WO2016123253A1 - Hydrazne derivatives for the treatment of cancer - Google Patents

Hydrazne derivatives for the treatment of cancer Download PDF

Info

Publication number
WO2016123253A1
WO2016123253A1 PCT/US2016/015195 US2016015195W WO2016123253A1 WO 2016123253 A1 WO2016123253 A1 WO 2016123253A1 US 2016015195 W US2016015195 W US 2016015195W WO 2016123253 A1 WO2016123253 A1 WO 2016123253A1
Authority
WO
WIPO (PCT)
Prior art keywords
cycloalkyl
independently selected
alkyl
alkenyl
alkynyl
Prior art date
Application number
PCT/US2016/015195
Other languages
French (fr)
Inventor
David J. Augeri
Anthony F. BENCIVENGA
Adam BLANDEN
Darren R. CARPIZO
John A. GILLERAN
Spencer David Kimball
Stewart N. LOH
Xin Yu
Original Assignee
Rutgers, The State University Of New Jersey
The Research Foundation For The State University Of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rutgers, The State University Of New Jersey, The Research Foundation For The State University Of New York filed Critical Rutgers, The State University Of New Jersey
Priority to US15/545,971 priority Critical patent/US10828288B2/en
Publication of WO2016123253A1 publication Critical patent/WO2016123253A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic 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
    • C07D403/12—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • TP53 is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists.
  • the majority of TP53 mutations (>70%) are mis-sense mutations that generate a defective protein that is generally found at high levels in cancer cells due to loss of MDM2 negative feedback.
  • Restoring the function of p53 in mouse models of cancer is highly therapeutic. Reactivating mutant p53 using small molecules has been highly sought after, yet remains an elusive goal in the development of cancer therapeutics.
  • the invention provides novel compounds, compositions, and methods for treating cancer. More specifically, one aspect of the present invention provides a compound of formula (1):
  • the ring A is a fused benzo or heteroaryl ring
  • X is S, O, -CH-CH-, or N-R a ;
  • HET is selected from the group consisting of:
  • HET is optionally substituted with one or more groups R independently selected from halo, cyano, hydroxy, nitro, -N(R a ) 2 , carboxy, phenyl, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C3-C 6 )cycloalkyl, (C C6)alkoxy, (C C 6 )alkanoyl, (Ci-C )alkoxycarbonyl, (C 2 - C 6 )alkanoyloxy,
  • groups R independently selected from halo, cyano, hydroxy, nitro, -N(R a ) 2 , carboxy, phenyl, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C3-C 6 )cycloalkyl, (C C
  • any phenyl, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (C?-C6)alkenyl, (C2-C 6 )alkynyl, and (C 3 - C 6 )cycIoalkyl is optionally substituted with one or more groups independently selected from halo, azido, cyano, hydroxy, nitro, -N(R b ) 2 , carboxy, (C 3 -C ⁇ ,)cycloalkyl, (CrQJalkanoyl, (Ci-C6)alkoxycarbonyl. (C 2 -C6)alkanoyloxy, and (C]-C 6 )alkoxy that is optionally substituted with carboxy;
  • each R is independently selected from the group consisting of H, phenyl, (C
  • n 0, 1, 2, 3, or 4;
  • each R 3 is independently selected from halo, cyano, hydroxy, nitro, -N(R d ) 2 , carboxy, phenyl, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (Ci -C 6 )alkoxy, (C C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, and (C 2 -C 6 )alkanoyloxy, wherein any phenyl, (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, and (C 3 -C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano,
  • R a is selected from the group consisting of H, (C i-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C6)cycloalkyl, (Ci-C 6 )alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (CrC 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (Ci -C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C6)cycloalkyl, -N(R g ) 2
  • each R b is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 - Cgjalkenyl, (C2-C6)alkynyl, (C3-C 6 )cycloalkyl, (C
  • each R c is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C2-C6)alkynyl, (C 3 -C6)cycloalkyl, (Ci-C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl, wherein any (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C
  • C )alkanoyl, and (Ci-C 6 )alkoxycarbonyl is optionally substituted with one or more groups independently selected from halo, (C 3 -C6)cycloaIkyl, and (C 1 -C 6 )alkoxy; or two R c taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
  • each R d is independently selected from the group consisting of H, (C C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C3-C 6 )cycloalkyl, (Ci-C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl, wherein any (C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C i- C 6 )alkanoyl, and (C i-C(j)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C6)cycloalkyl, and (Ci-C 6 )alkoxy; or two R d taken together with the nitrogen to which they are attached form a azet
  • R e is independently selected from the group consisting of H and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from halo, (C 3 - C 6 )cycloalkyl, -N(R f ) 2 , and (C C 6 )alkoxy;
  • each R r is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C6)cycloalkyl, (C]-C 6 )alkanoyl, and (d-C ⁇ alkoxycarbonyl, wherein any (d-Ceialkyl, (C 2 -C,j)a]kenyl, (C 2 -C 6 )alkynyl, (C 3 -C6)cycloalkyl, (C]- C 6 )alkanoyl 5 and (Q-Cejalkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyI, and (CrC 6 )alkoxy; or two R taken together with the nitrogen to which they are attached form a azetidino, pyrrolidin
  • each R g is independently selected from the group consisting of H, (Ci-C )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C3-C 6 )cycloalkyl, (Ci-C 6 )alkanoyI, and (Cj-C6)alkoxycarbonyl, wherein any (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C
  • C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl is optionally substituted with one or more groups independently selected from halo, (C3-C 6 )cycloalkyl, and (C i-C 6 )alkoxy; or two R 8 taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
  • HET is not substituted with one or more (e.g. 1 , 2, 3, or 4) groups R 1 , then R is not H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl.
  • Another aspect of the present invention provides a pharmaceutical composition, comprising, a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention provides a method of inhibiting cancer cell growth, comprising contacting the cancer cell with an effective amount of a compound of formula 1 or a salt thereof.
  • Another aspect of the present invention provides a method of treating cancer in an animal (e.g. a human), comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the invention further includes methods of preparing, methods of separating, and methods of purifying the compounds described herein.
  • Figure 1 illustrates the three day cell growth inhibition assays comparing compounds 1 and 2 tested against three human tumor cell lines, TOV 112D (p53-Rl 75H), H460 (p53- WT), and HI 299 (p53-null).
  • Figure 2 shows PAB1620 antibody recognition of wildtype conformation after treatment of mutant p53 with compounds 1 and 2.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • benzyl refers to a substituent, molecular fragment, or radical having the chemical formula -CH 2 C 6 H5.
  • butyl refers to a four-carbon alkyl radical, substituent, or molecular fragment having the chemical formula -C4H9.
  • cyclopropyl refers to a radical, substituent, or molecular fragment having a chemical structure derived from cyclopropane and having the chemical formula C3H5.
  • ethyl refers to an alkyl substituent, radical, or molecular fragment having the chemical formula -C 2 H S
  • isopropyl refers to a propyl with a group attached to the secondary carbon.
  • methyl refers to an alkyl derived from methane and containing one carbon atom bonded to three hydrogen atoms and having the chemical formula -CH3.
  • propyl refers to a linear three-carbon alkyl substituent, molecular fragment, or radical having the chemical formula -C3H7.
  • phenyl refers to a cyclic group of atoms, radical, substituent, or molecular fragment having the chemical formula -C6H5.
  • the atom to which the bond is attached includes all stereochemical possibilities.
  • a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted.
  • the compound may be at least 51% the absolute stereoisomer depicted.
  • the compound may be at least 60% the absolute stereoisomer depicted.
  • the compound may be at least 80% the absolute stereoisomer depicted.
  • the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.
  • (C[-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 1 -C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (C2-C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 ,-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl
  • the compound of formula (I) is a compound of formula (la):
  • X is S, O, N-H, or N-R a ;
  • HET is selected from the group consisting of:
  • HET is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups R 1 independently selected from halo, cyano, hydroxy, nitro, -N(R a )2, carboxy, phenyl, (Ci- C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (Ci-C 6 )alkoxy, (C,-C 6 )alkanoyl, (Ci-C 6 )alkoxycarbonyl, (C 2 -C 6 )alkanoyloxy, and wherein any phenyl, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (C2-C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 - C 6 )cycloalkyl, is optionally substituted
  • R 2 is selected from the group consisting of H, phenyl. (C i-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C3-C 6 )cycloalkyl, wherein any phenyl, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C3-C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(R C ) 2 , (C 3 -C 6 )cycloalkyl, (Ci-C 6 )alkoxy, and (C 2 - C 6 )alkanoyloxy;
  • n 1 , 2, 3, or 4;
  • each R 3 is independently selected from halo, cyano, hydroxy, nitro, -N(R d ) 2 , carboxy, phenyl, (C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (Ci-C 6 )alkoxy, (C r C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, and (C2-C 6 )alkanoyloxy, wherein any phenyl, (C ⁇ - Cejalkyl, (C 2 -C 6 )alkenyl, (C 2 -C )alkynyl, (C
  • R a is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C3-C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, and (Ci-Ce)alkoxycarbonyl, wherein any (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C i-C 6 )alkanoyl, and (C
  • each R b is independently selected from the group consisting of H, (Ci-C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl ; (Ci-C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl, wherein any (C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C
  • each R c is independently selected from the group consisting of H, (Ci-C 6 )alkyl, (C 2 - C 6 )alkenyl, (C2-C 6 )alk nyl, (C3-C 6 )cycloalkyl, (Ci-C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl J wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C ⁇ - C f i)alkanoyl, and (Ci-C 6 )alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C 6 )cycloalkyl, and (CrC 6 )alkoxy; or two R c taken together with the nitrogen to which they are attached form
  • each R d is independently selected from the group consisting of H, (Ci-C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C3-C 6 )cycloalkyl, (Ci-C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl, wherein any (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C r
  • C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl 5 and (C 1 -C 6 )alkoxy; or two R d taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
  • R e is independently selected from the group consisting of H and (C C6)alkyl that is optionally substituted with one or more groups independently selected from halo, (C 3 - C 6 )cycloalkyl, -N(R f ) 2 , and (Ci-C 6 )alkoxy; and
  • each R f is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (Ci-C 6 )alkanoyl, and (Ci-C 6 )alkoxycarbonyl, wherein any (C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C
  • C6)alkanoyl, and (Ci-C 6 )alkoxycarbonyl is optionally substituted with one or more groups independently selected from halo, (C 3 -C6)cycloalkyl, and (C C6)alkoxy; or two R f taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
  • HET is not substituted with one or more (e.g. 1 , 2, 3, or 4) groups R l , then R 2 is not H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl.
  • R l is selected from the group consisting of:
  • HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(R ) 2 , carboxy, phenyl, (C
  • R is selected from the group consisting of H, phenyl, (Ci-C6)alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C6)cycloalkyl, wherein any phenyl, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(R b ) 2 , (C3-C 6 )cycloalkyl, (Ci-C 6 )alkoxy, and (C 2 - C 6 )alkanoyloxy;
  • R and R taken together with the carbon to which they are attached form a bicyclic 9- or 10-membered nitrogen ring system comprising 1, 2, 3, or 4 nitrogen atoms and at least one aromatic ring;
  • n 1, 2, 3, or 4;
  • each R 3 is independently selected from halo, cyano, hydroxy, nitro, -N(R d ) 2 , carboxy, phenyl, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C2-C 6 )alkynyl, (C 3 -C )cycloalkyl, (C C 6 )alkoxy, (C,- C 6 )alkanoyl, (Ci-C 6 )alkoxycarbonyl, and (C 2 -C6)alkanoyloxy, wherein any phenyl, (Q- C 6 )alkyl, (C 2 -C 6 )alkenyl, (C2-C f i)alkynyl, (CrC 6 )alkoxy, and (C 3 -C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(
  • each R a is independently selected from the group consisting of H, (Ci-Cejalkyl, (C 2 - Q)alkenyl, (C2-C 6 )alkynyl, (C 3 -C6)cycloalkyl, (Ci-C 6 )alkanoyl, and (CrCeJalkoxycarbonyl, wherein any (C
  • each R b is independently selected from the group consisting of H, (Ci-C6)alkyl, (C 2 - C6)alkenyl, (C2-C 6 )alkynyl, (C3-C 6 )cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C 6 )alkoxycarbonyl, wherein any (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C3-C 6 )cycloalkyl, (Q- C 6 )alkanoyL and (Ci-C6)alkoxycarbanyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (Ci-C 6 )alkoxy; or two R taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, pipe
  • each R c is independently selected from the group consisting of H, (C 1 -C6)alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C3-C6)cycloalkyl, (Ci-C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyI.
  • any (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C,- C 6 )alkanoyl, and (C]-C 6 )alkoxycarbonyl is optionally substituted with one or more groups independently selected from halo, (C3-C 6 )cycloalkyl, and (Ci-C 6 )alkoxy; or two R c taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
  • each R d is independently selected from the group consisting of H, (CrC 6 )alkyl, (C 2 - C6)alkenyl, (C 2 -C )alkynyl, (C3-C 6 )cyc]oalkyl, (Ci-C6)alkanoyl, and
  • the compound of formula (I) is a compound of formula (la):
  • X is S, 0, N-H, or N-Me
  • HET is selected from the group consisting of:
  • HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(R a ) 2 , carboxy, phenyl, (C
  • R is selected from the group consisting of H, phenyl, (Ci-C 6 )alkyl, (C2-C 6 )alkenyl, (C2-C6)alkynyl, and (C3-C 6 )cycloalkyl, wherein any phenyl, (Ci-C 6 )alkyl, (C2-C 6 )alkenyl, (C 2 -C 6 )alkynyl, and (C 3 -C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(R b ) 2 , (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, and (C 2 - C 6 )alkanoyloxy;
  • n 0, 1 , 2, 3, or 4;
  • each R- 1 is independently selected from halo, cyano, hydroxy, nitro, -N(R C ) 2 , carboxy, phenyl, (C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (Ci-C 6 )aikoxy, (C,- C6)alkanoyl, (Ci-C 6 )alkoxycarbonyl, and (C 2 -C 6 )alkanoyloxy, wherein any phenyl, (Cj- C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, and (C3-C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy,
  • each R a is independently selected from the group consisting of H, (Ci-C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C6)cycloalkyl, (Ci-C 6 )alkanoyl, and (Ci- alkoxycarbonyl, wherein any (C,-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C )alkynyl, (C 3 -C 6 )cycloalkyl, (C
  • each R b is independently selected from the group consisting of H, (Ci-C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (Ci-C6)alkanoyl, and (C 1 -C 6 )alkoxycarbonyl, wherein any (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (CB-C ⁇ cycloalkyl, (Q- C 6 )alkanoyl, and (Ci -C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C 3 -C 6 )cycloalkyl, and (Ci-C 6 )alkoxy; or two R b taken together with the nitrogen to which they are attached form a azetidino
  • each R c is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C ! -C 6 )alkanoyl, and (Ci-C f i)alkoxycarbonyl, wherein any (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C
  • C 6 )alkanoyl, and (CrC ⁇ alkoxycarbonyl is optionally substituted with one or more groups independently selected from halo, (C3-C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy; or two R c taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring.
  • HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(R a ) 2 , carboxy, phenyl, (Ci-C 6 )alkyl, (C 2 -C(,)alkenyl, (C 2 - C 6 )alkynyl, (C3-C6)cycloalkyl, (Ci-C 6 )alkoxy, (Ci-C6)alkanoyl, (Ci-C 6 )alkoxycarbonyl, and (C 2 -C 6 )alkanoyloxy, wherein any phenyl, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C2-C 6 )alkynyl, and (C3-C 6 )cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(R a
  • HET is optionally substituted with one or more groups independently selected from (Ci-C 6 )alkyl and -N(R a ) 2 .
  • each R 2 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, rt-butyl, allyl, cyclopropyl, phenyl, benzyl, CH 2 CH 2 OCH3, and
  • each R 2 is selected from the group consisting of methyl, ethyl, isopropyl, and fert-butyl.
  • ZMC1 Zn -binding homolog
  • A6 structural homolog
  • NTA binds Zn 2+ with an affinity similar to that of ZMC1, but it cannot cross either liposomal or cellular membranes, likely because it possesses negative charges.
  • Zn + -binding proteins from the serum e.g. albumin
  • A6 therefore likely does not increase intracellular [Zn 2+ ]free in culture because ⁇ J,A6 is greater than extracellular [Zn 2+ ] free -
  • both an appropriate Zn 2+ K and ionophore activity influence ZMCl activity.
  • [Zn 2+ ] free gradient was reversed by adding a large excess of metal ion chelator EDTA to the solution outside of the liposomes; fluorescence was monitored in the presence and absence of ZMCl .
  • EDTA alone did not cause a significant decrease in RZ-3 fluorescence as the liposomal membranes are impermeable to EDTA.
  • ZMCl There was a time dependent decrease in RZ-3 fluorescence. This result indicates that free ZMCl crossed the liposomal membranes, bound internal Zn " , and transported it back outside the liposome where the metal was then bound by the much stronger chelator EDTA.
  • ZMC 1 can cross biological membranes both as free drug and drug-Zn 2+ complex
  • a liposomal leakage assay was performed using the self-quenching fluorophore calcein.
  • calcein When calcein is encapsulated at concentrations above 4 mM its fluorescence is decreased via self-quenching. Leakage is detected by a fluorescence increase as the dye dilutes and its fluorescence dequenches. At the highest concentrations of ZMCl and ZnCl 2 a significant fluorescence increase was not detected. Disruption of liposomes can also be detected by alteration of their size distribution.
  • ZMCl- mediated Zn 2+ transport was quantified in cells.
  • the kinetics of intracellular [Zn 2+ ] freL was quantified.
  • FZ3-AM, RZ-3 (K + salt), and cell culture media were purchased from Life
  • DOPC was purchased from Avanti Polar Lipids. ZMCI and A6 were similarly obtained. Zn (ZMC1) 2 was synthesized and crystallized.
  • HEK293 and TOV 112D cells were purchased from ATCC and maintained in DMEM + GlutaMAX with 10% FBS and I mg/mL penicillin-streptomycin under a 5% C0 2 atmosphere at 37 °C. All non-cell based experiments were conducted in 50 niM Tris pH 7.2, 0.1 M NaCl at 25 °C.
  • Initial Zn 2+ import export was quantified by fitting the first 10-30 s of data after each treatment to a line and converted to units of flux using the following Eqn 1 :
  • Jj is the initial flux
  • a F7 ⁇ t is the slope of the fit line
  • F raax is RZ-3 fluorescence in the presence of saturating Zn and 1% TritonX-100
  • F m i n is RZ-3 fluorescence in the presence of excess EDTA and 1% TritonX-100
  • [RZ3] is the concentration of encapsulated RZ-3
  • SA Vol is the surface area to volume ratio calculated assuming hollow spheres of the mean diameter determined by DLS.
  • Hoechst 33342 For nuclear colocalization, 1 u g/mL Hoechst 33342 was also included. Cells were imaged using a Zeiss LSM510 META NLO confocal microscope equipped with 37 °C environmental control chamber. FZ3 and Hoechst 33342 were excited at 488 nm (argon laser) and 790 nm
  • F, F max , and F m izie are fluorescence in the treatment, PYR/ZnCl 2 , and TPEN images, respectively, and K d is that of FZ3 for Zn 2+ (15 nM) (31).
  • K d is that of FZ3 for Zn 2+ (15 nM) (31).
  • the number of cells analyzed in each trial ranged from 54-163.
  • treated, PYR ZnCl 2 , and TPEN treated images costained with Hoechst 33342 were aligned and each pixel subjected to Eqn. 2 in MATLAB (Math Works).
  • the resultant images were Gaussian mean filtered and false- colored by calculated [Zn 2+ ] f y eE .
  • DMEM + 10% FBS was treated with 5 g Chelex 100 resin per 100 mL media for 1 hour with gentle shaking. The media was then decanted and filtered through 0.2 ⁇ m sterile filter. TOVl 12D cells were then incubated with 1 ⁇ M ZMC1 in untreated media, Chelex- treated media, or media + 10 n TPEN at 37 °C for 2 h, fixed, and stained with PAB240 and PAB1640.
  • Thiazolyl and benzothiazolyl hyrdrazones derived from a-(N)-acetylpyridines and diazines synthesis, antiproliferative activity and CoMFA studies. European Journal of Medicinal Chemistry 32, 397-408; Easmon, J., Purstinger, G., Thies, K. S. ⁇ Heinisch, G., and Hofmann, J. (2006) Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from alpha-(N)-acyl heteroaromatics.
  • 6-(2-methoxyethoxy)benzo[i ]thiazol-2-amine 120 mg, .54 mmol, 1 eq was added to a solution of hydrazine hydrate (156 ul, 1.87 mmol, 3.5eq) and cone. HCl (156 ul, 3.21 mmol, 6 eq) in ethylene glycol (3ml) and heated overnight at 130°C. The reaction was partitioned in DCM/water, extracted 3 x DCM, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-hydrazinyl- 6-(2-methoxyethoxy)benzo[i/]thiazole (78 mg, 61% yield) as a brown solid.
  • tert-butyl 2-((2-(l-methoxyvinyl)pyridin-4-yl)oxy)acetate (230mg, 0.824 mmol, 1 eq) was dissolved in DCM (10ml). To this solution was added HCl/ether (2M, 2 ml). The reaction was stirred 3 hours at RT and concentrated under reduced pressure. rt-Butyl 2- ((2-acetylpyridin-4-yl)oxy)acetate (110 mg, 53% yield) was isolated as a white solid after purification by silica gel chromatography. Method O.
  • 5-f uoropicolinonitrile (500mg, 4.09mmol, 1 eq) was taken up in a solution of dimethylamine (40% in water, 4 ml) and heated overnight at 100°C in sealed reaction vial. The reaction was then concentrated to dryness under reduced pressure and purified by silica gel chromatography (25% -> 50% EtOAc/Hex) to afford 5-(dimethylamino)picolinonitrile (336 mg, 56% yield) as a white solid.
  • the compounds of Examples 8-43 were prepared using the methods identified below.
  • the structures, names, NMR data and mass spectral data for the compounds of Examples 8- 43 are shown in Table 1.

