Pyridazinones and their use in the treatment of cancer

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  • Publication Date:
    September 07, 2021
  • Additional Information
    • Patent Number:
      11110,089
    • Appl. No:
      15/750817
    • Application Filed:
      August 05, 2016
    • Abstract:
      There is provided compounds of formula (I) or pharmaceutically-acceptable salts thereof, wherein W, X, Y, Z, R1, R2 and R3 have meanings provided in the description, which compounds are useful in the treatment of cancers. [chemical expression included]
    • Inventors:
      Arnér, Elias Set Jenö (Stockholm, SE); THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES (Bethesda, MD, US)
    • Assignees:
      The United States of America, as represented by the Secretary, Department of Health and Human Services (Bethesda, MD, US), Elias Set Jenö Arnér (Stockholm, SE)
    • Claim:
      1. A compound of formula I [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: W represents C 1 alkylene optionally substituted by one or more groups independently selected from R 4 ; X represents O; Y represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1a , heterocycloalkyl optionally substituted by one or more groups independently selected from G 1b , aryl optionally substituted by one or more groups independently selected from G 1c , or heteroaryl optionally substituted by one or more groups independently selected from G 1d ; Z represents O, S or NR 5 ; R 1 represents H, halo, R a1 , —CN, —C(Q a1)R b1 , —C(Q b1)N(R c1)R d1 , —C(Q c1)OR e1 , —S(O) n R f1 , —S(O) p N(R g1)R h1 , —S(O) p OR i1 or —NO 2 ; R 2 represents H, halo, —CN or —N 3 ; R 3 represents H, halo or Rd j1 ; R 4 represents halo, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1e , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1e , or C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1e ; R 5 represents H, R k1 , —OR 1l or —N(R m1)R n1 , Q a1 to Q c1 each independently represents ═O, ═S, ═NR o1 or ═N(OR p1); each R a1 , R f1 , R j1 and R k1 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b ; each R b1 , R c1 , R d1 , R e1 , R g1 , R h1 , R i1 , R j1 , R l1 , R m1 , R o1 and R p1 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b , or any two R c1 and R d1 , R g1 and R h1 and/or R m1 and R n1 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1a , G 1b , G 1c and G 1d represent halogen, R a2 , —CN, -A a1 -C(Q a2)R a2 , -A b1 -C(Q b2)N(R c2)R d2 , -A c1 -C(Q c2)OR e2 , -A d1 -S(O)R f2 , -A e1 -S(O) q C(O)R g2 , -A f1 -S(O) q N(R h2)R i2 , -A g1 -S(O) q OR j2 , —N 3 , —N(R k2)R l2 , —N(H)CN, —NO 2 , —OR m2 , —SR n2 or ═Q d2 , A a1 to A g1 each independently represents a single bond, —N(R 6)—, —C(Q e2)N(R 7)— or —O—; Q a2 to Q e2 each independently represents ═O, ═S, ═NR o2 or ═N(OR p2); each R 6 and R 7 independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; each R a2 and R f2 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; each R b2 , R c2 , R d2 , R e2 , R g2 , R h2 , R i2 , R j2 , R k2 , R l2 , R m2 , R n2 , R o2 and R p2 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; or any two R c2 and R d2 , R h2 and R i2 and/or R k2 and R l2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1e independently represents halo, R 2a , —CN, —N(R a3)R b3 , —OR c3 or —SR d3 ; R a3 , R b3 , R c3 and R d3 each independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; or R a3 and R b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 2a and G 2b independently represents halo, —CN, —N(R a4)R b4 , —OR c4 , —SR d4 or ═O; each R a4 , R b4 , R c4 and R d4 independently represents H, C 1-6 alkyl optionally substituted by one or more fluoro, C 2-6 alkenyl optionally substituted by one or more fluoro, or C 2-6 alkynyl optionally substituted by one or more fluoro; or R a4 and R b4 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 3a and G 3b independently represents halo, —CN, —N(R a5)R b5 , —OR c5 , —SR d5 or ═O; each R a5 , R b5 , RC c5 and R d5 independently represents H, C 1-6 alkyl optionally substituted by one or more fluoro, C 2-6 alkenyl optionally substituted by one or more fluoro, or C 2-6 alkynyl optionally substituted by one or more fluoro; or R a5 and R b5 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each n independently represents 0, 1 or 2, each p independently represents 1 or 2, each q independently represents 1 or 2, with the provisos that: (A) the compound of formula I is not a compound selected from 4,5-dichloro-2-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 4,5-dichloro-2-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 4,5-dichloro-2-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 