[go: up one dir, main page]

WO2006067445A2 - Composes chimiques - Google Patents

Composes chimiques Download PDF

Info

Publication number
WO2006067445A2
WO2006067445A2 PCT/GB2005/004985 GB2005004985W WO2006067445A2 WO 2006067445 A2 WO2006067445 A2 WO 2006067445A2 GB 2005004985 W GB2005004985 W GB 2005004985W WO 2006067445 A2 WO2006067445 A2 WO 2006067445A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
alkyl
methyl
sulphamoyl
mmol
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2005/004985
Other languages
English (en)
Other versions
WO2006067445A3 (fr
Inventor
Lynsie Almeida
Brian Aquila
Don Cook
Scott Cowen
Les Dakin
Jayachandran Ezhuthachan
Stephanos Ioannidis
Stephen Lee
Paul Lyne
Timothy Pontz
David Scott
Mei Su
Xiaolan Zheng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
AstraZeneca AB
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 AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2006067445A2 publication Critical patent/WO2006067445A2/fr
Publication of WO2006067445A3 publication Critical patent/WO2006067445A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to chemical compounds, or pharmaceutically acceptable salts thereof, which possess colony stimulating factor 1 receptor (CSF-IR) kinase inhibitory activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body.
  • CSF-IR colony stimulating factor 1 receptor
  • the invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm-blooded animal such as man.
  • Receptor tyrosine kinases RTK' s
  • RTK's are a sub- family of protein kinases that play a critical role in cell signalling and are involved in a variety of cancer related processes including cell proliferation, survival, angiogenesis, invasion and metastasis. There are believed to be at least 96 different RTK's including CSF-IR.
  • CSF-IR or c-fms was originally identified as the oncogene v-fms from the feline sarcoma virus.
  • CSF-IR is a member of the class III RTK's along with c-Kit, fms-related tyrosine kinase 3 (Flt3), Platelet-derived growth factor receptor ⁇ and ⁇ (PDGFR ⁇ and PDGFR ⁇ ) All of these kinases have been implicated in the process of tumorigenesis.
  • CSF-IR is normally expressed as an immature 130 kDa transmembrane protein and ultimately results in a mature 145-160 kDa cell surface TV-linked glycosylated protein.
  • Macrophage colony stimulating factor (M-CSF or CSF-I), the ligand for CSF-IR, binds to the receptor resulting in dimerization, auto-phosphorylation of the receptor and subsequent activation of downstream signal transduction cascades (CJ. Sherr, Biochim Biophys Acta, 1988, 948: 225- 243).
  • CSF-IR is normally expressed in myeloid cells of the mononuclear phagocytic lineage and their bone-marrow progenitors as well as the epithelial cells of the ducts and alveoli in the lactating, but not normal resting, breast tissue.
  • CSF-IR activation stimulates the proliferation, survival, motility and differentiation of cells of the monocyte/macrophage lineage.
  • the mature macrophage plays a key role in normal tissue development and immune defence (F.L. Pixley and E.R. Stanley, Trends in Cell Biology, 2004, 14(11): 628-638).
  • osteoblasts secrete CSF-I and activate the receptor on osteoclastic progenitors resulting in differentiation into mature osteoclasts (S.L.
  • the CSF-IR axis plays an important role in placental development, embryonic implantation, mammary gland ductal and lobuloalveolar development and lactation (E. Sapi, Exp Biol Med, 2004, 229:1-11).
  • CSF-IR Transfection of CSF-IR with or without CSF-I induces transformation and in vivo tumorigenicity of N1H3T3 (Rat2 and ovarian granulosa cells.
  • Autocrine and/or paracrine signaling mechanisms have been implicated in the activation of CSF-IR in the tumour epithelium and tumour associated macrophage.
  • Aberrant expression and activation of CSF-IR and/or its ligand have been found in human myeloid leukaemia, prostate, breast, ovarian, endometrial and a variety of other cancers.
  • a number of studies have demonstrated that the overexpression of CSF-IR is associated with poor prognosis in several of these cancers.
  • CSF-I /CSF- IR axis plays a key role in the regulation of tumour-associated macrophage, which have been postulated to play a significant role in tumour angiogenesis, invasion and progression (E. Sapi, Exp Biol Med, 2004, 229:1-11).
  • AstraZeneca application WO 00/55120 discloses certain amide derivatives which are inhibitors of the production of cytokines such as TNF, in particular of TNF ⁇ , and various interleukins, in particular IL-I .
  • the present inventors have surprisingly found that certain other, novel, amide derivatives are potent CSF-IR kinase inhibitors and are accordingly expected to be useful in the treatment of neoplastic disease.
  • Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 5 ;
  • R 1 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, Ci -6 alkanoyl, C
  • R 2 is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, Ci -6 alkanoyl, Ci -6 alkanoyloxy, N-(Ci -6 alkyl)amino, N,N-(C i -6 alkyl) 2 amino, Ci- 6 alkanoylamino, TV, TV-(C i -6 alkyl) 2 carbamoyl, Ci -6 alkylS(O) a wherein a is 0 to 2, C 1-6 alkoxycarbonyl, TV-(Ci -6 alkyl)sulphamoyl,
  • R is selected from halo, hydroxy, cyano, methyl, methoxy or hydroxymethyl
  • R is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C
  • R 4 may be optionally substituted on carbon by one or more R 16 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 17 ; m is selected from 0-4; wherein the values of R 4 may be the same or different;
  • R 8 and R 12 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C
  • R 16 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • R 6 , R 7 , R 10 , R", R 14 , R 15 , R 18 , R 19 , R 22 and R 23 are independently selected from a direct bond, -O-, -N(R 26 )-, -C(O)-, -N(R 27 )C(O)-, -C(O)N(R 28 )-, -S(O) 8 -, -SO 2 N(R 29 )- or -N(R 30 )SO 2 -; wherein R 26 , R 27 , R 28 , R 29 and R 30 are independently selected from hydrogen or
  • Ci -6 alkyl and s is 0-2;
  • R 5 , R 9 , R 13 , R 17 , R 21 and R 25 are independently selected from Ci -6 alkyl, Ci -6 alkanoyl,
  • Ci -6 alkylsulphonyl Ci -6 alkoxycarbonyl, carbamoyl, N-(C
  • R 20 and R 24 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, /V-methyl-/V-ethylamino, acetylamino, /V-methylcarbamoyl, /V-ethylcarbamoyl,
  • Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 5 ;
  • R 1 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C
  • Ci -6 alkynyl C] -6 alkoxy, Ci -6 alkanoyl, Ci -6 alkanoyloxy, N-(Ci -6 alkyl)amino, iV, ⁇ / -(Ci -6 alkyl) 2 amino, C
  • R 2 is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy,
  • Ci-6alkanoyl Ci -6 alkanoyloxy, TV-(C i -6 alkyl)amino, TV, TV-(C i. 6 alkyl) 2 amino,
  • R 4 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci ⁇ alkoxy,
  • Ci-6alkanoyl C ⁇ -6 alkanoyloxy, N-(Ci -6 alkyl)amino, N,N-(Ci-6alkyl) 2 amino, C ⁇ - 6 alkanoylamino, N-(C
  • R 6 , R 7 , R 10 , R 11 , R 14 , R 15 , R 18 , R 19 , R 22 and R 23 are independently selected from a direct bond, -O-, -N(R 26 )-, -C(O)-, -N(R 27 )C(O)-, -C(O)N(R 28 )-, -S(O) 5 -, -SO 2 N(R 29 )- or
  • R 26 , R 27 , R 28 , R 29 and R 30 are independently selected from hydrogen or
  • Ci -6 alkyl and s is 0-2; R 5 , R 9 , R 13 , R t7 , R 2 ' and R 25 are independently selected from C )-6 alkyl, C
  • R 20 and R 2 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, 7V-methyl-N-ethylamino, acetylamino, iV-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, ⁇ vV-diethylcarbamoyl, TV-methyl-iV-ethyl
  • alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • “Ci -6 alkyl” includes Cualkyl, Ci -3 alkyl, propyl, isopropyl and /-butyl.
  • phenylCi -6 alkyl includes phenylCualkyl, benzyl, 1 -phenylethyl and 2-phenylethyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, whereiti a -CH 2 - group can optionally be replaced by a -C(O)- and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomo ⁇ holino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, W-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-W-oxide.
  • heterocyclyl is pyrazolyl.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
  • Suitable values for "carbocyclyl” include cyclopropyl, cyclobutyl, 1 -oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • a particular example of “carbocyclyl” is phenyl.
  • -6 alkanoyloxy” is acetoxy.
  • Examples of "Ci -6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • Examples of "Ci -6 alkoxy” include methoxy, ethoxy and propoxy.