Landscapes

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

Abstract

The invention provides compounds of formula (I): and salts thereof, wherein ring A, R2, HET, X, n, and R3 have any of the meanings described in the specification, as well as compositions comprising such compounds and salts, and methods for treating cancer using such compounds and salts.

Description

HYDRAZNE DERIVATIVES FOR THE TREATMENT OF CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS
This patent application claims the benefit of priority of U.S. application serial No. 62/108,415, filed January 27, 2015, and of U.S. application serial No. 62/258,256, filed November 20, 2015, which applications are herein incorporated by reference.
BACKGROUND
TP53 is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists. The majority of TP53 mutations (>70%) are mis-sense mutations that generate a defective protein that is generally found at high levels in cancer cells due to loss of MDM2 negative feedback. Restoring the function of p53 in mouse models of cancer is highly therapeutic. Reactivating mutant p53 using small molecules has been highly sought after, yet remains an elusive goal in the development of cancer therapeutics.
SUMMARY
The invention provides novel compounds, compositions, and methods for treating cancer. More specifically, one aspect of the present invention provides a compound of formula (1):
Figure imgf000002_0001
or a salt thereof, wherein:
the ring A is a fused benzo or heteroaryl ring;
X is S, O, -CH-CH-, or N-Ra;
HET is selected from the group consisting of:
Figure imgf000002_0002
Figure imgf000003_0001
wherein HET is optionally substituted with one or more groups R independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (C C6)alkoxy, (C C6)alkanoyl, (Ci-C )alkoxycarbonyl, (C2- C6)alkanoyloxy,
Figure imgf000003_0002
wherein any phenyl, (Ci-C6)alkyl, (Ci-C6)alkoxy, (C?-C6)alkenyl, (C2-C6)alkynyl, and (C3- C6)cycIoalkyl, is optionally substituted with one or more groups independently selected from halo, azido, cyano, hydroxy, nitro, -N(Rb)2, carboxy, (C3-C{,)cycloalkyl, (CrQJalkanoyl, (Ci-C6)alkoxycarbonyl. (C2-C6)alkanoyloxy, and (C]-C6)alkoxy that is optionally substituted with carboxy;
each R is independently selected from the group consisting of H, phenyl, (C |- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (C\~ C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(RC)2, (C3-C6)cycloalkyl, (Ci- C6)alkoxy, and (C2-C6)alkanoyloxy;
n is 0, 1, 2, 3, or 4;
each R3 is independently selected from halo, cyano, hydroxy, nitro, -N(Rd)2, carboxy, phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci -C6)alkoxy, (C C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Cr C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (C C^alkanoyl,
(C1-C6)alkoxycarbonyL and (C2-C6)alkanoyloxy; Ra is selected from the group consisting of H, (C i-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci -C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, -N(Rg)2, morpholino, and (C1-C6)alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rb is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- Cgjalkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C|-C6)alkanoyl, and (Ci-C^alkoxycarbonyl, wherein any (CL-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C,- C6)alkanoyl, and (C1-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, heteroaryl, and (Q-Ce^lkoxy; or two Rb taken together with the nitrogen to which they are attached form an azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rc is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C )alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloaIkyl, and (C1-C6)alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rd is independently selected from the group consisting of H, (C C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C i- C6)alkanoyl, and (C i-C(j)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rd taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
Re is independently selected from the group consisting of H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo, (C3- C6)cycloalkyl, -N(Rf)2, and (C C6)alkoxy;
each Rr is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C]-C6)alkanoyl, and (d-C^alkoxycarbonyl, wherein any (d-Ceialkyl, (C2-C,j)a]kenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C]- C6)alkanoyl5 and (Q-Cejalkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyI, and (CrC6)alkoxy; or two R taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rg is independently selected from the group consisting of H, (Ci-C )alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyI, and (Cj-C6)alkoxycarbonyl, wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (C i-C6)alkoxy; or two R8 taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
wherein if HET is not substituted with one or more (e.g. 1 , 2, 3, or 4) groups R1, then R is not H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl.
Another aspect of the present invention provides a pharmaceutical composition, comprising, a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Another aspect of the present invention provides a method of inhibiting cancer cell growth, comprising contacting the cancer cell with an effective amount of a compound of formula 1 or a salt thereof.
Another aspect of the present invention provides a method of treating cancer in an animal (e.g. a human), comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof.
The invention further includes methods of preparing, methods of separating, and methods of purifying the compounds described herein.
Additional advantages and novel features of this invention shall be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following specification, or may be learned by the practice of the invention. The advantages of the invention may be realized and attained by means of the
instrumentalities, combinations, compositions, and methods particularly pointed out in the appended claims. BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates the three day cell growth inhibition assays comparing compounds 1 and 2 tested against three human tumor cell lines, TOV 112D (p53-Rl 75H), H460 (p53- WT), and HI 299 (p53-null).
Figure 2 shows PAB1620 antibody recognition of wildtype conformation after treatment of mutant p53 with compounds 1 and 2.
DETAILED DESCRIPTION
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
The term allyl as used herein refers to a substituent, molecular fragment, or radical having the chemical formula -CH2-CH=CH2.
The term "benzyl" as used herein refers to a substituent, molecular fragment, or radical having the chemical formula -CH2C6H5.
The term "butyl" as used herein refers to a four-carbon alkyl radical, substituent, or molecular fragment having the chemical formula -C4H9.
The term "cyclopropyl" as used herein refers to a radical, substituent, or molecular fragment having a chemical structure derived from cyclopropane and having the chemical formula C3H5.
The term "ethyl" as used herein refers to an alkyl substituent, radical, or molecular fragment having the chemical formula -C2HS
The term "isopropyl" as used herein refers to a propyl with a group attached to the secondary carbon.
The term "methyl" as used herein refers to an alkyl derived from methane and containing one carbon atom bonded to three hydrogen atoms and having the chemical formula -CH3.
The term "propyl" as used herein refers to a linear three-carbon alkyl substituent, molecular fragment, or radical having the chemical formula -C3H7.
The term "phenyl" refers to a cyclic group of atoms, radical, substituent, or molecular fragment having the chemical formula -C6H5.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.
Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Specifically, (C[-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 ,-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2- C6)alkynyl can be ethynyl, 1 -propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (CrC6)alkanoyl can be acetyl, propanoyl or butanoyl; (Ci-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; and (C2-C6)aikanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy.
In one embodiment of the invention, when HET is optionally substituted 2-pyridinyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyridazinyl, 2-quinolinyl, 2-isoquinolinyl, 3- isoquinolinyl, then R1 is not CH3, OCH3, OH, CI, Br, F, CF3, N02, NH2, NHCOCH3, N(CH3) 2, Phenyl, CN, C=NH(NH2), C-NH(NHOH), COOH, or COO-alkyl.
In one embodiment the compound of formula (I) is a compound of formula (la):
Figure imgf000008_0001
or a salt thereof, wherein:
X is S, O, N-H, or N-Ra;
HET is selected from the group consisting of:
Figure imgf000008_0002
wherein HET is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups R1 independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (Ci- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (C,-C6)alkanoyl, (Ci-C6)alkoxycarbonyl, (C2-C6)alkanoyloxy, and
Figure imgf000009_0001
wherein any phenyl, (Ci-C6)alkyl, (Ci-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3- C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Rb)2, carboxy, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (Cr
C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
R2 is selected from the group consisting of H, phenyl. (C i-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(RC)2, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, and (C2- C6)alkanoyloxy;
n is 1 , 2, 3, or 4;
each R3 is independently selected from halo, cyano, hydroxy, nitro, -N(Rd)2, carboxy, phenyl, (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (Cr C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (C\- Cejalkyl, (C2-C6)alkenyl, (C2-C )alkynyl, (C| -C6)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (Ci-C6)alkanoyl,
(Ci -C6)alkoxycarbonyl, and {C2-C6)alkanoyloxy;
Ra is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, and (Ci-Ce)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C i-C6)alkanoyl, and (C |-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidino, pyrrolidine, piperidino, or morpholino ring;
each Rb is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl; (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C| - C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, heteroaryl, and (Ci-C6)alkoxy; or two Rb taken together with the nitrogen to which they are attached form an azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rc is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alk nyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (C1-C6)alkoxycarbonylJ wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C{- Cfi)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (CrC6)alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rd is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Cr
C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl5 and (C1-C6)alkoxy; or two Rd taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
Re is independently selected from the group consisting of H and (C C6)alkyl that is optionally substituted with one or more groups independently selected from halo, (C3- C6)cycloalkyl, -N(Rf)2, and (Ci-C6)alkoxy; and
each R f is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (C C6)alkoxy; or two Rf taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
wherein if HET is not substituted with one or more (e.g. 1 , 2, 3, or 4) groups Rl, then R2 is not H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl. In one embodiment HET is selected from the group consisting of:
Figure imgf000011_0001
wherein HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(R )2, carboxy, phenyl, (C|-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyi, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (Ci-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, (C3-C6)cycloalkyl, (Ci-C6)aIkoxy, (Ci- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
R is selected from the group consisting of H, phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(Rb)2, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, and (C2- C6)alkanoyloxy;
1 2
or R and R taken together with the carbon to which they are attached form a bicyclic 9- or 10-membered nitrogen ring system comprising 1, 2, 3, or 4 nitrogen atoms and at least one aromatic ring;
n is 1, 2, 3, or 4;
each R3 is independently selected from halo, cyano, hydroxy, nitro, -N(Rd)2, carboxy, phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C )cycloalkyl, (C C6)alkoxy, (C,- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Q- C6)alkyl, (C2-C6)alkenyl, (C2-Cfi)alkynyl, (CrC6)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, (C3-C6)cycloalkyl, (CrC6)alkoxy, (d-C6)alkanoyl,
(CrC6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
each Ra is independently selected from the group consisting of H, (Ci-Cejalkyl, (C2- Q)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (CrCeJalkoxycarbonyl, wherein any (C|-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci- C6)alkanoyl, and (C|-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rb is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Q- C6)alkanoyL and (Ci-C6)alkoxycarbanyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two R taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring.
each Rc is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (C1-C6)alkoxycarbonyI. wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C,- C6)alkanoyl, and (C]-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rd is independently selected from the group consisting of H, (CrC6)alkyl, (C2- C6)alkenyl, (C2-C )alkynyl, (C3-C6)cyc]oalkyl, (Ci-C6)alkanoyl, and
Figure imgf000012_0001
wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyI, (Ci- C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C )cycloalkyl, and (Ci-C6)alkoxy; or two Rd taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring. In one embodiment the compound of formula (I) is a compound of formula (la):
Figure imgf000013_0001
or a salt thereof, wherein:
X is S, 0, N-H, or N-Me;
HET is selected from the group consisting of:
Figure imgf000013_0002
wherein HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (C| -C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (Ci-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (C]-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyI, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2j carboxy, (C3-C6)cycloalkyl, (Q-Cejalkoxy, (C - C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
R is selected from the group consisting of H, phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(Rb)2, (C3-C6)cycloalkyl, (C1-C6)alkoxy, and (C2- C6)alkanoyloxy;
n is 0, 1 , 2, 3, or 4;
each R-1 is independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, phenyl, (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)aikoxy, (C,- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Cj- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, (C3-C6)cycloa]kyl, (C C6) lkoxy, (C1-C6)alkanoyl,
(C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
each Ra is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci- alkoxycarbonyl, wherein any (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C )alkynyl, (C3-C6)cycloalkyl, (C |- C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (C|-C6)alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rb is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (C1-C6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CB-C^cycloalkyl, (Q- C6)alkanoyl, and (Ci -C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rb taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rc is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C!-C6)alkanoyl, and (Ci-Cfi)alkoxycarbonyl, wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C6)alkanoyl, and (CrC^alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (C1-C6)alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring.
In one embodiment each HET is independently selected from the rou consisting of:
Figure imgf000014_0001
wherein HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (Ci-C6)alkyl, (C2-C(,)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (Ci-C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, (C3-Cf,)cycloalkyl, (C i-C6)alkoxy, (Cr C6)alkanoyl. (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy.
In one embodiment each HET is independently selected from the group consisting of:
Figure imgf000015_0001
wherein HET is optionally substituted with one or more groups independently selected from (Ci-C6)alkyl and -N(Ra)2.
In one embodiment each R2 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, rt-butyl, allyl, cyclopropyl, phenyl, benzyl, CH2CH2OCH3, and
Figure imgf000015_0002
In one embodiment each R2 is selected from the group consisting of methyl, ethyl, isopropyl, and fert-butyl.
In one embodiment the compound is selected from the group consisting of:
Figure imgf000015_0003
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000017_0002
and salts thereof.
In one embodiment the invention provides a compound selected from the group consisting of:
Figure imgf000018_0001
embodiment the compound is selected from the group consisting of:
Figure imgf000018_0002
Figure imgf000019_0001

