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WO2025042769A1 - Composés et procédés d'inhibition de poly(adp-ribose)polymérases - Google Patents

Composés et procédés d'inhibition de poly(adp-ribose)polymérases Download PDF

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WO2025042769A1
WO2025042769A1 PCT/US2024/042763 US2024042763W WO2025042769A1 WO 2025042769 A1 WO2025042769 A1 WO 2025042769A1 US 2024042763 W US2024042763 W US 2024042763W WO 2025042769 A1 WO2025042769 A1 WO 2025042769A1
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benzo
imidazole
phenyl
carboxamide
carbonyl
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Ben Black
Tanaji TALELE
John PASCAL
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Universite de Montreal
St Johns University Taiwan
University of Pennsylvania Penn
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Universite de Montreal
St Johns University Taiwan
University of Pennsylvania Penn
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • PARPs BACKGROUND Poly (ADP-ribose) polymerases
  • PARPis may have beneficial effects in treating neurodegenerative diseases such as Alzheimer’s disease and related dementias (ADRDs), amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), and Lewy body dementia/Parkinson’s disease (LBD/PD).
  • ADRDs Alzheimer’s disease and related dementias
  • ALS/FTD amyotrophic lateral sclerosis/frontotemporal dementia
  • LBD/PD Lewy body dementia/Parkinson’s disease
  • Currently available PARPis are not ideal for treating all types of cancers (especially brain cancers) or neurodegenerative diseases.
  • Many of the PARPis have been shown to have off-target toxicities and suffer from, e.g., short serum half-life, cost, and resistance.
  • the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , and R 3 are defined elsewhere herein:
  • the compound of Formula (I) has a structure of Formula (II), wherein R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , and R 4 are defined elsewhere herein:
  • the compound of Formula (I) has a structure of Formula (III), wherein R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 4 , m, na, and nb are defined elsewhere herein: .
  • the compound of Formula (I) has a structure of Formula (IVA), wherein R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , and R 4 are defined elsewhere herein: .
  • the compound of Formula (I) has a structure of Formula (IVB), wherein R 1a , R 1b , R 1c , R 8 are defined elsewhere herein: .
  • the compound of Formula (I) has a structure of Formula (V), wherein R 1a , R 1b , R 1c , and R 7 , and p are defined elsewhere herein:
  • the compound of Formula (I) has a structure of Formula (VI), wherein R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 7 , m, na, nb, and p are defined elsewhere herein: .
  • the compound of Formula (I) has a structure of Formula (VII), wherein R 1a , R 1b , R 1c , and R 7 are defined elsewhere herein:
  • the compound of Formula (I) has a structure of Formula (VIII), wherein R 1a , R 1b , R 1c , R 7 , R 8 , L 1 , and p are defined elsewhere herein:
  • the disclosure provides a pharmaceutical composition comprising at least one compound of the disclosure, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, and at least one pharmaceutically acceptable carrier.
  • the disclosure provides a method of inhibiting at least one PARP, the method comprising contacting the PARP with the compound of the disclosure, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of the disclosure.
  • the disclosure provides a method of treating, ameliorating, and/or preventing a PARP-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the disclosure, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of the disclosure.
  • FIGs.1A-1B Veliparib core scaffold modifications modulate PARP1 allostery.
  • FIG. 1A representative FP DNA competition assay showing that UKTT15 (15) increases PARP1 retention on DNA damage similar to EB-47.
  • FIG.1B representative FP DNA binding assay showing that UKTT15 (15) increases PARP1 DNA binding affinity. Again, compounds 75 and 77 mildly increase PARP1 affinity while compounds 65 and 82 show little to no difference. Average KD values derived from the FP DNA binding assay.
  • FIGs.2A-2G Crystal structures of target compounds bound to CAT ⁇ HD.
  • FIG.2A crystal structure of PARP1 apo CAT domain (beige, PDB: 7AAA) with the nicotinamide binding pocket (N) and adenosine binding pocket (A) of PARP1 active site highlighted in green.
  • FIG.2B crystal structure of EB-47 bound to PARP1 CAT domain (PDB: 6VKQ). EB- 47 contacts both the nicotinamide binding pocket and the ADP-ribose binding pocket.
  • FIG. 2C crystal structure of UKTT15 (15) bound to PARP1 CAT domain (PDB: 6VKO).
  • FIGs. 2D-2F crystal structures of compounds 75 (FIG.2D), 82 (FIG.2E) and 65 (FIG.2F) bound to their respective PARP1 CAT ⁇ HD domain.
  • the HD of PARP1 is represented after having overlayed the structure of PARP1 apo CAT domain (PDB: 7AAA).
  • FIGs.3A-3F Compound 75 contacts helices ⁇ D and ⁇ F of the HD.
  • FIG.3A the ⁇ VE/compound 75 structure was determined at 3.9 ⁇ (one of the two complexes in the asymmetric unit is shown).
  • FIG.3B the CAT ⁇ HD/compound 75 structure is superposed to the CAT domain of the ⁇ VE structure highlighting that the compound contacts helices ⁇ D and ⁇ F of the HD following a rearrangement of its benzimidazole group (FIG.3C).
  • FIG.3D compound 75 with a 2FO-FC weighted electron density overlaid.
  • FIG.3E surface representation of the CAT domain structure of compound 75 bound to ⁇ VE highlighting that the compound substituent is buried at the interface of helices ⁇ D and ⁇ F and the ASL.
  • FIG. 3F surface representation of the CAT domain structure of UKTT15 (15) bound to the CAT domain (PDB 6VKO) highlighting that the compound contributes to a groove in between helices ⁇ D and ⁇ F and the ASL and remains accessible to the solvent.
  • FIGs.4A-4G Hydrogen/deuterium exchange-mass spectrometry (HXMS).
  • FIG.4A HXMS difference plots between PARP1/DNA complex and PARP1/DNA/75 complex at 100 s.
  • FIG.4B HXMS difference plots between PARP1/DNA complex and PARP1/DNA/65 complex at 100 s.
  • the consensus HX difference plot for the binding of the 65 is shown on the top.
  • FIG.4C HXMS difference plots between PARP1/DNA complex and PARP1/DNA/82 complex at 100 s.
  • the consensus HX difference plot for the binding of the 82 is shown on the top.
  • each thin horizontal bar represents a PARP1 peptide.
  • FIG.4D panels (i-iv) represents the HX of the representative peptides of Zn3, WGR, ⁇ B, and ⁇ F for PARP1+DNA, and PARP1+DNA+PARPi.
  • An average from three replicates with SD represented by error bars and asterisks indicating P ⁇ 0.05 from two-sided t-test between PARP1+DNA and PARP1+DNA+PARPi is shown.
  • Purple dotted line indicates maxD i.e., number of residues minus first two residues (back-exchange within experimental timescale) and minus number of prolines due to no backbone amide hydrogen.
  • FIG.4E consensus HXMS percentage differences with compounds 75 mapped to the crystal structure of PARP1 on DNA damage (PDB 4DQY).
  • FIG.4F consensus HXMS percentage differences with compound 65 mapped to the crystal structure of PARP1 on DNA damage (PDB 4DQY).
  • FIG.4G consensus HXMS percentage differences with compound 82 mapped to the crystal structure of PARP1 on DNA damage (PDB 4DQY).
  • FIGs.5A-5K PARP1 dose-response curves for certain exemplary compounds of the present disclosure and veliparib.
  • FIG.6A SDS-PAGE activity assay showing PARP1 inexistant or greatly reduced catalytic activity in the presence of veliparib, EB-47, and certain exemplary compounds of the present disclosure.
