417, 949 - 954 (2002)) and an N- terminal MDRGSH6 tag was expressed in SF9 insect cells.
  • Detergent soluble extracts from these cells were diluted 1:250 into an assay mixture containing GST-MEK-H6 (25 ⁇ g/ml) , GST-ERK-H6 (281.25 ⁇ g/ml) and MBP in a buffer containing appropriate concentrations of inhibitor or diluent as control.
  • the % inhibition of the B-raf kinase activity is calculated and plotted in order to determine the concentration of test compound required to inhibit 50% of the B-raf kinase activity (IC 50 ) .
  • Compounds 117, 128, 129, 132, 134 and 144 have an IC 50 of less than lOO ⁇ M.
  • Compounds 93, 95, 98, 102, 115, 151, 157, 181, 182 and 183 have an IC 50 of less than lO ⁇ M.
  • Compounds 99, 100, 101, 106, 125, 126, 127, 140, 153, 160, 161, 162, 178, 179 and 180 have an 1C 50 of less than l ⁇ M.
  • C-raf kinase Assay c-raf (human) is diluted to a lOx working stock in 50mM Tris pH 7.5, 0. ImM EGTA, 0. ImM sodium vanadate, 0.1% ⁇ -mercaptoethanol, lmg/ml BSA.
  • One unit equals the incorporation of 1 nmol of phosphate per minute into myelin basic protein per minute.
  • c-raf (5-10 mU) is incubated with 25mM Tris pH 7.5, 0.02mM EGTA, 0.66mg/ml myelin basic protein, lOmM MgAcetate, [ ⁇ - 33 P-ATP] (specific activity approx 500cpm/pmol, concentration as required) and appropriate concentrations of inhibitor or diluent as control .
  • the reaction is initiated by the addition of Mg 2 + [ ⁇ - 33 P-ATP] .
  • After incubation for 40 minutes at room temperature the reaction is stopped by the addition of 5 ⁇ l of a 3% phosphoric acid solution.
  • lO ⁇ l of the reaction is spotted onto a P30 filtermat and washed 3 times for 5 minutes in 75mM phosphoric acid and once in methanol prior to drying and counting to determine the C-raf activity.
  • the % inhibition of the C-raf kinase activity is calculated and plotted in order to determine the concentration of test compound required to inhibit 50% of the C-raf kinase activity (IC 50 ) .
  • the following compounds have an IC 50 of l ⁇ M or less: 44, 49, 76, 79 and 176.
  • the following further compounds have an IC 50 of 10 ⁇ M or less: 167, 168, 170, 171 and 174, whilst the following further compounds have an IC 50 of 100 ⁇ M or less: 169, 172, 173, 175 and 177.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de la formule I, un sel ou un solvate de ce dernier pharmaceutiquement acceptable, destiné à la fabrication d'un médicament servant dans le traitement d'un état amélioré par l'inhibition de raf kinase. X=Y- est choisi dans CR2=CR3- et CR2=N- ; R1 est choisi parmi H, halo, NRR', NHC(=O)NRR', NH2SO2R, et C(=O)NRR', R et R' étant choisis indépendamment parmi H et C1 4 alkyle et éventuellement substitués par OH, NH2, SO2-NH2, C5 20 carboaryle, C5 20 hétéroaryle et C3 20 hétérocyclyle, ou pouvant ensemble former, avec l'atome d'azote auquel ils sont liés, un azote éventuellement substitué contenant un groupe C5 7 hétérocyclyle ; R2 et R3 (le cas échéant) sont indépendamment choisis dans H, éventuellement substitué C1 7 alkyle, éventuellement substitué C5 20 aryle, éventuellement substitué C3 20 hétérocyclyle, halo, amino, amido, hydroxy, éther, thio, thioéther, acylamido, uréido et sulfonamino ; R4 représentant un groupe C5 20 carboaryle ou C5 20 hétéroaryle éventuellement substitué ; et R5 est choisi parmi R5', halo, NHR5', C(=O) NHR5', OR5', SR5', NHC(=O)R5', NHC(=O)NHR5', NHS(=O)2R5', R5' représentant H ou C1 3 alkyle (éventuellement substitué par halo, NH2, OH, SH).
PCT/GB2004/002877 2003-07-03 2004-07-02 Inhibiteurs de raf kinase WO2005002673A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US48430103P 2003-07-03 2003-07-03
US48430003P 2003-07-03 2003-07-03
US60/484,301 2003-07-03
US60/484,300 2003-07-03

Publications (1)