Figure imgf000020_0001
and sails thereof.
The ability of ZMC1 , NTA (Zn -binding homolog), and A6 (structural homolog) to increase intracellular [Zn2+]free was evaluated by treating cells with the fluorescent Zn2+ indicator FluoZin-3-AM (FZ3-AM) in complete media and imaging them using confocal microscopy. In both HEK293 (non-cancer, p53-WT) and TOVl ί 2D (ovarian cancer, p53- R175H) cells, ZMC1 increased intracellular [Zn2+]free as indicated by increased fluorescence, but NTA and A6 did not. This result is consistent with the metaHochaperone (MC) model for ZMC1 function and explains the inability of NTA and A6 to reactivate p53-R175H at micromolar concentrations.
Of the two control compounds, A6 shuttled Zn2+ into the liposomes, but NTA did not.
Figure imgf000020_0002
ZMC1 A6 NTA
NTA binds Zn2+ with an affinity similar to that of ZMC1, but it cannot cross either liposomal or cellular membranes, likely because it possesses negative charges. A6, on the other hand, lacks charges and is similar in structure to ZMC1, but binds Zn2+ weakly ( d = 1.1 μΜ). It can function as an ionophore in conditions of the liposome experiments where external [Zn +]free was 10 μΜ. However, in complete media containing 10% fetal bovine serum (FBS), Zn +-binding proteins from the serum (e.g. albumin) necessarily compete for Zn + with any putative MC, making the effective [Zn +]free much lower than [Zn2+]tota| . A6 therefore likely does not increase intracellular [Zn2+]free in culture because <J,A6 is greater than extracellular [Zn2+]free- Thus, both an appropriate Zn2+ K and ionophore activity influence ZMCl activity.
To determine whether ZMCl can traverse lipid bilayers as a free compound, the
[Zn2+]free gradient was reversed by adding a large excess of metal ion chelator EDTA to the solution outside of the liposomes; fluorescence was monitored in the presence and absence of ZMCl . EDTA alone did not cause a significant decrease in RZ-3 fluorescence as the liposomal membranes are impermeable to EDTA. After subsequent addition of ZMCl, there was a time dependent decrease in RZ-3 fluorescence. This result indicates that free ZMCl crossed the liposomal membranes, bound internal Zn" , and transported it back outside the liposome where the metal was then bound by the much stronger chelator EDTA. Thus, ZMC 1 can cross biological membranes both as free drug and drug-Zn2+ complex, and
2+
therefore can transport Zn into cells without becoming trapped as either species.
To ensure that the fluorescence results were due to Zn2+ transport and not to nonspecific disruption of liposomal membranes, a liposomal leakage assay was performed using the self-quenching fluorophore calcein. When calcein is encapsulated at concentrations above 4 mM its fluorescence is decreased via self-quenching. Leakage is detected by a fluorescence increase as the dye dilutes and its fluorescence dequenches. At the highest concentrations of ZMCl and ZnCl2 a significant fluorescence increase was not detected. Disruption of liposomes can also be detected by alteration of their size distribution. The size distribution of liposomes treated with the highest concentrations of ZnCl2 and ZMCl was identical to that of untreated liposomes. Together, these data indicate the liposomal membranes remained intact upon ZMCl treatment, and therefore the RZ-3 fluorescence changes are attributable only to specific Zn2+ transport.
Characterization of ZMCl-mediated Zn2+ transport in live cells
To extend the investigation of ZMCl as an ionophore to living systems, ZMCl- mediated Zn2+ transport was quantified in cells. The kinetics of intracellular [Zn2+]freL.
increase was measured by loading HE 293 and TOV112D cells with FZ3-AM, treating the cells with ZMCl and ZnCl2, and monitoring fluorescence by time-lapse microscopy. To minimize the potential for Zn2+ contamination and contributions from poorly defined elements in complete media (e.g. FBS), cells were treated and imaged in Ca2+ and Mg2+-free Earle's Balanced Salt Solution supplemented with 10 mM HEPES pH 7.4 (EBSS/H
(-)Ca/Mg). Excess ZnCl2 with the Zn ionophore pyrithione (PYR) was used as a positive control. Excess membrane-permeable Zn2 chelator N,N,N',N'-tetrakis(2- pyridylmethyl)ethane-l ,2-diamine (TP EN) was used as a negative control. When treated with ZnCi2 alone or ZMC1 alone, neither cell type showed an increase in intracellular
[Zn2+]free. When treated with both ZMC1 and ZnCl , both cell lines showed a time dependent increase at two different ZnCl2 concentrations, demonstrating that both ZMC1 and extracellular Zn are required. When the fluorescence increases were fit to first-order exponentials, both concentrations of ZnCl2 yielded identical half-lives in their respective cell types, which we combine to report t1 2 (HEK293) = 124 ± 20 s and lm (TOV112D) = 156 ± 50 s (mean ± SD, n=4).
The steady-state intracellular [Zn2+]free of both cell types was then quantified after treatment with the 2:1 ratio of ZMC1 :ZnCl2. Cells were again loaded with FZ3-AM, treated with 1 μΜ ZMCi and 0.5 μΜ ZnCl2 in EBSS/H (-)Ca/Mg, and imaged as above. To normalize for differential dye loading, cells were then sequentially treated with excess PYR/ZnCI2, imaged, treated with TPEN, and imaged again. PYR/ZnCl2 and TPEN served to saturate and apoize the intracellular FZ3, respectively. In the absence of drug an
intracellular [Zn2+]{Ke of 0.69 ± 0.25 nM was measured for IIEK293 cells and 0.71 ± 0.19 nM was measured for TOV 1 12D cells. These values reflect the lower limit of detection by FZ3- AM and are likely overestimates. Upon treatment with ZMCI and ZnCl2 intracellular
[Zn2+]iree rose to 18.1 ± 4.7 nM for HE 293 cells and 15.8 ± 2.5 nM for TOV 112D cells. These concentrations are theoretically sufficient to reactivate -90 % of p53-R175H based on the Kdi value of 2.1 nM measured for DBD-R175H.
MATERIALS AND METHODS
Reagents
FZ3-AM, RZ-3 (K+ salt), and cell culture media were purchased from Life
Technologies. DOPC was purchased from Avanti Polar Lipids. ZMCI and A6 were similarly obtained. Zn (ZMC1)2 was synthesized and crystallized. HEK293 and TOV 112D cells were purchased from ATCC and maintained in DMEM + GlutaMAX with 10% FBS and I mg/mL penicillin-streptomycin under a 5% C02 atmosphere at 37 °C. All non-cell based experiments were conducted in 50 niM Tris pH 7.2, 0.1 M NaCl at 25 °C.
Liposome Import Assay
DOPC -liposomes were prepared by film rehydration and extrusion followed by gel filtration and diluted to an OD500 = 0.06 in buffer. The size distribution of the liposomes was determined by dynamic light scattering (DLS) using a Malvern Zetasizer Nano ZS. Fluorescence measurements were taken on a Horiba Fluoromax-4 spectrofluorimeter in a 5 x 5 mm quartz cuvette with λ ex/ λ cm = 550/572 nra for RZ-3 and 490/515 nm for calcein. Initial Zn2+ import export was quantified by fitting the first 10-30 s of data after each treatment to a line and converted to units of flux using the following Eqn 1 :
Eqn 1 :
Figure imgf000023_0001
where Jj is the initial flux, A F7 Δ t is the slope of the fit line, Fraax is RZ-3 fluorescence in the presence of saturating Zn and 1% TritonX-100, Fmin is RZ-3 fluorescence in the presence of excess EDTA and 1% TritonX-100, [RZ3] is the concentration of encapsulated RZ-3, and SA Vol is the surface area to volume ratio calculated assuming hollow spheres of the mean diameter determined by DLS.
Intracellular [Zn2+]free Imaging
TO VI 12D or HEK293 cells (40,000 cells/well) were plated on either 8-well BD Falcon chambered culture slides (Coming Life Sciences) or 8-chambered #1.5 Nunc Lab-Tek II chambered coverglasses (Thermo Scientific) treated with poly-L-lysine. After 48 h, cells were washed 2 x 5 m in serum-free media and incubated with 1 μ M FZ3-AM for 40 m at 37 °C. Cells were then washed 2 x 5 m in either EBSS/H (-)Ca/Mg or phenol-red free DMEM + 10% FBS containing the indicated treatments for 20 m before imaging. For nuclear colocalization, 1 u g/mL Hoechst 33342 was also included. Cells were imaged using a Zeiss LSM510 META NLO confocal microscope equipped with 37 °C environmental control chamber. FZ3 and Hoechst 33342 were excited at 488 nm (argon laser) and 790 nm
(Chameleon Ti:sapphire laser), respectively. To determine the kinetics of fluorescence change, each background -subtracted image in the time-lapse series was integrated in ImageJ and normalized to the integrated fluorescence of the first frame after treatment. For quantification of intracellular [Zn +]free, each cell was analyzed in the treated, 50 u M
PYR/ZnCl2 (1 : 1 ), and 100 μ M TPEN images by taking the mean fluorescence of an ROI inside the cell subtracted by an ROI immediately outside the cell measured in ImageJ. The [Zn2+]free for each cell was then calculated by Eqn 2:
Eqn. 2: π∞χ -
Where F, Fmax, and Fmi„ are fluorescence in the treatment, PYR/ZnCl2, and TPEN images, respectively, and Kd is that of FZ3 for Zn2+ (15 nM) (31). To minimize the effects of outliers the lowest and highest 5% of cells in each series were rejected, and the remaining values averaged to give the value from that experiment. The number of cells analyzed in each trial ranged from 54-163. For nuclear colocalization, treated, PYR ZnCl2, and TPEN treated images costained with Hoechst 33342 were aligned and each pixel subjected to Eqn. 2 in MATLAB (Math Works). The resultant images were Gaussian mean filtered and false- colored by calculated [Zn2+]fyeE.
p53-R175H Immunofluorescence
DMEM + 10% FBS was treated with 5 g Chelex 100 resin per 100 mL media for 1 hour with gentle shaking. The media was then decanted and filtered through 0.2 μ m sterile filter. TOVl 12D cells were then incubated with 1 μ M ZMC1 in untreated media, Chelex- treated media, or media + 10 n TPEN at 37 °C for 2 h, fixed, and stained with PAB240 and PAB1640.
Assays:
Cell growth inhibition assay using human tumor cell lines with different p53 status (wildtype, null, p53-R175H) were employed to determine if wildtype structure is restored to mutant p53 after treatment with a zinc metallochaperone. Compounds 1 and 2 shown in Figure 1 selectively killed the p53-R175H tumor cell line (TOVl 12D) while leaving the p53 wildtype (H460) and p53 null (H1299) cell lines undisturbed.
An immunofluorescence assay using conformation specific antibodies was used to determine if a test compound could induce a wildtype conformation of mutant p53.
