WO2013177168A1 - Pyrimidine compounds for the treatment of cancer - Google Patents

Pyrimidine compounds for the treatment of cancer Download PDF

Info

Publication number
WO2013177168A1
WO2013177168A1 PCT/US2013/042033 US2013042033W WO2013177168A1 WO 2013177168 A1 WO2013177168 A1 WO 2013177168A1 US 2013042033 W US2013042033 W US 2013042033W WO 2013177168 A1 WO2013177168 A1 WO 2013177168A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
mmol
group
cancer
Prior art date
Application number
PCT/US2013/042033
Other languages
English (en)
French (fr)
Inventor
Xiaodong Wang
Weihe Zhang
Dmitri Kireev
Dehui Zhang
Andrew MCIVER
Original Assignee
The University Of North Carolina At Chapel Hill
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
Priority to KR1020147032028A priority Critical patent/KR20150018789A/ko
Priority to BR112014028424A priority patent/BR112014028424A2/pt
Priority to CA2873878A priority patent/CA2873878A1/en
Priority to CN201380025291.3A priority patent/CN104302627A/zh
Priority to RU2014145121A priority patent/RU2014145121A/ru
Priority to JP2015514115A priority patent/JP2015517574A/ja
Priority to MX2014013632A priority patent/MX2014013632A/es
Priority to EP13793925.2A priority patent/EP2852579A4/en
Application filed by The University Of North Carolina At Chapel Hill filed Critical The University Of North Carolina At Chapel Hill
Priority to AU2013266438A priority patent/AU2013266438B2/en
Priority to IN9610DEN2014 priority patent/IN2014DN09610A/en
Priority to US14/384,789 priority patent/US9567326B2/en
Publication of WO2013177168A1 publication Critical patent/WO2013177168A1/en
Priority to IL235726A priority patent/IL235726A0/en
Priority to HK15106878.7A priority patent/HK1206338A1/xx

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48Two nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/04Heterocyclic 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 directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/06Heterocyclic 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 carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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 three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/04Heterocyclic 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 directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/14Heterocyclic 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 three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/02Heterocyclic 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
    • C07D417/04Heterocyclic 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 directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/14Heterocyclic 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 three or more hetero rings