  • FIG.6B additional representative curves for FP DNA competition assay comparing PARP1 release from DNA damage in the presence of veliparib, EB-47, and certain exemplary compounds of the present disclosure.
  • FIG.6C additional representative curves for FP DNA binding assay to monitor PARP1 DNA damage binding affinity in the presence of veliparib, EB-47, and certain exemplary compounds of the present disclosure.
  • values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.
  • veliparib is a catalytic inhibitor of PARP-1 and has been shown to possess very poor PARP-trapping efficiency, which has been known to produce potent cytotoxicity in vitro and in vivo.
  • PARP-mediated neurodegenerative disease(s) and/or disorder(s) The human PARP family of proteins includes >17 members with distinctive multi- domain structures and diverse roles in a wide variety of cellular processes. Of which, PARP-1, PARP-2, TNKS1/PARP5a, and TNKS2/PARP5b catalyze the addition of poly(ADP-ribose) (PAR) chains.
  • PARP-1 The most studied PARP enzyme is PARP-1, whose catalytic activity is acutely stimulated upon binding to DNA breaks in the cellular response to DNA damage.
  • PARPs activate DNA repair in response to oxidative DNA damage by mediating the attachment of PAR polymers on itself (auto-modification) and other proteins (hetero-modification).
  • PARP-1 is responsible for the 90% of the NAD + -dependent synthesis of PAR polymers.
  • DNA single-strand break (SSB) repair and protein post-translational modifying PARPs plays an important role in the cellular defense against oxidative stress. Overactivation of PARPs in response to oxidative DNA SSBs causes depletion of NAD + and ATP leading to necrotic dopamine (DA) neuronal cell death.
  • DA necrotic dopamine
  • ADRDs Alzheimer’s Disease and related dementias
  • AD Alzheimer’s Disease
  • ALS/FTD amyotrophic lateral sclerosis/frontotemporal dementia
  • LBD/PD Lewy body dementia/Parkinson’s Disease
  • Transactive response DNA binding protein 43 kDa (TDP-43) is an abundant nuclear protein that is mislocalized to the cytoplasm of degenerating neurons in ALS/FTD patients, where it undergoes a liquid-to-solid state transition from liquid- liquid phase separation (LLPS) and forms insoluble protein aggregates. TDP-43 inclusions are found in approximately 97% of ALS patients and >40% of FTD patients, thus serving as a key pathological hallmark for both diseases. Further, hippocampal atrophy in AD is associated with the abundance of TDP-43. Further evidence suggested that Tau and TDP-43 misfolded proteins were co-localized in neuronal cells.
  • TDP-43 noncovalently binds to PAR polymers via PAR-binding motifs embedded in the nuclear localization signal of TDP- 43.
  • TDP-43-PAR interaction promotes LLPS of TDP-43 and is required for pathologic accumulation of TDP-43 in stress granules in mammalian neurons.
  • Inhibition of PARPs has been shown to reduce TDP-43 recruitment in stress granules and combined inhibition of PARP1/2 and TNKS resulted in decreased formation of cytoplasmic inclusions of TDP-43. Based on this concept, PARPi veliparib and olaparib were able to reduce PAR levels and partially rescue TDP-43-induced cell death in neuronal cells.
  • TNKS2 inhibitor XAV939
  • TNKS2 inhibitor also partially rescued the accumulation of TDP-43 in cytoplasmic foci.
  • high (potentially toxic) oral doses would be required for existing PARPi to serve as effective anti-neurodegenerative treatments.
  • existing PARPi strongly trap PARP-1 on DNA breaks, a cause for cellular toxicity.
  • NAD + also serves as a co-enzyme for PARP enzymatic activity
  • PARP1 is a major NAD + -consuming nuclear enzyme involved in repairing cellular DNA SSBs. Prolonged activation of PARP leads to reduced cellular NAD + pools, which in turn results in ATP depletion and bioenergetics collapse. High PARP activity causes loss of DA neurons and mitochondrial dysfunction.
  • the pathological hallmark of PD is the presence of Lewy bodies that are accumulations of the protein ⁇ -synuclein.
  • ⁇ -Synuclein noncovalently binds to PAR through its basic N-terminus and this interaction leads to the formation of more toxic ⁇ -synuclein fibrils (more potent fibril strain) that is also readily transmitted to nearby cells.
  • Pathologic ⁇ -synuclein via feed-forward mechanism activates PARP1 and increases PAR levels leading to acceleration of the formation of pathologic ⁇ -synuclein and PARP1-mediated cell death.
  • Increased PAR levels in the cerebrospinal fluid and brains of patients suggests that PARP activation is involved in the pathogenesis of PD.
  • PARP activation and dopaminergic neuron loss has been shown in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, a selective complex I inhibitor) and other neurotoxins-induced Parkinsonism in mouse models.
  • MPTP methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Overactivation of PARP-1 also contributes to the PAR-mediated translocation of mitochondrial protein apoptosis-inducing factor (AIF) into the nucleus to induce caspase- independent programmed cell death (Parthanatos) that occurs in PD.
  • PARP-1 gene knockout mice were rescued from MPTP-induced neurotoxicity.
  • Potent PARPi demonstrated amelioration of MPP + (active form of MPTP)- and ⁇ -synuclein-induced cytotoxicity in in vitro and in vivo PD models.
  • PARPi attenuated toxin-induced neurotoxicity in animal models of PD.
  • These preclinical findings clearly demonstrated the therapeutic potential of novel anti-trapping brain- penetrable least cytotoxic PARPi in PD. Consequently, inhibiting PARP activity or supplying NAD + -containing dietary supplements leads to improved mitochondrial function and PD-related phenotypes and also prevent degeneration of DA neurons in the substantia nigra pars compacta.
  • Repurposing of novel PARPi for non-oncological indications such as neurodegenerative diseases will require conceptual changes in how PARPi targeted to these diseases are designed.
  • PARPi used in the cancer clinic, (i) newly developed PARPi must efficiently cross the blood-brain-barrier (BBB), (ii) unlike PARP-trapping (PARP poisoning) that leads to cell death as a desirable property to treat cancers, new PARPi targeted to the brain for treating ADRDs should be pure catalytic PARPi that do not accelerate PARP-trapping potential in order to ensure acceptable therapeutic index, (iii) unlike existing PARPi, new PARPi should be PARP- 1/2/TNKS-isoform selective, and (iv) new PARPi should not be substrates of ABC transporters located in the BBB to ensure delivery of therapeutically effective amounts of PARPi into the brain.
  • BBB blood-brain-barrier
  • PARPi targeted to the brain for treating ADRDs should be pure catalytic PARPi that do not accelerate PARP-trapping potential in order to ensure acceptable therapeutic index, (iii) unlike existing PARPi, new PARPi should be PARP- 1/2/TNKS-isoform selective,
  • the present study relates to the discovery that PARPis can be specifically designed such that the inhibitors are able to “trap” the PARP protein allosterically at a DNA break, or does not do so.
  • PARPis that allosterically trap PARP proteins at DNA breaks causes robust cytotoxicity and is sometimes more desirable for being used as anti-cancer agents, as treating cancers requires cancer cells to be killed.
  • PARPis that do not allosterically trap PARP proteins at DNA breaks causes significantly less cytotoxicity and is sometimes more desirable for being used to treat neurodegenerative diseases, as neurons and other types of cells are not supposed to be damaged when treating neurodegenerative diseases.