Publication Number Publication Date
WO2005002673A1 true WO2005002673A1 (fr) 2005-01-13

Family

ID=33567719

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/002877 WO2005002673A1 (fr) 2003-07-03 2004-07-02 Inhibiteurs de raf kinase

Country Status (1)

Country Link
WO (1) WO2005002673A1 (fr)

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006124780A2 (fr) * 2005-05-12 2006-11-23 Kalypsys, Inc. Inhibiteurs de la b-raf kinase
US7351834B1 (en) 1999-01-13 2008-04-01 Bayer Pharmaceuticals Corporation ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
WO2008044688A1 (fr) * 2006-10-11 2008-04-17 Daiichi Sankyo Company, Limited Dérivé de l'urée
WO2008058341A1 (fr) * 2006-11-15 2008-05-22 Cytopia Research Pty Ltd Inhibiteurs de l'activité kinase
WO2009044160A1 (fr) * 2007-10-05 2009-04-09 Senexis Limited Dérivés de pyridine pour le traitement de maladies se rapportant aux amyloïdes
JP2010506850A (ja) * 2006-10-11 2010-03-04 デシフェラ ファーマシューティカルズ，エルエルシー 慢性骨髄増殖疾患および他の増殖性疾患の治療のために有用なキナーゼ阻害剤
US7678811B2 (en) 2002-02-11 2010-03-16 Bayer Healthcare Llc Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
WO2010073011A2 (fr) 2008-12-23 2010-07-01 Betagenon Ab Composés utiles comme médicaments
US7807672B2 (en) 2006-02-16 2010-10-05 Schering Corporation Compounds that are ERK inhibitors
JP2010533729A (ja) * 2007-07-17 2010-10-28 プレキシコン，インコーポレーテッド キナーゼ調節のための化合物と方法、及びそのための適応
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7858643B2 (en) 2004-08-26 2010-12-28 Agouron Pharmaceuticals, Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
JP2012504591A (ja) * 2008-10-02 2012-02-23 レスピバート・リミテツド ｐ３８ＭＡＰキナーゼ阻害剤
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8143293B2 (en) 2007-04-20 2012-03-27 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
JP2012511564A (ja) * 2008-12-11 2012-05-24 レスピバート・リミテツド ｐ３８ＭＡＰキナーゼ阻害剤
US8207166B2 (en) 2004-04-30 2012-06-26 Bayer Healthcare Llc Substituted pyrazolyl urea derivatives useful in the treatment of cancer
US8455658B2 (en) 2006-01-25 2013-06-04 Synta Pharmaceuticals Corp. Thiazole and thiadiazole compounds for inflammation and immune-related uses
WO2013129369A1 (fr) * 2012-02-28 2013-09-06 アステラス製薬株式会社 Composé hétérocyclique aromatique contenant de l'azote
US8546404B2 (en) 2005-12-13 2013-10-01 Merck Sharp & Dohme Compounds that are ERK inhibitors
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8642773B2 (en) 2009-04-03 2014-02-04 Respivert Ltd. P38MAP kinase inhibitor
US8716483B2 (en) 2008-02-21 2014-05-06 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
JP2016510774A (ja) * 2013-03-15 2016-04-11 ハチソン メディファーマ リミテッド 新規なピリミジン及びピリジン化合物並びにその利用
AU2013273769B2 (en) * 2006-11-15 2016-05-12 Ym Biosciences Australia Pty Ltd Inhibitors of Kinase Activity
CN106866627A (zh) * 2017-01-24 2017-06-20 南方医科大学 3‑(1‑(氨基吡啶氧基)乙基)苯甲酰胺衍生物及其合成方法和应用
US9815815B2 (en) 2013-01-10 2017-11-14 Pulmokine, Inc. Non-selective kinase inhibitors
US9925184B2 (en) 2013-10-11 2018-03-27 Pulmokine, Inc. Spray-dry formulations
US10231966B2 (en) 2016-10-27 2019-03-19 Pulmokine, Inc. Combination therapy for treating pulmonary hypertension
CN110128299A (zh) * 2019-05-13 2019-08-16 浙江大学 一种二苯基脲类抗肿瘤小分子抑制剂及其制备方法
WO2019174601A1 (fr) * 2018-03-15 2019-09-19 Fujian Haixi Pharmaceuticals Co., Ltd Composés hétéroaryle utilisés en tant qu'inhibiteur de kinase
US10464896B2 (en) 2015-06-11 2019-11-05 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof
WO2019225920A1 (fr) * 2018-05-23 2019-11-28 아주대학교산학협력단 Série de composés tac5 antagonistes à petites molécules ayant une fonction inhibitrice du récepteur de type toll 3/7/8/9
WO2019232275A1 (fr) * 2018-05-30 2019-12-05 Washington University Inhibiteurs de protéines kinases activés par mitogène, procédés de production et procédés d'utilisation associés
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
CN115246787A (zh) * 2021-04-28 2022-10-28 吉林省达凯生物医药有限公司 间位双取代化合物及其制备和在防治蚊虫、植物病菌病中的应用
US11629155B2 (en) 2018-05-23 2023-04-18 Ajou University Industry-Academic Cooperation Foundation Small molecule antagonist compound TAC5 series having toll-like receptor 3/7/8/9 inhibitory function
US11753376B2 (en) 2021-03-19 2023-09-12 Autotac Inc. Benzyloxy pyridine derivatives and uses thereof
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
US12102620B2 (en) 2018-01-31 2024-10-01 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of mastocytosis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5409943A (en) * 1992-01-27 1995-04-25 Smithkline Beecham Intercredit B.V. [(alkoxy)pyridinyl]amine compounds which are useful in the treatment of gastrointestinal disorders
US5990133A (en) * 1995-02-02 1999-11-23 Smithkline Beecham P.L.C. Indole derivatives as 5-HT receptor antagonist
WO2004004720A1 (fr) * 2002-07-03 2004-01-15 Astex Technology Limited 3-(hetero) arylmethoxy pyridines et leurs analogues en tant qu'inhibiteurs de la p38 map kinase
WO2004007472A1 (fr) * 2002-07-10 2004-01-22 Ono Pharmaceutical Co., Ltd. Antagoniste du ccr4 et utilisation medicinale correspondante