The invention will now be illustrated by the following non-limiting Examples.
Examples
Chemistry: General Method for the synthesis of monomers.
A general synthetic approach to the preparation of molecules with structural features that contribute to optimal zinc binding d, potency, and efficacy in the TOV1 12D cell line is shown in Scheme 1. The chemistry shown in Scheme 1 may also be used to make the corresponding benzoxazole or N-methylbenzimidazole-substituted target as well. (Easmon, J., Heinisch G., Hofman, J., Langer, T., Gunicke, HH., Fink, J., Purstinger G. (1997)
Thiazolyl and benzothiazolyl hyrdrazones derived from a-(N)-acetylpyridines and diazines: synthesis, antiproliferative activity and CoMFA studies. European Journal of Medicinal Chemistry 32, 397-408; Easmon, J., Purstinger, G., Thies, K. S.} Heinisch, G., and Hofmann, J. (2006) Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from alpha-(N)-acyl heteroaromatics. Journal of Medicinal Chemistry 49, 6343-6350; Purstinger, G., Heinisch, G., Easmon, J., Hofmann, J., Heinz-Herbert, F. (2002) Heterocyclic Hydrazones for Use as Anti-cancer agents. (Office, C. I. P. ed.)
Scheme 1
Figure imgf000025_0001
substitute ¾ correspor¾fii¾ substitute with corres onding enzoxaMie & N-methylbemifiidaMie benzoxazole or i-meibyi- ben&mioa ete
a. NH2NH2, EtOH b. Rs acetylpyridine, cat. AcOH, EtOH or MeCN
Exa -2-(2-(l-(pyridin-2-yl)ethylidene)hydrazinyl)benzo[iilthiazo]e
Figure imgf000025_0002
2-Acetylpyridine (2.00 g, 16.5 mmol, 1 equiv.) was dissolved in DCM (50 mL) and stirred at ambient temperature. 2-Hydrazinylbenzo[-i]thiazole (2.73 g, 16.5 mmol, 1 equiv.) was added in a single portion. Acetic acid (catalytic, 4 drops) and MeOH (3 mL) were added and the reaction mixture stirred at ambient temperature overnight. The reaction was concentrated to dryness and the resulting residue was recrystallized from MeOH to give (£)- 2-(2-(l -(pyridin-2-yl)ethylidene)hydrazinyl)benzo[i ]thiazole (0.520 g, 1 .94 mmol, 12% yield) as a white solid. Ή-NMR (400 MHz, CDC13) δ 2.44 (s, 3H), 7.19 (dt, J = 7.2 Hz, 1.01 Hz, 1 H), 7.26 (m, 1H), 7.36 (dt, J = 7.2 Hz, 1.01 Hz, 1H), 7.62 (d, J = 7.96 Hz, 1H). 7.71 (d, J = 7.08 Hz, 1H), 7.74 (dt, J = 7.76 Hz, 1.76 Hz, 1 H), 8.18 (d, J = 8.12 Hz, 1H), 8.60 (br. d, J = 4.32 Hz, 1H), 9.14 (br. s, 1 H, NH). MS: 269.0 [M + H]+.
Example 2
Figure imgf000026_0001
(E)-2-(2-(l-(pyridin-2-yl)ethylidene)hydrazinyl)benzo[d]oxazole (2): Following Method A for the condensation of 2 ydrazinylbenzo[cr]oxazole and l -(pyridin-2-yl)ethan-l-one the title compound 2 was isolated as a white solid after recrystallization from MeOH. Ή-NMR (400 MHz, CDCI3) 5 2.48 (s, 3H), 7.16 (br. t, J = 7.28 Hz, 1H). 7.28 (m, 2H), 7.44 (br. d, J = 7.28 Hz, 1 H), 7.51 (br. d, J = 7.04 Hz), 7.73 (t, J = 7.40 Hz, 1 H), 8.27 (br. d, J = 7.28 Hz, 1 H), 8.60, (d, J = 4.72 Hz, 1 H), 8.85 (br. s, 1H„ NH). MS: 253.1 [M + Hf.
Example 3
Figure imgf000026_0002
(E)-2-(2-(6,7-dihydroquinolin-8(5H)-ylidene)hydrazinyl)benzold]thiazole (3): Following Method A for the condensation of 2-hydrazinylbenzo[i/|thiazole and 6,7-dihydroquinolin-8{5H)-one the title compound 3 was isolated as a white solid after recrystallization from MeOH. 'H-NMR (400 MHz, CDC1. δ 1.98 (m, 2H), 2.72 (br. t, J = 6.48 Hz, 2H), 2.81 (br. t, J = 5.88 Hz, 2H), 7.18 (m, 2H), 7.34 (t, J = 7.40 Hz, 1H), 7.47 (d, J = 7.44 Hz, 1H), 7.59 (d, J = 7.92 Hz, 1H), 7.70 (d, J = 7.72 Hz, 1H), 8.65 (d, J = 3.92 Hz, 1H), 9.37 (br. s, 1 H, NH). MS: 295.0 [M + H]+.
Example 4
Figure imgf000026_0003
(E)-2-(2-(6,7-dihydroquinoIin-8(5H)-ylidene)hydrazioyl)benzo[d]oxazole (4): Following Method A for the condensation of 2-hydrazinylbenzo[i/]oxazole and 6,7-dihydroquinolin-8(5//)-one the title compound 4 was isolated as a white solid after recrystallization from MeOH. Ή-NMR (400 MHz, CDC ) δ 2.02 (m, 2H), 2.88 (t, J = 6.00 Hz, 2H), 3.00 (br. t, J = 5.64 Hz, 2H), 7.09 (m, 1H), 7.19 (m, 2H), 7.3 1 (m, 2H), 7.61 (d, J = 7.60 Hz, 1 H), 8.81 (br. s, 1 H). MS: 279.1 [M + H]+.
Example 5
Figure imgf000027_0001
(E)-2-((l-(lH-benzo[d]imidazol-2-yl)ethyl)diazenyl)benzo|dIthiazole (5): Following Method A for the condensation of 2-hydrazinylbenzo[i/]thiazole and l-(lH-benzo[ /]imidazol-2-yl)ethan-l - one the title compound 5 was isolated as a white solid after recrystallization from MeOH. Ή-NMR (400 MHz, MeOD) δ 2.51 (s, 3H), 7.1 5 (t, S = 7.60 Hz, 1H), 7.28 (m, 2H), 7.33 (t, J = 7.28 Hz, 1 H), 7.47 (s, 1 H), 7.65 (m, 3H). MS: 308.1 [M + H]+.
Example 6
Figure imgf000027_0002
(E)-2-(l-(benzo[d]thiazol-2-yIdiazenyl)ethy])phenoI (6): Following Method A for the condensation of 2-hydrazinylbenzo[t/]thiazole and l -(2-hydroxyphenyl)ethan-l -one the title compound 6 was isolated as a white solid after recrystallization from MeOH. LH-NMR (400 MHz,
CDC13) 5 2.49 (s, 3H), 6.91 (dt, J - 8.04 Hz, 1.16 Hz, 1H), 7.04 (dd, J = 8.20 Hz, 1.0 Hz, 1 H), 7.13 (dt, J = 7.72 Hz, 1 .1 Hz, 1 H), 7.25 (m, 1 H), 7.30 (m, 2H), 7.52 (m, 2H), 12.42 (s, 1H, NH). MS: 284.0 [M + Hf.
Example 7
Figure imgf000027_0003
(£)-2-(2-(l-(lH-imidazol-2-yl)ethylidene)hydrazinyl)benzo[rf]thiazole (7): Following
Method A for the condensation of 2-hydrazinylbenzo[i ]thiazole and l-(lH-imidazol-2-yl)ethan-l - one the title compound 7 was isolated as a white solid after recrystallization from MeOH. 'H-NMR (400 MHz, CDCI3) δ 2.42 (s, 3H), 7.17 (m, 3H), 7.34 (t, J = 7.36 Hz, 1 H), 7.53 (d, J = 7.92 Hz, 1H), 7.66 (d, J = 7.84 Hz, 1 H), 9.89 (br. s, 1 H, NH). MS: 258.2 [M + H]+. Methods B-O
Method B.
Figure imgf000028_0001
2-Hydrazinylbenzo[rfJthiazole-6-carbonitrile
To a solution of 2-chlorobenzo[if|thiazole-6-carbonitrile (lOOmg, 0.51mmol, leq) in MeOH (1ml) was added hydrazine hydrate (1ml). The reaction was stirred for 1 hour, and the white precipitate was filtered and washed with MeOH to give 2- hydrazinylbenzo[i ]thiazole-6-carbonitrile as a white solid (88 mg, 90% yield).
Method C.
Figure imgf000028_0002
2-Hydrazinyl-6-(2-raethoxyethoxy)benzo[rf|thiazole
6-(2-methoxyethoxy)benzo[i ]thiazol-2-amine (120 mg, .54 mmol, 1 eq) was added to a solution of hydrazine hydrate (156 ul, 1.87 mmol, 3.5eq) and cone. HCl (156 ul, 3.21 mmol, 6 eq) in ethylene glycol (3ml) and heated overnight at 130°C. The reaction was partitioned in DCM/water, extracted 3 x DCM, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-hydrazinyl- 6-(2-methoxyethoxy)benzo[i/]thiazole (78 mg, 61% yield) as a brown solid.
Method
Figure imgf000028_0003
4-(2-(dimethylamino)ethoxy)picoIinonitrile
A solution of NaH (60% in mineral oil, 0.867 g, 21.65 mmol, 1.2 equiv.) in DMF (75 mL) was cooled to 0°C. 2-Dimethylaminoethanol (1.61 g, 18 mmol, 1 equiv) was added dropwise and the solution was allowed to warm to ambient temperature. The mixture was allowed to stir at ambient temperature for 45 minutes. The reaction was cooled to 0°C and 4- chloro-2-pyridinecarbonitrile (2.50 g, 18 mmol, 1 equiv.) was added in one portion and the reaction stirred overnight. The reaction was poured into brine and the resulting solution was diluted with water. The mixture was extracted with EtOAc (3x), the combined extracts were washed with water (2x) and brine (l x), dried over Na2S04 and concentrated. The resulting oil was purified by column chromatography (2%TEA/5%MeOH/DCM) to give 4-(2- (dimethylamino)ethoxy)picolinonitrile as a pale yellow oil (2.85 g, 14.9 mmol, 83%).
Figure imgf000029_0001
l-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)ethan-l-one
4-(2-(dimethylamino)ethoxy)picolinonitrile (2.85 g, 14.9 mmol, 1 equiv.) was dissolved in dry THF (30 mL). A solution of MeMgl (3M in ether, 7.45 mL, 22.4 mmol, 1.5 equiv) was added dropwise and the mixture continued to stir at 0 °C for 8 hours. The reaction was quenched with water (50 mL) and acidified to pH 1-2 with 1M aqueous HC1. The mixture was extracted with EtOAc and the organic layer was discarded. The mixture was basified to pH 9-11 with 1M aqueous NaOH and extracted with of EtOAc (5x). The combined extracts were dried over Na2S04 and concentrated to give 1 -(4-(2- (dimethylamino)ethoxy)pyridin-2-yl)ethan-l -one (2.68 g, 12.9 mmol, 86%) as a yellow oil, which was used crude without further purification.
Method E
Figure imgf000029_0002
4-((2-chlorobenzo[i/|thiazol-4-yl)oxy)butaneiiitrile
2-chlorobenzo[</]thiazol-4-ol (0.305g, 1.64 mmol, 1 equiv.) was dissolved in acetone (5.5 mL) and the mixture stirred at ambient temperature. 4-Bromobutyronitrile (0.267 g, 1.81 mmol, 1.1 equiv.) and K2CO3 (1.14 g, 8.22 mmol, 5 equiv.) were added and the resulting solution was heated to 60 "C for 3 hours. The reaction was cooled to ambient temperature and filtered through a thin pad of celite. The filtrate was concentrated and the resulting residue was dissolved in chloroform and filtered. The filtrate was concentrated and the resulting solid was triturated with hexanes to give 4-((2-chlorobenzo[ ]thiazol-4- yl)oxy)butanenitrile (0.227 g, 0.898 mmol, 55%) as a pale off-white solid which was used without further purification.
Method G.
Figure imgf000030_0001
To a solution of 2-aminobenzo[i/]fhiazol-6-ol (500mg, 3.0mmol, 1 eq) in DMF (30ml) was added cesium carbonate (4.9g, 15.0 mmol, 5 eq), and 1 -bromo-2-methox ethane (310 ul, 3.3 mmol, 1.1 eq). The reaction was stirred overnight at room temperature and subsequently taken up in EtOAc. The EtOAc layer was washed 2 x water, 1 x brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography and recrystallized from EtOAc to give 6-(2-methoxyethoxy)benzo[ /]thiazol-2-amine (251 mg, 37 yield) as a white solid.
Method H.
/
Figure imgf000030_0002
l-il-chloro-lJ^-benzot^imidazol-l-y^-N^N-dimethylethan-l-amine
To a solution of 2-chloro-lH-benzo[-flimidazole (500mg, 3.2 mmol, 1 eq) in DMF (7ml) at 0°C, was added sodium hydride (60%dispersion, 394mg, 9.84 mmol, 3.0 eq). After stirring for 5 min at 0°C, 2-chloro-N,N-dimethylethan-l -amine hydrochloride (709mg, 4.92 mmol, 1.5eq) was added, and the reaction was stirred overnight at room temperature. The reaction was quenched with water and partitioned in a mixture of ethyl acetate and water. The organic layer was washed 2x water, lx brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography and isolated 2-(2-chloro-lH-benzo[i ]imidazol-l-yl)-A',N-dimethylethan-l -amine (311 mg, 1.4mmol, 42% yield) as a white solid.
Method I.
Figure imgf000031_0001
l-(6-((methyl(pyridin-2-ylmethyl)amino)methyl)pyridin-2-yl)ethan-1-one
