WO2023139536A1 - Composés (4-pipérazin-1yl)-4-alkyl-phtalazin-1(2h)-one en tant qu'inhibiteurs de parp7 - Google Patents

Composés (4-pipérazin-1yl)-4-alkyl-phtalazin-1(2h)-one en tant qu'inhibiteurs de parp7 Download PDF

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WO2023139536A1
WO2023139536A1 PCT/IB2023/050507 IB2023050507W WO2023139536A1 WO 2023139536 A1 WO2023139536 A1 WO 2023139536A1 IB 2023050507 W IB2023050507 W IB 2023050507W WO 2023139536 A1 WO2023139536 A1 WO 2023139536A1
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substituted
unsubstituted
phthalazin
mmol
compound
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PCT/IB2023/050507
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Swaroop Kumar Venkata Satya VAKKALANKA
Debnath Bhuniya
Venkata Satyanarayana ELESWARAPU
Govindarajulu Babu
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Rhizen Pharmaceuticals Ag
Incozen Therapeutics Pvt. Ltd.
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Publication of WO2023139536A1 publication Critical patent/WO2023139536A1/fr

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    • 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
    • C07D487/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D401/14—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

Definitions

  • the present invention provides compounds of formula (I) as poly (ADP-ribose) polymerase 7 (PARP7) inhibitors, methods of preparing them, pharmaceutical compositions containing them, and their use in methods of treatment, prevention and/or amelioration of diseases or disorders involving PARP7.
  • PARP7 poly (ADP-ribose) polymerase 7
  • PARP Poly (ADP-ribose) polymerase
  • Poly (ADP-ribosyl)ation is involved in the regulation of many cellular processes such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability PARsylation, in addition to its well-studied role in DNA repair, and has been shown to modulate diverse processes, including cellular proliferation, DNA methylation, apoptosis, transcriptional regulation, and WNT signaling.
  • the PARP family are categorised based in part on their catalytic activity: the poly PARP’s catalyse the transfer of poly-ADP- ribose units onto their substrates, including PARP1, PARP2, PARP5A, PARP5b, and PARP 13 which is the only PARP family member whose catalytic activity could not be demonstrated ether in vitro or in vivo.
  • the mono PARP’s catalyse the transfer of mono-ADP-ribose units onto their substrates, including the majority of PARP family members.
  • the mono PARP protein family plays important roles in multiple stress responses associated with the development of inflammatory diseases, cancer, and neuro degenerative diseases.
  • PARP7 belongs to the mono PARP family and has been demonstrated to be overactive in tumors and plays a key role in cancer cell survival. Inhibition of PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, which effectively prevents cancer cells from evading the immune system.
  • the aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix/period-ARNT-single- minded ligand-activated transcription factor essential in mediating the adaptive responses to xenobiotics. It is activated by the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) but also by numerous other endogenous and dietary compounds (Denison et.
  • the AHR can be activated by a broad number of ligands including endogenous tryptophan metabolites such as kynurenine (Opitz et al., Nature, 478, 197-203, 2011) and certain polycyclic aromatic hydrocarbons such as 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) (Bock, Biochem. Pharmacol., 112, 1-5, 2016). Activation of the AHR induces target gene expression, including genes involved in metabolism such as cytochrome P4501A1 and P4501B1.
  • AHR target gene TCDD-inducible poly (ADP-ribose) polymerase (TIPARP, also referred to as PARP7), which functions as a negative regulator of certain AHR transcriptional targets (MacPherson et al., Int. J. Mol. Sci., 15, 7939-7957, 2014).
  • Aryl hydrocarbon receptor repressor and TIPARP use similar, but distinct, mechanisms to repress aryl hydrocarbon receptor signalling.
  • PARP7 is a gene regulated by AHR and an important member of the PARP family. PARP7 can only transfer a single ADP-ribose (MAR), which belongs to monoPARP.