4,5-dichloro-2-(1-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)propyl)pyridazin-3(2H)-one, 4,5-dichloro-2-(1-(5-phenyl-1,3,4-oxadiazol-2-yl)propyl)pyridazin-3(2H)-one, 4,5-dichloro-2-(1-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)propyl)pyridazin-3(2H)-one, and 4,5-dichloro-2-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)propyl)pyridazin-3(2H)-one; and (B) the compound of formula I is not a compound selected from 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-6-(trifluoromethyl)pyridazin-3(2H)-one, 4,5-dibromo-2-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 5-iodo-2-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 2-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-5-iodopyridazin-3(2H)-one, 4,5-dichloro-2-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 4,5-dibromo-2-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 4,5-dichloro-2-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 2-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)methyl)-4,5-dichloropyridazin-3(2H)-one, 2-((5-isopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(trifluoromethyl)pyridazin-3(2H)-one, 6-(tert-butyl)-2-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 2-((5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-6-methylpyridazin-3(2H)-one, 6-methyl-2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 5,6-diethyl-2-((5-isopropyl-1,3,4-oxadiazol-2-yl)methyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile, 2-((5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)methyl)-5,6-diethyl-3-oxo-2,3-dihydropyridazine-4-carbonitrile, 4,5-dichloro-2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 4,5-dichloro-2-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3(2H)-one, 2-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-5,6-diethyl-3-oxo-2,3-dihydropyridazine-4-carbonitrile, 6-cyclopropyl-2-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one, 2-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-cyclopropyl-2-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one, 6-cyclopropyl-2((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-4-(trifluoromethyl)pyridazin-3(2H)-one, 5,6-dimethyl-2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methyl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile, 5,6-dimethyl-3-oxo-2-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-2,3-dihydropyridazine-4-carbonitrile, 2-((5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropyl-4-(trifluoromethyl)pyridazin-3(2H)-one, 2-((5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)methyl)-6-cyclopropyl-4-(trifluoromethyl)pyridazin-3 (2H)-one, 6-cyclopropyl-4-(trifluoromethyl)-2-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadi azol-2-yl)methyl)pyridazin-3 (2H)-one, 2-((5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)methyl)-4,5-dichloropyridazin-3 (2H)-one, 4,5-dichloro-2-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3 (2H)-one, 2-((5-(5-bromofuran-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-4,5-dichloropyridazin-3 (2H)-one, 5,6-dimethyl-3-oxo-2-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)-2,3-dihydropyridazine-4-carbonitrile, 2-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-5,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-carbonitrile, 2-((5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)methyl)-4,5-dichloropyridazin-3 (2H)-one, 4,5-dichloro-2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)pyridazin-3 (2H)-one, 2-((5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)methyl)-4,5-dichloropyridazin-3(2H)-one.
    • Claim:
      2. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 represents F or C 1 alkyl optionally substituted by one or more F.
    • Claim:
      3. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein W represents —CH 2 —.
    • Claim:
      4. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y represents phenyl optionally substituted by one or more groups independently selected from G 1c .
    • Claim:
      5. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1c represents halo, R 2a , —NO 2 or —OR m2 .
    • Claim:
      6. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z represents O.
    • Claim:
      7. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 1 represents H, halo, R a1 , —CN, —C(O)R b1 , —C(O)OR e1 , —S(O) 2 R f1 or —NO 2 ; and R a1 , R b1 , R e1 and R f1 represents C 1-6 alkyl optionally substituted by one or more F.
    • Claim:
      8. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 represents halo.
    • Claim:
      9. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 represents H.
    • Claim:
      10. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein: both of R 1 and R 2 represent Cl; and/or R 3 represents H.