To a solution of l-(6-(hydroxymethyl)pyridin-2-yl)ethan-l-one (500mg, 3.3 mmol, 1 eq) in DCM (20ml) was added TEA (693 ul, 4.97 mmol, 1 .5 eq) followed by mesyl chloride (256 ul, 3.3 mmol, 1 eq). The reaction was partitioned in DCM/water, washed 2 x water, 1 x brine, dried over sodium sulfate and concentrated under reduced pressure to give (6- acetylpyridin-2-yl)methyl methanesulfonate (663 mg, 87% yield) as a waxy orange solid. To a solution of (6-acetylpyridin-2-yl)methyl methanesulfonate (l OOmg, 0.44 mmol, 1 eq) in MeCN (4ml) was added N-methyl-l-(pyridin-2-yl)methanamine (54ul, 0.44 mmol, 1 eq) and potassium carbonate (241mg, 1.7 mmol, 4 eq). The reaction was stirred overnight at room temperature, partitioned in EtOAc/water, washed 2 x water, dried over sodium sulfate and concentrated to afford l-(6-((methyl(pyridin-2-ylmethyl)amino)methyl)pyridin-2-yl)ethan-l- one (97mg, 87% yield) as a yellow oil that was used without further purification.
Method J (Example 30).
Figure imgf000031_0002
(£ -(6-(l-(2-(benzo[rf]thiazol-2-yl)hydrazono)ethy])pyridin-2-yI)raethanamine
(E)-2-(2-(l-(6-(azidomethyl)pyridin-2-yl)eth)didene)hydraz was synthesized using general method F and general method A as described.
To a solution of (E)-2-(2-(l-(6-(azidomethyl)pyridin-2-yl)ethylidene)hydrazinyl) benzo[i/]thiazole (60mg, 0.186mmol, 1 eq) in THF (4ml) and water (0.20ml) was added triphenylphosphine (58.5mg, 0.223 mmol, 1.2 eq). The reaction was stirred overnight at room temperature and partitioned in dilute aqueous HC1 and DCM. The aqueous layer was washed 2 x DCM to remove non-basic impurities, and then made basic with IN NaOH. The basic aqueous layer was extracted 3 x DCM, dried over sodium sulfate and concentrated. The residue was further purified by Prep HPLC to yield (£)-(6-(l-(2-(benzo[i ]thiazol-2- yl)hydrazono)ethyl)pyridin-2-yl)methanamine (lO.Omg) as a yellow solid.
Method K.
Figure imgf000032_0001
tert-Buty\ 2-((6-acetylpyridin-2-yl)methoxy)acetate
To a solution of l -(6-(hydroxymethyl)pyridin-2-yl)ethan-l-one (100 mg, 0.66mmol, 1 eq) in DMF (2ml) at 0°C was added NaH (60% dispersion, 32 mg, 0.79 mmol, 1.2 eq). After stirring for 2 min at 0°C, tert-butyl 2-bromoacetate (117ul, 0.79mmol, 1.2 eq) was added, and the reaction was allowed to stir 1 hour the same temperature. The reaction was quenched with water and partitioned in EtO Ac/water. The organic layer was washed 3 x water, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography to yield tert-butyl 2-((6-acetylpyridin-2-yl)methoxy)acetate (75 mg, 43% yield) as a clear oil.
Figure imgf000032_0002
l-(6-vinylpyridin-2-yl)ethan-l-one
l-(6-bromopyridin-2-yl)ethan-l-one (250mg, 1.25 mmol, 1 eq), potassium vinyl trifluoroborate (335mg, 2.5mmol, 2eq), PdCl2(PPh3)2 (44mg, 0.063 mmol, 0.05 eq) in dioxane (3ml) and 2M Na2C03 (2ml) were heated in a microwave reactor for 10 minutes at 120°C. The reaction was partitioned in EtOAc/water, extracted 2 x EtOAc, dried over sodium sulfate and concentrated. The crude product was purified by silica gel
chromatography to give l -(6-vinylpyridin-2-yI)ethan-l-one (140mg, 76% yield) as a clear oil.
Method M.
Figure imgf000033_0001
l-(6-ethyny]pyridin-2-yl)ethan-l-one
l-(6-bromopyridin-2-yl)ethan-l-one (l .Og. 5.0mmol, leq), Cul (38mg, 0.2mmol, 0.04 eq), PdCl2(PPh3)2 (140mg, 0.2mmol, 0.04 eq) in THF (10ml), TEA (1.5ml) was degassed under bubbling nitrogen for 10 min. To this solution was added TMS-acetylene (1.42 ml, 10 mmol, 2 eq) and the reaction was stirred for 2 hours at RT. The reaction was diluted in hexanes and filtered over a plug of silica gel to remove the majority of impurities. The eluent was concentrated under reduced pressure and further purified by silica gel chromatography (5% EtOAc/Hexanes) to afford l-(6-((trimethylsilyl)ethynyl)pyridin-2-yl)ethan-l-one (1.09g) as a yellow oil that was used without further purification. To a solution of l-(6- ((trimethylsilyl)ethynyl)pyridin-2-yl)ethan-l -one (crude from previous reaction) in methanol (20ml) was added a large excess of potassium carbonate. The reaction was stirred 2 hours at RT and concentrated under reduced pressure. The concentrate was partitioned in DCM/water, extracted 2 x DCM, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography to give l-(6-ethynylpyridin-2-yl)ethan-l -one (402 mg, 55% yield over 2 steps) as a white solid. Method N.
Figure imgf000034_0001
tert-Butyl 2-((2-acetylpyridin-4-yl)oxy)acetate
To a solution of 2-chloropyridin-4-ol (500mg, 3.9mmol, l eq) in DMF (10ml) at 0°C, was added NaH (60%, 188mg, 4.7mmol, 1.2 eq). After stirring 10 min at 0°C, tert-butyl 2- bromoacetate (694ul, 4.7 mmol, 1.2 eq) was added, and the reaction was stirred an additional 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride and partitioned in EtOAc/water. The organic was washed 2 x water, 1 x brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography to yield tert-butyl 2-((2-chloropyridin-4-yl)oxy)acetate (793 mg, 83% yield) as a clear oil.
2-chloropyridin-4-ol (lOOmg, 0.41mmol, l eq), tributyl(l-ethoxyvinyl)stannane (166ul, 0.49mmol, 1 .2eq), PdCl2(PPh3)2 (14mg, 0.021mmol, 0.05 eq), in DMF (1 ml) was degassed under bubbling nitrogen and heated in a microwave reactor for 10 minutes at 140°C. The reaction was partitioned in EtO Ac/water, extracted 3 x EtOAc, washed 3 x water, 1 x brine, dried over sodium sulfate and concentrated. The product was purified by silica gel chromatography to afford tert-butyl 2-((2-( l -methoxyvinyl)pyridin-4-yl)oxy)acetate (65 mg, 57% yield) as a light orange oil.
tert-butyl 2-((2-(l-methoxyvinyl)pyridin-4-yl)oxy)acetate (230mg, 0.824 mmol, 1 eq) was dissolved in DCM (10ml). To this solution was added HCl/ether (2M, 2 ml). The reaction was stirred 3 hours at RT and concentrated under reduced pressure. rt-Butyl 2- ((2-acetylpyridin-4-yl)oxy)acetate (110 mg, 53% yield) was isolated as a white solid after purification by silica gel chromatography. Method O.
Figure imgf000035_0001
5-(dimethylamino)picolinonitrilc
5-f uoropicolinonitrile (500mg, 4.09mmol, 1 eq) was taken up in a solution of dimethylamine (40% in water, 4 ml) and heated overnight at 100°C in sealed reaction vial. The reaction was then concentrated to dryness under reduced pressure and purified by silica gel chromatography (25% -> 50% EtOAc/Hex) to afford 5-(dimethylamino)picolinonitrile (336 mg, 56% yield) as a white solid.
Method P (Example 39).
Figure imgf000035_0002
(iE)-2-((2-(l-(2-(benzo[i ]thiazol-2-yl)hydrazono)ethyl)pyridin-4-yl)oxy)acetic acid
To a solution of tert-butyl (E)-2-((2-(l-(2-(benzo[i ]thiazol-2- yl)hydrazono)ethyl)pyridm-4-yl)oxy)acetate (60mg, 0.151 mmol, 1 eq) in DCM (3 ml) was added TFA (500 uL). The reaction was stirred overnight at RT and concentrated under reduced pressure and dried under high vacuum to afford (E)-2-((2-(l -(2-(benzo[i/)thiazol-2- yl)hydrazono)ethyl)pyridin-4-yl)oxy)acetic acid (49 mg, 95% yield) as a yellow solid.
Method Q (Example 40).
Figure imgf000035_0003
(£)-4-((2-(2-{l-(pyridin-2-yl)ethylidene)hydrazinyl)benzo[ ]thiazol-4-yl)oxy)butanoic acid (E)-4-((2-(2-(l-(pyridin-2-yl)ethylidene)hydrazinyl)benzo[(:/]thiazol-4- yl)oxy)butanenitrile (0.076 g, 0.216 mmol, 1 equiv.) was dissolved in ethanol (4.5 mL) and water (1.5 mL) was added as the mixture stirred. NaOH (0.043 g. 1.08 mmol, 5 equiv.) was added and the mixture was heated to 75 °C for 72 hours. The mixture was cooled to ambient temperature and the solvent was removed via rotovap. The resulting residue was dissolved in water and acidified with 1M HCl(aq) to pH 5. The orange solid that precipitated was filtered and washed with methanol and ether to give (E)-4-((2-(2-(l -(pyridin-2- yl)ethylidene)hydrazinyl)benzo[i/]thiazol-4-yl)oxy)butanoic acid (0.024 g, 0.065 mmol, 30%) as a red-orange solid.
Examples 8-43
The compounds of Examples 8-43 were prepared using the methods identified below. The structures, names, NMR data and mass spectral data for the compounds of Examples 8- 43 are shown in Table 1.
Table 1
Figure imgf000036_0001
Figure imgf000037_0001
yl)ethylidene)hydrazinyl)quinolrne
Figure imgf000038_0001
ol-4-yl)oxy)ethan-l-amine (MS+H)+ 356.05
Figure imgf000039_0001
Figure imgf000040_0001
ylmethyl)methanamine 402.75
Figure imgf000041_0001
¾ NMR (500 MHz, Chloroforms?) δ
9.03 (s, IH), 8.05 (dd, J= 7.9, 0.9 Hz, 1 H), 7.75 - 7.66 (m, 2H), 7.62 (ddd, J = 8.1, 1.2, 0.6 Hz, IH), 7.36 (ddd, J =8.0,
L, A 7.3, 1.3 Hz, IH), 7.29-7.26 (m, IH), 7.19 (ddd, J= 7.9, 7.3, 1.2 Hz, IH), 6.83
(E)-2-(2-(l-(6-vinylpyridin-2- (dd,J = 17.3, 10.7 Hz, IH), 6.32 (dd, J = yl)ethyIidene)hydrazinyl)benzo[d]thiaz 17.3, 1.5 Hz, 1H),5.49 (dd,/= 10.7, 1.5 ole Hz, IH), 2.47 (s, 3H). (MS+H)+ 294.95
Ή NMR (500 MHz, Chloroform-^ δ 8.15 (dd, J= 8.1, 1.0 Hz, IH), 7.74 - 7.69
M, A (m, 211), 7.62 (ddd, J= 8.1, 1.1, 0.6 Hz,
IH), 7.47 (dd,J= 7.6, 1.0 Hz, IH), 7.39
I I (ddd, J =8.1, 7.3, 1.2 Hz, IH), 7.22 (ddd,
(E)-2-(2-( I -(6-ethynylpyridin-2- J=7.9, 7.3, 1.1 Hz, IH), 3.17 (s, IH), yl)ethylidene)hydrazinyl)benzo[d]thiaz 2.48 (s, 3H). (MS+H)+ 292.8 ole
0)
Ή NMR (HCI salt) (400 MHz, Methanol-
CH3 d4) δ 8.79 (ddd, J= 5.9, 1.6, 0.7 Hz, IH),
H, C, A 8.61 (ddd, J= 8.2, 7.7, 1.6 Hz, IH), 8.32
-8.27(m, IH), 7.94 (ddd, J= 7.6, 5.8, 1.1 Hz, IH), 7.55 (dd,J= 5.9, 3.2 Hz, IH), 7.48-7.42 (m, IH), 7.28 (dd,J= 5.9, 3.1
(E)-4-(2-(2-(2-(l-(pyridin-2- Hz, 2H), 4.81 (t, J= 6.4 Hz, 2H), 3.97 (s, y 1 )ethy 1 i dene)hydrazinyl)- 1 H- 4H), 3.76 (t, J= 6.4 Hz, 2H), 3.59 (s, 4H), benzo[d]imidazol-l- 2.57 (s, 3H). (MS+H)+ 364.95 (437.37) yl)ethyl)morpholine
'H NMR (500 MHz, DMSO-<¾ δ 12.09
B, A
V (s, IH), 8.65 - 8.55 (m, IH), 8.22 - 7.80 N (m, 4H), 7.52 (d, J= 7.9 Hz, IH), 7.39
(E)-2-(2-(l-(pyridin-2- (ddd, J= 7.3, 4.8, 1.2 Hz, IH), 2.43 (s, yl)ethylidene)hydrazinyl)benzo[d]thiaz 3H).
ole-5-carbonitriIe (MS+H)+ 293.85
'HNMR (500 MHz, DMSO-t/6) ? 12.16 (s, IH), 8.60 (ddd, J = 4.8, 1.8, 0.9 Hz, IH), 8.30 (s, IH), 8.06 (dt, J= 8.2, 1.1
B, A Hz, IH), 7.87 (td,./= 7.8, 1.8 Hz, IH),
7.71 (dd, J=8.4, 1.8 Hz, IH), 7.53 (s,
(E)-2-(2-(l-(pyridin-2- IH), 7.40 (ddd, .7=7.5, 4.8, 1.2 Hz, IH), yl)ethylidene)hydrazinyl)benzo[d]thiaz 2.44 (s,3H). (MS+H)+ 293.85 ole-6-carbonitrile
Figure imgf000043_0001
Figure imgf000044_0001
Cell-based TOVl 12D activity and zinc binding for representative compounds is shown in Table 2.
Table 2.
Figure imgf000044_0002
Figure imgf000045_0001
** +++, tight binding; ++, moderately binding; +, weaker binding; - no measurable binding All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