Definitions

  • the present invention concerns compounds, compositions and methods for the treatment of cancer.
  • ALL Acute Lymphoblastic Leukemia
  • T cell and rare B cell subsets represent less than 2000 cases yearly and thus can be classified as a rare disease; these subsets have a poorer prognosis.
  • resistance to and relapse from therapy is a major cause of pediatric cancer death.
  • ALL chemotherapies can cause late complications that are increasingly recognized in pediatric survivor populations.
  • a first aspect of the invention is active compounds of Formula I or II:
  • ring A is a 5- or 6-membered heteroaryl group (for example, pyridyl, pyrimidyl, thiazol, furanyl, pyridazinyl, pyrazinyl, imidazol, etc.).
  • the dashed lines are optional double bonds.
  • X is N or O.
  • Y is a carbon atom or an S or N heteroatom in ring A in any suitable location.
  • R 1 is -R 5 R 6 , where R 5 is a covalent bond, CI to C3 alkyl or a linker group (for example, sulfonamide, ether, ester, amine, amide, etc.) and R 6 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl or alkyl, and wherein R 6 is optionally substituted one, two or three times with independently selected polar groups;
  • R 2 is -R 7 R 8 , where R 7 is a covalent bond or CI to C3 alkyl and R 8 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl, and wherein R 8 is optionally substituted one, two or three times with independently selected polar groups;
  • R 3 is selected from the group consisting of H, alkyl, aryl, arylalkyl; cycloalkylalkyl, heterocycloalkylalkyl, heteroaryalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
  • R 4 is H, loweralkyl, halo, or loweralkoxy
  • a further aspect of the invention is an active compound as described herein in a pharmaceutically acceptable carrier.
  • a further aspect of the invention is a method of treating cancer in a subject in need thereof, comprising administering said subject an active compound as described herein in an amount effective to treat the cancer.
  • a further aspect of the invention is an active compound as described herein for use in treating cancer, and/or for the preparation of a medicament for the treatment of cancer.
  • Alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • Lower alkyl as used herein, is a subset of alkyl, in some embodiments preferred, and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
  • alkyl or “loweralkyl” is intended to include both substituted and unsubstituted alkyl or loweralkyl unless otherwise indicated and these groups may be substituted with groups selected from halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(0) m , haloalkyl-S(0) m , alkenyl-S(0) n al
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to 4 double bonds in the normal chain.
  • alkenyl include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4- pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like.
  • alkenyl or “loweralkenyl” is intended to include both substituted and unsubstituted alkenyl or loweralkenyl unless otherwise indicated and these groups may be substituted with groups as described in connection with alkyl and loweralkyl above.
  • Alkynyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkynyl 1 to 4 carbon atoms) which include 1 triple bond in the normal chain.
  • Representative examples of alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2- butynyl, 4-pentynyl, 3- pentynyl, and the like.
  • alkynyl or “loweralkynyl” is intended to include both substituted and unsubstituted alkynyl or loweralkynyl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in a heterocyclic group as discussed below).
  • Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with additional substituents as described herein such as halo or loweralkyl.
  • the term “cycloalkyl” is generic and intended to include heterocyclic groups as discussed below unless specified otherwise.
  • Heterocyclic group refers to an aliphatic (e.g., fully or partially saturated heterocyclo) or aromatic (e.g., heteroaryl) monocyclic- or a bicyclic-ring system.
  • Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1 , 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1 ,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetraz
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3- benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinoliz
  • These rings include quaternized derivatives thereof and may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(0) m , haloalkyl-S(0) m , alkenyl- S(0) m , alkynyl-S(0) m , cycloalkyl-S(0) m , cycloalkylalkyl-S(0) m , aryl-S(0) m , arylalky
  • Aryl refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings.
  • Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
  • aryl is intended to include both substituted and unsubstituted aryl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.
  • Arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2- phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • Heteroaryl as used herein is as described in connection with heterocyclo above.
  • Alkoxy refers to an alkyl or loweralkyl group, as defined herein (and thus including substituted versions such as polyalkoxy), appended to the parent molecular moiety through an oxy group, -0-.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • Halo refers to any suitable halogen, including -F, -CI, -Br, and -I.
  • Cyano as used herein refers to a -CN group.
  • Forml refers to a -C(0)H group.
  • Carboxylic acid as used herein refers to a -C(0)OH group.
  • Hydrophill refers to an -OH group.
  • Niro refers to an -N0 2 group.
  • Alkyl as used herein alone or as part of another group refers to a -C(0)R radical, where R is any suitable substituent such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl or other suitable substituent as described herein.
  • Alkylthio as used herein alone or as part of another group, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
  • Amino as used herein means the radical -NH 2 .
  • Alkylamino as used herein alone or as part of another group means the radical - NHR, where R is an alkyl group.
  • Arylalkylamino as used herein alone or as part of another group means the radical - NHR, where R is an arylalkyl group.
  • Disubstituted-amino as used herein alone or as part of another group means the radical -NR a R b , where R a and Rb are independently selected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
  • Acylamino as used herein alone or as part of another group means the radical - NR a Rb, where R a is an acyl group as defined herein and Rb is selected from the groups hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
  • Acyloxy as used herein alone or as part of another group means the radical -OR, where R is an acyl group as defined herein.