  • the present study further realized that PARPis able to cross the blood-brain barrier simplifies the delivery of compounds when treating, ameliorating, and/or preventing neurodegenerative diseases. Based on such realizations, the present invention developed a series of PARPis useful in treating, ameliorating, and/or preventing cancer and/or have disease-modifying modalities for neurodegenerative diseases.
  • the present invention is directed to PARPis useful for treating, ameliorating, and/or preventing a cancer, as well as compositions/kits including the same and methods thereof.
  • the present invention is directed to PARPis useful for treating, ameliorating and/or preventing a neurodegenerative disease, as well as compositions/kits including the same and methods thereof.
  • Definitions The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group comprising at least one carbon atom connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • alkoxy includes (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy. Unless stated otherwise, the alkoxy may be optionally substituted.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl.
  • alkyl such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n- hexyl and cyclopropylmethyl. Unless stated otherwise, alkyl may be optionally substituted.
  • alkylene or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia).
  • the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g., -CH2-) different (e.g., -CH2CH2-) carbon atoms.
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized ⁇ (pi) electrons, where n is an integer.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings, wherein at least one ring is aromatic) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. In certain embodiments, aryl includes phenyl and naphthyl. Unless stated otherwise, aryl may be optionally substituted.
  • binding refers to the adherence of molecules to one another, such as, but not limited to, enzymes to substrates, antibodies to antigens, DNA strands to their complementary strands. Binding occurs because the shape and chemical nature of parts of the molecule surfaces are complementary. A common metaphor is the “lock-and-key” used to describe how enzymes fit around their substrate.
  • cancer refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • cycloalkyl by itself or as part of another substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C3-C6 means a cyclic group comprising a ring group consisting of three to six carbon atoms).
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Certain specific examples include (C 3 -C 6 )cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, cycloalkyl may be optionally substituted.
  • the term “cycloalkylene” or “cycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical (e.g., , inter alia).
  • an “effective amount” or “therapeutically effective amount” of a compound is that amount of compound sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. In some embodiments, halogen is fluorine, chlorine, or bromine. In some embodiments, halogen is fluorine or chlorine.
  • haloalkyl refers to an alkyl substituted with one or more independently selected fluorine, chlorine, bromine and/or iodine atoms.
  • the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms.
  • the haloalkyl group is a C 1-10 haloalkyl group.
  • the haloalkyl group is a C1-6 haloalkyl group.
  • the haloalkyl group is a C1-4 haloalkyl group.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group comprising carbon atoms and one or more heteroatoms selected from the group consisting of O, N, and S, and wherein the N and S atoms may be optionally oxidized, and the N heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • heteroarylene or “heteroarylenyl” as used herein refers to a bivalent heteroaryl radical (e.g., 2,4-pyridylene).
  • the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from one or more rings of a heteroaryl moiety, wherein the hydrogen atoms may be removed from the same or different rings, preferably the same ring.
  • heterocycloalkyl refers to a unsubstituted or substituted, stable, mono- or multi-cyclic ring system that contains at least one carbon atom and one to six heteroatoms selected from the group consisting of N, O, and S, and wherein the N and S heteroatoms may be optionally oxidized, and the N atom may be optionally quaternized.
  • heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. Unless stated otherwise, heterocyclyl may be optionally substituted.
  • the term heterocycloalkyl group can also be a C2 heterocycloalkyl, C2-C3 heterocycloalkyl, C 2 -C 4 heterocycloalkyl, C 2 -C 5 heterocycloalkyl, C 2 -C 6 heterocycloalkyl, C 2 -C 7 heterocycloalkyl, C 2 -C 8 heterocycloalkyl, C 2 -C 9 heterocycloalkyl, C 2 -C 10 heterocycloalkyl, C 2 - C11 heterocycloalkyl, and the like, up to and including a C2-145 heterocycloalkyl.
  • a C2 heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocycloalkyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, and the like.
  • heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring.
  • the heterocycloalkyl group can be substituted or unsubstituted.
  • heterocycloalkylene or “heterocycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical (e.g., , inter alia).
  • the term may be regarded as a product of removal of two hydrogen atoms from the corresponding heterocycloalkane (e.g., piperidine) by removal of two hydrogen atoms from the same (e.g., ) different (e.g., ) carbon atom(s) and/or heteroatom(s).
  • a heterocycloalkane e.g., piperidine
  • Non-limiting examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin and hexam
  • heteroaryl refers to a 5- to 20-membered heterocycle having aromatic character.
  • the ring one to thirteen carbon atoms, one to six heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a heteroaryl may include one or more rings, provided that at least one ring is aromatic.
  • the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • Non-limiting examples of polycyclic heteroaryls include indolyl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8- naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2- benzisoxazolyl, benzothien
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of PARP, in an assay that measures such response.
  • the phrase “inhibit,” as used herein, means to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and/or a protein’s expression, stability, function, or activity by a measurable amount or to prevent entirely.
  • Inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate a protein, a gene, and an mRNA stability, expression, function, and activity, e.g., antagonists.
  • PARP poly (ADP-ribose) polymerase
  • PARP-1 poly (ADP-ribose) polymerase-1
  • PARP-2 poly (ADP-ribose) polymerase-2
  • PARP inhibitor refers to a composition or compound that reduces at least in part, as compared to a control system that lacks the inhibitor, PARP activity, PARP expression or both, either directly or indirectly, using any method known to the skilled artisan. In certain embodiments, the presence of an inhibitor results in complete inhibition of PARP.
  • a “PARP-modulated disease” refers to a disease associated with excess PARP activity (cancer and inflammatory disorders) or a pathological lack of PARP activity (genotoxicity).
  • the terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject or individual is a human.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • the language “pharmaceutically acceptable salt” or “therapeutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. Unless specified otherwise, all groups disclosed herein may be optionally substituted. For example, reference to heterocyclyl, such as piperidin-3-yl herein is understood to include both unsubstituted and substituted piperidin-3-yl.
  • substituted refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet another embodiments, the substituents vary in number between one and two.
  • the compound of Formula (I) is a compound of Formula (IVB), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: .
  • the compound of Formula (I) is a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof:
  • the compound of Formula (I) is a compound of Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof:
  • the compound of Formula (I) is a compound of Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof:
  • the compound of Formula (I) is a compound of Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: .
  • the compound of Formula (I), (II), or (V) is not methyl 2-(4-(4- (4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5-carboxylate.
  • at least one of R 1a , R 1b , and R 1c is H.
  • R 1a , R 1b , and R 1c are H. In certain embodiments, each of R 1a , R 1b , and R 1c are H. In certain embodiments, R 1a and R 1b are H and R 1c is F. In certain embodiments, R 1a , R 1b , and R 1c are each H. In certain embodiments, R 1a is H. In certain embodiments, R 1a is F. In certain embodiments, R 1b is H. In certain embodiments, R 1b is F. In certain embodiments, R 1c is H. In certain embodiments, R 1c is F.
  • R 2a , R 2b , and R 2c are each independently selected from the group consisting of H and C 1 -C 6 alkyl.
  • R 2a is H.
  • R 2b is H.
  • R 2c is H.
  • R 3 in the compound of Formula (I) is .
  • A is selected from the group consisting .
  • L 2 is selected from the group consisting of a bond, -C2-C8 heterocycloalkylenyl-, and -C 2 -C 8 heteroarylenyl-.