Claims
What is claimed is:
1. A compound of formula (1):
Figure imgf000047_0001
or a salt thereof, wherein:
the ring A is a fused benzo or heteroaryl ring;
X is S, O, -CH-CH-, or N-Ra;
HEX is selected from the group consisting of:
Figure imgf000047_0002
wherein HEX is optionally substituted with one or more groups Rl independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (Q-QJalkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (Ci-Ceialkoxy, (C1-C6)alkanoyl, (Ci-C6)alkoxycarbonyl, (C - C6)alkanoyloxy,
Figure imgf000047_0003
wherein any phenyl, (Ci-C6)alkyl, (Ci-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3- C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, azido, cyano, hydroxy, nitro, -N(Rb)2, carboxy, (C3-C6)cycloalkyl,
Figure imgf000048_0001
(C]-C6)alkoxycarbonyl, (C2-C6)alkanoyloxy, and (CrC6)alkoxy that is optionally substituted with carboxy;
each R2 is independently selected from the group consisting of H, phenyl, (C\- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (C|- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alky yl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(RL)2, (C3-C6)cycloalkyl, (C - C6)alkoxy, and (C2-C6)alkanoyIoxy;
n is 0, 1 , 2, 3, or 4;
each R3 is independently selected from halo, cyano, hydroxy, nitro, -N(Rd)2, carboxy, phenyl, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloaIkyl, (C C6)alkoxy, (C ,- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Ci- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(R°)2, carboxy, (CVC6)cycloalkyl, (Ci-C6)alkoxy, (C |-C6)alkanoyl,
(CrC6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
R is selected from the group consisting of H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (C1-C.6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, and (CrC6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, -N(RS)2, morpholino, and (Ci-C6)alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidmo, pyrrolidino, piperidino, or morpholino ring;
each R is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyi. (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (C^Ceialkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C6)alkanoyl, and (Ci-C^alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, heteroaryl, and (Ci-C6)alkoxy; or two Rb taken together with the nitrogen to which they are attached form an azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rc is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C]-C6)alkanoyl, and (C1-C6)aIkoxycarbonyI, wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (d- C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Q-C^alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rd is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, ( VC^alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Cr
C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Q-Cei lkoxy; or two Rd taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
Re is independently selected from the group consisting of H and (C Ceialkyl that is optionally substituted with one or more groups independently selected from halo, (C3- C6)cycloalkyl, -N(Rf)2, and (C C6)aIkoxy;
each R is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C -C6)cycloalkyl, (Ci-Csjalkanoyl, and (CrC6)alkoxycarbonyl, wherein any (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C,- C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rr taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or mo holino ring; and
each Rg is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- Ce)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, and (C]-C6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (d- C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Q-C^alkoxy; or two R taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
wherein if HET is not substituted with one or more groups R1 , then R2 is not H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyl.
2. The compound of claim 1 which is a compound of formula (la):
Figure imgf000050_0001
L salt thereof, wherein:
X is S, O, N-H, or N-Ra;
HET is selected from the group consisting
Figure imgf000050_0002
wherein HET is optionally substituted with one or more groups R independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl! (C1-C6)alkoxy, (C C6)alkanoyl,
(C|-C6)alkoxycarbonyl, (C2-C6)alkanoyloxy, and
Figure imgf000050_0003
wherein any phenyl, (Ci-C6)alkyl, (Q-C^alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3- C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Rb)2, carboxy, (C3-Cf,)cycloalkyl, (Ci-C6)alkoxy, (CL- C6)alkanoyl, (Ci-Q)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
R2 is selected from the group consisting of H; phenyl, (Ci-C6)alkyl, (C2-C6)alkcnyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(RC)2, (C3-C6)cycloalkyl, (Q-QJalkoxy, and (C2- C6)alkanoyloxy;
n is 1, 2, 3, or 4;
each R3 is independently selected from halo, cyano, hydroxy, nitro, -N(Rd)2, carboxy, phenyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)cycloalkyl, (Ci-C6)alkoxy, (d- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Ci- Qjalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6.)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, (C3-C6)cycloalkyl, (d-Ceialkoxy, (C|-C6)alkanoyl}
(C[-C6)aIkoxycarbonyl, and (C2-C6)alkanoyloxy;
Ra is selected from the group consisting of H, (C]-C6)alk l, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (Ct-Ce^lkanoyl, and (C|-C6)alkoxycarbonyl, wherein any (C|-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C,-C6)alkanoyl, and (C|-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rb is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C|-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (d-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, heteroaryl, and (Ci-C6)alkoxy; or two Rb taken together with the nitrogen to which they are attached form an azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rc is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycIoalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyI, (C
C6)alkanoyl, and (C]-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rd is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (CrC6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C\- C6)alkanoyl, and (C1-C6)alkoxycarbonylJ is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rd taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
Re is independently selected from the group consisting of H and (Ci-C6)alkyl that is optionally substituted with one or more groups independently selected from halo, (C3- C6)cycloalkyl, -N(R )2, and (C i-C6)alkoxy; and
each Rf is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyI, (C1-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Cr
C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl., and (Ci-C6)alkoxy; or two Rf taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
wherein if HET is not substituted with one or more groups R , then R is not H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl, benzyl or 2-pyridyI.
The compound of claim 1 or 2, or a salt thereof, wherein
HET is selected from the group consisting of:
Figure imgf000053_0001
wherein HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (C1-Ce)alkoxy, (Ci-C6)alkanoyl, (C|-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (Ci- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
R2 is selected from the group consisting of H, phenyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (Ci-Ci)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(Rb)2, (C3-C6)cycloalkyl, (C}-C6)alkoxy, and (C2- C6)alkanoyloxy;
or R1 and R2 taken together with the carbon to which they are attached form a bicyclic 9- or 10-membered nitrogen ring system comprising 1, 2, 3, or 4 nitrogen atoms and at least one aromatic ring;
n is 1, 2, 3, or 4;
each R3 is independently selected from halo, cyano, hydroxy, nitro, -N(Rd)2, carboxy, phenyl, (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C,-C6)alkoxy, (C,- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Cr C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C] -C6)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, (C3-C6)c cloalkyl, (Ci-C6)alkoxy, (Ci-C6)alkanoyl,
(CrC6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
each Ra is independently selected from the group consisting of H, (C!-C6)alkyl, (C2- Cf alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Q-Ce^lkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci- C6)alkanoyl, and (d-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Q-C^alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rb is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C^CeJalkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C,-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C6)alkanoyl, and (Q-Cejalkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rb taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring.
each Rc is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C6)alkanoylJ and (C1-C6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (Ca-C^alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C
C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rd is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (CrC6)alkoxycarbonyl, wherein any (C|-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C C6)alkanoyl, and {Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Q-Ceialkoxy; or two Rd taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring. A compound of formula (I):
Figure imgf000055_0001
excluding ZMC1, or a salt thereof, wherein:
X is S, O, N-H, or N-Me;
HET is selected from the group consisting
Figure imgf000055_0002
wherein HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (Ci-C6)alkyl, (C2-Cg)alkenyl, (C2- C6)alkynyl. (C3-C6)cycloalkyl, (C|-C6)alkoxy, (Q-Cejalkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyIoxy, wherein any phenyl, (Cj[-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, (C3-C6)cycloalkyl, (Cj-CeJalkoxy, (Ci- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
R" is selected from the group consisting of H, phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, wherein any phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, -N(Rb)2, (C3-C6)cycloalkyl, (C1-C6)alkoxy, and (C2- C6)alkanoyloxy;
n is 0, 1, 2, 3, or 4;
each R3 is independently selected from halo, cyano, hydroxy, nitro, -N(RC)2, carboxy, phenyl, (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C ^alkoxy, (C C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Ci- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, and (C3-C6)cycloalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(R )2, carboxy, (C3-C6)cycloalkyl, (C]-C6)alkoxy, (Ci-C6)alkanoyl,
(C1-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy;
each Ra is independently selected from the group consisting of H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Q-Ceialkanoyl, and (CrC6)alkoxycarbonyl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl., (C3-C6)cycloalkyl, (Ci- C6)alkanoyl, and (Ci-C6)a]koxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (C(-C6)alkoxy; or two Ra taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring;
each Rb is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Ci-C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C,-C6)alkyl, (C2-C6)alkeny], (C2-C6)alkynyl, (C3-C6)cycloalkyl, (Cr
C6)alkanoyl, and (Ci-Cgjalkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (Ci-C6)alkoxy; or two Rb taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring; and
each Rc is independently selected from the group consisting of H, (Ci-Q alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (CrC6)alkanoyl, and (Ci-C6)alkoxycarbonyl, wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C,- C6)alkanoyl, and (Ci-C6)alkoxycarbonyl, is optionally substituted with one or more groups independently selected from halo, (C3-C6)cycloalkyl, and (C]-C6)alkoxy; or two Rc taken together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, or morpholino ring.
5. The compound or salt of claim 4 wherein each HET is independently selected from the group consisti
Figure imgf000056_0001
wherein HET is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, phenyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)a]kynyl, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (CrC6)alkanoyl, (Ct-C^alkoxycarbonyl, and (C2-C6)alkanoyloxy, wherein any phenyl, (Ci-Cejalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C -C6)cycIoalkyl, is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, nitro, -N(Ra)2, carboxy, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, (Cj- C6)alkanoyl, (Ci-C6)alkoxycarbonyl, and (C2-C6)alkanoyloxy.
6. The compound or salt of claim 4 wherein each HET is independently selected from the group consisti
Figure imgf000057_0001
wherein HET is optionally substituted with one or more groups independently selected from (Ci-C6)alkyl and -N(Ra)2.
7. The compound or salt of claim 4 wherein R is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, allyl, cyclopropyl, phenyl, benzyl, CH2CH2OCH3, and CH2CH2-N(CH3)2
8. The compound or salt of claim 4 wherein R2 is selected from the group consisting of methyl, ethyl, isopropyl, and tert-buty\.
9. The compound of claim 1 that is selected from the group consisting of:
Figure imgf000057_0002
Figure imgf000058_0001
and salts thereof.
10. The compound of claim 1 that is selected from the group consisting of:
Figure imgf000059_0001
and salts thereof.
1 1. A compound selected from the group consisting of:
Figure imgf000060_0001
12. The compound of claim 1 that is selected from the group consisting of:
Figure imgf000060_0002
Figure imgf000061_0001
60
Figure imgf000062_0001
and salts thereof.
13. A pharmaceutical composition, comprising a compound any one of claims 1-12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. An injectable pharmaceutical formulation comprising, a compound any one of claims 1-12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A method of treating cancer in an animal comprising administering a compound any one of claims 1-12 or a pharmaceutically acceptable salt thereof to the animal.
16. The method of claim 15, further comprising administering zinc to the animal.
17. The method of any one of claims 15-16, wherein the cancer is caused by mutations affecting zinc binding proteins.
18. The method of any one of claims 15-16, wherein the cancer is associated with a zinc binding p53 mutation.
19. The method of any one of claims 15-18, wherein the cancer is associated with a zinc binding p53 mutation selected from R175, CI 76, HI 79, C238, C242, and G245.
20. A compound of any one of claims 1 -12 or a pharmaceutically acceptable salt thereof, for use in medical treatment.
21. A compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of cancer.
22. The compound or pharmaceutically acceptable salt of claim 21 wherein the cancer is caused by mutations affecting zinc binding proteins.
23. The compound or pharmaceutically acceptable salt of claim 21, wherein the cancer is associated with a zinc binding p 3 mutation.
24. The compound or pharmaceutically acceptable salt of claim 21 , wherein the cancer is associated with a zinc binding p53 mutation selected from R175, CI 76, HI 79, C238, C242, and G245.
25. The use of a compound of any one of claims 1 -12 or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating cancer in an animal.
26. The use of claim 25 wherein the cancer is caused by mutations affecting zinc binding proteins.
27. The use of claim 25, wherein the cancer is associated with a zinc binding p53 mutation.
28. The use of claim 25, wherein the cancer is associated with a zinc binding p53 mutation selected from R175, C176, H179, C238, C242, and G245.
PCT/US2016/015195 2015-01-27 2016-01-27 Hydrazne derivatives for the treatment of cancer WO2016123253A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/545,971 US10828288B2 (en) 2015-01-27 2016-01-27 Hydrazone derivatives for the treatment of cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562108415P 2015-01-27 2015-01-27
US62/108,415 2015-01-27
US201562258256P 2015-11-20 2015-11-20
US62/258,256 2015-11-20