    • Claim:
      11. A method of treating cancer, wherein the cancer is selected from pharyngeal squamous cell carcinoma, colorectal carcinoma, epidermoid (skin) carcinoma and lung carcinoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound, wherein the compound is represented by formula I [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: W represents C 1 alkylene optionally substituted by one or more groups independently selected from R 4 ; X represents O; Y represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1a , heterocycloalkyl optionally substituted by one or more groups independently selected from G 1b , aryl optionally substituted by one or more groups independently selected from G 1c , or heteroaryl optionally substituted by one or more groups independently selected from G 1d ; Z represents O, S or NR 5 ; R 1 represents H, halo, R a1 , —CN, —C(Q a1)R b1 , —C(Q b1)N(R c1)R d1 , —C(Q c1)OR e1 , —S(O) n R f1 , —S(O) p N(R g1)R h1 , —S(O) p OR i1 or —NO 2 ; R 2 represents H, halo, —CN or —N 3 ; R 3 represents H, halo or R j1 ; R 4 represents halo, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1e , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1e , or C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1e ; R 5 represents H, R k1 , —OR l1 or —N(R m1)R n1 ; Q a1 to Q c1 each independently represents ═O, ═S, ═NR o1 or ═N(OR p1); each R a1 , R f1 , R j1 and R k1 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b ; each R b1 , R c1 , R d1 , R e1 , R g1 , R h1 , R i1 , R l1 , R m1 , R n1 , R o1 and R p1 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b ; or any two R c1 and R d1 , R g1 and R h1 and/or R m1 and R n1 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1a , G 1b , G 1c and G 1d represent halogen, R A2 , —CN,-A a1 -C(Q a2)R b2 , -A b1 -C(Q b2)N(R c2)R d2 , -A c1 -C(Q c2)OR e2 , -A d1 -S(O) q R f2 , -A e1 -S(O) q C(O)R g2 , -A f1 -S(O) q N(R h2)R i2 , -A g1 -S(O) q OR j2 , —N 3 , —N(R k2)R l2 , —N(H)CN, —NO 2 , —OR m2 , —SR n2 or ═Q d2 ; A a1 to A g1 each independently represents a single bond, —N(R 6)—, —C(Q e2)N(R 7)— or —O—; Q a2 to Q e2 each independently represents ═O, ═S, ═NR o2 or ═N(OR p2); each R 6 and R 7 independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; each R a2 and R f2 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; each R b2 , R c2 , R d2 , R e2 , R g2 , R h2 , R i2 , R j2 , R k2 , R l2 , R m2 , R n2 , R o2 and R p2 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; or any two R c2 and R d2 , R h2 and R i2 and/or R k2 and R l2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1e independently represents halo, R a2 , —CN, —N(R a3)R b3 , —OR c3 or —SR d3 ; R a3 , R b3 , R c3 and R d3 each independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; or R a3 and R b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 2a and G 2b independently represents halo, —CN, —N(R a4)R b4 , —OR c4 , —SR d4 or ═O; each R a4 , R b4 , R c4 and R d4 independently represents H, C 1-6 alkyl optionally substituted by one or more fluoro, C 2-6 alkenyl optionally substituted by one or more fluoro, or C 2-6 alkynyl optionally substituted by one or more fluoro; or R a4 and R b4 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 3a and G 3b independently represents halo, —CN, —N(R a5)R b5 , —OR c5 , —SR d5 or ═O; each R a5 , R b5 , R c5 and R d5 independently represents H, C 1-6 alkyl optionally substituted by ONE OR MORE FLUORO, C 2-6 ALKENYL OPTIONALLY SUBSTITUTED BY ONE OR MORE FLUORO, OR C 2-6 ALKYNYL optionally substituted by one or more fluoro; or R a5 and R b5 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each n independently represents 0, 1 or 2, each p independently represents 1 or 2, and each q independently represents 1 or 2.