  • R 4 is selected from the group consisting of H, C 1 -C 6 alkoxy, -C 2 - C8 heterocycloalkyl, -C6-C10 aryl, and heteroaryl, wherein the -C2-C8 heterocycloalkyl is independently substituted with 0, 1, 2, or 3 of R 8 or R 9 , and each of -C6-C10 aryl and heteroaryl is independently substituted with 0, 1, 2, or 3 of R 7 or R 9 .
  • R 4 when both L 1 and L 2 are a bond, R 4 is not H.
  • L 2 and R 4 can combine with the atoms to which they are bound to form a monocyclic or bicyclic C 2 -C 12 heterocyclyl substituted with 0, 1, 2, or 3 R 7 .
  • A is selected from the group consisting of . , . In certain embodiments, .
  • L 1 is . In certain embodiments, L 1 is . In certain embodiments, L 1 is . In certain embodiments, L 1 is . L 2 In certain embodiments of Formula (I), L 2 in the compound of Formula (I) is selected from the group consisting of a bond, -C2-C8 heterocycloalkylenyl-, and -C2-C8 heteroarylenyl-. In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, L 2 is . In certain embodiments, . In certain embodiments, L 2 is . In certain embodiments, . In certain embodiments, . ., L 2 is . In certain embodiments, . In certain embodiments, . In certain embodiments, . . In certain
  • R 5a is H.
  • R 5b is H.
  • R 5c is H.
  • R 5d is H.
  • R 6 in the compound of Formula (I) and (VIII) is selected from the group consisting of H and C 1 -C 6 alkyl.
  • R 6 is H.
  • R A and R B In certain embodiments, each occurrence of R A and R B is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl.
  • each occurrence of R A and R B is independently H or C1-C6 alkyl. occurrence of R A and R B is independently H.
  • R 4 in the compound of Formula (I), (II), (III), and (IVA) is selected from the group consisting of H, C1-C6 alkoxy, -C2-C8 heterocycloalkyl, -C6-C10 aryl, and heteroaryl, wherein the -C 2 -C 8 heterocycloalkyl is independently substituted with 0, 1, 2, or 3 of R 8 or R 9 , and each of -C 6 -C 10 aryl and heteroaryl is independently substituted with 0, 1, 2, or 3 of R 7 or R 9 .
  • R 4 is selected from the group consisting of H, C1-C6 alkoxy, s .
  • R 4 is .
  • R 4 . R 4 -R 7 In certain embodiments, R 4 comprises R 7 substitution. In such embodiments, R 4 refers to the combination of R 4 and R 7 .
  • R 4 is H. In certain embodiments, R 4 is OCH3. In certain embodiments, R 4 is . In certain embodiments, R 4 is . In certain embodiments, . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, certain embodiments, R 4 is . In certain embodiments, embodiments, R 4 is certain embodiments, R 4 is . In certain embodiments, . In certain embodiments, R 4 is . In certain * embodiments, R 4 is . In certain embodiments, R 4 is .
  • R 4 is . In certain embodiments, . certain embodiments, R 4 is . In certain embodiments, R 4 is . In certain embodiments, R 4 is . In certain embodiments, certain embodiments, embodiments, certain embodiments, certain embodiments, certain embodiments, R 4 is embodiments, certain embodiments, . In certain embodiments, certain embodiments, R 4 is In certain embodiments, R 4 embodiments, . certain embodiments, . n certain embodiments, certain embodiments, n certain embodiments, certain embodiments, R 4 is , L 2 and R 4 In certain embodiments, L 2 and R 4 in the compound of Formula (I) combine to form .
  • R 8 is H.
  • R 8 is CH3.
  • L 2 -R 4 -R 7 In certain embodiments of Formula (I), L 2 and R 4 combine to form certain embodiments, L 2 and R 4 combine to form certain embodiments, L 2 and R 4 combine to form certain embodiments, L 2 and R 4 combine to form . In certain embodiments, L 2 and R 4 combine to form certain embodiments, L 2 and R 4 combine to form 2 and R 4 combine to form .
  • B is . In certain embodiments, B is certain embodiments, B is . In certain embodiments, B is . In certain embodiments, embodiments, embodiments, certain embodiments, B is embodiments, certain embodiments, B is embodiments, certain embodiments, certain embodiments, B is embodiments, certain embodiments, certain embodiments, B is embodiments, certain embodiment
  • B is . In certain embodiments, certain embodiments, B is certain embodiments, certain embodiments, B is
  • n a is 0, 1, 2, or 3. In certain embodiments, n a is 0. In certain embodiments, n a is 1.
  • n a is 2. In certain embodiments, n a is 3. In certain embodiments, n b is 0, 1, 2, or 3. In certain embodiments, n b is 0. In certain embodiments, n b is 1. In certain embodiments, n b is 2. In certain embodiments, n b is 3. In certain embodiments, the sum of n a + n b is 2, 3, or 4. In certain embodiments, the sum of n a + n b is 2. In certain embodiments, the sum of n a + n b is 3. In certain embodiments, the sum of n a + n b is 4. m In certain embodiments, m is 0, 1, 2, or 3. In certain embodiments, m is 0.
  • m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. p In certain embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.
  • the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl either of which is optionally substituted with at least one of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, and -OH.
  • the substituted alkyl is -CH2OH, CH(CH3)OH, -CH2F, -CHF2, -CF3, or - CH2CF3.
  • the alkyl is -CH3.
  • the alkyl is -CH2CH3. In some embodiments, the alkyl is -CH2CH2OCH3. In some embodiments, the alkyl is - CH(CH 3 ) 2 . In some embodiments, the alkyl is -(CH 2 ) 2 CH 3 . In some embodiments, the alkyl is - (CH2)3CH3. In some embodiments, the alkyl is - C(CH3)3. In some embodiments, the alkyl is - CH2CH(CH3)2. In some embodiments, the alkyl is -CH(CH3)CH2CH3. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the halogen is F.
  • the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, the halogen is I.
  • the heterocyclyl is piperidinyl. In some embodiments, the piperidinyl is piperidin-4-yl. In some embodiments, the piperidinyl is piperidin-3-yl. In some embodiments, the piperidinyl is piperidin-2-yl. In some embodiments, the piperidinyl is piperidin-1-yl. In some embodiments, the piperidinyl is 4-hydroxy-piperidin-1-yl. In some embodiments, the heterocyclyl is pyrrolidinyl.
  • the pyrrolidinyl is pyrrolidin-2-yl. In some embodiments, the pyrrolidinyl is pyrrolidin-3-yl. In some embodiments, the heterocyclyl is azetidinyl. In some embodiments, the azetidinyl is azetidin-3-yl. In some embodiments, the heterocyclyl is oxetanyl. In some embodiments, the oxetanyl is oxetan-3-yl. In some embodiments, the heterocyclyl is morpholinyl. In some embodiments, the morpholinyl is morpholin-2-yl.
  • the morpholinyl is morpholin-3-yl. In some embodiments, the morpholinyl is morpholin-4-yl. In some embodiments, the heterocyclyl is tetrahydropyranyl. In some embodiments, the heterocyclyl is tetrahydro-2H-pyran-4-yl. In some embodiments, the heteroaryl is pyridinyl. In some embodiments, the pyridinyl is pyridin-2-yl. In some embodiments, the pyridinyl is pyridin-3-yl. In some embodiments, the pyridinyl is pyridin-4-yl. In some embodiments, the heteroaryl is pyrimidinyl.
  • the pyrimidinyl is pyrimidin-2-yl. In some embodiments, the pyrimidinyl is pyrimidin-4-yl. In some embodiments, the pyrimidinyl is pyrimidin-5-yl.