  • MAR ADP-ribose
  • the PARP catalytic domain of PARP7 contains a zinc finger motif that can confer DNA binding and a WE domain that can mediate protein interaction (Ma et al., Biochem., 289, 499-506, 2001).
  • PARP7 mediated single ADP ribosylation is a reversible post-translational modification involving a variety of important biological processes, such as immune cell function, transcription regulation, protein expression and DNA repair.
  • PARP7 is part of the negative feedback loop that regulates AHR activity, and AHR can regulate immune function, inflammation and stem cell differentiation, and play a role in cancer.
  • PARP7 has been shown to be overactive in certain tumors and plays a key role in cancer cell survival.
  • PARP7 can enable cancer cells to "hide” out of the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signal transduction and suppression of the "brake” of innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors have shown long-lasting tumor growth inhibitory effects, effective anti-proliferative activity, and restoration of interferon signalling.
  • RBN-2397 being developed by Ribon Therapeutics, is the first PARP7 inhibitor that is in early phase of clinical trials demonstrated anti-tumor growth effect and induced tumor- specific adaptive immune memory in preclinical models (M.Gozgit et al., Cancer Cell, 39(9), 1214-1226, 2021). This indicates that PARP7 inhibitors may be excellent tumor treatment drugs.
  • PARP7 inhibitors may be excellent tumor treatment drugs.
  • PARP7 inhibitors there are still no PARP7 inhibitors widely used in clinical practice, and the function of PARP7 still needs to be elucidated. Whether it is to deepen the research on the mechanism and effects of PARP7 and/or to benefit cancer patients, there is a need for new PARP7 inhibitors.
  • the present invention relates to compounds of formula (I), methods for their preparation, pharmaceutical compositions containing them, and methods of treatment using them.
  • the compounds of formula (I), and pharmaceutically acceptable salts thereof are useful in the treatment, prevention and/or amelioration of diseases or disorders involving PARP7.
  • each occurrence of R 4 and R 4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, and substituted or unsubstituted carbocyclyl; or both R 4 and R 4a together with the carbon atom to which they are attached can form a carbonyl group, spiro group, substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted heterocyclyl ring; (b) when Ring is (ii), each occurrence of R 4 and R 4a is independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy
  • each ------ (dotted line) represents a bond. In one embodiment, each ------ (dotted line) does not represent a bond.
  • the compound of formula (I) is a compound of formula (IA): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond;
  • W 1 , W 2 , W 3 , and W 4 are independently selected from N, NR 1 , CR 1 , and CR 1 R 1a ; each occurrence of R 1 and R 1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino;
  • L 1 is selected from –(CR a R b )n-, -(CR a R
  • each ------ (dotted line) represents a bond. In one embodiment, each ------ (dotted line) does not represent a bond. [11] In one embodiment, the ring in formula (I) or (IA) is , , , , , , , or .
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein each ----- (dotted line) is a bond.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein each ----- (dotted line) is not a bond.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W 1 , W 2 , W 3 and W 4 are independently CR 1 or N.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W 1 , W 2 , and W 3 are independently CR 1 .
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W 4 is CR 1 or N, and R 1 is hydrogen or halogen (e.g., fluoro).
  • W 4 is CR 1 or N
  • R 1 is hydrogen or halogen (e.g., fluoro).
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein W 4 is N.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 1 is - (CR a R b ) n - wherein R a and R b are hydrogen, and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 1 is - (CR a R b )n- wherein one of R a and R b is substituted or unsubstituted alkyl (e.g., methyl) and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 1 is - (CR a R b ) n -O- wherein R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 1 is -O-.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 1 is - (CR a R b ) n -NR a -, R a and R b are each independently hydrogen or alkyl and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 1 is –CH 2 - NH-.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 1 is –CH 2 - N(CH3)-.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein R 2 and R 3 are hydrogen.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 2 is absent.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 2 is -O-.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 2 is - (CR a R b ) n -, R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein L 2 is - (CR a R b ) n -, R a is hydrogen, R b is hydroxy and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein R 2a and R 3a are hydrogen.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein X is absent.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein X is -C(O)- or -S(O) 2 -.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkyl.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is cyclopropyl or methyl.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is substituted or unsubstituted heterocyclyl.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is substituted or unsubstituted heteroaryl.