  • Ester as used herein alone or as part of another group refers to a -C(0)OR radical, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Amide as used herein alone or as part of another group refers to a -C(0)NR a Rb radical, where R a and Rb are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Sulfoxyl refers to a compound of the formula -S(0)R, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Sulfonyl refers to a compound of the formula -S(0)(0)R, where R is any suitable substituent such as amino, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Sulfonate refers to a compound of the formula -S(0)(0)OR, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Sulfonamide as used herein alone or as part of another group refers to a - S(0) 2 NR a R b radical, where R a and Rb are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • “Urea” as used herein alone or as part of another group refers to an -N(R c )C(0)NR a R b radical, where R a , R b and R c are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Alkoxyacylamino as used herein alone or as part of another group refers to an- N(R a )C(0)OR b radical, where R a , R b are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • aminoacyloxy as used herein alone or as part of another group refers to an- OC(0)NR a R b radical, where R a and R b are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Poly group refers to a group wherein the nuclei of the atoms covalently bound to each other to form the group do not share the electrons of the covalent bond(s) joining them equally; that is the electron cloud is denser about one atom than another. This results in one end of the covalent bond(s) being relatively negative and the other end relatively positive; i.e., there is a negative pole and a positive pole.
  • polar groups include, without limitations, halo, hydroxy, alkoxy, carboxy, nitro, cyano, amino (primary, secondary and tertiary), amido, ureido, sulfonamido, sulfinyl, sulfhydryl, silyl, S- sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido, N-amido, sulfonyl, N-tert- butoxycarbonyl (or "t-BOC”) groups, phosphono, morpholino, piperazinyl, tetrazolo, and the like.
  • the polar group can be an ionic group.
  • Ionic group as used herein includes anionic and cationic groups, and includes groups (sometimes referred to as "ionogenic” groups) that are uncharged in one form but can be easily converted to ionic groups (for example, by protonation or deprotonation in aqueous solution). Examples include but are not limited to carboxylate, sulfonate, phosphate, amine, N-oxide, and ammonium (including quaternized heterocyclic amines such as imidazolium and pyridinium) groups. See, e.g., U.S. Pat. Nos. 6,478,863; 6,800,276; and 6,896,246.
  • Additional examples include uronic acids, carboxylic acid, sulfonic acid, amine, and moieties such as guanidinium, phosphoric acid, phosphonic acid, phosphatidyl choline, phosphonium, borate, sulfate, etc.
  • Deuterium as used herein alone or as part of another group, refers to a safe, nonradioactive relative of hydrogen. Any hydrogen in a group or substituent described above may be replaced with deuterium to provide a "deuterated” compound, in some embodiments to modify and/or improve metabolic stability, resulting in better safety, tolerability and/or efficacy.
  • Linker group or “linking group” as used herein are generally bivalent aromatic, aliphatic, or mixed aromatic and aliphatic groups.
  • linking groups include linear or branched, substituted or unsubstituted aryl, alkyl, alkylaryl, or alkylarylalkyl linking groups, where the alkyl groups are saturated or unsaturated, and where the alkyl and aryl groups optionally containing independently selected heteroatoms such as 1 , 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S.
  • heteroatoms such as 1 , 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S.
  • shorter linking groups containing from 2 to 5, 10, or 20 carbon atoms are preferred, along with any heteroatoms as described above.
  • linking groups are known, including but not limited to those described in, US Patents Nos. 8,247,572; 8,097,609; 6,624,317; 6,613,345; 6,596,935; and 6,420,377, the disclosures of which are incorporated by reference herein in their entirety.
  • Treat refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, delay in onset of the disease, etc.
  • “Pharmaceutically acceptable” as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • Active compounds of the present invention may optionally be administered in conjunction with other compounds useful in the treatment of cancer.
  • the other compounds may optionally be administered concurrently.
  • the word "concun-ently” means sufficiently close in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occurring within a short time period before or after each other).
  • the present invention is primarily concerned with the treatment of human subjects, but the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes.
  • Subjects may be of any age, including infant, juvenile, adolescent, adult, and geriatric subjects. 1. Active compounds.
  • ring A is a 5- or 6-membered heteroaryl group (for example, pyridyl, pyrimidyl, thiazol, furanyl, pyridazinyl, pyrazinyl, imidazol, etc.).
  • the dashed lines are optional double bonds.
  • X is N or O.
  • Y is a carbon atom or an S or N heteroatom in ring A in any suitable location.
  • R 1 is -R 5 R 6 , where R 5 is a covalent bond, CI to C3 alkyl or a linker group (for example, sulfonamide, ether, ester, amine, amide, etc.) and R 6 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl or alkyl, and wherein R 6 is optionally substituted one, two or three times with independently selected polar groups;
  • R 2 is -R 7 R 8 , where R 7 is a covalent bond or CI to C3 alkyl and R 8 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl, and wherein R 8 is optionally substituted one, two or three times with independently selected polar groups;
  • R 3 is selected from the group consisting of H, alkyl, aryl, arylalkyl; cycloalkylalkyl, heterocycloalkylalkyl, heteroaryalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
  • R 4 is H, loweralkyl, halo, or loweralkoxy
  • R 5 is a covalent bond; in other embodiments, R 5 is CI to C3 alkylene such as -CH 2 - or R 5 is a linker group (for example, sulfonamide, amide, etc.)
  • R 7 is a covalent bond; in other embodiments, R 7 is CI to C3 alkylene such as -CH 2 -.
  • R 6 is phenyl, piperidyl, or C1-C8 alkyl, or C3 to C8 cycloalkyl, which phenyl, pipyridyl, alkyl, or cycloalkyl alkyl is unsubstituted or substituted from 1 to 3 times with sulfono, halo, amino, nitro, alkyl, alkoxyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • R is C1-C8 alkyl or cyclohexyl, which alkyl or cyclohexyl is unsubstituted or substituted from 1 to 3 times with hydroxyl or amino.
  • R 3 is C1-C8 alkyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C3-C8 heterocycloalkyl, C4-C12 heterocycloalkylalkyl, C4-C12 arylalkyl, C4-C12 heteroarylalkyl, each of which is unsubstituted or substituted from one to three times with hydroxyl, halo, or alkoxy.
  • R 4 is H.
  • the active compounds disclosed herein can, as noted above, be provided in the form of their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
  • Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid,
  • Active compounds as described herein can be prepared in accordance with known procedures, or variations thereof that will be apparent to those skilled in the art.
  • the active compounds described above may be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9 th Ed. 1995).
  • the active compound (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight of the active compound.
  • One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients.
  • the formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical (i.e., both skin and mucosal surfaces, including airway surfaces), transdermal administration, and intraventricular injection (injection into a ventricle of the brain, e.g., by an implanted catheter or omman reservoir, such as in the case of morbid obesity) and although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