  • the heteroaryl is pyrazolyl. In some embodiments, the heteroaryl is 1H-pyrazol-4-yl, which is optionally substituted. In some embodiments, the heteroaryl is 1- methyl-1H-pyrazol-4-yl.
  • the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclobutyl.
  • the cycloalkyl is cyclohexyl. In some embodiments, the cycloalkyl is bicyclo[1.1.1]pentyl.
  • the heteroaryl is pyridinyl. In some embodiments, the pyridinyl is pyridin-2-yl. In some embodiments, the pyridinyl is pyridin-3-yl. In some embodiments, the pyridinyl is pyridin-4-yl. In some embodiments, the heteroaryl is pyrimidinyl. In some embodiments, the pyrimidinyl is pyrimidin-2-yl. In some embodiments, the pyrimidinyl is pyrimidin-4-yl.
  • the pyrimidinyl is pyrimidin-5-yl.
  • the compound is selected from the group consisting of: 2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 6-fluoro-2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((azetidin-3-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(azetidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(2,6-d
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises at least one additional therapeutically effective agent.
  • the compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers.
  • Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity.
  • Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non- labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols.
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • each protective group is removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t- butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.
  • carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively- removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t-butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para- methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC).
  • Bn benzyl
  • Cbz benzyloxycarbonyl
  • Alloc allyloxycarbonyl
  • the present disclosure provides a method of treating, ameliorating, and/or preventing a PARP-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure or the pharmaceutical composition of the present disclosure.
  • the disease or disorder is cancer.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, liver cancer, melanoma, lung cancer, malignant pancreatic cancer, stomach cancer, colon cancer, neuroblastoma, glioblastoma, multiple myeloma, Kaposi’s sarcoma, skin cancer, and prostate cancer.
  • the disease or disorder is a neurodegenerative disease or disorder.
  • the neurodegenerative disease or disorder is selected from the group consisting of Parkinson’s disease (PD), Alzheimer’s disease (AD), Lewy body dementia, Alzheimer’s disease related dementia, and Amyotrophic lateral sclerosis (ALS).
  • the at least one compound or pharmaceutical composition is administered to the subject by at least one route selected from the group consisting of oral, topical, nasal, inhalational, vaginal, buccal, rectal, peritoneal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous.
  • the subject is a mammal.
  • the mammal is a human.
  • the present disclosure relates in part to the identification of novel PARP inhibitors, which find use in treating, ameliorating, and/or preventing PARP-related neurodegenerative diseases and disorders.
  • the present disclosure provides novel inhibitors of PARPs, as well as compositions comprising the same, and their use in treating, ameliorating, and/or preventing PARP-mediated disease(s) and/or disorder(s).
  • the compounds of the disclosure bind to and inhibit at least one PARP.
  • the disclosure provides a method of inhibiting at least one PARP in a subject (e.g., at least one of PARP-1, PARP-2, TNKS-1, TNKS-2, PARP-6, PARP-7, PARP-8, PARP-10, or PARP-14).
  • more than one PARP are inhibited.
  • the method comprises administering to the subject a compound and/or composition of the disclosure.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either prior to or after the onset of the disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or disorder in the patient.
  • an effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • the compositions described herein are administered to the patient in dosages that range from one to five times per day or more.
  • the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors.
  • a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, or reduce one or more symptoms of a disease or disorder in a patient.
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
  • routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein.
  • the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
  • Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.
  • a suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day.
  • the amount of each dosage may be the same or different.
  • a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.
  • the amount of compound dosed per day may be administered, in non- limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
  • a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced to a level at which the improved disease is retained.
  • patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.
  • the compounds described herein can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • experimental reagents such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation.
  • 1 H NMR chemical shifts were reported with reference to tetramethylsilane peak (TMS as an internal standard) in parts per million (o ppm).
  • the 1 H NMR data were represented as: chemical shift (multiplicity s (singlet), bs (broad singlet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of triplets), tt (triplet of triplets), h (hextate), m (multiplet), number of protons and coupling constant).
  • Column chromatography Column chromatography Column chromatography purifications were performed using silica gel (40-63 ⁇ m) and flash chromatography was conducted using REVELERIS® X2 flash chromatography system.
  • Preparative TLC was performed using Silica Gel GF 1000 ⁇ m 20 x 20 cm glass backed plates. Purity and mass analysis for target compounds was performed on an Agilent 1260 infinity series liquid chromatography (LC) system (using Agilent Eclipse plus C18, 3.5 ⁇ m, 4.6 mm ⁇ 100 mm column) connected with Agilent 6120 quadrupole mass spectrometer (MS). Acetonitrile (ACN) and water (0.1% formic acid) mixtures were used as mobile phase for the analysis. A 12 min gradient run was performed with 30-70% ACN in water.
  • Agilent 1260 infinity series liquid chromatography (LC) system using Agilent Eclipse plus C18, 3.5 ⁇ m, 4.6 mm ⁇ 100 mm column
  • MS Agilent 6120 quadrupole mass spectrometer
  • HRMS High-resolution mass spectroscopy
  • EI LockSpray electrospray ionization
  • PARP1 enzyme inhibition assay The IC50 values for target compounds against PARP1 enzyme were calculated from a 10-point concentration-response curve using the BPS PARP1 Chemiluminescence Activity Assay Kit (Catalog #80551) (BPS Bioscience).
  • PARP1 WT (residues 1-1014), CAT ⁇ HD (residues 678-787) and Zn1-Zn3 ⁇ Zn2 domains (residues 1-366 ⁇ 97-206).
  • the WGR-CAT domain (518-1014) with the ⁇ VE mutation was expressed from a pET24 expression vector (Novagen) with a C-terminal hexahistidine tag. All mutations and deletions were performed using the QuickChange protocol (Stratagene) and verified by automated Sanger DNA sequencing.
  • PARP1 WT and mutant proteins were expressed and purified as described previously using three chromatography steps: Ni 2+ -affinity, heparin, and gel filtration.
  • Crystallization and data collection PARP1 CAT ⁇ HD was mixed with either compound 82, compound 65 or compound 75 in the following buffer: 25 mM HEPES pH 8.0, 150 mM NaCl, 1 mM EDTA, and 0,1 mM TCEP at the following concentrations: CAT ⁇ HD (30 mg/mL) and compound 82 (1.1 mM in DMSO, 10% final), CAT ⁇ HD (20 mg/mL) and compound 65 (0.73 mM in DMSO, 10% final), CAT ⁇ HD (10 mg/mL) and compound 75 (0.365 mM in DMSO, 7% final).
  • the PARP1 ⁇ VE/DNA complex was formed by mixing Zn1-Zn3 ⁇ Zn2 and WGR- CAT ⁇ VE at 300 ⁇ M each with a 5-bp DNA duplex at 165 ⁇ M (5’-CGACG-3’) in the following buffer: 25 mM HEPES pH 8.0, 150 mM NaCl, 1mM EDTA, and 0.1 mM TCEP. Crystals were grown by sitting drop vapor diffusion at 20 °C by mixing the PARP1 ⁇ VE/DNA complex with an equal amount of 12% PEG 6000 and 100 mM MES pH 6.5.
  • compound 75 bound to a PARP1 ⁇ VE/DNA complex
  • compound 75 in DMSO, final concentration of 625 mM was spiked into wells containing PARP1 ⁇ VE/DNA crystals (5% DMSO final). The compound heavily precipitated upon addition to the wells. Nevertheless, the crystals were kept in the presence of the compound for three days and then were rapidly transferred to a solution of 10% PEG 6000, 100 mM MES pH 6.5, 25% glycerol, 0.1 mM TCEP, 75 mM NaCl and 700 ⁇ M compound 75 (6% DMSO final) prior to flash cooling in liquid nitrogen.