  • Examples of “Ci -6 alkanoylamino” include formamido, acetamido and propionylamino.
  • Examples of "Ci -6 alkylS(O) a wherein a is 0 to 2” include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples include propionyl and acetyl.
  • -6 alkyl)amino include methylamino and ethylamino.
  • -6 alkyl) 2 amino” include di-N-methylamino, di-(W-ethyl)amino and N-ethyl-W-methylamino.
  • Examples of "C 2-6 alkenyl” are vinyl, allyl and 1-propenyl.
  • Examples of "C 2-6 alkynyl” are ethynyl, 1-propynyl and 2-propynyl.
  • Examples of 'W-(Ci -6 alkyl)sulphamoyl are W-(methyl)sulphamoyl and W-(ethyl)sulphamoyl.
  • -6 alkyl) 2 sulphamoyl" are 7V,W-(dimethyl)sulphamoyl and jV-(methyl)-N-(ethyl)sulphamoyl.
  • Examples of 'W-(Ci - 6 alkyl)carbamoyl are
  • 'W,/V-(C ⁇ -6 alkyl) 2 carbamoyl are W,7V-(Cualkyl) 2 carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl.
  • . 6 alkylsulphonyl” are mesyl, ethylsulphonyl and isopropylsulphonyl.
  • Examples of "Ci- ⁇ alkylsulphonylamino” are mesylamino, ethyl sulphonylamino and isopropylsulphonylamino. are methoxycarbonylamino and /-butoxycarbonylamino.
  • -6 alkyl)-N-(Ci -6 alkoxy)sulphamoyl are N-(methyl)-N-(methoxy)sulphamoyl and N-(ethyl)-N-(propoxy)sulphamoyl.
  • Example of "N,N'-(Ci- 6 alkyl) 2 ureido” are N,jV'-dimethylureido and N-methyl-N'-propylureido.
  • Examples of "N'N'-(Ci -6 alkyl) 2 ureido” are N' N'-diethylureido and jV'-methyl-N'-propylureido.
  • N-(C ⁇ -6 alkyl)-N',N'-(Ci -6 alkyl) 2 ureido are N-(methyl)-N'-ethyl-N'-isopropylureido and N-ethyl-N',N -diethylureido.
  • Examples of 'W-(C i -6 alky I)-N-(C i -6 alkoxy)amino are N-(methyl)-N-(propoxy)amino and N-methyl-N-methoxyamino.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess CSF-IR kinase inhibitory activity.
  • the invention further relates to any and all tautomeric forms of the compounds of the formula (I) that possess CSF-IR kinase inhibitory activity.
  • Ring A is carbocyclyl
  • Ring A is phenyl
  • Ring A is heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 5 .
  • Ring A is pyridyl.
  • Ring A is pyrazolyl; wherein said pyrazolyl may be optionally substituted on nitrogen by a group selected from R 5 .
  • Ring A is thienyl
  • Ring A is imidazo[l,2-a]pyridinyl. Ring A is indolyl.
  • Ring A is 2,3-dihydrobenzofuranyl.
  • Ring A is isoxazolyl.
  • Ring A is benzimidazolyl.
  • Ring A is 2-oxoindolinyl. Ring A is furanyl.
  • Ring A is 1,3-thiazolyl.
  • Ring A is pyrimidinyl
  • Ring A is pyrrolyl
  • Ring A is cyclopropyl. Ring A is tetrahydrofuranyl.
  • Ring A is cyclohexyl
  • Ring A is cycloheptyl
  • Ring A is pyrrolidinyl
  • Ring A is phenyl, pyridyl, pyrazolyl, thienyl, indolyl, 2,3-dihydrobenzofuranyl, imidazofl,2-a]pyridinyl, isoxazolyl, benzimidazolyl, 2-oxoindolinyl, furanyl, 1,3-thiazolyl, pyrimidinyl, pyrrolyl, cyclopropyl, tetrahydrofuranyl, cyclohexyl, cycloheptyl and pyrrolidinyl; wherein said pyrazolyl, indolyl, pyrrolyl or pyrrolidinyl may be optionally substituted on nitrogen by a group selected from R 5 ; wherein
  • R 5 is selected from C ⁇ -6 alkyl, Ct- ⁇ alkanoyl or Ci -6 alkoxycarbonyl.
  • Ring A is phenyl, pyridyl, pyrazolyl, thienyl, indolyl, 2,3-dihydrobenzofuranyl and imidazo[l,2-a]pyridinyl; wherein said pyrazolyl may be optionally substituted on nitrogen by a group selected from R 5 ; wherein
  • R 5 is Ci -6 alkyl.
  • Ring A is phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, l-methylpyrazol-5-yl, 1-/- butylpyrazol-5-yl, thien-2-yl, thien-3-yl, indol-2-yl, 1 -methylindol-2-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, 2,3-dihydrobenzofuran-7-yl, imidazofl,2-a]pyridin-2-yl, isoxazol-3-yl, pyrrol-2-yl, benzimidazol-6-yl, 1 -methyl-2-oxoindolin-5-yl, furan-2-yl, l,3-thiazol-5-yl, pyrimidin-4-yl
  • Ring A is phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, l-methylpyrazol-5-yl, thien-2-yl, thien-3-yl, indol-5-yl, indol-6-yl, 2,3-dihydrobenzofuran-7-yl or imidazo[l,2-a]pyridinyl. Ring A is not pyridyl.
  • Ring A is not pyrid-4-yl.
  • R 1 is a substituent on carbon and is selected from halo, cyano, hydroxy, sulphamoyl, Ci- ⁇ alkyl, C 2-6 alkynyl, Ci- ⁇ alkoxy, N,N-(Ci -6 alkyl) 2 amino, Ci -6 alkylS(O) a wherein a is 0 to 2, C ⁇ - 6 alkoxycarbonylamino, N-(Ci -6 alkyl)sulphamoyl, NN-(Ci -6 alkyl) 2 Sulphamoyl, TV-(C i -6 alky I)-N-(C i- 6 alkoxy)sulphamoyl, N'N'-(Ci -6 alkyl) 2 ureido, Ci -6 alkylsulphonylamino, carbocyclyl-R 6 - or heterocyclyl-R 7 -; wherein R 1 may be optionally substituted on carbon by one or more R ;
  • R 8 is selected from halo, cyano, hydroxy, Ct -6 alkyl, Ci -6 alkoxy, NN-(Ci -6 alkyl) 2 amino, NN-(Ci -6 alkyl) 2 carbamoyl, Ci- 6 alkylS(O) a wherein a is 0 to 2, NN-(Ci -6 alkyl) 2 sulphamoyl, N-(C i -6 alky I)-N-(C i -6 alkoxy)amino, carbocyclyl-R 18 - or heterocyclyl-R 9 -; wherein R 8 may be optionally substituted on carbon by one or more R 20 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 21 ;
  • R 6 , R 7 , R 18 and R 19 are independently selected from a direct bond, -O-, -S(O) 5 - or -N(R 30 )SO 2 -; wherein R 30 is selected from hydrogen and s is 2;
  • R 21 is selected from Cj -6 alkyl
  • R 20 is selected from cyano or hydroxy.
  • R is a substituent on carbon and is selected from halo, cyano, Ci -6 alkyl, C 2-6 alkynyl, C ⁇ -6 alkoxy, NN-(C] -6 alkyl) 2 amino, Ci-6alkylS(O) a wherein a is 0 to 2, NN-(Ci -6 alkyl) 2 sulphamoyl, C] -6 alkylsulphonylamino, carbocyclyl-R 6 - or heterocyclyl-R 7 -; wherein R may be optionally substituted on carbon by one or more R ; R 8 is selected from halo, cyano, hydroxy, ⁇ / ,N-(Ci. 6 alkyl) 2 amino or heterocyclyl-R 9 -; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 2 ;
  • R 6 , R 7 and R 19 are independently selected from a direct bond, -S(O) 5 - or -N(R 30 )SO 2 -; wherein R 30 is hydrogen and s is 0-2;
  • R 21 is Ci- ⁇ alkyl.
  • R is a substituent on carbon and is selected from fluoro, chloro, bromo, iodo, cyano, hydroxy, sulphamoyl, methyl, ethyl, isopropyl, sec-butyl, t-butyl, 2-methylbut-2-yl, 3- methylbut-2-yl, l,l-dimethylprop-2-yn-l-yl, l,l-dimethylbut-2-yn-l-yl, 3,3-dimethylbut-l- yn- 1 -yl, 3-methylbut- 1 -yn- 1 -yl, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 7V,N-dimethylamino, jV,7V-diethylamino, methylthio, mesyl, t-butoxycarbonylamino, 7V-methylsulphamoyl, jV-methyl-TV-propyl
  • R 8 is selected from fluoro, cyano, hydroxy, methyl, methoxy, ⁇ jV-dimethylamino, •tyiV-dimethylcarbamoyl, methylthio, mesyl, 7V,iV-dimethylsulphamoyl, N-(methyl)-jV-(methoxy)sulphamoyl, cyclopropyl-R 18 -, piperazinyl-R 19 -, pyrrolyl-R 19 - or tetrahydrofuryl-R 19 -; wherein R 8 may be optionally substituted on carbon by one or more R 20 ; and wherein said piperazinyl may be optionally substituted on nitrogen by a group selected from R 21 ;
  • R 6 , R 7 , R 18 and R 19 are independently selected from a direct bond, -O-, -S(O) 5 - or -N(R 30 )SO 2 -; wherein R 30 is selected from hydrogen and s is 2;
  • R 21 is selected from methyl or ethyl
  • R 20 is selected from cyano or hydroxy.
  • R is a substituent on carbon and is selected from fluoro, chloro, bromo, iodo, cyano, methyl, isopropyl, t-butyl, 3-methylbut- 1-yn-l-yl, 3,3-dimethylbut-l-yn-l-yl, methoxy, propoxy, isopropoxy, isobutoxy, dimethylamino, methylthio, mesyl, jV,yV-dimethylsulphamoyl, mesylamino, cyclopropyl-R 6 - or azetidin-1-yl-R 7 -; wherein R may be optionally substituted on carbon by one or more R 8 ;
  • R 8 is selected from fluoro, cyano, hydroxy, dimethylamino or piperazin-1-yl-R 9 -; wherein said piperazinyl may be optionally substituted on nitrogen by a group selected from R 21 ;
  • R 6 , R 7 and R 19 are independently selected from a direct bond, -S(O) 5 - or -N(R 30 )SO 2 -; wherein R 30 is hydrogen and s is 2;
  • R 21 is methyl or ethyl.
  • R 1 is a substituent on carbon and is selected from fluoro, chloro, bromo, iodo, cyano, hydroxy, sulphamoyl, methyl, trifluoromethyl, 1 -cyano- 1 -methylethyl, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, /V,/V-dimethylamino, difluoromethylthio, yV./V-dimethylsulphamoyl, /-butyl, mesyl, cyclopropylaminosulphonyl, azetidin-1-ylsulphonyl, tetrahydrofuran-2-ylmethylaminosulphonyl, N-methyl-N-(2,3-dihydroxypropyl)sulphamoyl, mesylamino, morpholinosulphonyl, l-methylpiperazin-4-ylmethyl, 1 -ethylpiperaz