  • the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
  • the formulations may be presented in unit ⁇ dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • an injectable, stable, sterile composition comprising a compound of Formula (I), or a salt thereof, in a unit dosage form in a sealed container.
  • the compound or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
  • the unit dosage form typically comprises from about 10 mg to about 10 grams of the compound or salt.
  • emulsifying agent which is physiologically acceptable may be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier.
  • emulsifying agent is phosphatidyl choline.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis ⁇ tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
  • the present invention provides liposomal formulations of the compounds disclosed herein and salts thereof.
  • the technology for forming liposomal suspensions is well known in the art.
  • the compound or salt thereof is an aqueous-soluble salt, using conventional liposome technology, the same may be incorporated into lipid vesicles. In such an instance, due to the water solubility of the compound or salt, the compound or salt will be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed may be of any conventional composition and may either contain cholesterol or may be cholesterol-free.
  • the salt may be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome.
  • the liposomes which are produced may be reduced in size, as through the use of standard sonication and homogenization techniques.
  • liposomal formulations containing the compounds disclosed herein or salts thereof may be lyophilized to produce a lyophilizate which may be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
  • a pharmaceutically acceptable carrier such as water
  • compositions may be prepared from the water-insoluble compounds disclosed herein, or salts thereof, such as aqueous base emulsions.
  • the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound or salt thereof.
  • Particularly useful emulsifying agents include phosphatidyl cholines, and lecithin.
  • the pharmaceutical compositions may contain other additives, such as pH-adjusting additives.
  • useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
  • the compositions may contain microbial preservatives.
  • Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use.
  • the pharmaceutical compositions of the present invention may be lyophilized using techniques well known in the art.
  • the present invention provides pharmaceutical formulations comprising the active compounds (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration.
  • the therapeutically effective dosage of any specific compound will vary somewhat from compound to compound, and patient to patient, and will depend upon the condition of the patient and the route of delivery.
  • a dosage from about 0.1 to about 50 mg/kg will have therapeutic efficacy, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed.
  • Toxicity concerns at the higher level may restrict intravenous dosages to a lower level such as up to about 10 mg/kg, with all weights being calculated based upon the weight of the active base, including the cases where a salt is employed.
  • a dosage from about 10 mg/kg to about 50 mg/kg may be employed for oral administration.
  • a dosage from about 0.5 mg/kg to 5 mg/kg may be employed for intramuscular injection.
  • dosages are 1 ⁇ /kg to 50 ⁇ /kg, and more preferably 22 ⁇ /kg and 33 ⁇ /kg of the compound for intravenous or oral administration.
  • the duration of the treatment can be once per day for a period of two to three weeks or until the condition is essentially controlled.
  • Active compounds may be administered as pharmaceutically acceptable prodrugs, which are those prodrugs of the active compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Examples include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of active compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazohdine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described in US Patent No. 6,680,324 and US Patent No. 6,680,322.
  • Example cancers that may be treated by the compounds and methods of the invention include, but are not limited to, myeloid leukemia, lymphoblastic leukemia, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancer.
  • Table 1 describes compounds prepared following procedures described in Example 1 (General Procedure A), using appropriate reagents.
  • Mer IC50 ++++ means ⁇ 10 nM; +++ means between 10-lOOnM, ++ means between 100 nM-1 ⁇ ; + means between 1-30 ⁇ ; - means inactive.
  • Table 2 describes compounds prepared following procedures described in Example 2 (General Procedure B), using appropriate reagents.
  • Table 4 describes compounds prepared following procedures described in Example 4 (General Procedure D), using appropriate reagents.
  • Table 5 describes compounds prepared following procedures described in Example 5 General Procedure E), using appropriate reagents.
  • the reaction mixture was heated at 120 °C for 30 min, and then diluted with EtOAc (15 mL) after cooled to room temperature.
  • the resulting suspension was filtered tlirough a short pad of celite, which was washed with ethyl acetate.
  • the filtrate was washed with water (2x30 mL), dried (MgS0 4 ), and concentrated.
  • the residue was purified by the flash chromatography to provide /ra «j , -4-((2-(methylthio)-5-(pyridin-2-yl)pyrimidin-4- yl)amino)cyclohexanol as a white solid (1.06 g, 53%).
  • Table 7 describes compounds prepared following procedures described in Example 7 General Procedure G), using appropriate reagents.
  • Table 8 describes compounds that can also be prepared following procedures described in Example 7 (General Procedure G), using appropriate reagents.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/US2013/042033 2012-05-22 2013-05-21 Pyrimidine compounds for the treatment of cancer WO2013177168A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
MX2014013632A MX2014013632A (es) 2012-05-22 2013-05-21 Compuestos de pirimidina para el tratamiento de cancer.
CA2873878A CA2873878A1 (en) 2012-05-22 2013-05-21 Pyrimidine compounds for the treatment of cancer
CN201380025291.3A CN104302627A (zh) 2012-05-22 2013-05-21 用于治疗癌症的嘧啶化合物
RU2014145121A RU2014145121A (ru) 2012-05-22 2013-05-21 Пиримидиновые соединения для лечения злокачественной опухоли
JP2015514115A JP2015517574A (ja) 2012-05-22 2013-05-21 がん治療のためのピリミジン化合物
KR1020147032028A KR20150018789A (ko) 2012-05-22 2013-05-21 암의 치료를 위한 피리미딘 화합물
EP13793925.2A EP2852579A4 (en) 2012-05-22 2013-05-21 PYRIMIDINE COMPOUNDS FOR THE TREATMENT OF CANCER
BR112014028424A BR112014028424A2 (pt) 2012-05-22 2013-05-21 compostos de pirimidina para o tratamento de câncer
AU2013266438A AU2013266438B2 (en) 2012-05-22 2013-05-21 Pyrimidine compounds for the treatment of cancer
IN9610DEN2014 IN2014DN09610A (US07138402-20061121-C00069.png) 2012-05-22 2013-05-21
US14/384,789 US9567326B2 (en) 2012-05-22 2013-05-21 Pyrimidine compounds for the treatment of cancer
IL235726A IL235726A0 (en) 2012-05-22 2014-11-16 Pyrimidine compounds for cancer treatment
HK15106878.7A HK1206338A1 (en) 2012-05-22 2015-07-20 Pyrimidine compounds for the treatment of cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261650000P 2012-05-22 2012-05-22
US61/650,000 2012-05-22