  • X-ray diffraction data for all PARP1/compound complexes was collected at beamline 8.3.1 of the Advanced Light Source.
  • the data was processed using XDS. Structure determination of PARP1/compound complexes All PARP1/compound complex structures were determined by molecular replacement (MR) using the program PHASER as implemented in the CCP4 suite.
  • the structure of PARP1 CAT domain bound to A968427 (PDB 3GJW) was used as search model for CAT ⁇ HD after deleting the HD and ligand A968427 from the PDB file.
  • the structure of PARP1 apo ⁇ VE (PDB 7S6M) was used as search model for the PARP1 ⁇ VE/compound 75 complex.
  • a competitor unlabeled DNA of the same sequence was added at 2 ⁇ M and FP was measured over time on a VictorV plate reader (Perkin Elmer).
  • increasing concentrations of PARP1 WT was incubated for 30 min at RT with 5 nM of an 18- bp DNA duplex (5’-GGGTTGCGGCCGCTTGGG-3’) (SEQ ID NO:2) that carried a fluorescent FAM group on the complementary 5’ terminus in the following buffer: 12 mM HEPES pH 8.0, 300 mM NaCl, 4% glycerol, 5.7 mM BME, 0.075 mg/ml BSA, 5% DMSO with or without Veliparib, EB-47 or target compounds (150 ⁇ M).
  • SDS-PAGE PARP1 activity assay The SDS-PAGE PARP1 activity assay was performed essentially as described. PARP1 WT (300 nM) was preincubated with 300 nM of an 18-bp DNA duplex with or without Veliparib, EB-47 or target compounds (75 ⁇ M) for 10 min at RT in the presence of 5% DMSO.4 mM NAD + was added to the reaction and the mixture was incubated for 1 min or 5 min before quenching with addition of SDS loading buffer containing 0.1 M EDTA.
  • HXMS Hydrogen/deuterium exchange-mass spectrometry
  • ND samples of PARP1 were prepared in 10 mM HEPES, pH 7.0, 150 mM NaCl buffer and each 20 ⁇ L aliquot was quenched into 30 ⁇ L of quench buffer.
  • pepsin (Sigma) was immobilized to POROS 20 AL support (Applied Biosystems) in a 64 ⁇ L column (2 mm x 2 cm, Upchurch).
  • TARGA C85 ⁇ m Piccolo HPLC column (1.0 x 5.0 mm, Higgins Analytical) was used to trap the peptic peptides and later these peptides were analyzed through C18 HPLC column (0.3 x 75 mm, Agilent) with a 12- 100% buffer B gradient at 6 ⁇ L/ min (Buffer A: 0.1% formic acid; Buffer B: 0.1% formic acid, 99.9% acetonitrile). The effluent was electrosprayed into the Exactive Plus EMR- Orbitrap (Thermo Fisher Scientific). MS data acquisition over the mass range 200-2000 m/z were acquired on the Exactive Plus EMR- Orbitrap (Thermo Fisher Scientific) at 60,000 resolution.
  • the effluent was electrosprayed with ion spray voltage of 3.5 kV and capillary temperature operated at 250 °C.
  • PARP1 peptide identification ND samples were injected into LTQ orbitrap XL, (Thermo Fisher Scientific) for tandem mass spectroscopy (MS/MS) to identify PARP1 peptides.
  • MS/MS tandem mass spectroscopy
  • ions were fragmented by CID with normalized collision energy.
  • the SEQUEST from Bioworks was employed to identify the potential PARP1 peptides.
  • a 4 ppm of peptide tolerance and 0.1 AMU of fragment tolerance was used against an extensive decoy sequence database (custom database) containing the sequence of PARP1, pepsin and other common contaminants identified in prior HXMS studies. Non-specific digestion was employed to search the PARP1 peptic peptides.
  • a MATLAB based program called ExMS2 was used with P pep score of 0.1. With this exclusion list, MS/MS on second ND second was employed to collect the MS2 scan of the less intense peptides that were not identified in the previous ND sample. To increase the number of unique peptides and sequence coverage of the protein, the above steps were repeated four times.
  • Example 1 Compound synthesis General Methods Method A N,N-Diisopropylethylamine (3 equiv) and O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate (HBTU) (1.1 equiv) was added at 0 °C to a stirred solution of the appropriate carboxylic acid (1 equiv) in N,N-dimethylformamide (DMF), and the reaction was stirred for 30 min at the same temperature.
  • N,N-Dimethylformamide DMF
  • Reagents and conditions (a) 4-formylbenzoic acid, NH4OAc, DMF, 100 °C, 7 h, 80-85%; (b) N- Boc piperazine, HBTU, DIPEA, DMF, 0 °C to rt, overnight, 75-79%; (c) 4 N HCl/dioxane, DCM, 0 °C to rt, 6 h, 72-81%.
  • Reagents and conditions (a) NaN3 or N3R4, Cu(I)I, Et3N, DMSO, mw, 150 °C, 4-8 h.
  • Reagents and conditions (a) appropriately substituted 2-chloropyrimidines, DIPEA, dioxane/DMF (9:1), microwave, 160 °C, 45-60 min, 32-66%. Ring het refers to a monocyclic or bicyclic heterocycloalkyl (e.g., piperidinyl, azetidinyl, and 2,6-diazaspiro[3.3]heptanyl, inter alia).
  • Scheme 4 Reagents and conditions: (a) HBTU, DIPEA, substituted triazolopiperazine or substituted benzimidazole, DMF, 0 °C to rt, overnight, 55-72%.
  • L refers to a bond or optionally substituted C1-C3 alkylenyl.
  • the reaction was then diluted with ethyl acetate and the mixture was then extracted 3X with saturated NaHCO 3 and 3X with brine solutions, each time discarding the aqueous portion after each extraction.
  • the organic layer was then dried using MgSO4 and filtered through a celite.
  • the solution thus obtained was then dried under vacuum and washed with methanol to obtain Boc- protected intermediate (110 mg, 61% yield). Without further characterization the N-boc intermediate was then treated with conc. HCl for overnight.
  • the reaction was concentrated under vacuum and washed with methanol to obtain the title compound as cream colored solid in quantitative yield.
  • N-(bicyclo[1.1.1]pentan-1-yl)-2-chloropyrimidine-4-carboxamide 50A
  • 2-chloropyrimidine-4-carboxylic acid 200 mg, 1.26 mmol
  • dichloromethane 5.0 mL
  • oxalyl chloride 162 ⁇ L, 1.89 mmol
  • a catalytic amount of DMF was added and the reaction mixture was refluxed for two hours.
  • the reaction mixture was concentrated under reduced pressure and obtained residue was re-dissolved in tetrahydrofuran (5.0 mL).
  • Compound 81 was prepared by treating compound 15 (100 mg, 0.21 mmol) with NaOH (17 mg, 0.42 mmol) and THF/H2O in 1:1 ratio. The reaction was then subjected to reverse phase flash purification by using 0-100% methanol in water as the mobile phase, in a gradient manner to obtain 81 as a pale-yellow powder which was re-dissolved in water and subjected to freeze drying process. (50 mg, 49% yield), mp >310 °C.
  • the resultant organic layer was dried using MgSO 4 .