  • One embodiment is a compound of formula (I), (IA), or (IA-a), wherein Y is , , , , , , , , , , , , , , , , . , , or .
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein each ----- (dotted line) is a bond.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein each ----- (dotted line) is not a bond.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W 1 , W 2 , W 3 , and W 4 are CR 1 or N.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W 1 , W 2 , W 3 , are CR 1 .
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W 4 is CR 1 or N and R 1 is hydrogen or halogen (e.g., fluoro).
  • W 4 is CR 1 or N and R 1 is hydrogen or halogen (e.g., fluoro).
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein W 4 is N.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L 1 is - (CR a R b )n- wherein R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L 1 is - (CR a R b ) n -NR a - wherein R a and R b are each, independently, hydrogen or substituted or unsubstituted alkyl and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L 1 is -CH 2 - or –CH2-NH-,
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein R 2 and R 3 are hydrogen.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein L 2 is - (CR a R b ) n - wherein R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein R 2a and R 3a , together with the carbon atom to which they are attached, form a -C(O)- group.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein X is absent.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein Y is substituted or unsubstituted heterocyclyl.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein Y is substituted or unsubstituted heteroaryl.
  • One embodiment is a compound of formula (I), (IA), or (IA-b), wherein Y is , , , , , , , , , , , , , or .
  • the compound of formula (I) is a compound of formula (IB): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond;
  • W 1 , W 2 , W 3 , and W 4 are independently selected from N, NR 1 , CR 1 , and CR 1 R 1a ; each occurrence of R 1 and R 1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino;
  • One embodiment is a compound of formula (I) or (IB), wherein each ----- (dotted line) is a bond. [59] One embodiment is a compound of formula (I) or (IB), wherein each ----- (dotted line) is not a bond. [60] One embodiment is a compound of formula (I) or (IB), wherein W 1 , W 2 , W 3 , and W 4 are CR 1 ; and R 1 is hydrogen. [61] One embodiment is a compound of formula (I) or (IB), wherein L 1 is -(CR a R b )n- wherein R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I) or (IB), wherein R 2 and R 3 are hydrogen.
  • One embodiment is a compound of formula (I) or (IB), wherein L 2 is -(CR a R b )n- wherein R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I) or (IB), wherein R 2a and R 3a , together with the carbon atom to which they are attached, form a -C(O)- group.
  • One embodiment is a compound of formula (I) or (IB), wherein X is absent.
  • One embodiment is a compound of formula (I) or (IB), wherein X is -NH-.
  • One embodiment is a compound of formula (I) or (IB), wherein Y is substituted or unsubstituted heterocyclyl.
  • One embodiment is a compound of formula (I) or (IB), wherein Y is substituted or unsubstituted heteroaryl.
  • One embodiment is a compound of formula (I) or (IB), wherein Y is , , or .
  • the compound of formula (I) is a compound of formula (IC): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof; wherein each ------ (dotted line) independently represents an optional bond;
  • W 1 , W 2 , W 3 , and W 4 are independently selected from N, NR 1 , CR 1 , or CR 1 R 1a ; each occurrence of R 1 and R 1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino;
  • One embodiment is a compound of formula (I) or (IC), wherein each ----- (dotted line) is a bond.
  • One embodiment is a compound of formula (I) or (IC), wherein each ----- (dotted line) is not a bond.
  • One embodiment is a compound of formula (I) or (IC), wherein W 1 , W 2 , W 3 , and W 4 are CR 1 ; and R 1 is hydrogen.
  • One embodiment is a compound of formula (I) or (IC), wherein L 1 is -(CR a R b )n-; wherein R a and R b are hydrogen; and n is an integer “1”.