Publications (1)

Publication Number Publication Date
WO2013177168A1 true WO2013177168A1 (en) 2013-11-28

Family

ID=49624289

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/042033 WO2013177168A1 (en) 2012-05-22 2013-05-21 Pyrimidine compounds for the treatment of cancer

Country Status (14)

Country Link
US (1) US9567326B2 (US07138402-20061121-C00069.png)
EP (1) EP2852579A4 (US07138402-20061121-C00069.png)
JP (1) JP2015517574A (US07138402-20061121-C00069.png)
KR (1) KR20150018789A (US07138402-20061121-C00069.png)
CN (1) CN104302627A (US07138402-20061121-C00069.png)
AU (1) AU2013266438B2 (US07138402-20061121-C00069.png)
BR (1) BR112014028424A2 (US07138402-20061121-C00069.png)
CA (1) CA2873878A1 (US07138402-20061121-C00069.png)
HK (1) HK1206338A1 (US07138402-20061121-C00069.png)
IL (1) IL235726A0 (US07138402-20061121-C00069.png)
IN (1) IN2014DN09610A (US07138402-20061121-C00069.png)
MX (1) MX2014013632A (US07138402-20061121-C00069.png)
RU (1) RU2014145121A (US07138402-20061121-C00069.png)
WO (1) WO2013177168A1 (US07138402-20061121-C00069.png)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926801A (zh) * 2014-03-22 2015-09-23 浙江大学 取代氮杂环类衍生物、含其的药物组合物及其在抗肿瘤中的应用
WO2015157127A1 (en) * 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Therapuetic uses of selected pyrimidine compounds with anti-mer tyrosine kinase activity
US9273056B2 (en) 2011-10-03 2016-03-01 The University Of North Carolina At Chapel Hill Pyrrolopyrimidine compounds for the treatment of cancer
US9290499B2 (en) 2010-05-19 2016-03-22 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
EP2903617A4 (en) * 2012-10-08 2016-05-18 Merck Sharp & Dohme INHIBITORS OF IRAQ4 ACTIVITY
US9562047B2 (en) 2012-10-17 2017-02-07 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
US9567326B2 (en) 2012-05-22 2017-02-14 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
WO2017059280A1 (en) * 2015-10-02 2017-04-06 The University Of North Carolina At Chapel Hill Novel pan-tam inhibitors and mer/axl dual inhibitors
US9771330B2 (en) 2012-11-27 2017-09-26 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2017197055A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Heterocyclic degronimers for target protein degradation
WO2017197036A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Spirocyclic degronimers for target protein degradation
CN110831937A (zh) * 2017-05-02 2020-02-21 韩国化学研究院 嘧啶衍生物化合物、其光学异构体或其药学上可接受的盐及包含其为有效成分的Tyro3相关疾病的预防或治疗用组合物
WO2020132561A1 (en) 2018-12-20 2020-06-25 C4 Therapeutics, Inc. Targeted protein degradation
US10709708B2 (en) 2016-03-17 2020-07-14 The University Of North Carolina At Chapel Hill Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor
US11524955B2 (en) 2016-06-27 2022-12-13 Rigel Pharmaceuticals, Inc. 2,4-diamino-pyrimidine compounds and method for making and using the compounds

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106749173A (zh) * 2016-11-25 2017-05-31 吉林化工学院 一种嘧啶联吡啶类化合物的制备方法
WO2022059996A1 (ko) * 2020-09-15 2022-03-24 서울대학교 기술지주 주식회사 혈액 순환 미세체외소체 매개 암 치료용 조성물
KR102616469B1 (ko) * 2020-09-15 2023-12-28 주식회사 유엔에스바이오 혈액 순환 미세체외소체 매개 암 치료용 조성물

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006035067A2 (en) * 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-heterocyclyl pyrimidines
US20070078140A1 (en) * 2005-09-30 2007-04-05 Bristol-Myers Squibb Company MET kinase inhibitors
WO2011090760A1 (en) * 2009-12-29 2011-07-28 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
WO2012053606A1 (ja) * 2010-10-22 2012-04-26 アステラス製薬株式会社 アリールアミノヘテロ環カルボキサミド化合物