Publications (1)

Publication Number Publication Date
WO2016123253A1 true WO2016123253A1 (en) 2016-08-04

Family

ID=55315782

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/015195 WO2016123253A1 (en) 2015-01-27 2016-01-27 Hydrazne derivatives for the treatment of cancer

Country Status (2)

Country Link
US (1) US10828288B2 (en)
WO (1) WO2016123253A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018081612A1 (en) * 2016-10-31 2018-05-03 Actavalon, Inc. Compounds and methods for treating cancer
US10221133B2 (en) 2015-01-27 2019-03-05 Rutgers, The State University Of New Jersey (Thio, oxo, and seleno) semicarbazone complexes with zinc and their use for treating cancer
WO2019065570A1 (en) 2017-09-26 2019-04-04 住友化学株式会社 Heterocyclic compound and harmful arthropod controlling agent containing same
CN109651357A (en) * 2017-10-11 2019-04-19 中国科学院上海有机化学研究所 6,7- dihydro -5H- quinoline -8- hydrazone analog derivative iron chelating agents and its purposes for preparing anti-tumor drug
WO2019124548A1 (en) 2017-12-22 2019-06-27 住友化学株式会社 Heterocyclic compound and harmful arthropod controlling agent containing same
US10604480B2 (en) 2015-01-27 2020-03-31 Rutgers, The State University Of New Jersey (Thio, oxo, and seleno) semicarbazone derivatives and their use for treating cancer
US10729671B2 (en) 2015-01-27 2020-08-04 Rutgers, The State University Of New Jersey Zinc complexes of hydrazones and (thio)semicarbazones and their use for the treatment of cancer
WO2021141106A1 (en) 2020-01-09 2021-07-15 住友化学株式会社 Heterocyclic compound and harmful arthropod-controlling composition including same
US11253517B2 (en) * 2016-04-08 2022-02-22 Baylor College Of Medicine Small molecule regulators of steroid receptor coactivators and methods of use thereof
WO2022071428A1 (en) 2020-09-30 2022-04-07 住友化学株式会社 Heterocyclic compound and harmful arthropod-controlling composition including same
WO2022086079A1 (en) * 2020-10-19 2022-04-28 고려대학교 산학협력단 Derivative of semicarbazone or pharmaceutically acceptable salt thereof, and use thereof
WO2022181793A1 (en) 2021-02-26 2022-09-01 住友化学株式会社 Phenylacetic acid derivative, use therefor, and production intermediate thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001094340A1 (en) * 2000-06-05 2001-12-13 Innovationsagentur Gesellschaft M.B.H. Heterocyclic hydrazones for use as anti-cancer agents
WO2006101740A2 (en) * 2005-03-18 2006-09-28 The Regents Of The University Of California Compounds having activity in correcting mutant-cftr processing and uses thereof
WO2009039553A1 (en) * 2007-09-27 2009-04-02 The Walter And Eliza Hall Institute Of Medical Research Benzothiazole compounds
WO2015021456A1 (en) * 2013-08-09 2015-02-12 The Regents Of The University Of California Small molecules to enhance p53 activity