  • One embodiment is a compound of formula (I) or (IC), wherein R 2 and R 3 are hydrogen.
  • One embodiment is a compound of formula (I) or (IC), wherein L 2 is -(CR a R b )n-; wherein R a and R b are hydrogen; and n is an integer “1”.
  • One embodiment is a compound of formula (I) or (IC), wherein R 2a and R 3a are taken together with the carbon atom to which they are attached to form a -C(O)- group.
  • One embodiment is a compound of formula (I) or (IC), wherein X is absent.
  • One embodiment is a compound of formula (I) or (IC), wherein Y is optionally substituted heterocyclyl.
  • One embodiment is a compound of formula (I) or (IC), wherein Y is optionally substituted heteroaryl.
  • One embodiment is a compound of formula (I) or (IC), wherein Y is .
  • the compound of formula (I) is a compound of formula (ID):
  • W 1 , W 2 , W 3 , and W 4 are independently selected from N, NR 1 , CR 1 , or CR 1 R 1a ; each occurrence of R 1 and R 1a is independently selected from hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted amino;
  • One embodiment is a compound of formula (I) or (ID), wherein each ----- (dotted line) is a bond.
  • One embodiment is a compound of formula (I) or (ID), wherein each ----- (dotted line) is not a bond.
  • One embodiment is a compound of formula (I) or (ID), wherein W 1 , W 2 , W 3 , and W 4 are CR 1 and R 1 is hydrogen.
  • One embodiment is a compound of formula (I) or (ID), wherein L 1 is -(CR a R b ) n - wherein R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I) or (ID), wherein R 2 and R 3 are hydrogen.
  • One embodiment is a compound of formula (I) or (ID), wherein L 2 is -(CR a R b ) n - wherein R a and R b are hydrogen and n is 1.
  • One embodiment is a compound of formula (I) or (ID), wherein R 2a and R 3a together with the carbon atom to which they are attached form a -C(O)- group.
  • One embodiment is a compound of formula (I) or (ID), wherein X is absent.
  • One embodiment is a compound of formula (I) or (ID), wherein Y is substituted or unsubstituted heterocyclyl.
  • One embodiment is a compound of formula (I) or (ID), wherein Y is substituted or unsubstituted heteroaryl.
  • One embodiment is a compound of formula (I) or (ID), wherein Y is .
  • Representative compounds of the present invention include those recited below.
  • the present invention should not be construed to be limited to the compounds recited below: 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)phthalazin- 1(2H)-one, 4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-4-oxobutyl)phthalazin-1(2H)-one, 4-(4-(4-(methylsulfonyl)piperazin-1-yl)-4-oxobutyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)phthalazin-1(2H)-one, 4-(4-oxo-4-(4-(pyrazin-2-yl)piperazin-1-yl)butyl)phthalazin-1(2H)-one, 4-(
  • the present invention includes the compounds in Table 1 and tautomers thereof, prodrugs thereof, N-oxides thereof, stereoisomers thereof, pharmaceutically acceptable esters thereof and pharmaceutically acceptable salts thereof.
  • Table 1 Ex. Structure Ex. Structure Ex. Structure No. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 [96] Additional representative compounds are shown in Table 2.
  • the present invention includes the compounds in Table 2 and tautomers thereof, prodrugs thereof, N-oxides thereof, stereoisomers thereof, pharmaceutically acceptable esters thereof and pharmaceutically acceptable salts thereof.
  • Table 2 Ex. Structure Ex. Structure Ex. Structure No. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
  • Yet another aspect of the present invention is a method for inhibiting PARP (such as PARP7) in a patient (e.g., a patient in need thereof) comprising administering to the patient an effective amount of at least one compound of the present invention (for example, a compound of formula (I), as defined above).
  • Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune, or proliferative disease (e.g., via inhibition of PARP (such as PARP7)) by administering to a patient in need of such treatment an effective amount of at least one compound of the present invention.
  • the compound of the present invention inhibits PARP (i.e., an effective amount of the compound is administered to inhibit PARP).