  • R 1 is a substituent on carbon and is selected from fluoro, chloro, bromo, iodo, cyano, methyl, t-butyl, trifluoromethyl, dimethylaminomethyl, 1 -methyl- 1-cyanoethyl, A- methylpiperazin-1 -ylmethyl, 4-ethylpiperazin-l -ylmethyl, 3-hydroxy-3-methylbut-l-yn-l-yl, 3,3-dimethylbut-l-yn-l-yl, methoxy, propoxy, isopropoxy, isobutoxy, dimethylamino, difluoromethylthio, /V,/V-dimethylsulphamoyl, mesyl, cyclopropylaminosulphonyl, azetidin-1- ylsulphonyl or mesylamino.
  • R 1 is a substituent on carbon and is selected from 1 -methyl- 1-cyanoethyl.
  • R 1 is a substituent on carbon and is selected from trifluoromethyl. n is selected from 0-2; wherein the values of R 1 may be the same or different. n is 0. n is 1. n is 2; wherein the values of R may be the same or different. R 2 is hydrogen.
  • R 3 is selected from halo, methyl or methoxy.
  • R 3 is selected from halo or methyl.
  • R 3 is selected from fluoro, chloro, methyl or methoxy.
  • R 3 is selected from fluoro, chloro or methyl.
  • R 3 is fluoro
  • R 3 is chloro
  • R 3 is methyl
  • R 3 is methoxy. R 3 is not chloro.
  • R 4 is selected from halo, cyano, hydroxy, amino, carbamoyl, ureido, Ci -6 alkyl, C 2-6 alkynyl, Ci- ⁇ alkoxy, TV-(C i -6 alkyl)amino, TV, TV-(C i -6 alkyl) 2 amino, C] -6 alkanoylamino, TV-(C ⁇ -6 alkyl)carbamoyl, Ci- ⁇ alkoxycarbonyl, TV, TV-(C i- 6 alkyl) 2 sulphamoyl, Ci -6 alkylsulphonylamino, carbocyclyl-R 1 - or heterocyclyl-R 5 -; wherein R may be optionally substituted on carbon by one or more R 6 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 7 ;
  • R 6 is selected from halo, hydroxy, amino, Ci -6 alkoxy, TV-(C ]. 6 alkyl)amino, TV, TV-(C i -6 alkyl) 2 amino, carbocyclyl-R 22 - or heterocyclyl-R 23 -; wherein R 16 may be optionally substituted on carbon by one or more R 24 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 25 ;
  • R 14 , R 15 , R 22 and R 23 are independently selected from a direct bond, -N(R 26 )- or -C(O)N(R 28 )-; wherein R 26 and R 28 are hydrogen;
  • R 7 and R 25 are independently selected from and Ci -6 alkoxycarbonyl
  • R 24 is methyl or phenyl.
  • R 4 is selected from halo, cyano, amino, C
  • R 15 is a direct bond.
  • R is selected from fluoro, chloro, bromo, cyano, hydroxy, amino, carbamoyl, ureido, methyl, ethyl, propyl, prop-1-ynyl, methoxy, ethoxy, propoxy, isopropoxy, acetyl, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, TV- methyl-TV-ethylamino, TV-methyl-7V-propylamino, formylamino, acetylamino, propanoylamino, 2,2-dimethylpropanoylamino, TV-methylcarbamoyl, methoxycarbonyl, TV.TV-dimethylsulphamoyl, mesylamino, cyclopropyl-R -, cyclobutyl-R -, piperazinyl-R 5 -, pyr
  • R 16 is selected from fluoro, hydroxy, amino, methoxy, methylamino, ⁇ jV-dimethylamino, cyclopropyl-R 22 -, 1,3-dioxolanyl-R 23 -, imidazolyl-R 23 -, morpholino-R 23 -, piperazinyl-R 23 -, piperidinyl-R 23 - or pyrrolidinyl-R 23 -; wherein R 16 may be optionally substituted on carbon by one or more R 24 ; and wherein said piperazinyl or pyrrolidinyl may be optionally substituted on nitrogen by a group selected from R 25 ;
  • R 14 , R 15 , R 22 and R 23 are independently selected from a direct bond, -N(R 26 )- or -C(O)N(R 28 )-; wherein R 26 and R 28 are hydrogen;
  • R 17 and R 25 are independently selected from methyl and /-butoxycarbonyl; R 24 is methyl or phenyl.
  • R 4 is selected from fluoro, chloro, bromo, cyano, amino, methyl, methoxy, methylamino, acetylamino, 7V-methylcarbamoyl or morpholino.
  • R 4 is selected from fluoro, chloro, bromo, cyano, hydroxy, amino, carbamoyl, ureido, methyl, ethyl, methoxy, methylamino, isopropylamino, morpholino, 2- (dimethylamino)ethylamino, 2-(hydroxy)ethylamino, 2-(amino)ethylamino, 3-(pyrrolidin-l- yl)propylamino, 7V-methylcarbamoyl, acetylamino, 2-hydroxyacetylamino, trifluoromethyl, mesylamino, 2,2-dimethylpropanoylamino, 3-methoxypropanoylamino
  • Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 5 ;
  • R 1 is a substituent on carbon and is selected from halo, cyano, hydroxy, sulphamoyl, Ci -6 alkyl, C 2-6 alkynyl, N,N-(C
  • R 2 is hydrogen
  • R 3 is selected from halo, methyl or methoxy;
  • R 4 is selected from halo, cyano, hydroxy, amino, carbamoyl, ureido,
  • R 5 is selected from Cualkyl, Ci- ⁇ alkanoyl or C] -6 alkoxycarbonyl; m is selected from 0-2; wherein the values of R 4 may be the same or different;
  • R 6 , R 7 , R 18 and R 19 are independently selected from a direct bond, -O-, -S(O) 5 - or -N(R 30 )SO 2 -; wherein R 30 is selected from hydrogen and s is 2; R is selected from halo, cyano, hydroxy, Ci -6 alkyl, C
  • R 14 , R 15 , R 22 and R 23 are independently selected from a direct bond, -N(R 26 )- or
  • R 26 and R 28 are hydrogen;
  • R 16 is selected from halo, hydroxy, amino, 7V-(Ci -6 alkyl)amino,
  • R 17 and R 25 are independently selected from Ci -6 alkyl and C
  • R 20 is selected from cyano or hydroxy;
  • R 24 is methyl or phenyl; or a pharmaceutically acceptable salt thereof; with the proviso that said compound is not: N- [4-chloro-3 -( ⁇ [6-(4-methy lpiperazin- 1 -y l)pyridin-3 -y l]amino ⁇ carbony l)phenyl]-2- morpholin-4-ylisonicotinamide; jV-[4-chloro-3-( ⁇ t6-(4-ethylpiperazin-l-yl)pyridin-3-yl]amino ⁇ carbonyl)phenyl]-2-morpholin-
  • Ring A is phenyl, pyridyl, pyrazolyl, thienyl, indolyl, 2,3-dihydrobenzofuranyl and imidazo[l ,2-a]pyridinyl; wherein said pyrazolyl may be optionally substituted on nitrogen by a group selected from R 5 ; R 1 is a substituent on carbon and is selected from halo, cyaho, C]. 6 alkyl, C 2-6 alkynyl,
  • R 2 is hydrogen
  • R 3 is selected from halo or methyl
  • R 4 is selected from halo, cyano, amino, Ci -6 alkyl, Ci -6 alkoxy, N-(Ci -6 alkyl)amino, Ci -6 alkanoylamino, N-(Ci -6 alkyl)carbamoyl or heterocyclyl-R 15 -; m is selected from 0-2; wherein the values of R 4 may be the same or different;
  • R 5 is Ci -6 alkyl
  • R 6 , R 7 and R 19 are independently selected from a direct bond, -S(O) 5 - or -N(R 30 )SO 2 -; wherein R 30 is hydrogen and s is 0-2; R 8 is selected from halo, cyano, hydroxy, iY,N-(Ci. 6 alkyl) 2 amino or heterocyclyl-R 19 -; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 2 ;
  • R 15 is a direct bond
  • R 21 is Cualkyl; or a pharmaceutically acceptable salt thereof; with the proviso that said compound is not:
  • Ring A is phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 1 -methy lpyrazol-5-yl, l-t- butylpyrazol-5-yl, thien-2-yl, thien-3-yl, indol-2-yl, 1 -methy lindol-2-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, 2,3-dihydrobenzofuran-7-yl, imidazo[l ,2-a]pyridin-2-yl, isoxazol-3-yl, pyrrol-2-yl, benzimidazol-6-yl, l-methyl-2-oxoindolin-5-yl, furan-2-yl, l,3-thiazol-5-yl, pyrimidin-4-yl, 1
  • N N-dimethylcarbamoyl- 1 -methylethyl, 4-methylimidazol- 1 -yl, 1 -(cyclopropyl)- 1 - methylethyl, 2-methyl-3,4-dihydroxybut-2-yl, 2-methylbut-2-yl, 1 -hydroxy-l- cyclopropylethyl, 1-cyanoethyl, 2-cyano-3-methylbut-2-yl, 2-cyanobut-2-yl, l-hydroxy-2- cyanoprop-2-yl and 2-cyanopyrrol-l-ylmethyl; n is selected from 0-2; wherein the values of R 1 may be the same or different;
  • R 2 is hydrogen
  • R 3 is selected from fluoro, chloro, methyl or methoxy
  • R is selected from fluoro, chloro, bromo, cyano, hydroxy, amino, carbamoyl, ureido, methyl, ethyl, methoxy, methylamino, isopropylamino, morpholino, 2- (dimethylamino)ethylamino, 2-(hydroxy)ethylamino, 2-(amino)ethylamino, 3-(pyrrolidin-l- yl)propylamino, 7V-methylcarbamoyl, acetylamino, 2-hydroxyacetylamino, trifluoromethyl, mesylamino, 2,2-dimethylpropanoylamino, 3-methoxypropanoylamino, cyclobutylcarbonylamino, cyclopropyl amino, 2,3-dihydroxypropylamino, 1 ,3-dihydroxyprop- 2-ylamino, 1 -methylpiperazin-4-yl,
  • Ring A is phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 1 -methylpyrazol-5-yl, thien-2-yl, thien-3-yl, indol-5-yl, indol-6-yl, 2,3-dihydrobenzofuran-7-yl or imidazo[l,2-a]pyridinyl;
  • R is a substituent on carbon and is selected from fluoro, chloro, bromo, iodo, cyano, methyl, t-butyl, trifluoromethyl, dimethylaminomethyl, 1 -methyl- 1-cyanoethyl, 4- methylpiperazin-1-ylmethyl, 4-ethylpiperazin-l-ylmethyl, 3-hydroxy-3-methylbut-l-yn-l-yl, 3,3-dimethylbut-l-yn-l-yl, methoxy, propoxy, isopropoxy, isobutoxy, dimethylamino, difluoromethylthio, TV.jV-dimethylsulphamoyl, mesyl, cyclopropylaminosulphonyl, azetidin-1- ylsulphonyl or mesylamino; n is selected from 0-2; wherein the values of R may be the same or different;
  • R 2 is hydrogen
  • R 3 is selected from fluoro, chloro or methyl
  • R 4 is selected from fluoro, chloro, bromo, cyano, amino, methyl, methoxy, methylamino, acetylamino, N-methylcarbamoyl or morpholino; m is selected from 0-2; wherein the values of R may be the same or different, or a pharmaceutically acceptable salt thereof.
  • preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.
  • preferred compounds of the invention are Examples 18, 44, 50, 56, 105, 130, 135, 163, 216 and 384 or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: Process a) reacting an amine of the formula (II)
  • Process a) and Process b) Amines and acids may be coupled together in the presence of a suitable coupling reagent.
  • Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for Example carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for Example triethylamine, pyridine, or 2,6-di- ⁇ /£y/-pyridines such as 2,6-lutidine or
  • Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.
  • the coupling reaction may conveniently be performed at a temperature in the range of -40 to 40 °C.
  • Suitable activated acid derivatives include acid halides, for Example acid chlorides, and active esters, for Example pentafluorophenyl esters.
  • the reaction of these types of compounds with amines is well known in the art, for Example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above.
  • the reaction may conveniently be performed at a temperature in the range of -40 to 40 0 C.
  • Pg is an acid protecting group, for example such as those described herein below.
  • Compounds of formula (III), (V), (Ila) and (IVa) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or f-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a /-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • the compounds defined in the present invention possess anti-cancer activity which is believed to arise from the CSF-IR kinase inhibitory activity of the compounds. These properties may be assessed, for example, using the procedure set out below.
  • the His-tagged kinase domain of CSF-IR i.e., amino acids 568-912, GeneBank ID NM_005211;
  • the phosphorylation of the CSF-IR substrate in the presence and absence of the compound of interest was determined. Briefly, 0.2pM of purified CSF-IR, 5nM pEY substrate, and compound were preincubated in Ix buffer for 30 minutes at 25°C.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically-acceptable diluent or carrier.
  • composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • sterile solution emulsion
  • topical administration as an ointment or cream or for rectal administration as a suppository.
  • compositions may be prepared in a conventional manner using conventional excipients.
  • the compound of formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 1-1000 mg/kg, and this normally provides a therapeutically-effective dose.
  • a daily dose in the range of 10- 100 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the compounds defined in the present invention are effective anti-cancer agents which property is believed to arise from their CSF-I R kinase inhibitory properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by CSF-IR kinase, i.e. the compounds may be used to produce a CSF-IR kinase inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention provide a method for treating cancer characterised by inhibition of CSF-IR kinase, i.e. the compounds may be used to produce an anti-cancer effect mediated alone or in part by the inhibition of CSF-IR kinase.
  • Such a compound of the invention is expected to possess a wide range of anti-cancer properties including but not limited to melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament is provided.
  • a method for producing a CSF-IR kinase inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • a method of treating melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein before.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a CSF-IR kinase inhibitory effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for Use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore in the production of a CSF-IR kinase inhibitory effect in a warm-blooded animal such as man.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore in the production of an anti-cancer effect in a warm-blooded animal such as man.
  • the CSF-IR kinase inhibitory treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine
  • Agents which inhibit cancer cell invasion for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-(3-(3-chloro-4-fluor
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • vastinTM anti-vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WOO 1/92224, WO02/04434 and WO02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or, BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies;
  • Cell cycle inhibitors including for example CDK inhibitiors (eg flavopiridol) and other inhibitors of cell cycle checkpoints (eg checkpoint kinase); inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation (eg mitotic kinesins); and histone deacetylase inhibitors; and
  • endothelin antagonists including endothelin A antagonists, endothelin B antagonists and
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of CSF-IR kinase in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
  • organic solutions were dried over anhydrous sodium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60 0 C;
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio dimethyl sulphoxide (DMSO-d 6 ) as solvent unless otherwise indicated;
  • ISCO refers to normal phase flash column chromatography using 12 g and 40 g prepacked silica gel cartridges used according to the manufacturers instruction obtained from ISCO, Inc, 4700 superior street Lincoln, NE, USA.;
  • Glass HPLC refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 30 20 mm/100 and 50 mm/250 in water/MeCN with 0.1 % TFA as mobile phase, obtained
  • Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psig) and temperatures to 80 0 C.
  • Example 1 Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psig) and temperatures to 80 0 C.
  • Example 55 The following compounds were prepared by the procedure in Example 1 using 5- amino-2-methyl-N-pyridin-3-ylbenzamide (Method 68) or 5-amino-2-chloro-N-(5- fluoropyridin-3-yl)benzamide for (Method 79) Example 55 and the appropriate SM. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • Example 121 The following compounds were prepared by the procedure in Example 121 using 5- amino-2-chloro-iV-pyridin-3-ylbenzamide (Method 76) and the appropriate SM with the exception of Example 165 which was prepared from 2-chloro-5- ⁇ [3-(trifluoromethyl)benzoyl] amino ⁇ benzoic acid (Method 224) and JV-(5-aminopyridin-2-yl)acetamide. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • Example 166 The following compounds were prepared by the procedure in Example 166 using 5- amino-2-fluoro-jV-pyridin-3-ylbenzamide (Method 75) and the appropriate SM. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • Example 183 The following compounds were prepared by the procedure in Example 183 using the appropriate SMs. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • the tube was heated in microwave (Smith, Personal ChemistryTM) and heated at 180°C for 2000 seconds.
  • the solution was filtered, and separated between EtOAc and water. Organic layer was dried and evaporated under reduced pressure.
  • the crude product was purified by reverse phase ⁇ PLC (5-75% MeCN/ ⁇ 2 O, 15 min) and the title compound (75.6 mg, 30%) was collected by evaporation.
  • the resulting reaction mixture was warmed to 80 °C and was allowed to stir for 12 h before being cooled and diluted with EtOAc ( ⁇ 100 ml).
  • the organic phase was poured into a separator funnel and washed with saturated aqueous NaHCO 3 ( ⁇ 100 ml).
  • the organic extract was dried with MgSO 4 , filtered, and concentrated in vacuo to yield the crude product, which was purified on a 40 g SiO 2 column using MeOH/EtOAc (1 :10) as eluent giving 144 mg (77%) of the title compound as a white solid.
  • N-(S- 5 bromopyridin-3-yl)-2-methyl-5- ⁇ f3-(trifluoromethyl)benzoyl]amino) benzamide (Example 193; 200 mg, 0.418 mmol) and MeCN (1.75 ml).
  • Et 3 N (0.293 ml, 2.10 mmol) was added followed by prop-2-yn-l -amine (58 mg, 1.05 mmol), CuI ( 25 mg, 0.125 mmol), and Pd(PPh 3 ) 4 (96 mg, 0.084 mmol).
  • the reaction was warmed to 50 0 C with stirring for 12 h before being cooled to room temperature, diluted with 50 ml of EtOAc, and filtered through a
  • the reaction was allowed to stir for 12 h at room temperature before being purged with argon, diluted with ⁇ 15 ml of EtOAc 5 and filtered through a pad of SiO 2 .