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5409943A (en) * 1992-01-27 1995-04-25 Smithkline Beecham Intercredit B.V. [(alkoxy)pyridinyl]amine compounds which are useful in the treatment of gastrointestinal disorders
US5990133A (en) * 1995-02-02 1999-11-23 Smithkline Beecham P.L.C. Indole derivatives as 5-HT receptor antagonist
WO2004004720A1 (fr) * 2002-07-03 2004-01-15 Astex Technology Limited 3-(hetero) arylmethoxy pyridines et leurs analogues en tant qu'inhibiteurs de la p38 map kinase
WO2004007472A1 (fr) * 2002-07-10 2004-01-22 Ono Pharmaceutical Co., Ltd. Antagoniste du ccr4 et utilisation medicinale correspondante

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG H-P ET AL: "Preparation and antitumor activities of [beta]-azatyrosinamides", JOURNAL OF FOOD AND DRUG ANALYSIS 2000 TAIWAN, vol. 8, no. 3, 2000, pages 159 - 165, XP009038682, ISSN: 1021-9498 *

Cited By (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US7351834B1 (en) 1999-01-13 2008-04-01 Bayer Pharmaceuticals Corporation ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US7678811B2 (en) 2002-02-11 2010-03-16 Bayer Healthcare Llc Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US8071616B2 (en) 2002-02-11 2011-12-06 Bayer Healthcare Llc Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8207166B2 (en) 2004-04-30 2012-06-26 Bayer Healthcare Llc Substituted pyrazolyl urea derivatives useful in the treatment of cancer
US8785632B2 (en) 2004-08-26 2014-07-22 Agouron Pharmaceuticals, Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
US7858643B2 (en) 2004-08-26 2010-12-28 Agouron Pharmaceuticals, Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
WO2006124780A3 (fr) * 2005-05-12 2007-01-11 Kalypsys Inc Inhibiteurs de la b-raf kinase
WO2006124780A2 (fr) * 2005-05-12 2006-11-23 Kalypsys, Inc. Inhibiteurs de la b-raf kinase
US8546404B2 (en) 2005-12-13 2013-10-01 Merck Sharp & Dohme Compounds that are ERK inhibitors
US8455658B2 (en) 2006-01-25 2013-06-04 Synta Pharmaceuticals Corp. Thiazole and thiadiazole compounds for inflammation and immune-related uses
US7807672B2 (en) 2006-02-16 2010-10-05 Schering Corporation Compounds that are ERK inhibitors
JP2010506850A (ja) * 2006-10-11 2010-03-04 デシフェラ ファーマシューティカルズ，エルエルシー 慢性骨髄増殖疾患および他の増殖性疾患の治療のために有用なキナーゼ阻害剤
WO2008044688A1 (fr) * 2006-10-11 2008-04-17 Daiichi Sankyo Company, Limited Dérivé de l'urée
JP2014065713A (ja) * 2006-11-15 2014-04-17 Ym Biosciences Australia Pty Ltd キナーゼ活性の阻害剤
JP2018024670A (ja) * 2006-11-15 2018-02-15 ワイエム・バイオサイエンスィーズ・オーストラリア・ピーティーワイ・リミテッドＹＭ Ｂｉｏｓｃｉｅｎｃｅｓ Ａｕｓｔｒａｌｉａ Ｐｔｙ Ｌｔｄ キナーゼ活性の阻害剤
US20130137660A1 (en) * 2006-11-15 2013-05-30 Ym Biosciences Australia Pty Ltd Inhibitors of kinase activity
WO2008058341A1 (fr) * 2006-11-15 2008-05-22 Cytopia Research Pty Ltd Inhibiteurs de l'activité kinase
US8461161B2 (en) 2006-11-15 2013-06-11 Ym Biosciences Australia Pty Ltd Substituted pyrazines as inhibitors of kinase activity
AU2013273769B2 (en) * 2006-11-15 2016-05-12 Ym Biosciences Australia Pty Ltd Inhibitors of Kinase Activity
JP2015164925A (ja) * 2006-11-15 2015-09-17 ワイエム・バイオサイエンスィーズ・オーストラリア・ピーティーワイ・リミテッドＹＭ Ｂｉｏｓｃｉｅｎｃｅｓ Ａｕｓｔｒａｌｉａ Ｐｔｙ Ｌｔｄ キナーゼ活性の阻害剤
US9029386B2 (en) 2006-11-15 2015-05-12 Gilead Sciences, Inc. Pyridine derivatives useful as kinase inhibitors
AU2007321719B2 (en) * 2006-11-15 2013-11-21 Ym Biosciences Australia Pty Ltd Inhibitors of kinase activity
JP2010509375A (ja) * 2006-11-15 2010-03-25 サイトピア・リサーチ・ピーティーワイ・リミテッド キナーゼ活性の阻害剤
US8143293B2 (en) 2007-04-20 2012-03-27 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
JP2010533729A (ja) * 2007-07-17 2010-10-28 プレキシコン，インコーポレーテッド キナーゼ調節のための化合物と方法、及びそのための適応
JP2015007100A (ja) * 2007-07-17 2015-01-15 プレキシコン，インコーポレーテッド キナーゼ調節のための化合物と方法、及びそのための適応