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US397408A (en) * 1889-02-05 Knitting-machine
JPS5116212B2 (en) * 1973-04-05 1976-05-22
US4665173A (en) 1982-03-31 1987-05-12 Klayman Daniel L 2-acetyl- and 2-propionylpyridine selenosemicarbazones
WO2006019955A2 (en) 2004-07-14 2006-02-23 President And Fellows Of Harvard College Antiviral methods and compositions
AU2006292482A1 (en) 2005-09-16 2007-03-29 Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods of treating or preventing cancer using pyridine carboxaldehyde pyridine thiosemicarbazone radiosensitizing agents
US20080118576A1 (en) * 2006-08-28 2008-05-22 Dan Theodorescu Prediction of an agent's or agents' activity across different cells and tissue types
WO2011133748A1 (en) 2010-04-21 2011-10-27 University Of Medicine And Dentistry Of New Jersey Treatments for cellular proliferative disorders and identification thereof
CN106278943B (en) * 2011-04-27 2019-07-30 日本瑞翁株式会社 Optical thin film, polymerizable compound, polymerizable composition, polymerizable composition, macromolecule, optically anisotropic body and hydrazine compound
GB201110390D0 (en) 2011-06-20 2011-08-03 Medical Res Council Compounds for use in stabilising p53 mutants
US10604480B2 (en) 2015-01-27 2020-03-31 Rutgers, The State University Of New Jersey (Thio, oxo, and seleno) semicarbazone derivatives and their use for treating cancer
WO2016123250A1 (en) 2015-01-27 2016-08-04 Rutgers, The State University Of New Jersey Zinc complexes of hydrazones and (thio)semicarbazones and their use for the treatment of cancer
US10221133B2 (en) 2015-01-27 2019-03-05 Rutgers, The State University Of New Jersey (Thio, oxo, and seleno) semicarbazone complexes with zinc and their use for treating cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001094340A1 (en) * 2000-06-05 2001-12-13 Innovationsagentur Gesellschaft M.B.H. Heterocyclic hydrazones for use as anti-cancer agents
WO2006101740A2 (en) * 2005-03-18 2006-09-28 The Regents Of The University Of California Compounds having activity in correcting mutant-cftr processing and uses thereof
WO2009039553A1 (en) * 2007-09-27 2009-04-02 The Walter And Eliza Hall Institute Of Medical Research Benzothiazole compounds
WO2015021456A1 (en) * 2013-08-09 2015-02-12 The Regents Of The University Of California Small molecules to enhance p53 activity

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BRAD E. SLEEBS ET AL: "Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-X L", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 13, 11 July 2013 (2013-07-11), US, pages 5514 - 5540, XP055259632, ISSN: 0022-2623, DOI: 10.1021/jm400556w *
EASMON J HEINISCH G HOFMANN J LANGER T GRUNICKE HH FINK J PURSTINGER G: "Thiazolyl and benzothiazolyl hydrazones derived from alpha-(N)-acetylpyridines and diazines: synthesis, antiproliferative activity and CoMFA studies", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 32, no. 5, 1 May 1997 (1997-05-01), pages 397 - 408, XP004085514, ISSN: 0223-5234, DOI: 10.1016/S0223-5234(97)81677-7 *
EASMON, J.; HEINISCH G.; HOFMAN, J.; LANGER, T.; GUNICKE, HH.; FINK, J.; PFRSTINGER G.: "Thiazolyl and benzothiazolyl hyrdrazones derived from a-(N)-acetylpyridines and diazines: synthesis, antiproliferative activity and CoMFA studies", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 32, 1997, pages 397 - 408
EASMON, J.; PURSTINGER, G.; THIES, K. S.; HEINISCH, G.; HOFMANN, J.: "Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from alpha-(N)-acyl heteroaromatics", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, 2006, pages 6343 - 6350
HALL I H ET AL: "INVESTIGATIONS ON THE MECHANISM OF ACTION OF THE NOVEL ANTITUMOR AGENTS 2-BENZOTHIAZOLYL, 2-BENZOXAZOLYL, AND 2-BENZIMIDAZOLYL HYDRAZONES DERIVED FROM 2-ACETYLPYRIDINE", ARCHIV DER PHARMAZIE, WILEY VERLAG, WEINHEIM, vol. 332, no. 4, 1 January 1999 (1999-01-01), pages 115 - 123, XP001013551, ISSN: 0365-6233, DOI: 10.1002/(SICI)1521-4184(19994)332:4<115::AID-ARDP115>3.3.CO;2-7 *
HARI NARAYANA MOORTHY N S ET AL: "QSAR analysis of 2-benzoxazolyl hydrazone derivatives for anticancer activity and its possible target prediction", MEDICINAL CHEMISTRY RESEARCH, BIRKHÄUSER-VERLAG, BOSTON, vol. 21, no. 2, 2 December 2010 (2010-12-02), pages 133 - 144, XP019997542, ISSN: 1554-8120, DOI: 10.1007/S00044-010-9510-3 *
HUANG Y ET AL: "CORRELATING GENE EXPRESSION WITH CHEMICAL SCAFFOLDS OF CYTOTOXIC AGENTS: ELLIPTICINES AS SUBSTRATES AND INHIBITORS OF MDR1", PHARMACOGENOMICS JOURNAL, NATURE PUBLISHING GROUP, GB, vol. 5, 1 January 2005 (2005-01-01), pages 112 - 125, XP008051244, ISSN: 1470-269X, DOI: 10.1038/SJ.TPJ.6500297 *
JOHNNY EASMON ET AL: "2-benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine: A novel class of antitumor agents", INTERNATIONAL JOURNAL OF CANCER, vol. 94, no. 1, 1 October 2001 (2001-10-01), US, pages 89 - 96, XP055259741, ISSN: 0020-7136, DOI: 10.1002/ijc.1427 *
JOHNNY EASMON ET AL: "Synthesis, Structure-Activity Relationships, and Antitumor Studies of 2-Benzoxazolyl Hydrazones Derived from Alpha-( N )-acyl Heteroaromatics", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 21, 1 October 2006 (2006-10-01), US, pages 6343 - 6350, XP055259743, ISSN: 0022-2623, DOI: 10.1021/jm060232u *
PURSTINGER, G.; HEINISCH, G.; EASMON, J.; HOIMANN, J.; HEINZ-HERBERT, F.: "Heterocyclic Hydrazones for Use as Anti-cancer agents", 2002
R PRIYADHARSINI ET AL: "DOCKING, SYNTHESIS, CHARACTERIZATION AND EVALUATION OF NOVEL CDK2 INHIBITORS: BENZOTHIAZOLE DERIVATIVES", INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, vol. 4, 1 January 2012 (2012-01-01), pages 574 - 584, XP055259736 *
XIN YU ET AL: "Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism", ONCOTARGET, vol. 5, no. 19, 3 September 2014 (2014-09-03), United States, pages 8879 - 8892, XP055259320, ISSN: 1949-2553, DOI: 10.18632/oncotarget.2432 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10604481B2 (en) 2015-01-27 2020-03-31 Rutgers, The State University Of New Jersey (Thio, oxo and seleno) semicarbazone complexes with zinc and their use for treating cancer
US10221133B2 (en) 2015-01-27 2019-03-05 Rutgers, The State University Of New Jersey (Thio, oxo, and seleno) semicarbazone complexes with zinc and their use for treating cancer
US10729671B2 (en) 2015-01-27 2020-08-04 Rutgers, The State University Of New Jersey Zinc complexes of hydrazones and (thio)semicarbazones and their use for the treatment of cancer
US10604480B2 (en) 2015-01-27 2020-03-31 Rutgers, The State University Of New Jersey (Thio, oxo, and seleno) semicarbazone derivatives and their use for treating cancer
US11253517B2 (en) * 2016-04-08 2022-02-22 Baylor College Of Medicine Small molecule regulators of steroid receptor coactivators and methods of use thereof
WO2018081612A1 (en) * 2016-10-31 2018-05-03 Actavalon, Inc. Compounds and methods for treating cancer
WO2019065570A1 (en) 2017-09-26 2019-04-04 住友化学株式会社 Heterocyclic compound and harmful arthropod controlling agent containing same
CN109651357A (en) * 2017-10-11 2019-04-19 中国科学院上海有机化学研究所 6,7- dihydro -5H- quinoline -8- hydrazone analog derivative iron chelating agents and its purposes for preparing anti-tumor drug
WO2019124548A1 (en) 2017-12-22 2019-06-27 住友化学株式会社 Heterocyclic compound and harmful arthropod controlling agent containing same
WO2021141106A1 (en) 2020-01-09 2021-07-15 住友化学株式会社 Heterocyclic compound and harmful arthropod-controlling composition including same
WO2022071428A1 (en) 2020-09-30 2022-04-07 住友化学株式会社 Heterocyclic compound and harmful arthropod-controlling composition including same
WO2022086079A1 (en) * 2020-10-19 2022-04-28 고려대학교 산학협력단 Derivative of semicarbazone or pharmaceutically acceptable salt thereof, and use thereof
WO2022181793A1 (en) 2021-02-26 2022-09-01 住友化学株式会社 Phenylacetic acid derivative, use therefor, and production intermediate thereof

Also Published As

Publication number Publication date
US10828288B2 (en) 2020-11-10
US20180000806A1 (en) 2018-01-04

Similar Documents

Publication Publication Date Title
WO2016123253A1 (en) Hydrazne derivatives for the treatment of cancer
AU2016244017B2 (en) Compositions and methods of targeting mutant K-ras
US10729671B2 (en) Zinc complexes of hydrazones and (thio)semicarbazones and their use for the treatment of cancer
JP6621486B2 (en) Pyrido-azaheterocyclic compound and production method and use thereof
CA2971872C (en) Mutant idh1 inhibitors useful for treating cancer
US10221133B2 (en) (Thio, oxo, and seleno) semicarbazone complexes with zinc and their use for treating cancer
AU2014241152A1 (en) Benzimidazolone derivatives as bromodomain inhibitors
EP3041470A1 (en) Methods and compositions for selective and targeted cancer therapy
US10604480B2 (en) (Thio, oxo, and seleno) semicarbazone derivatives and their use for treating cancer
EP0125756A2 (en) Fused imidazole compounds, processes for the preparation thereof and pharmaceutical compositions containing them
JP2009521464A (en) Nitroimidazole compounds
WO2004087641A1 (en) Hydrazone derivative
EP2099789A1 (en) Inhibitors of hiv replication
CA3047002A1 (en) Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
CZ306598B6 (en) A method of preparation and purification of new and known polymorphs and dasatinib solvates
JPWO2020004443A1 (en) Arenavirus growth inhibitor containing polycyclic carbamoylpyridone derivative
WO2021224818A1 (en) Isoindolone compounds as hpk1 inhibitors
WO2021202900A1 (en) 1,6-naphthyridine compounds and methods for csk modulation and indications therefor
CA3021185C (en) Fused heterocyclic compound
JP2019511466A (en) Halo substituted piperidines as orexin receptor modulators
JP2021070688A (en) Pharmaceutical composition for prevention and/or treatment of hearing loss
CN110680813B (en) Use of naphthoquinone derivatives as IDO1 and/or TDO inhibitors
HUE026012T2 (en) 2-methoxy-pyridin-4-yl derivatives
WO2023079294A1 (en) Phthalazine derivatives as pyruvate kinase modulators
CN114853812A (en) Phosphine oxide group-containing compound, preparation method thereof and application thereof in medicine

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: 16703694

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15545971

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16703694

Country of ref document: EP

Kind code of ref document: A1