  • the SiO 2 pad was rinsed with an additional 25 ml of EtOAc and the combined filtrate was concentrated in vacuo to yield the crude product, which was purified on a 40 g SiO 2 column using EtOAc as eluent giving 44 mg (98%) of the title compound as an off-white solid.
  • Example 341 The following compounds were prepared by the procedure in Example 341 and the appropriate SM. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • Examples 345-351 The following compounds were prepared by the procedure in Example 344 using the appropriate SMs. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • Example 244 N- (5-aminopyridin-3-yl)-2-methyl-5- ⁇ f3-(trifluoromethyl)benzoyl]amino) benzamide (Example 244), and the appropriate SM. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • Example 202 The following compound was prepared by the procedure in Example 357, using 7V-(6- aminopyridin-3-yl)-5- ⁇ [3-(l-cyano-l-methylethyl)benzoyl]amino ⁇ -2-methylbenzamide (Example 202) and the appropriate SM. Further purification was required (column chromatography utilizing an ISCO system).
  • Example 359 i ⁇ -f5-(Acetylamino ' )pyridin-3-vn-2-methyl-5- ⁇ f3-(trifluoromethyl)benzoyl1amino ⁇ benzamide
  • N-(5- aminopyridin-3-yl)-2-methyl-5- ⁇ [3-(trifluoromethyl)benzoyl]amino ⁇ benzamide (Example 244; 200 mg, 0.482 mmol).
  • Pyridine 5.0 ml
  • acetyl chloride 0.044 ml, 0.603 mmol
  • Example 202 N-(6- aminopyridin-3-yl)-5- ⁇ f3-(l-cyano-l-methylethyl)benzoyl]amino ⁇ -2-methylbenzamide (Example 202) and the appropriate SM. In some cases, further purification was required (supercritical fluid, Gilson reverse phase preparatory HPLC or column chromatography utilizing an ISCO system).
  • N-(5-Aminopyridm-3-yl)-5- ⁇ [3-(l-cyano-l-methylethyl)benzoyl]amino ⁇ -2- methylbenzamide (Example 205; 164 mg, 0.398 mmol) was combined with acetone and sodium triacetoxyborohydride (337 mg, 1.59 mmol) in 0.80 ml of THF and heated at 30°C in a sealed tube overnight. LC/MS confirmed the formation of the product and the mixture was partitioned between H 2 O and EtOAc. The organic layer was washed with brine and dried with MgSO 4 .
  • Methods 76-82 The following compounds were prepared by the procedure of Method 75, using the appropriate starting material.
  • reaction mixture was extracted with EtOAc (2 x 250 ml) and the combined organic phase was dried with MgSO 4 and concentrated in vacuo to yield the crude reaction product which was purified on 120 g SiO 2 using hexanes/EtOAc 10:1 as eluent giving 3.70 g of the title compound as a yellow oil (76 %) m/z 447.
  • reaction mixture was extracted with EtOAc (2 x 50 ml) and the combined organic phase was dried with MgSO 4 and concentrated in vacuo to yield the crude reaction product which was purified on 40 g SiO 2 using hexanes/EtOAc 2:1 as eluent giving 0.270 g of the title compound as a colourless oil (71 %) m/z 182.
  • Triethylamine (0.718 g, 7.40 mmol) was then added and the reaction was allowed to warm to 25 °C with stirring over 1 h before being quenched with NaHCO 3(sat ) (250 ml).
  • the reaction mixture was then extracted with EtOAc (2 x 50 ml) and the combined organic phase was dried with MgSO 4 and concentrated in vacuo to yield the crude reaction product which was purified on 40 g SiO 2 using hexanes/EtOAc 10:1 as eluent giving 0.262 g of the title compound as a colourless oil (99 %) m/z 180.
  • Method 119 The following compounds were prepared by the procedure of Method 1 18, using the appropriate starting material.
  • 5-Amino-N-methylnicotinamide A solution of 5-aminonicotinic acid (414 mg, 3 mmol), DIEA (1.57 ml, 9 mmol) and methyl amine (2.0 M in THF, 4.5 ml, 9 mmol) in DMF (10 ml) was treated with HATU (1.71 g, 4.5 mmol). The reaction was stirred for 5 h and then quenched with H 2 O (30 ml). The reaction mixture was extracted with EtOAc (50 ml), washed with NaCl (sat) (20 ml) and dried with MgSO 4 . The organics were removed under reduced pressure; m/z 151.
  • Method 161 The following compounds were prepared by the procedure of Method 160, using the appropriate starting material.
  • DeoxoFluorTM was stirred overnight at 85 0 C. The reaction was allowed to cool to room temperature and quenched with brine. The mixture was poured into a separator funnel and extracted with EtOAc. The organic extract was dried over Na 2 SO 4 , filtered, and concentrated in vacuo to yield the crude product. The crude oil was then subjected to ISCO purification using EtOAc/hexanes (1 :4) as eluent to yield 396 mg (50%) of the title compound as a colourless oil.
  • 2-amino-3-chloro-5- nitropyridine was obtained (10.8 g, 62%) and it was used in the next step without further purification. M/z 175.
  • 2-amino-3-chloro-5-nitropyridine (8.72g, 50mmol) was dissolved in MeOH (125 ml).
  • a solution of ammonium chloride (13.5 g, 250mmol) in H 2 O (125 ml) were added, followed by 14g of iron powder.
  • the solution was stirred with mechanic stirring at 78 °C for 2 hours.
  • the solution was filtered at 50 0 C and the isolated solid was washed by hot MeOH.
  • the solvent was evaporated by vacuum and the crude product was extracted by acetone and filtered.
  • Method 187 The following compound was prepared by the procedure of Method 186, using the appropriate starting material.
  • N-(2- ⁇ ttert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-5-nitropyridin-2-amine (Method 156; 1.29 g, 4.34 mmol) was dissolved in 20 ml of MeOH and 260 mg of palladium (10 wt. % on activated carbon-Degussa®) was added. The reaction was subjected to 1 atmosphere of hydrogen overnight. LC/MS confirmed the formation of the product. The reaction mixture was filtered through diatomaceous earth and washed with MeOH and EtOAc. The title compound (970 mg) was collected by evaporation as a thick red oil. M/z 268.
  • 3-(l-Cvano-l ,2-dimethylpropyl)benzoic acid To a solution of 3-(l-cyanoethyl)benzoic acid (500 mg) in THF (50ml) at -78°C was added slowly a solution of LiHMDS (60ml, 1.0M in THF) and the resulting red solution was allowed to stir at his temperature for 30 minutes. Isopropyl iodide (10 ml) was added slowly and the resulting mixture was warmed up to room temperature and stirred for 10 hours. The mixture was partitioned between EtOAc and H 2 O and the aqueous layer was acidified with IN HCl until pH 3.
  • LiHMDS 60ml, 1.0M in THF
  • Methyl 1 ,3,3-trimethyl-2-oxoindoline-5-carboxylate To a solution of methyl 2-oxoindoline-5-carboxylate (400 mg, 2.09 mmol) in THF (10 ml) at -78 0 C was added LiHMDS (1.0 M, 16.7 ml, 16.75 mmol) and MeI (1.3 ml, 20.9 mmol). The reaction was allowed to stir overnight to room temperature. The reaction was then quenched with ⁇ 25 ml aqueous NH 4 Cl.
  • Methyl 5- ⁇ [3-(l-cyano-l-methylethyl)benzoyl]amino ⁇ -2- chlorobenzoate was collected by evaporation as a reddish-brown oil.
  • Methyl 5- ⁇ [3-(l-cyano-l-methylethyl)benzoyl]amino ⁇ -2-chlorobenzoate 120 mg was dissolved in a 3:1 :1 (v/v/v) solution of THF/MeOH/H 2 O and lithium hydroxide (50 ing) was added slowly. The reaction was then stirred overnight at 25°C. LC/MS confirmed the formation of the product. The organic solvents were evaporated and the remaining material was separated between EtOAc and H 2 O.
  • the aqueous layer was collected and acidified to a pH of between 3 and 4 with 2N HCl.
  • the mixture was partitioned between H 2 O and EtOAc, and the organic layer was washed with brine and dried with MgSO 4 .
  • the title compound (85 mg) was collected by evaporation as a white solid.
  • Methyl 3-[(2-cyano-lH-pyrrol-l-yl)methyl]benzoate (300 mg) was dissolved in MeO ⁇ / ⁇ 2 O (10 ml, 3:1 v/v) and LiOH (60 mg) was added. The resulting mixture was stirred at room temperature for 10 hours. The aqueous phase was filtered and washed with EtOAc. The basic aqueous layer was acidified by the addition of IN HCl until pH 3. The aqueous layer was extracted with EtOAc (3x) and then dried with Na 2 SO 4(S ). Evaporation of the solvent afforded the title compound as a white solid (210 mg); m/z 226.
  • the reaction was heated to 80 0 C with stirring for 5 h before being cooled to room temperature and quenched with ⁇ 200 ml saturated aqueous NaHCO 3 .
  • the mixture was poured into a separator funnel and extracted with ⁇ 200 ml of EtOAc.
  • the combined organic extract was dried with MgSO 4 , filtered, and concentrated in vacuo to yield the crude product, which was purified on a 120 g SiO 2 column using hexanes/EtOAc (9:1) as eluent giving 5.26 g (82%) of the title compound as a white solid m/z 527.