    • Claim:
      12. A pharmaceutical composition comprising a compound, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier, wherein the compound is represented by formula I [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: W represents C 1 alkylene optionally substituted by one or more groups independently selected from R 4 ; X represents O; Y represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1a , heterocycloalkyl optionally substituted by one or more groups independently selected from G 1b , aryl optionally substituted by one or more groups independently selected from G 1c , or heteroaryl optionally substituted by one or more groups independently selected from G 1d ; Z represents O, S or NR 5 ; R 1 represents H, halo, R a1 , —CN, —C(Q a1)R b1 , —C(Q b1)N(R c1)R d1 , —C(Q c1)OR e1 , —S(O) n R f1 , —S(O) p N(R g1)R h1 , —S(O) p OR i1 or —NO 2 ; R 2 represents H, halo, —CN or —N 3 ; R 3 represents H, halo or R j1 ; R 4 represents halo, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1e , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1e , or C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1e ; R 5 represents H, R k1 , —OR l1 or —N(R m1)R n1 ; Q a1 to Q c1 each independently represents ═O, ═S, ═NR o1 or ═N(OR p1); each R a1 , R f1 , R j1 and R k1 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b ; each R b1 , R c1 , R d1 , R e1 , R g1 , R h1 , R i1 , R l1 , R m1 , R n1 , R o1 and R p1 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b ; or any two R c1 and R d1 , R g1 and R h1 and/or R m1 and R n1 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1a , G 1b , G 1c and G 1d represent halogen, R a2 , —CN, -A a1 -C(Q a2)R b2 , -A b1 -C(Q b2)N(R c2)R d2 , -A c1 -C(Q c2)OR e2 , -A d1 -S(O) q R f2 , -A e1 -S(O) q C(O)R g2 , -A f1 -S(O) q N(R h2)R i2 , -A g1 -S(O) q OR j2 , —N 3 , —N(R k2)R l2 , —N(H)CN, —NO 2 , —OR m2 , —SR n2 or ═Q d2 ; A a1 to A g1 each independently represents a single bond, —N(R 6)—, —C(Q e2)N(R 7)— or —O—; Q a2 to Q c2 each independently represents ═O, ═S, ═NR o2 or ═N(OR p2); each R 6 and R 7 independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; each R a2 and R f2 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; each R b2 , R c2 , R d2 , R e2 , R g2 , R h2 , R i2 , R j2 , R k2 , R l2 , R m2 , R n2 , R o2 and R p2 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; or any two R c2 and R d2 , R h2 and R i2 and/or R k2 and R l2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1e independently represents halo, R a2 , —CN, —N(R a3)R b3 , —OR c3 or —SR d3 ; R a3 , R b3 , R c3 and R d3 each independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; or R a3 and R b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 2a and G 2b independently represents halo, —CN, —N(R a5)R b5 , —OR c5 , —SR d5 or ═O; each R a4 , R b4 , R c4 and R d4 independently represents H, C 1-6 alkyl optionally substituted by one or more fluoro, C 2-6 alkenyl optionally substituted by one or more fluoro, or C 2-6 alkynyl optionally substituted by one or more fluoro; or R a4 and R b4 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 3a and G 3b independently represents halo, —CN, —N(R a5)R b5 , —OR c5 , —SR d5 or ═O; each R a5 , R b5 , R c5 and R d5 independently represents H, C 1-6 alkyl optionally substituted by one or more fluoro, C 2-6 alkenyl optionally substituted by one or more fluoro, or C 2-6 alkynyl optionally substituted by one or more fluoro; or R a5 and R b5 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each n independently represents 0, 1 or 2, each p independently represents 1 or 2, and each q independently represents 1 or 2.
    • Claim:
      13. A combination product comprising: (I) a pharmaceutical formulation as defined in claim 12 ; and (II) one or more other therapeutic agent that is useful in the treatment of cancer, wherein the cancer is selected from the group consisting of pharyngeal squamous cell carcinoma, colorectal carcinoma, epidermoid (skin) carcinoma and lung carcinoma, wherein each of components (I) and (II) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier, wherein the compound is represented by formula I [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: W represents C 1 alkylene optionally substituted by one or more groups independently selected from R 4 ; X represents O; Y represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1a , heterocycloalkyl optionally substituted by one or more groups independently selected from G 1b , aryl optionally substituted by one or more groups independently selected from G 1c , or heteroaryl optionally substituted by one or more groups independently selected from G 1d ; Z represents O, S or NR 5 ; R 1 represents H, halo, R a1 , —CN, —C(Q a1)R b1 , —C(Q b1)N(R c1)R d1 , —C(Q c1)OR e1 , —S(O) n R f1 , —S(O) p N(R g1)R h1 , —S(O) p OR i1 or —NO 2 ; R 2 represents H, halo, —CN or —N 3 ; R 3 represents H, halo or R j1 ; R 4 represents halo, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 1e , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 1e , or C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 