WO2009044160A1 (fr) * 2007-10-05 2009-04-09 Senexis Limited Dérivés de pyridine pour le traitement de maladies se rapportant aux amyloïdes
CN101888877A (zh) * 2007-10-05 2010-11-17 塞内希斯有限公司 用于治疗淀粉样蛋白相关性疾病的吡啶衍生物
US8716483B2 (en) 2008-02-21 2014-05-06 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
US8975285B2 (en) 2008-10-02 2015-03-10 Respivert Ltd. P38 MAP kinase inhibitors
US8618140B2 (en) 2008-10-02 2013-12-31 Respivert Ltd P38 MAP kinase inhibitors
JP2012504591A (ja) * 2008-10-02 2012-02-23 レスピバート・リミテツド ｐ３８ＭＡＰキナーゼ阻害剤
JP2012511564A (ja) * 2008-12-11 2012-05-24 レスピバート・リミテツド ｐ３８ＭＡＰキナーゼ阻害剤
WO2010073011A2 (fr) 2008-12-23 2010-07-01 Betagenon Ab Composés utiles comme médicaments
US8642773B2 (en) 2009-04-03 2014-02-04 Respivert Ltd. P38MAP kinase inhibitor
US9242960B2 (en) 2009-04-03 2016-01-26 Respivert, Ltd. P38MAP kinase inhibitors
US9464077B2 (en) 2012-02-28 2016-10-11 Astellas Pharma Inc. Nitrogen-containing aromatic heterocyclic compound
CN104144915A (zh) * 2012-02-28 2014-11-12 安斯泰来制药有限公司 含氮芳香族杂环化合物
WO2013129369A1 (fr) * 2012-02-28 2013-09-06 アステラス製薬株式会社 Composé hétérocyclique aromatique contenant de l'azote
CN104144915B (zh) * 2012-02-28 2016-08-24 安斯泰来制药有限公司 含氮芳香族杂环化合物
JP5343177B1 (ja) * 2012-02-28 2013-11-13 アステラス製薬株式会社 含窒素芳香族へテロ環化合物
EA026953B1 (ru) * 2012-02-28 2017-06-30 Астеллас Фарма Инк. Азотсодержащее ароматическое гетероциклическое соединение
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US10532994B2 (en) 2013-01-10 2020-01-14 Pulmokine, Inc. Non-selective kinase inhibitors
US9815815B2 (en) 2013-01-10 2017-11-14 Pulmokine, Inc. Non-selective kinase inhibitors
US10246438B2 (en) 2013-01-10 2019-04-02 Pulmokine, Inc Non-selective kinase inhibitors
JP2016510774A (ja) * 2013-03-15 2016-04-11 ハチソン メディファーマ リミテッド 新規なピリミジン及びピリジン化合物並びにその利用
US9925184B2 (en) 2013-10-11 2018-03-27 Pulmokine, Inc. Spray-dry formulations
US10464896B2 (en) 2015-06-11 2019-11-05 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof
US10231966B2 (en) 2016-10-27 2019-03-19 Pulmokine, Inc. Combination therapy for treating pulmonary hypertension
US11364238B2 (en) 2016-10-27 2022-06-21 Pulmokine, Inc. Combination therapy for treating pulmonary hypertension
CN106866627A (zh) * 2017-01-24 2017-06-20 南方医科大学 3‑(1‑(氨基吡啶氧基)乙基)苯甲酰胺衍生物及其合成方法和应用
CN106866627B (zh) * 2017-01-24 2021-09-14 南方医科大学 3-(1-(氨基吡啶氧基)乙基)苯甲酰胺衍生物及其合成方法和应用
US12102620B2 (en) 2018-01-31 2024-10-01 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of mastocytosis
US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
WO2019174601A1 (fr) * 2018-03-15 2019-09-19 Fujian Haixi Pharmaceuticals Co., Ltd Composés hétéroaryle utilisés en tant qu'inhibiteur de kinase
US11767296B2 (en) * 2018-03-15 2023-09-26 Fujian Haixi Pharmaceuticals Co., Ltd Heteroaryl compounds as kinase inhibitor
KR102556742B1 (ko) * 2018-03-15 2023-07-18 푸지안 하이시 파마슈티칼스 컴퍼니 리미티드 키나제 억제제로서의 헤테로아릴 화합물
AU2019233207B2 (en) * 2018-03-15 2021-05-27 Fujian Haixi Pharmaceuticals Co., Ltd Heteroaryl compounds as kinase inhibitor
JP2021516250A (ja) * 2018-03-15 2021-07-01 フーチェン ハイシィ ファーマシューティカルズ シーオー．，エルティーディーＦｕｊｉａｎ Ｈａｉｘｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏ．， Ｌｔｄ キナーゼ阻害剤としてのヘテロアリール化合物
KR20200119850A (ko) * 2018-03-15 2020-10-20 푸지안 하이시 파마슈티칼스 컴퍼니 리미티드 키나제 억제제로서의 헤테로아릴 화합물
CN111601790A (zh) * 2018-03-15 2020-08-28 福建海西新药创制有限公司 作为蛋白激酶抑制剂的杂芳基化合物
JP7034512B2 (ja) 2018-03-15 2022-03-14 フーチェン ハイシィ ファーマシューティカルズ シーオー．，エルティーディー キナーゼ阻害剤としてのヘテロアリール化合物
US11629155B2 (en) 2018-05-23 2023-04-18 Ajou University Industry-Academic Cooperation Foundation Small molecule antagonist compound TAC5 series having toll-like receptor 3/7/8/9 inhibitory function
WO2019225920A1 (fr) * 2018-05-23 2019-11-28 아주대학교산학협력단 Série de composés tac5 antagonistes à petites molécules ayant une fonction inhibitrice du récepteur de type toll 3/7/8/9