  • a slurry of filtrate with silica was prepared and concentrated.
  • the mixture was then purified by flash chromatography using DMC:MeOH ( ⁇ 9:1) as eluent to obtain 82 as a white powder.
  • the mixture was then subjected to flash chromatographic purification using DCM:MeOH (usually in the ratio of 90:10; run time varied depending on column size) as mobile phase, with gradient elution to obtain products in 23-63% yields (60 mg, 42% yield).
  • Example 2 PARP inhibitors (PARPis) for treating cancer and/or neurodegenerative disease(s)
  • PARPis PARP inhibitors
  • the inhibition assay described herein and a PARP isoform selectivity assays were used to study the activity of certain exemplary compounds disclosed herein.
  • the data provided herein regarding inhibition of one or more PARP isoforms demonstrates that certain compounds provided herein are useful for treating cancer (Tables 2-3).
  • the data provided herein regarding inhibition of one or more PARP isoforms demonstrates that certain compounds provided herein are useful for treating neurodegenerative disease(s) (Tables 2-3).
  • a compound which demonstrates at least about 10-fold greater inhibition for a first PARP isoform as compared to a second PARP isoform is considered a selective inhibitor of the first PARP isoform over the second PARP isoform.
  • a compound which demonstrates at least about 100-fold greater inhibition for a first PARP isoform as compared to a second PARP isoform is considered a selective inhibitor of the first PARP isoform over the second PARP isoform.
  • a compound which inhibits a first PARP isoform and does not significantly inhibit a second PARP isoform is considered selective. Table 2.
  • the active site pocket of PARP1 is located in the ART fold and is composed of two distinct binding sites: the nicotinamide (N) binding pocket and the adenosine (A) binding pocket (FIG.2A).
  • PARPi that contact these two sites include EB-47 (FIG.2B), BAD and olaparib, while veliparib being a relatively small compound only contacts the N binding pocket.
  • Talazoparib, niraparib and rucaparib all protrude from the N binding pocket and shoulder helix ⁇ F of the HD on its central region. Co-crystallization of compounds 75, 82 and 65 with PARP1 CAT ⁇ HD was attempted, thus representing the minimal catalytic region.
  • the substituents of both compounds also display high crystallographic B- factors relative to their respective compound core, which indicates that both substituents have a high degree of motion relative to a more stable core. Therefore, without wishing to be bound by any theory, it is possible that the poor pro-retention behavior of compounds 82 and 65 stems from their flexible interaction with the ART fold.
  • the co-crystal structure of 15 with PARP1 ART fold was previously disclosed.
  • the co-crystal structure revealed that while compound 15 was indeed interacting with the N binding pocket, it was not bound to the A binding pocket. Rather, compound 15 extends towards the active site loop (ASL) of the ART fold, a binding pose that would presumably severely clash with the HD.
  • ASL active site loop
  • FIG.3A Zn1, Zn3, WGR and CAT domains
  • FIG.3B-3C The crystal structure shows that compound 10 has inserted itself in between the HD and the ASL following a repositioning of its benzimidazole group (FIGs.3B-3C).
  • the electron density confirms this distinct binding pose (FIG.3D).
  • Compound 75 contacts helices ⁇ D and ⁇ F but in a manner that differs from 75, which could explain compound 75 milder phenotype. While compound 75 extends towards the hydrophobic core of the HD and appears buried (FIG.3E), 15 specifically shoulders the very N-terminal portion of helix ⁇ F, and is exposed to the solvent (FIG.3F).
  • Example 5 HXMS and PARP1 dynamics in the presence of the target compounds
  • HXMS was employed to measure the changes in the protein backbone dynamics of PARP1 in the presence of PARPi.
  • HXMS has successfully identified the allosteric communication that drives PARP1 activation upon binding to a DNA break and the reverse allostery from PARPi compounds EB-47 and 15.
  • Type I PARPi Type I behavior has been clearly observed at a timepoint of 100 s of HX, so that timepoint was monitored for three compounds: 75, 65, and 82 (FIGs.4A- 4G).
  • compound 75 destabilized ⁇ B, the adjacent linker region, and the C- terminal portion of ⁇ F (FIG.4A), in a manner similar to that of 15. It also stabilized other regions of the HD, namely ⁇ D, ⁇ E, the N-terminal portion of ⁇ F, and nearby linker residues bridging these helices. Moreover, compound 75 appears to protect other regions of PARP1 such as portions of both the Zn3 and WGR domains (FIG.4A and FIGs.4D-4E).
  • HX behavior is conferred by EB-47 and BAD when PARP1 is bound to a DNA break: i.e., destabilizing the critical regions within HD ( ⁇ B and ⁇ F helices) and strengthening the contacts between DNA-binding domain, WGR and HD, thereby confirming that compound 75 displays type I behavior.
  • Compound 65 displayed HX behavior more consistent with a Type II inhibitor (FIG.4B) talazoparib. It confers modest deprotection in the HD of helix ⁇ B and the adjacent linker region, which includes ⁇ C, and strong deprotection of the C-terminal portion of ⁇ F (FIG.4B, FIG.4D, and FIG.4F).
  • Example 6 Additional exemplary compounds which exhibit Type I PARPi behavior
  • certain triazolyl-piperidinyl compounds of the present disclosure exhibited Type I PARPi behavior, including carbamate, urea, amide, and N-alkyl piperidine triazolyl-piperidinyl compounds.
  • Non-limiting generic formulae for exemplary compounds exhibiting Type I PARPi behavior include: , wherein R C is independently selected from the group consisting of methyl, cyclopropyl, cyclobutyl, bicyclopentyl, oxetanyl, alkenyl, and alkynyl.
  • R C is independently selected from the group consisting of methyl, cyclopropyl, cyclobutyl, bicyclopentyl, oxetanyl, alkenyl, and alkynyl.
  • certain benzimidazolyl compounds of the present disclosure exhibited Type I PARPi behavior, including ethylenimine- and piperazine-linked compounds.
  • R 7a is H and R 7b is CH3.
  • R 7a is H and R 7b is Cl.
  • R 7a is Cl and R 7b is H.
  • R 7a is H and R 7b is F. In certain embodiments, R 7a is F and R 7b is H. In certain embodiments, R 7a is H and R 7b is Br. In certain embodiments, R 7a is Br and R 7b is H. In certain embodiments, R 7a is H and R 7b is CF3. In certain embodiments, R 7a is CF3 and R 7b is H. In certain embodiments, R 7a is H and R 7b is OCF 3 . In certain embodiments, R 7a is OCF 3 and R 7b is H. In certain embodiments, R 7a is H and R 7b is OCHF 2 . In certain embodiments, R 7a is OCHF 2 and R 7b is H.
  • R 7a is CF 3 and R 7b is F. In certain embodiments, R 7a is CF 3 and R 7b is Br. In certain embodiments, R 7a is Br and R 7b is CF 3 . In certain embodiments, R 7a is Br and R 7b is F. In certain embodiments, R 7a is F and R 7b is Br. In certain embodiments, R 7a is OCH 3 and R 7b is Br. In certain embodiments, R 7a is Br and R 7b is OCH 3 . In certain embodiments, R 7a is CN and R 7b is Cl. In certain embodiments, R 7a is Cl and R 7b is CN. In certain embodiments, R 7a is CN and R 7b is F.