1e ; R 5 represents H, R k1 , —OR l1 or —N(R m1)R n1 ; Q a1 to Q c1 each independently represents ═O, ═S, ═NR o1 or ═N(OR p1); each R a1 , R f1 , R j1 and R k1 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b ; each R b1 , R c1 , R d1 , R e1 , R g1 , R h1 , R i1 , R l1 , R m1 , R n1 , R o1 and R p1 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 2a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 2a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 2b , or any two R c1 and R d1 , R g1 and R h1 and/or R m1 and R n1 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1a , G 1b , R 1c and G 1d represent halogen, R a2 , —CN, -A a -C(Q a2)R b2 , -A b1 -C(Q b2)N(R c2)R d2 , -A c1 -C(Q c2)OR e2 , -A d1 -S(O) q R f2 , -A e1 -S(O) q C(O)R g2 , -A f1 -S(O) q N(R h2)R i2 , -A g1 -S(O) q OR j2 , —N 3 , —N(R k2)R l2 , —N(H)CN, —NO 2 , —OR m2 , —SR n2 or ═Q d2 ; A a1 to A g1 each independently represents a single bond, —N(R 6)—, —C(Q e2)N(R 7)— or —O—; Q a2 to Q e2 each independently represents ═O, ═S, ═NR o2 or ═N(OR p2); each R 6 and R 7 independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; each R a2 and R f2 independently represents C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; each R b2 , R c2 , R d2 , R e2 , R g2 , R h2 , R i2 , R j2 , R k2 , R l2 , R m2 , R n2 , R o2 and R p2 independently represents H, C 1-6 alkyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkenyl optionally substituted by one or more groups independently selected from G 3a , C 2-6 alkynyl optionally substituted by one or more groups independently selected from G 3a , or heterocycloalkyl optionally substituted by one or more groups independently selected from G 3b ; or any two R c2 and R d2 , R h2 and R i2 and/or R k2 and R l2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C 1-3 alkyl optionally substituted by one or more halogens, C 2-3 alkenyl optionally substituted by one or more halogens, C 2-3 alkynyl optionally substituted by one or more halogens, and ═O; each G 1e independently represents halo, R a2 , —CN, —N(R a3)R b3 , —OR c3 or —SR d3 ; R a3 , R b3 , R c3 and R d3 each independently represents H, C 1-6 alkyl optionally substituted by one or more F, C 2-6 alkenyl optionally substituted by one or more F, or C 2-6 alkynyl optionally substituted by one or more F; or R a3 and R b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 2a and G 2b independently represents halo, —CN, —N(R a4)R b4 , —OR c4 , —SR d4 or ═O; each R a4 , R b4 , R c4 and R d4 independently represents H, C 1-6 alkyl optionally substituted by one or more fluoro, C 2-6 alkenyl optionally substituted by one or more fluoro, or C 2-6 alkynyl optionally substituted by one or more fluoro; or Ra a4 and R b4 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each G 3a and G 3b independently represents halo, —CN, —N(R a5)R b5 , —OR c5 , —SR d5 or ═O; each R a5 , R b5 , R c5 and R d5 independently represents H, C 1-6 alkyl optionally substituted by one or more fluoro, C 2-6 alkenyl optionally substituted by one or more fluoro, or C 2-6 alkynyl optionally substituted by one or more fluoro; or R a5 and R b5 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C 1-3 alkyl optionally substituted by one or more fluoro, C 2-3 alkenyl optionally substituted by one or more fluoro, C 2-3 alkynyl optionally substituted by one or more fluoro, and ═O; each n independently represents 0, 1 or 2, each p independently represents 1 or 2, and each q independently represents 1 or 2.
    • Claim:
      14. A kit-of-parts comprising: (a) a pharmaceutical formulation as defined in claim 12 ; and (b) one or more other therapeutic agent that is useful in the treatment of cancer, wherein the cancer is selected from the group consisting of pharyngeal squamous cell carcinoma, colorectal carcinoma, epidermoid (skin) carcinoma and lung carcinoma, and wherein the one or more other therapeutic agent is optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
    • Claim:
      15. A process for the preparation of a compound as defined in claim 1 , which process comprises: (i) reaction of a compound of formula II [chemical expression included] wherein W, X and Y are as defined in claim 1 and LG 1 represents a suitable leaving group, with a compound of formula III [chemical expression included] wherein R 1 to R 3 and Z are as defined in claim 1 , in the presence of a suitable base and in the presence of a suitable solvent; or (ii) reaction of a compound of formula IV [chemical expression included] wherein W, X, Z and R 1 to R 3 are as defined in claim 1 and LG 2 represents a suitable leaving group, with a compound of formula V Y-B 1   (V) wherein Y is as defined in claim 1 and B 1 represents a group suitable for participating in a coupling reaction in the presence of a suitable catalyst and in the presence of a suitable solvent.
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    • Primary Examiner:
      Leeser, Erich A
    • Attorney, Agent or Firm:
      McCarter & English, LLP
      Davis, Steven G.
      Bai, Mei
    • Accession Number:
      edspgr.11110089