  • the compound of the present invention inhibits PARP7 (i.e., an effective amount of the compound is administered to inhibit PARP7).
  • Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune, or proliferative disease (e.g., via inhibition of PARP (such as PARP7)) by administering to a patient in need of such treatment an effective amount of at least one compound of the present invention, in combination (simultaneously or sequentially) with at least one other anti-inflammatory, immunomodulator or anti-cancer agent.
  • the compound of the present invention inhibits PARP (such as PARP7).
  • the compounds of formula (I), and pharmaceutically acceptable esters or salts thereof can be administered for the treatment, prevention and/or amelioration of diseases or disorders associated with PARP (such as PARP7), in particular the amelioration of diseases or disorders mediated by PARP7, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, and cancer and other proliferative diseases or disorders.
  • PARP7 diseases or disorders associated with PARP
  • the compounds of the present invention are useful in the treatment of a variety of cancers, including, but not limited to: • solid tumours of breast, non-small cell lung, pancreatic, endometrial, colon, oesophageal, prostate, ovary, urothelial cancer, head and neck cancer.
  • carcinoma including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; • hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma and Burkett's lymphoma; • hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; • tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; • brain cancers such as glioblast
  • the compounds of the present invention are useful in the treatment of cancer (including, but not limited to, those types mentioned herein), viral infections (including but not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anaemia, ischemic injury associated with myocardial infarctions
  • cancer including, but not limited to, those types mentioned herein
  • viral infections
  • the compounds of the present invention are useful in the treatment of cancer metabolic pathway diseases or disorders, non-alcoholic fatty liver disease, diabetes, abnormal lipid metabolism, hypothyroidism, metabolic syndrome, Cushing’s syndrome, and polycystic ovary syndrome (PCOS).
  • the compounds of present invention can modulate the level of cellular RNA and DNA synthesis.
  • the compounds of present invention are therefore useful in the treatment of viral infections (including, but not limited to, HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
  • the compounds of the present invention are useful in the chemoprevention of cancer.
  • Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.
  • the compounds described herein are also useful in inhibiting tumor angiogenesis and metastasis.
  • One embodiment of the invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need thereof by administering to the patient an effective amount of one or more compounds of the present invention.
  • Another embodiment of the present invention is a method of treating an immune system-related disease (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis and disorders of the immune system), cancer or other proliferative disease, a hepatic disease or disorder, a renal disease or disorder, or a metabolic pathway disease or disorder comprising administering to a patient in need thereof an effective amount of one or more compounds of the present invention.
  • an immune system-related disease e.g., an autoimmune disease
  • a disease or disorder involving inflammation e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis and disorders of the immune system
  • immune disorders include, but are not limited to, psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease (e.g., allergic rhinitis), vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune haemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepati
  • allergic disease
  • the compounds described herein are used as immunosuppressants to prevent transplant graft rejections, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), and graft - versus - host disease.
  • transplant graft rejections result from tissue or organ transplants.
  • graft-versus-host disease results from bone marrow or stem cell transplantation.
  • One embodiment is a method of preventing or decreasing the risk of transplant graft rejection, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), or graft - versus - host disease by administering to a patient in need of such treatment an effective amount of one or more compounds of the present invention.
  • the compounds of the present invention are also useful in combination (administered together or sequentially) with known anti-cancer treatments, such as, but not limited to, radiation therapy or with cytostatic, cytotoxic or anticancer agents, such as, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; PI3K inhibitors; EGF inhibitors;
  • the compounds of the present invention are also useful in combination (administered together or sequentially) with one or more steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or immune selective anti-inflammatory derivatives (ImSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ImSAIDs immune selective anti-inflammatory derivatives
  • the present invention further provides a pharmaceutical composition comprising one or more compounds of the present invention (such as a compound having formula (I), or a pharmaceutically acceptable salt thereof) together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may further comprise one or more of the additional active ingredients identified above, such as other anti-cancer agents.