Landscapes

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

Abstract

L'invention concerne des composés chimiques, ou des sels pharmaceutiquement acceptables de ceux-ci, représentés par la formule (I). Lesdits composés possèdent une activité inhibitrice de kinases CSF-1R et sont par conséquent utiles pour leur activité anticancéreuse et donc dans des méthodes de traitement du corps d'un être humain ou d'un animal. L'invention concerne également des procédés de fabrication desdits composés chimiques, des compositions pharmaceutiques les contenant ainsi que leur utilisation dans la fabrication de médicaments destinés à être utilisés dans la production d'un effet anticancéreux chez un animal à sang chaud tel que l'homme.
PCT/GB2005/004985 2004-12-22 2005-12-22 Composes chimiques Ceased WO2006067445A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US63917704P 2004-12-22 2004-12-22
US60/639,177 2004-12-22

Publications (2)

Publication Number Publication Date
WO2006067445A2 true WO2006067445A2 (fr) 2006-06-29
WO2006067445A3 WO2006067445A3 (fr) 2006-09-14

Family

ID=36602125

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2005/004985 Ceased WO2006067445A2 (fr) 2004-12-22 2005-12-22 Composes chimiques

Country Status (3)

Country Link
AR (1) AR053992A1 (fr)
TW (1) TW200635899A (fr)
WO (1) WO2006067445A2 (fr)

Cited By (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071955A1 (fr) * 2005-12-22 2007-06-28 Astrazeneca Ab Composes chimiques
FR2903107A1 (fr) * 2006-07-03 2008-01-04 Sanofi Aventis Sa Derives d'imidazopyridine-2-carboxamides, leur preparation et leur application en therapeutique
WO2008057775A3 (fr) * 2006-10-27 2008-07-31 Bristol Myers Squibb Co Composés d'amide hétérocyclique utiles comme inhibiteurs de kinase
WO2009111280A1 (fr) 2008-02-29 2009-09-11 Array Biopharma Inc. Dérivés de n-(6-aminopyridin-3-yl)-3-(sulfonamido) benzamide comme inhibiteurs de b-raf pour le traitement du cancer
US7723337B2 (en) 2007-01-25 2010-05-25 Astrazeneca Ab 3-cinnolinecarboxamide derivatives and their use for treating cancer
EP2253617A1 (fr) 2009-05-20 2010-11-24 Bayer CropScience AG Composés halogénés comme pesticides
US7902219B2 (en) 2006-07-03 2011-03-08 Sanofi-Aventis 2-benzoylimidazopyridine derivatives, preparation and therapeutic use thereof
WO2012068450A1 (fr) 2010-11-19 2012-05-24 Incyte Corporation Dérivés pyrrolopyridine et pyrrolopyrimidine à substitution cyclobutyle utilisés comme inhibiteurs des jak
US8247436B2 (en) 2010-03-19 2012-08-21 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
WO2012124825A1 (fr) 2011-03-16 2012-09-20 Mitsubishi Tanabe Pharma Corporation Composés sulfonamides ayant une activité d'antagoniste de trpm8
US8389553B2 (en) 2007-06-27 2013-03-05 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
US8461189B2 (en) 2007-06-27 2013-06-11 Merck Sharp & Dohme Corp. Pyridyl derivatives as histone deacetylase inhibitors
US8722693B2 (en) 2007-06-13 2014-05-13 Incyte Corporation Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US20140206727A1 (en) * 2004-01-28 2014-07-24 Mitsui Chemicals, Inc. Amide derivatives, process for preparation thereof and use thereof as insecticide
US8883819B2 (en) 2011-09-01 2014-11-11 Irm Llc Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
WO2014184234A1 (fr) 2013-05-14 2014-11-20 Active Biotech Ab Dérivés de n-(hétéroaryl)-sulfonamide utiles comme inhibiteurs de s100
JP2015506927A (ja) * 2011-12-21 2015-03-05 ノヴィラ・セラピューティクス・インコーポレイテッド Ｂ型肝炎抗ウイルス剤
US8987443B2 (en) 2013-03-06 2015-03-24 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US9023840B2 (en) 2011-06-20 2015-05-05 Incyte Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
WO2015074123A1 (fr) * 2013-11-25 2015-05-28 Novogen ltd Indoles fonctionnalisés et substitués utilisés en tant qu'agents anti-cancéreux
US9073921B2 (en) 2013-03-01 2015-07-07 Novartis Ag Salt forms of bicyclic heterocyclic derivatives
US9079912B2 (en) 2005-12-13 2015-07-14 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as Janus kinase inhibitors
WO2015131031A1 (fr) 2014-02-28 2015-09-03 Incyte Corporation Inhibiteurs des jak1 pour le traitement de syndromes myélodysplasiques
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9400280B2 (en) 2014-03-27 2016-07-26 Novira Therapeutics, Inc. Piperidine derivatives and methods of treating hepatitis B infections
US9623029B2 (en) 2009-05-22 2017-04-18 Incyte Holdings Corporation 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane- or heptane-nitrile as JAK inhibitors
US9655854B2 (en) 2013-08-07 2017-05-23 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US9718834B2 (en) 2011-09-07 2017-08-01 Incyte Corporation Processes and intermediates for making a JAK inhibitor
EP3079682A4 (fr) * 2013-12-13 2017-08-30 Dana-Farber Cancer Institute, Inc. Procédé pour traiter un lymphome lymphoplasmocytaire
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US9999619B2 (en) 2010-03-10 2018-06-19 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10112957B2 (en) 2014-10-22 2018-10-30 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
WO2018214867A1 (fr) * 2017-05-24 2018-11-29 上海和誉生物医药科技有限公司 Dérivé de n-(azaaryl)cyclolactame-1-carboxamide, son procédé de préparation et son utilisation
US10166191B2 (en) 2012-11-15 2019-01-01 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US20190071400A1 (en) * 2016-03-09 2019-03-07 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2020002563A1 (fr) 2018-06-29 2020-01-02 Syngenta Participations Ag Composés azole-amide à action pesticide
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US10633348B2 (en) 2013-12-13 2020-04-28 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US10633375B2 (en) 2016-08-31 2020-04-28 Jinagsu Hengrui Medicine Co., Ltd Oxopicolinamide derivative, preparation method therefor and pharmaceutical use thereof
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10758543B2 (en) 2010-05-21 2020-09-01 Incyte Corporation Topical formulation for a JAK inhibitor
WO2020182649A1 (fr) 2019-03-08 2020-09-17 Syngenta Crop Protection Ag Composés azole-amide à action pesticide
WO2020188027A1 (fr) 2019-03-20 2020-09-24 Syngenta Crop Protection Ag Composés azole-amides à action pesticide
WO2020193341A1 (fr) 2019-03-22 2020-10-01 Syngenta Crop Protection Ag Dérivés de n-[1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)éthyl]-2-cyclopropyl-6-(trifluorométhyl)pyridine-4-carboxamide et composés apparentés servant d'insecticides
WO2020201398A1 (fr) 2019-04-05 2020-10-08 Syngenta Crop Protection Ag Composés de diazine-amide à action pesticide
WO2020201079A1 (fr) 2019-03-29 2020-10-08 Syngenta Crop Protection Ag Composés de diazine-amide à action pesticide
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10899736B2 (en) 2018-01-30 2021-01-26 Incyte Corporation Processes and intermediates for making a JAK inhibitor
WO2021026436A1 (fr) 2019-08-08 2021-02-11 Agios Pharmaceuticals, Inc. Procédé de préparation d'ivosidenib et d'un intermédiaire de celui-ci
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
WO2021037614A1 (fr) 2019-08-23 2021-03-04 Syngenta Crop Protection Ag Composés de pyrazine-amide à action pesticide
US10954220B2 (en) 2016-03-09 2021-03-23 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
WO2021122645A1 (fr) 2019-12-20 2021-06-24 Syngenta Crop Protection Ag Composés azole-amide à action pesticide
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2021170881A1 (fr) 2020-02-27 2021-09-02 Syngenta Crop Protection Ag Composés de diazine-bisamide à action pesticide
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11304949B2 (en) 2018-03-30 2022-04-19 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2022247786A1 (fr) * 2021-05-24 2022-12-01 上海和誉生物医药科技有限公司 Sel d'acide d'un inhibiteur de csf-1r cristallin, son procédé de préparation et son utilisation
WO2022258481A1 (fr) 2021-06-09 2022-12-15 Syngenta Crop Protection Ag Composés diazine-amides à action pesticide
CN115611806A (zh) * 2022-11-08 2023-01-17 江苏中旗科技股份有限公司 一种4-三氟甲基-3-氰基吡啶的制备方法
CN115724791A (zh) * 2022-10-10 2023-03-03 安徽金禾化学材料研究所有限公司 一种2-甲基-3-硝基-5-胺基吡啶的制备方法
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
US12384773B2 (en) 2023-11-02 2025-08-12 Arcus Biosciences, Inc. Thiazole compounds and methods of use thereof
US12440481B2 (en) 2019-01-10 2025-10-14 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
US12441703B2 (en) 2019-01-10 2025-10-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2487542T3 (es) 2009-05-22 2014-08-21 Incyte Corporation Derivados de N-(hetero)aril-pirrolidina de pirazol-4-il-pirrolo[2,3-d]pirimidinas y pirrol-3-il-pirrolo[2,3-d]pirimidinas como inhibidores de cinasas Janus
WO2011028685A1 (fr) 2009-09-01 2011-03-10 Incyte Corporation Dérivés hétérocycliques de pyrazol-4-yl-pyrrolo[2,3-d] pyrimidines en tant qu'inhibiteurs de janus kinase
ES2536415T3 (es) 2010-11-19 2015-05-25 Incyte Corporation Pirrolopiridinas y pirrolopirimidinas sustituidas heterocíclicas como inhibidores de JAK
TW201313721A (zh) 2011-08-18 2013-04-01 Incyte Corp 作為ｊａｋ抑制劑之環己基氮雜環丁烷衍生物
WO2013173720A1 (fr) 2012-05-18 2013-11-21 Incyte Corporation Dérivés de pyrrolopyridine et de pyrrolopyrimidine substitués par un pipéridinylcyclobutyle à titre d'inhibiteurs jak
WO2015184305A1 (fr) 2014-05-30 2015-12-03 Incyte Corporation Traitement de la leucémie neutrophile chronique (cnl) et de la leucémie myéloïde chronique atypique (acml) par des inhibiteurs de jak1

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9623833D0 (en) * 1996-11-16 1997-01-08 Zeneca Ltd Chemical compound
HUP0105136A3 (en) * 1999-03-17 2002-05-28 Astrazeneca Ab Amide derivatives, process for their preparation and medicaments containing them
GB0414631D0 (en) * 2004-06-30 2004-08-04 Reckitt Benckiser Nv Packaging for moisture sensitive material