  • R 7a is F and R 7b is CN. In certain embodiments, R 7a is Cl and R 7b is Br. In certain embodiments, R 7a is Br and R 7b is Cl. In certain embodiments, R 7a is Cl and R 7b is OCH 3 . In certain embodiments, R 7a is OCH 3 and R 7b is Cl. Sequence Listing SEQ ID NO:1
  • Embodiment 2 provides the compound of Embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 5a , R 5b , R 5c , and R 5d , if present, are each independently H.
  • Embodiment 3 provides the compound of Embodiment 2, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein A is selected from the group consisting of: .
  • Embodiment 4 provides the compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L 1 is selected from the group consisting of: .
  • Embodiment 5 provides the compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L 2 is selected from the group consisting of:
  • Embodiment 6 provides the compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (II):
  • Embodiment 7 provides the compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (III): , wherein: m is 0, 1, 2, or 3; n a is 0, 1, 2, or 3; n b is 0, 1, 2, or 3; and and the sum of n a + n b is 2, 3, or 4.
  • Embodiment 8 provides the compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (IVA): .
  • Embodiment 9 provides the compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: (a) at least one of R 1a , R 1b , and R 1c is H; (b) at least two of R 1a , R 1b , and R 1c are H; or (c) each of R 1a , R 1b , and R 1c are H.
  • Embodiment 10 provides the compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 1a , R 1b , and R 1c are each independently selected from the group consisting of H and F.
  • Embodiment 11 provides the compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein one of the following applies: (a) R 1a and R 1b are H and R 1c is F; and (b) R 1a , R 1b , and R 1c are each H.
  • Embodiment 12 provides the compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 2a , R 2b , and R 2c are each independently H.
  • Embodiment 16 provides the compound of any one of Embodiments 13-15, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein q is 0.
  • Embodiment 17 provides the compound of any one of Embodiments 13-16, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 4 is selected from the group consisting of H, OCH 3 , , .
  • Embodiment 22 provides the compound of Embodiment 20 or 21, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein n a is 1 and n b is 1.
  • Embodiment 24 provides the compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 4 is H.
  • Embodiment 25 provides the compound of any one of Embodiments 7 and 9-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 4 is H and m is 0 or 1, and one of the following applies: (a) n a is 1 and n b is 1; (b) n a is 2 and n b is 2; or (c) n a is 2 and n b is 1.
  • Embodiment 26 provides the compound of any one of Embodiments 8 and 9-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R 4 is C 2 -C 8 heterocycloalkyl.
  • Embodiment 27 provides the compound of Embodiment 26, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the C2-C8 heterocycloalkyl is pyrrolidinyl.
  • Embodiment 28 provides the compound of any one of Embodiments 1, 10-13, and 23, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L 2 and R 4 combine to form , , , , Embodiment 29 provides the compound of any one of Embodiments 1-4 and 10-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, ,
  • Embodiment 34 provides the compound of any one of Embodiments 1-33, which is selected from the group consisting of: 2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 6-fluoro-2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((azetidin-3-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(azetidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-((piperidin-4
  • Embodiment 35 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, and at least one pharmaceutically acceptable carrier.
  • Embodiment 36 provides the composition of Embodiment 35, further comprising at least one additional therapeutic agent that treats, ameliorates, or prevents cancer.
  • Embodiment 37 provides the composition of Embodiment 35, further comprising at least one additional therapeutic agent that treats, ameliorates, or prevents a neurodegenerative disease or disorder.
  • Embodiment 38 provides a method of inhibiting at least one PARP, the method comprising contacting the PARP with the compound of any one of Embodiments 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of any one of Embodiments 35-37.
  • Embodiment 39 provides the method of Embodiment 38, wherein the at least one PARP comprises PARP-1 and/or PARP-2.
  • Embodiment 40 provides the method of Embodiment 38 or 39, wherein the PARP is within a cell.
  • Embodiment 41 provides the method of Embodiment 40, wherein the cell is in vivo.
  • Embodiment 42 provides a method of treating, ameliorating, and/or preventing a PARP- mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any one of Embodiments 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of any one of Embodiments 35-37.
  • Embodiment 43 provides the method of Embodiment 42, wherein the disease or disorder is cancer.
  • Embodiment 44 provides the method of Embodiment 43, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, liver cancer, melanoma, lung cancer, malignant pancreatic cancer, stomach cancer, colon cancer, neuroblastoma, glioblastoma, multiple myeloma, Kaposi’s sarcoma, skin cancer, and prostate cancer.
  • Embodiment 45 provides the method of Embodiment 42, wherein the disease or disorder is a neurodegenerative disease or disorder.
  • Embodiment 46 provides the method of Embodiment 45, wherein the neurodegenerative disease or disorder is selected from the group consisting of Parkinson’s disease (PD), Alzheimer’s disease (AD), Lewy body dementia, Alzheimer’s disease related dementia, and Amyotrophic lateral sclerosis (ALS).
  • Embodiment 47 provides the method of any one of Embodiments 38-46, wherein the at least one compound or pharmaceutical composition is administered to the subject by at least one route selected from the group consisting of oral, topical, nasal, inhalational, vaginal, buccal, rectal, peritoneal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous.
  • Embodiment 48 provides the method of any one of Embodiments 38-47, wherein the subject is a mammal.
  • Embodiment 49 provides the method of Embodiment 48, wherein the mammal is a human.
  • the terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application.

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Abstract

L'invention concerne des composés qui inhibent la poly(ADP-ribose)polymérase (PARP) et des compositions pharmaceutiques les comprenant. Dans certains modes de réalisation, les composés sont appropriés pour traiter, améliorer et/ou prévenir le cancer. Dans certains modes de réalisation, les composés sont appropriés pour traiter, améliorer et/ou prévenir des maladies et/ou des troubles neurodégénératifs, comprenant, entre autres, la maladie de Parkinson, la maladie d'Alzheimer, la démence à corps de Lewy, la démence liée à la maladie d'Alzheimer ou la sclérose latérale amyotrophique.
PCT/US2024/042763 2023-08-18 2024-08-16 Composés et procédés d'inhibition de poly(adp-ribose)polymérases Pending WO2025042769A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6737421B1 (en) * 1999-04-22 2004-05-18 Abbott Gmbh & Co. Kg Cyclo-alkyl substituted benzimidazoles and their use as PARP inhibitors
US20060229289A1 (en) * 2005-04-11 2006-10-12 Gui-Dong Zhu 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors
US20160346306A1 (en) * 2014-01-21 2016-12-01 The Johns Hopkins University Therapy regimen and methods to sensitize cancer cells treated with epigenetic therapy to parp inhibitors in multiple cancers
US20200109156A1 (en) * 2017-05-24 2020-04-09 The Trustees Of The University Of Pennsylvania Radiolabeled and fluorescent parp inhibitors for imaging and radiotherapy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6737421B1 (en) * 1999-04-22 2004-05-18 Abbott Gmbh & Co. Kg Cyclo-alkyl substituted benzimidazoles and their use as PARP inhibitors
US20060229289A1 (en) * 2005-04-11 2006-10-12 Gui-Dong Zhu 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors
US20160346306A1 (en) * 2014-01-21 2016-12-01 The Johns Hopkins University Therapy regimen and methods to sensitize cancer cells treated with epigenetic therapy to parp inhibitors in multiple cancers
US20200109156A1 (en) * 2017-05-24 2020-04-09 The Trustees Of The University Of Pennsylvania Radiolabeled and fluorescent parp inhibitors for imaging and radiotherapy

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Title
DATABASE PubChem 17 February 2021 (2021-02-17), "CHEMBL81723", XP093283573, Database accession no. SID 103283845 *

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