US12006337B2 (en) 2018-05-30 2024-06-11 Washington University Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof
WO2019232275A1 (fr) * 2018-05-30 2019-12-05 Washington University Inhibiteurs de protéines kinases activés par mitogène, procédés de production et procédés d'utilisation associés
EP4219489A3 (fr) * 2018-05-30 2023-11-15 Washington University Inhibiteurs de protéine kinase activée par mitogène, procédés de fabrication et procédés d'utilisation de ceux-ci
US11407771B2 (en) 2018-05-30 2022-08-09 Washington University Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof
CN110128299B (zh) * 2019-05-13 2020-11-10 浙江大学 一种二苯基脲类抗肿瘤小分子抑制剂及其制备方法
CN110128299A (zh) * 2019-05-13 2019-08-16 浙江大学 一种二苯基脲类抗肿瘤小分子抑制剂及其制备方法
US11969414B2 (en) 2019-08-12 2024-04-30 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11529336B2 (en) 2019-08-12 2022-12-20 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11534432B2 (en) 2019-08-12 2022-12-27 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11576904B2 (en) 2019-08-12 2023-02-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12059411B2 (en) 2019-08-12 2024-08-13 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12059410B2 (en) 2019-08-12 2024-08-13 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11433056B1 (en) 2019-08-12 2022-09-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12023326B2 (en) 2019-08-12 2024-07-02 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11426390B2 (en) 2019-08-12 2022-08-30 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12023325B2 (en) 2019-08-12 2024-07-02 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12023327B2 (en) 2019-08-12 2024-07-02 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11813251B2 (en) 2019-08-12 2023-11-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11344536B1 (en) 2019-08-12 2022-05-31 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11903933B2 (en) 2019-12-30 2024-02-20 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11850241B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11896585B2 (en) 2019-12-30 2024-02-13 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11844788B1 (en) 2019-12-30 2023-12-19 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11911370B1 (en) 2019-12-30 2024-02-27 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11918564B1 (en) 2019-12-30 2024-03-05 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US12226406B2 (en) 2019-12-30 2025-02-18 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11969415B1 (en) 2019-12-30 2024-04-30 Deciphera Pharmaceuticals, Llc (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11801237B2 (en) 2019-12-30 2023-10-31 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11850240B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11793795B2 (en) 2019-12-30 2023-10-24 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US12213967B2 (en) 2019-12-30 2025-02-04 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US12213968B2 (en) 2019-12-30 2025-02-04 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US12023328B2 (en) 2019-12-30 2024-07-02 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11576903B2 (en) 2019-12-30 2023-02-14 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11612591B2 (en) 2019-12-30 2023-03-28 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US12064422B2 (en) 2019-12-30 2024-08-20 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11753376B2 (en) 2021-03-19 2023-09-12 Autotac Inc. Benzyloxy pyridine derivatives and uses thereof
CN115246787A (zh) * 2021-04-28 2022-10-28 吉林省达凯生物医药有限公司 间位双取代化合物及其制备和在防治蚊虫、植物病菌病中的应用
CN115246787B (zh) * 2021-04-28 2024-03-12 吉林省达凯生物医药有限公司 间位双取代化合物及其制备和在防治蚊虫、植物病菌病中的应用
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Similar Documents