Cited By (180)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10995081B2 (en) 2004-01-28 2021-05-04 Mitsui Chemicals, Inc. Amide derivatives, process for preparation thereof and use thereof as insecticide
US9920026B2 (en) 2004-01-28 2018-03-20 Mitsui Chemicals, Inc. Amide derivatives, process for preparation thereof and use thereof as insecticide
US20140206727A1 (en) * 2004-01-28 2014-07-24 Mitsui Chemicals, Inc. Amide derivatives, process for preparation thereof and use thereof as insecticide
US10435385B2 (en) 2004-01-28 2019-10-08 Mitsui Chemicals, Inc. Amide derivatives, process for preparation thereof and use thereof as insecticide
US9185912B2 (en) * 2004-01-28 2015-11-17 Mitsui Chemicals, Inc. Amide derivatives, process for preparation thereof and use thereof as insecticide
US11760742B2 (en) 2004-01-28 2023-09-19 Mitsui Chemicals, Inc. Amide derivatives, process for preparation thereof and use thereof as insecticide
US10639310B2 (en) 2005-12-13 2020-05-05 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors
US10398699B2 (en) 2005-12-13 2019-09-03 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors
US9079912B2 (en) 2005-12-13 2015-07-14 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as Janus kinase inhibitors
US9662335B2 (en) 2005-12-13 2017-05-30 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as janus kinase inhibitors
US9814722B2 (en) 2005-12-13 2017-11-14 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as janus kinase inhibitors
US11331320B2 (en) 2005-12-13 2022-05-17 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors
US9974790B2 (en) 2005-12-13 2018-05-22 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as janus kinase inhibitors
US11744832B2 (en) 2005-12-13 2023-09-05 Incyte Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors
WO2007071955A1 (fr) * 2005-12-22 2007-06-28 Astrazeneca Ab Composes chimiques
CN101484453B (zh) * 2006-07-03 2012-07-04 赛诺菲-安万特 咪唑并[1,2-α]吡啶-2-甲酰胺的衍生物，它们的制备和它们在治疗中的用途
JP2009541471A (ja) * 2006-07-03 2009-11-26 サノフイ−アベンテイス イミダゾ［１，２−ａ］ピリジン−２−カルボキサミド誘導体、その調製方法および治療におけるその使用
US7704989B2 (en) 2006-07-03 2010-04-27 Sanofi-Aventis Derivatives of imidazo[1,2-a]pyridine-2-carboxamides, preparation method thereof and use of same in therapeutics
US8404848B2 (en) 2006-07-03 2013-03-26 Sanofi Derivatives of imidazo[1,2-a]pyridine-2-carboxamides, preparation method thereof and use of same in therapeutics
US7902219B2 (en) 2006-07-03 2011-03-08 Sanofi-Aventis 2-benzoylimidazopyridine derivatives, preparation and therapeutic use thereof
RU2441003C2 (ru) * 2006-07-03 2012-01-27 Санофи-Авентис ПРОИЗВОДНЫЕ ИМИДАЗО[1,2-α]ПИРИДИН-2-КАРБОКСАМИДОВ, ИХ ПОЛУЧЕНИЕ И ПРИМЕНЕНИЕ В ТЕРАПИИ
FR2903107A1 (fr) * 2006-07-03 2008-01-04 Sanofi Aventis Sa Derives d'imidazopyridine-2-carboxamides, leur preparation et leur application en therapeutique
WO2008003856A1 (fr) * 2006-07-03 2008-01-10 Sanofi-Aventis Dérivés d'imidazo[1,2-a]pyridine-2-carboxamides leur préparation et leur application en thérapeutique
WO2008057775A3 (fr) * 2006-10-27 2008-07-31 Bristol Myers Squibb Co Composés d'amide hétérocyclique utiles comme inhibiteurs de kinase
US7935696B2 (en) 2006-10-27 2011-05-03 Bristol-Myers Squibb Company Heterocyclic amide compounds useful as kinase inhibitors
US8404689B2 (en) 2006-10-27 2013-03-26 Bristol-Myers Squibb Company Heterocyclic amide compounds useful as kinase inhibitors
US7723337B2 (en) 2007-01-25 2010-05-25 Astrazeneca Ab 3-cinnolinecarboxamide derivatives and their use for treating cancer
US8829013B1 (en) 2007-06-13 2014-09-09 Incyte Corporation Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US8822481B1 (en) 2007-06-13 2014-09-02 Incyte Corporation Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US10016429B2 (en) 2007-06-13 2018-07-10 Incyte Corporation Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US8722693B2 (en) 2007-06-13 2014-05-13 Incyte Corporation Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US11213528B2 (en) 2007-06-13 2022-01-04 Incyte Holdings Corporation Salts of the janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US9376439B2 (en) 2007-06-13 2016-06-28 Incyte Corporation Salts of the janus kinase inhibitor (R)-3(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US10610530B2 (en) 2007-06-13 2020-04-07 Incyte Corporation Salts of the Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile
US9096559B2 (en) 2007-06-27 2015-08-04 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
US8461189B2 (en) 2007-06-27 2013-06-11 Merck Sharp & Dohme Corp. Pyridyl derivatives as histone deacetylase inhibitors
US8389553B2 (en) 2007-06-27 2013-03-05 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
WO2009111280A1 (fr) 2008-02-29 2009-09-11 Array Biopharma Inc. Dérivés de n-(6-aminopyridin-3-yl)-3-(sulfonamido) benzamide comme inhibiteurs de b-raf pour le traitement du cancer
EP2253617A1 (fr) 2009-05-20 2010-11-24 Bayer CropScience AG Composés halogénés comme pesticides
US9623029B2 (en) 2009-05-22 2017-04-18 Incyte Holdings Corporation 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane- or heptane-nitrile as JAK inhibitors
US10695337B2 (en) 2010-03-10 2020-06-30 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
US11285140B2 (en) 2010-03-10 2022-03-29 Incyte Corporation Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
US9999619B2 (en) 2010-03-10 2018-06-19 Incyte Holdings Corporation Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
US8247436B2 (en) 2010-03-19 2012-08-21 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
USRE46757E1 (en) 2010-03-19 2018-03-20 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
US9365552B2 (en) 2010-03-19 2016-06-14 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
US10117858B2 (en) 2010-03-19 2018-11-06 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
US11911371B2 (en) 2010-03-19 2024-02-27 Novartis Ag Pyridine and pyrazine derivative for the treatment of chronic bronchitis
US8476269B2 (en) 2010-03-19 2013-07-02 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
US11590136B2 (en) 2010-05-21 2023-02-28 Incyte Corporation Topical formulation for a JAK inhibitor
US10758543B2 (en) 2010-05-21 2020-09-01 Incyte Corporation Topical formulation for a JAK inhibitor
US12226419B2 (en) 2010-05-21 2025-02-18 Incyte Corporation Topical formulation for a JAK inhibitor
US11219624B2 (en) 2010-05-21 2022-01-11 Incyte Holdings Corporation Topical formulation for a JAK inhibitor
US10869870B2 (en) 2010-05-21 2020-12-22 Incyte Corporation Topical formulation for a JAK inhibitor
US11571425B2 (en) 2010-05-21 2023-02-07 Incyte Corporation Topical formulation for a JAK inhibitor
WO2012068450A1 (fr) 2010-11-19 2012-05-24 Incyte Corporation Dérivés pyrrolopyridine et pyrrolopyrimidine à substitution cyclobutyle utilisés comme inhibiteurs des jak
US10640506B2 (en) 2010-11-19 2020-05-05 Incyte Holdings Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidines derivatives as JAK inhibitors
WO2012124825A1 (fr) 2011-03-16 2012-09-20 Mitsubishi Tanabe Pharma Corporation Composés sulfonamides ayant une activité d'antagoniste de trpm8
US11214573B2 (en) 2011-06-20 2022-01-04 Incyte Holdings Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
US9023840B2 (en) 2011-06-20 2015-05-05 Incyte Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
US9611269B2 (en) 2011-06-20 2017-04-04 Incyte Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
US10513522B2 (en) 2011-06-20 2019-12-24 Incyte Corporation Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors
US9751876B2 (en) 2011-09-01 2017-09-05 Novartis Ag Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
US8883819B2 (en) 2011-09-01 2014-11-11 Irm Llc Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
US9718834B2 (en) 2011-09-07 2017-08-01 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9751857B2 (en) 2011-12-21 2017-09-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
JP2015506927A (ja) * 2011-12-21 2015-03-05 ノヴィラ・セラピューティクス・インコーポレイテッド Ｂ型肝炎抗ウイルス剤
US9676747B2 (en) 2011-12-21 2017-06-13 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10995064B2 (en) 2012-08-28 2021-05-04 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US11337927B2 (en) 2012-11-15 2022-05-24 Incyte Holdings Corporation Sustained-release dosage forms of ruxolitinib
US10166191B2 (en) 2012-11-15 2019-01-01 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US11576865B2 (en) 2012-11-15 2023-02-14 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US11576864B2 (en) 2012-11-15 2023-02-14 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US10874616B2 (en) 2012-11-15 2020-12-29 Incyte Corporation Sustained-release dosage forms of ruxolitinib
US11896717B2 (en) 2012-11-15 2024-02-13 Incyte Holdings Corporation Sustained-release dosage forms of ruxolitinib
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10941113B2 (en) 2013-02-28 2021-03-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US9073921B2 (en) 2013-03-01 2015-07-07 Novartis Ag Salt forms of bicyclic heterocyclic derivatives
US8987443B2 (en) 2013-03-06 2015-03-24 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US9714233B2 (en) 2013-03-06 2017-07-25 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10398677B2 (en) 2013-04-03 2019-09-03 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9873687B2 (en) 2013-05-14 2018-01-23 Active Biotech Ab N-(heteroaryl)-sulfonamide derivatives useful as S100-inhibitors
WO2014184234A1 (fr) 2013-05-14 2014-11-20 Active Biotech Ab Dérivés de n-(hétéroaryl)-sulfonamide utiles comme inhibiteurs de s100
US10125125B2 (en) 2013-05-14 2018-11-13 Active Biotech Ab N-(heteroaryl)-sulfonamide derivatives useful as S100-inhibitors
US10457638B2 (en) 2013-05-17 2019-10-29 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10561616B2 (en) 2013-08-07 2020-02-18 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US11045421B2 (en) 2013-08-07 2021-06-29 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US12151026B2 (en) 2013-08-07 2024-11-26 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US9655854B2 (en) 2013-08-07 2017-05-23 Incyte Corporation Sustained release dosage forms for a JAK1 inhibitor
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10377709B2 (en) 2013-10-23 2019-08-13 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2015074123A1 (fr) * 2013-11-25 2015-05-28 Novogen ltd Indoles fonctionnalisés et substitués utilisés en tant qu'agents anti-cancéreux
CN105916841A (zh) * 2013-11-25 2016-08-31 诺沃根公司 作为抗癌药物的功能化的和取代的吲哚
USRE50030E1 (en) 2013-12-13 2024-07-02 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
EP3079682A4 (fr) * 2013-12-13 2017-08-30 Dana-Farber Cancer Institute, Inc. Procédé pour traiter un lymphome lymphoplasmocytaire
AU2014361800B2 (en) * 2013-12-13 2020-05-07 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US10633348B2 (en) 2013-12-13 2020-04-28 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US9339510B2 (en) 2014-01-16 2016-05-17 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9505722B2 (en) 2014-01-16 2016-11-29 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10632112B2 (en) 2014-02-05 2020-04-28 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2015131031A1 (fr) 2014-02-28 2015-09-03 Incyte Corporation Inhibiteurs des jak1 pour le traitement de syndromes myélodysplasiques
US9400280B2 (en) 2014-03-27 2016-07-26 Novira Therapeutics, Inc. Piperidine derivatives and methods of treating hepatitis B infections
US10464949B2 (en) 2014-10-22 2019-11-05 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
US10844077B2 (en) 2014-10-22 2020-11-24 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
US10112957B2 (en) 2014-10-22 2018-10-30 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US11535593B2 (en) 2016-03-09 2022-12-27 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US12264132B2 (en) 2016-03-09 2025-04-01 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US10954220B2 (en) 2016-03-09 2021-03-23 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US11634412B2 (en) 2016-03-09 2023-04-25 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
EP4234552A3 (fr) * 2016-03-09 2023-10-18 Raze Therapeutics, Inc. Inhibiteurs de la 3-phosphoglycérate déshydrogénase et leurs utilisations
US11014882B2 (en) 2016-03-09 2021-05-25 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US20190071400A1 (en) * 2016-03-09 2019-03-07 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
EP3426244A4 (fr) * 2016-03-09 2019-11-06 Raze Therapeutics Inc. Inhibiteurs de la 3-phosphoglycérate déshydrogénase et leurs utilisations
US11129834B2 (en) 2016-04-15 2021-09-28 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US11084808B2 (en) 2016-08-31 2021-08-10 Jiangsu Hengrui Medicine Co., Ltd. Oxopicolinamide derivative, preparation method therefor and pharmaceutical use thereof
US10633375B2 (en) 2016-08-31 2020-04-28 Jinagsu Hengrui Medicine Co., Ltd Oxopicolinamide derivative, preparation method therefor and pharmaceutical use thereof
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11987580B2 (en) 2017-01-11 2024-05-21 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US10696673B2 (en) 2017-01-11 2020-06-30 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
AU2018274043B2 (en) * 2017-05-24 2020-10-08 Abbisko Therapeutics Co., Ltd. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method therefor, and use thereof
RU2765785C2 (ru) * 2017-05-24 2022-02-02 Аббиско Тхерапеутицс Цо., Лтд. Производное n-(азаарил)циклолактам-1-карбоксамида, метод его получения и его применение
WO2018214867A1 (fr) * 2017-05-24 2018-11-29 上海和誉生物医药科技有限公司 Dérivé de n-(azaaryl)cyclolactame-1-carboxamide, son procédé de préparation et son utilisation
AU2018274043C1 (en) * 2017-05-24 2021-08-19 Abbisko Therapeutics Co., Ltd. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method therefor, and use thereof
US11149021B2 (en) 2017-05-24 2021-10-19 Abbisko Therapeutics Co., Ltd. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method therefor, and use thereof
US12281057B2 (en) 2017-07-11 2025-04-22 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11278541B2 (en) 2017-12-08 2022-03-22 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
US10899736B2 (en) 2018-01-30 2021-01-26 Incyte Corporation Processes and intermediates for making a JAK inhibitor
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US12280054B2 (en) 2018-03-30 2025-04-22 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
US11304949B2 (en) 2018-03-30 2022-04-19 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
WO2020002563A1 (fr) 2018-06-29 2020-01-02 Syngenta Participations Ag Composés azole-amide à action pesticide
US12441703B2 (en) 2019-01-10 2025-10-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US12440481B2 (en) 2019-01-10 2025-10-14 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2020182649A1 (fr) 2019-03-08 2020-09-17 Syngenta Crop Protection Ag Composés azole-amide à action pesticide
WO2020188027A1 (fr) 2019-03-20 2020-09-24 Syngenta Crop Protection Ag Composés azole-amides à action pesticide
WO2020193341A1 (fr) 2019-03-22 2020-10-01 Syngenta Crop Protection Ag Dérivés de n-[1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)éthyl]-2-cyclopropyl-6-(trifluorométhyl)pyridine-4-carboxamide et composés apparentés servant d'insecticides
WO2020201079A1 (fr) 2019-03-29 2020-10-08 Syngenta Crop Protection Ag Composés de diazine-amide à action pesticide
WO2020201398A1 (fr) 2019-04-05 2020-10-08 Syngenta Crop Protection Ag Composés de diazine-amide à action pesticide
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2021026436A1 (fr) 2019-08-08 2021-02-11 Agios Pharmaceuticals, Inc. Procédé de préparation d'ivosidenib et d'un intermédiaire de celui-ci
WO2021037614A1 (fr) 2019-08-23 2021-03-04 Syngenta Crop Protection Ag Composés de pyrazine-amide à action pesticide
WO2021122645A1 (fr) 2019-12-20 2021-06-24 Syngenta Crop Protection Ag Composés azole-amide à action pesticide
WO2021170881A1 (fr) 2020-02-27 2021-09-02 Syngenta Crop Protection Ag Composés de diazine-bisamide à action pesticide
US12440495B2 (en) 2020-06-03 2025-10-14 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
WO2022247786A1 (fr) * 2021-05-24 2022-12-01 上海和誉生物医药科技有限公司 Sel d'acide d'un inhibiteur de csf-1r cristallin, son procédé de préparation et son utilisation
WO2022258481A1 (fr) 2021-06-09 2022-12-15 Syngenta Crop Protection Ag Composés diazine-amides à action pesticide
CN115724791A (zh) * 2022-10-10 2023-03-03 安徽金禾化学材料研究所有限公司 一种2-甲基-3-硝基-5-胺基吡啶的制备方法
CN115611806B (zh) * 2022-11-08 2024-11-19 江苏中旗科技股份有限公司 一种4-三氟甲基-3-氰基吡啶的制备方法
CN115611806A (zh) * 2022-11-08 2023-01-17 江苏中旗科技股份有限公司 一种4-三氟甲基-3-氰基吡啶的制备方法
US12384773B2 (en) 2023-11-02 2025-08-12 Arcus Biosciences, Inc. Thiazole compounds and methods of use thereof