Family Cites Families (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH549339A (de) * 1971-05-12 1974-05-31 Ciba Geigy Ag Herbizides mittel.
US5958930A (en) 1991-04-08 1999-09-28 Duquesne University Of The Holy Ghost Pyrrolo pyrimidine and furo pyrimidine derivatives
AU3176297A (en) 1996-06-25 1998-01-14 Novartis Ag Substituted 7-amino-pyrrolo{3,2-d}pyrimidines and the use thereof
US20080248046A1 (en) 1997-03-17 2008-10-09 Human Genome Sciences, Inc. Death domain containing receptor 5
GB9828511D0 (en) * 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
AU2001241142B2 (en) * 2000-04-28 2005-09-22 Tanabe Seiyaku Co., Ltd. Cyclic compounds
GB0016877D0 (en) * 2000-07-11 2000-08-30 Astrazeneca Ab Chemical compounds
EP1432714B1 (en) 2001-10-02 2008-08-06 Smithkline Beecham Corporation Chemical compounds
CA2490888C (en) * 2002-06-28 2011-05-24 Yamanouchi Pharmaceutical Co., Ltd. Diaminopyrimidinecarboxamide derivative
DE10239042A1 (de) 2002-08-21 2004-03-04 Schering Ag Makrozyclische Pyrimidine, deren Herstellung und Verwendung als Arzneimittel
WO2004106340A2 (en) 2003-05-28 2004-12-09 Università Degli Studi Di Siena 4-SUBSTITUTED DERIVATIVES OF PYRAZOLO [3,4-d] PYRIMIDINE AND PYRROLO [2,3-d] PYRIMIDINE AND USES THEREOF
US7504396B2 (en) 2003-06-24 2009-03-17 Amgen Inc. Substituted heterocyclic compounds and methods of use
US7129244B2 (en) 2003-09-18 2006-10-31 Conforma Therapeutics Corporation Triazolopyrimidines and related analogs as HSP90-inhibitors
JP5520433B2 (ja) 2004-01-21 2014-06-11 エモリー ユニバーシティー 病原体感染を処置するためのチロシンキナーゼインヒビターの組成物および使用
JP2007520559A (ja) 2004-02-03 2007-07-26 アボット・ラボラトリーズ 治療薬としてのアミノベンゾオキサゾール類
AU2005214352B2 (en) 2004-02-14 2009-11-12 Irm Llc Compounds and compositions as protein kinase inhibitors
JPWO2005095382A1 (ja) * 2004-03-30 2007-08-16 協和醗酵工業株式会社 抗腫瘍剤
EP2522670A1 (en) 2004-04-07 2012-11-14 Takeda Pharmaceutical Company Limited Heterocyclic CRF receptor antagonists
GB0420719D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
WO2006042102A2 (en) 2004-10-05 2006-04-20 Neurogen Corporation Pyrrolo-pyridine, pyrrolo-pyrimidine and related heterocyclic compounds
EP1710246A1 (en) 2005-04-08 2006-10-11 Schering Aktiengesellschaft Sulfoximine-pyrimidine Macrocycles and the salts thereof, a process for making them, and their pharmaceutical use against cancer
WO2007032445A1 (ja) * 2005-09-16 2007-03-22 Kyowa Hakko Kogyo Co., Ltd. タンパク質キナーゼ阻害剤
EP1937258A2 (en) 2005-09-23 2008-07-02 Conforma Therapeutics Corporation Anti-tumor methods using multi drug resistance independent synthetic hsp90 inhibitors
CN101321751A (zh) * 2005-09-30 2008-12-10 布里斯托尔-迈尔斯·斯奎布公司 Met激酶抑制剂
CA2624826A1 (en) 2005-10-06 2007-04-19 Schering Corporation Pyrazolopyrimidines as protein kinase inhibitors
WO2007067730A2 (en) 2005-12-08 2007-06-14 Medarex, Inc. Human monoclonal antibodies to protein tyrosine kinase 7 ( ptk7 ) and their use
US20080299113A1 (en) 2005-12-19 2008-12-04 Arnold Lee D Combined treatment with and composition of 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitor and anti-cancer agents
EP1803723A1 (de) 2006-01-03 2007-07-04 Bayer Schering Pharma Aktiengesellschaft (2,4,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononaphan-3^4-yl)-sulfoximid derivate als selektive inhibitoren der aurora kinase zur behandlung von krebs
KR20080114741A (ko) * 2006-03-30 2008-12-31 티보텍 파마슈티칼즈 리미티드 Hiv를 억제하는 5-아미도 치환 피리미딘
JP2009535393A (ja) 2006-05-01 2009-10-01 ファイザー・プロダクツ・インク 置換2−アミノ縮合複素環式化合物
GB0610242D0 (en) 2006-05-23 2006-07-05 Novartis Ag Organic compounds
JO3235B1 (ar) 2006-05-26 2018-03-08 Astex Therapeutics Ltd مركبات بيررولوبيريميدين و استعمالاتها
WO2008111441A1 (ja) * 2007-03-05 2008-09-18 Kyowa Hakko Kirin Co., Ltd. 医薬組成物
AU2008296479A1 (en) 2007-08-28 2009-03-12 Dana Farber Cancer Institute Amino substituted pyrimidine, pyrollopyridine and pyrazolopyrimidine derivatives useful as kinase inhibitors and in treating proliferative disorders and diseases associated with angiogenesis
DK2212297T3 (da) 2007-10-12 2011-09-05 Ingenium Pharmaceuticals Gmbh Inhibitorer af proteinkinaser
JP2011514881A (ja) 2007-11-09 2011-05-12 ザ ソルク インスティテュート フォー バイオロジカル スタディーズ 免疫増強剤としてのtam受容体阻害剤の使用および免疫抑制剤としてのtam活性化剤の使用
KR101892989B1 (ko) * 2008-06-27 2018-08-30 셀젠 카르 엘엘씨 헤테로아릴 화합물 및 이의 용도
US8399206B2 (en) 2008-07-10 2013-03-19 Nodality, Inc. Methods for diagnosis, prognosis and methods of treatment
US20120230991A1 (en) 2008-07-29 2012-09-13 Douglas Kim Graham Methods and compounds for enhancing anti-cancer therapy
WO2010030781A2 (en) 2008-09-10 2010-03-18 Numed International, Inc. Aromatic carboxylic acid derivatives for treatment and prophylaxis of gastrointestinal diseases including colon cancer
WO2010038081A2 (en) * 2008-10-03 2010-04-08 Astrazeneca Ab Heterocyclic derivatives and methods of use thereof
GB0819105D0 (en) 2008-10-17 2008-11-26 Chroma Therapeutics Ltd Pyrrolo-pyrimidine compounds
US8513242B2 (en) 2008-12-12 2013-08-20 Cystic Fibrosis Foundation Therapeutics, Inc. Pyrimidine compounds and methods of making and using same
WO2010085597A1 (en) 2009-01-23 2010-07-29 Incyte Corporation Macrocyclic compounds and their use as kinase inhibitors
TW201102391A (en) 2009-03-31 2011-01-16 Biogen Idec Inc Certain substituted pyrimidines, pharmaceutical compositions thereof, and methods for their use
UA107791C2 (en) 2009-05-05 2015-02-25 Dow Agrosciences Llc Pesticidal compositions
US8367689B2 (en) * 2009-05-06 2013-02-05 Portola Pharmaceuticals, Inc. Inhibitors of JAK
CA2769822C (en) 2009-08-13 2019-02-19 The Johns Hopkins University Methods of modulating immune function
CA2773661A1 (en) 2009-09-10 2011-03-17 Novartis Ag Ether derivatives of bicyclic heteroaryls
WO2011065800A2 (ko) * 2009-11-30 2011-06-03 주식회사 오스코텍 피리미딘 유도체, 이의 제조방법 및 이를 함유하는 약학적 조성물
EP2536410B1 (en) 2010-02-18 2015-09-23 Merck Sharp & Dohme Corp. Substituted pyrimidine derivatives and their use in treating viral infections
GB201004311D0 (en) 2010-03-15 2010-04-28 Proximagen Ltd New enzyme inhibitor compounds
EP2560488B1 (en) 2010-04-23 2015-10-28 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
EP2571361A4 (en) 2010-05-19 2013-11-13 Univ North Carolina PYRAZOLOPYRIMIDINE COMPOUNDS FOR CANCER TREATMENT
WO2011153553A2 (en) 2010-06-04 2011-12-08 The Regents Of The University Of California Methods and compositions for kinase inhibition
AU2011330730B2 (en) 2010-11-18 2016-02-18 Kasina Laila Innova Pharmaceuticals Private Limited Substituted 4-(selenophen-2(or 3)-ylamino)pyrimidine compounds and methods of use thereof
US8362023B2 (en) 2011-01-19 2013-01-29 Hoffmann-La Roche Inc. Pyrazolo pyrimidines
US8889684B2 (en) 2011-02-02 2014-11-18 Boehringer Ingelheim International Gmbh Azaindolylphenyl sulfonamides as serine/threonine kinase inhibitors
WO2012158795A1 (en) 2011-05-17 2012-11-22 Principia Biopharma Inc. Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors
MX2014002542A (es) * 2011-08-29 2014-07-09 Infinity Pharmaceuticals Inc Compuestos heterociclicos y usos de los mismos.
MD20140023A2 (ro) 2011-09-22 2014-06-30 Pfizer Inc. Derivaţi de pirolpirimidină şi purină
KR102063098B1 (ko) 2011-10-03 2020-01-08 더 유니버시티 오브 노쓰 캐롤라이나 엣 채플 힐 암 치료를 위한 피롤로피리미딘 화합물
EP2817328A1 (en) 2012-02-21 2014-12-31 Institut National de la Santé et de la Recherche Médicale Tam receptors as virus entry cofactors
DK2840080T3 (da) 2012-04-17 2018-01-29 Fujifilm Corp Nitrogenholdig heterocyklisk forbindelse eller salt deraf
CN104662018B (zh) 2012-04-20 2017-10-24 阿迪维纳斯治疗有限公司 取代的杂双环化合物、组合物及其医疗应用
WO2013177168A1 (en) 2012-05-22 2013-11-28 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
US9562047B2 (en) 2012-10-17 2017-02-07 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
WO2014085225A1 (en) 2012-11-27 2014-06-05 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
US20170202847A1 (en) 2014-04-04 2017-07-20 The University Of North Carolina At Chapel Hill Methods for the treatment of tumors
WO2015157122A1 (en) 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Mertk-specific pyrazolopyrimidine compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006035067A2 (en) * 2004-09-30 2006-04-06 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-heterocyclyl pyrimidines
US20070078140A1 (en) * 2005-09-30 2007-04-05 Bristol-Myers Squibb Company MET kinase inhibitors
WO2011090760A1 (en) * 2009-12-29 2011-07-28 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
WO2012053606A1 (ja) * 2010-10-22 2012-04-26 アステラス製薬株式会社 アリールアミノヘテロ環カルボキサミド化合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
REMINGTON: "The Science And Practice of Pharmacy", 1995
See also references of EP2852579A4