  • the pharmaceutical composition includes a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a method of treating cancer in a patient in need thereof by administering a therapeutically effective amount of a compound of the present invention.
  • the compounds of the present invention are effective for treating hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia.
  • the compounds of the present invention are also effective for treating carcinoma of the bladder, carcinoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • Yet another embodiment is a method of treating leukemia in a patient in need thereof comprising administering a therapeutically effective amount of a compound of the present invention.
  • the compounds of the present invention are effective for treating carcinoma of the breast, ovarian cancer, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer or stomach cancer.
  • DETAILED DESCRIPTION OF THE INVENTION [115] As used herein the following definitions shall apply unless otherwise indicated. Further, many of the groups defined herein can be optionally substituted. The listing of substituents in the definition is exemplary and is not to be construed to limit the substituents defined elsewhere in the specification.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl).
  • C1-6 alkyl refers to an alkyl group as defined above having 1 to 6 carbon atoms.
  • C 2-4 alkyl refers to an alkyl group as defined above having 2 to 4 carbon atoms.
  • C1-3 alkyl refers to an alkyl group as defined above having 1 to 3 carbon atoms.
  • alkyl refers to a hydrocarbon chain radical as mentioned above which is bivalent.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Examples of multicyclic cycloalkyl groups include, for example, perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • C 3-6 cycloalkyl refers to a cycloalkyl group as defined above having 3 to 6 carbon atoms.
  • aryl refers to an aromatic radical having 6 to 20 carbon atoms, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, and indanyl.
  • heterocyclic ring refers to a non-aromatic 3-to- 15-member ring radical which consists of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulphur.
  • the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized.
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • heterocyclyl refers to a heterocylic ring radical as defined above.
  • the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • heteroaryl refers to an optionally substituted 5- to14-membered aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • heterocyclic ring or “heteroaryl” radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, qui
  • heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • Substitution or the combinations of substituents envisioned by this invention are preferably those that result in the formation of a stable or chemically feasible compound.
  • stable refers to the compounds or the structure that are not substantially altered when subjected to conditions to allow for their production, detection and preferably their recovery, purification and incorporation into a pharmaceutical composition.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl” cannot be “substituted alkenyl”.
  • halo means fluoro, chloro, bromo or iodo.
  • haloalkyl means alkyl, alkenyl, alkynyl and alkoxy structures, respectively, that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Suitable carboxy-protecting groups include, but are not limited to, -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Intermediate mixtures include a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78.
  • Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • tautomer and “tautomers” refer to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention. “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond.
  • tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached.
  • An example of tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • a "leaving group or atom” is any group or atom that, under the reaction conditions, cleaves from the starting material, thus promoting reaction at a specified site. Suitable examples of leaving groups, unless otherwise specified, are halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.
  • the term “prodrug” refers to a compound, which is an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes. Prodrug design is discussed generally in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996).
  • prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product.
  • the prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life.
  • prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate.
  • the resulting conjugate can be inactivated and excreted in the urine or rendered more potent than the parent compound.
  • High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into circulation, thereby effectively increasing the biological half-life of the originally administered compound.
  • ester refers to a compound, which is formed by reaction between an acid and an alcohol with elimination of water.
  • An ester can be represented by the general formula RCOOR' wherein, e.g., R’ is alkyl.
  • the instant invention also includes the compounds which differ only in the presence of one or more isotopically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabelled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • salts forming part of this invention include, but are not limited to, salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine,
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • compositions which both active agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or simultaneous administration in a composition in which both agents are present.
  • effective amount or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to show the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • the specific dose will vary depending on the compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • the amount of compound administered ranges from about 0.1 mg to about 5 g, from about 1 mg to about 2.0 g, from about 100 mg to about 1.5 g, from about 200 mg to about 1.5 g, from about 400 mg to about 1.5 g, or from about 400 mg to about 1 g.
  • treatment As used herein, “treatment,” “treating,” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • a "therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the term "subject" or “patient” refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics and veterinary applications (e.g., dogs, cats, cows, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese).