Also Published As

Publication number Publication date
WO2006067445A3 (fr) 2006-09-14
AR053992A1 (es) 2007-05-30
TW200635899A (en) 2006-10-16

Similar Documents

Publication Publication Date Title
WO2006067445A2 (fr) Composes chimiques
EP1831198B1 (fr) Dérivés de pyridinecarboxamide employés en tant qu'agents anticancéreux
US20080207616A1 (en) Quinoxalines as B Baf Inhhibitors
CN101910168B (zh) 托烷化合物
MX2007002434A (es) Derivados de quinazolinona y su uso como inhibidores de b-raf.
US20070259849A1 (en) Azine-Carboxamides as Anti-Cancer Agents
KR101342184B1 (ko) 사치환된 피리다진 헷지호그 경로 길항제
AU2005254771A1 (en) Substituted quinazolones as anti-cancer agents
JP2009541268A (ja) Ｍｎｋキナーゼ阻害剤としてのピリジンおよびピラジン誘導体
WO2008056148A1 (fr) Composés chimiques
KR20010032643A (ko) 아닐리드 유도체, 그의 제조 및 용도
JP2010500988A (ja) ３−シンノリンカルボキサミド誘導体および癌を処置するためのそれらの使用
EP2081894A1 (fr) Derives d'acide 1h-indole-2-carboxylique en tant que modulateurs de ppar
MX2007002612A (es) Compuestos de benzamida.
EP1966174A1 (fr) Composes chimiques
CN102089286A (zh) 化合物
EP1907385A2 (fr) Composes

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

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 KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM 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: A2

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 IS IT LT LU LV 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

NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 05850642

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 05850642

Country of ref document: EP

Kind code of ref document: A2

WWW Wipo information: withdrawn in national office

Ref document number: 5850642

Country of ref document: EP