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9744172B2 (en) 2010-05-19 2017-08-29 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
US9290499B2 (en) 2010-05-19 2016-03-22 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
US10179133B2 (en) 2011-10-03 2019-01-15 The University Of North Carolina At Chapel Hill Pyrrolopyrimidine compounds for the treatment of cancer
US9273056B2 (en) 2011-10-03 2016-03-01 The University Of North Carolina At Chapel Hill Pyrrolopyrimidine compounds for the treatment of cancer
US9795606B2 (en) 2011-10-03 2017-10-24 The University Of North Carolina At Chapel Hill Pyrrolopyrimidine compounds for the treatment of cancer
US9567326B2 (en) 2012-05-22 2017-02-14 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
US9598440B2 (en) 2012-10-08 2017-03-21 Merck Sharp & Dohme Corp. Inhibitors of IRAK4 activity
EP2903617A4 (en) * 2012-10-08 2016-05-18 Merck Sharp & Dohme INHIBITORS OF IRAQ4 ACTIVITY
US9562047B2 (en) 2012-10-17 2017-02-07 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
US9771330B2 (en) 2012-11-27 2017-09-26 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
US10233180B2 (en) 2014-03-22 2019-03-19 Zhejiang University Substituted nitrogen-containing heterocyclic derivatives, pharmaceutical compositions comprising the same and applications of antitumor thereof
CN104926788B (zh) * 2014-03-22 2018-08-28 浙江大学 取代哌啶类衍生物、含其的药物组合物及其在抗肿瘤中的应用
CN104926801A (zh) * 2014-03-22 2015-09-23 浙江大学 取代氮杂环类衍生物、含其的药物组合物及其在抗肿瘤中的应用
CN104926801B (zh) * 2014-03-22 2019-06-04 浙江大学 取代氮杂环类衍生物、含其的药物组合物及其在抗肿瘤中的应用
CN104926788A (zh) * 2014-03-22 2015-09-23 浙江大学 取代哌啶类衍生物、含其的药物组合物及其在抗肿瘤中的应用
US9555031B2 (en) 2014-04-11 2017-01-31 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrrolopyrimidine compounds with anti-mer tyrosine kinase activity
US9555030B2 (en) 2014-04-11 2017-01-31 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrazolopyrimidine compounds with anti-Mer tyrosine kinase activity
US9649309B2 (en) 2014-04-11 2017-05-16 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrimidine compounds with anti-Mer tyrosine kinase activity
US9603850B2 (en) 2014-04-11 2017-03-28 The University Of North Carolina At Chapel Hill MerTK-specific pyrazolopyrimidine compounds
CN106459063A (zh) * 2014-04-11 2017-02-22 北卡罗来纳-查佩尔山大学 Mertk‑特异性嘧啶化合物
WO2015157127A1 (en) * 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Therapuetic uses of selected pyrimidine compounds with anti-mer tyrosine kinase activity
US20150291609A1 (en) * 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Mertk-specific pyrimidine compounds
WO2015157115A1 (en) * 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Mertk-specific pyrimidine compounds
US10004755B2 (en) 2014-04-11 2018-06-26 The University Of North Carolina At Chapel Hill Therapeutic uses of selected pyrrolopyrimidine compounds with anti-mer tyrosine kinase activity
US10526309B2 (en) 2015-10-02 2020-01-07 The University Of North Carolina At Chapel Hill Pan-TAM inhibitors and Mer/Axl dual inhibitors
WO2017059280A1 (en) * 2015-10-02 2017-04-06 The University Of North Carolina At Chapel Hill Novel pan-tam inhibitors and mer/axl dual inhibitors
US10709708B2 (en) 2016-03-17 2020-07-14 The University Of North Carolina At Chapel Hill Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor
WO2017197036A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Spirocyclic degronimers for target protein degradation
WO2017197055A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Heterocyclic degronimers for target protein degradation
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
US11524955B2 (en) 2016-06-27 2022-12-13 Rigel Pharmaceuticals, Inc. 2,4-diamino-pyrimidine compounds and method for making and using the compounds
CN110831937A (zh) * 2017-05-02 2020-02-21 韩国化学研究院 嘧啶衍生物化合物、其光学异构体或其药学上可接受的盐及包含其为有效成分的Tyro3相关疾病的预防或治疗用组合物
EP3620457A4 (en) * 2017-05-02 2021-01-06 Korea Research Institute of Chemical Technology COMPOUND DERIVED FROM PYRIMIDINE, OPTICAL ISOMER, OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND COMPOSITION FOR PREVENTING OR TREATING A TYRO 3-RELATED DISEASE, CONSIDERING IT AS AN ACTIVE INGREDIENT
US11053225B2 (en) 2017-05-02 2021-07-06 Korea Research Institute Of Chemical Technology Pyrimidine derivative compound, optical isomer thereof, or pharmaceutically acceptable salt thereof, and composition for preventing or treating Tyro 3 related disease comprising same as active ingredient
WO2020132561A1 (en) 2018-12-20 2020-06-25 C4 Therapeutics, Inc. Targeted protein degradation