Publication Publication Date Title
WO2005002673A1 (fr) Inhibiteurs de raf kinase
WO2004004720A1 (fr) 3-(hetero) arylmethoxy pyridines et leurs analogues en tant qu'inhibiteurs de la p38 map kinase
JP4926973B2 (ja) 治療化合物としての、イミダゾ［４，５−ｂ］ピリジン−２−オンおよびオキサゾロ［４，５−ｂ］ピリジン−２−オン化合物ならびにそれらの類似体
US7951819B2 (en) Imidazo[4, 5-B]pyridin-2-one and oxazolo[4, 5-B] pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds
EP1831184B1 (fr) Pyrazines, pyridines et leurs derives, utilises comme composes therapeutiques
KR101541203B1 (ko) 피라지논 유도체 및 폐 질환의 치료에서 그의 용도
EP1442019B1 (fr) Derives amides utilises en tant qu'inhibiteurs de la glycogene synthase kinase 3-beta
EP1305026B1 (fr) Analogues de l'acide barbiturique utilises comme agents therapeutiques
WO2017101803A1 (fr) Nouveau double inhibiteur de egfr et de alk
MX2011012840A (es) Compuestos inhibidores de cinasa janus y metodos.
CN109843858A (zh) 某些化学实体、组合物及方法
TW200808771A (en) Novel compounds II
EP3412670B1 (fr) Dérivés de pyridine comme inhibiteurs de rak kinase et du récepteur de facteur de croissance endothélial vasculaire, composition pharmaceutique les contenant et leur utilisation
EP3426635B1 (fr) Dérivés de 3-oxa-8-azabicyclo [3.2.1]octane et leur utilisation dans le traitement du cancer et d'hémoglobinopathies
NZ572246A (en) Imidazo[4,5-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds
WO2003068227A1 (fr) Antagonistes du recepteur 5-ht2b
CN119698413A (zh) 双环四氢硫氮杂䓬衍生物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载