Also Published As

Publication number Publication date
BR112014028424A2 (pt) 2018-04-24
IN2014DN09610A (US07138402-20061121-C00069.png) 2015-07-31
US9567326B2 (en) 2017-02-14
CA2873878A1 (en) 2013-11-28
MX2014013632A (es) 2015-02-05
JP2015517574A (ja) 2015-06-22
RU2014145121A (ru) 2016-07-10
EP2852579A1 (en) 2015-04-01
US20150038481A1 (en) 2015-02-05
CN104302627A (zh) 2015-01-21
AU2013266438B2 (en) 2017-09-07
KR20150018789A (ko) 2015-02-24
HK1206338A1 (en) 2016-01-08
IL235726A0 (en) 2015-02-01
EP2852579A4 (en) 2015-12-30
AU2013266438A1 (en) 2014-12-04

Similar Documents

Publication Publication Date Title
AU2013266438B2 (en) Pyrimidine compounds for the treatment of cancer
US10179133B2 (en) Pyrrolopyrimidine compounds for the treatment of cancer
US9771330B2 (en) Pyrimidine compounds for the treatment of cancer
US9744172B2 (en) Pyrazolopyrimidine compounds for the treatment of cancer
US9562047B2 (en) Pyrazolopyrimidine compounds for the treatment of cancer
US20080319044A1 (en) Compounds and Methods of Use Thereof
US20090005344A1 (en) Compounds and Methods of Use Thereof
BR112021011147A2 (pt) Benzamidas de derivados de pirazolil-amino-pirimidinila e composições e métodos das mesmas
KR20230170644A (ko) 선택적 bcl-xl protac 화합물 및 사용 방법
CA3172830A1 (en) Potent and selective irreversible inhibitors of irak1
US8334292B1 (en) Pyrimidine compounds and methods of making and using same

Legal Events

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

Ref document number: 13793925

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 14384789

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: MX/A/2014/013632

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2015514115

Country of ref document: JP

Kind code of ref document: A

Ref document number: 20147032028

Country of ref document: KR

Kind code of ref document: A

Ref document number: 2873878

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 235726

Country of ref document: IL

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2013266438

Country of ref document: AU

Date of ref document: 20130521

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2013793925

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2014145121

Country of ref document: RU

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112014028424

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112014028424

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20141114