  • the patient is a mammal, and in some embodiments, the patient is human.
  • Radionuclides e.g., actinium and thorium radionuclides
  • LET low linear energy transfer
  • beta emitters i.e. beta emitters
  • conversion electron emitters e.g. strontium-89 and samarium-153- EDTMP
  • high-energy radiation including without limitation x-rays, gamma rays, and neutrons.
  • compositions include, but is not limited to, all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the methods of the invention may be applied to cell populations in vivo or ex vivo.
  • "In vivo" means within a living individual, as within an animal or human or in a subject's body. In this context, the methods of the invention may be used therapeutically or prophylactically in an individual.
  • “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including, but not limited to, fluid or tissue samples obtained from individuals. Such samples may be obtained by methods known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the invention may be used ex vivo or in vitro to determine the optimal schedule and/or dosing of administration of a PARP inhibitor, more specifically a PARP7 inhibitor, for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental or diagnostic purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art.
  • Pharmaceutical Compositions [148]
  • the present invention also provides a pharmaceutical composition comprising one or more compounds of the present invention.
  • the pharmaceutical composition may include one or more additional active ingredients as described herein.
  • the pharmaceutical composition may be administered for any of the disorders described herein.
  • compositions described herein are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient.
  • the pharmaceutical compositions contain a compound of the present invention as the active ingredient and one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • pharmaceutical compositions described herein can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions.
  • the subject compounds and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
  • Methods described herein include administration of a compound of the present invention by itself, or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants, flavorings, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.
  • Preparations of various pharmaceutical compositions are known in the art.
  • the compounds and pharmaceutical compositions of the present invention can be administered by any route that enables delivery of the compounds to the site of action, such as oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal and infusion), topical administration (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • the compounds and pharmaceutical compositions can also be administered intraadiposally or intrathecally.
  • the pharmaceutical compositions can be administered in solid, semi-solid, liquid or gaseous form, or may be in dried powder form, such as lyophilized form.
  • the pharmaceutical compositions can be packaged in forms convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, and lozenges.
  • the type of packaging will generally depend on the desired route of administration.
  • Implantable sustained release formulations are also contemplated, as are transdermal formulations.
  • Method of Treatment [155]
  • the present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of PARP and/or due to an excess of PARP.
  • One embodiment is a method of inhibiting PARP (e.g., PARP7) in a subject (e.g., a human subject) in need thereof comprising administering an effective amount of a compound described herein.
  • the present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of PARP7 and/or due to an excess of PARP7.
  • the treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention.
  • the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention.
  • the individual to be treated may be a mammal, preferably human, or another animal.
  • individuals include but are not limited to farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
  • the present invention also relates to a method of treating a hyperproliferative disorder in a subject (e.g., a mammal) that comprises administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the method relates to the treatment of cancer, such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS- related (e.g.
  • cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral
  • the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • BPH benign prostatic hypertrophy
  • the present invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a subject (e.g., a mammal) that comprises administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma
  • diabetes diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangio
  • Patients that can be treated with compounds of the present invention according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; pancreatic cancer such as epitheliod carcinoma in the pancreatic
  • the present invention further provides methods of inhibiting PARP7 by contacting a PARP7 enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the PARP7 enzyme. In some embodiments, the present invention provides methods of inhibiting PARP7 enzyme activity by contacting a PARP7 enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the PARP7 enzyme. In some embodiments, the present invention provides methods of inhibiting PARP7 enzyme activity.
  • the present invention provides methods of inhibiting PARP7 activity in an animal (including a mammal such as a human) by contacting the animal with an amount of a compound of the present invention sufficient to inhibit the activity of the PARP7 enzyme in the animal.
  • a compound of formula (I) can be synthesized by an amide coupling reaction of a compound of formula (1) where both R 2a and R 3a together with the carbon atom to which they are attached form a carbonyl group, with a compound of formula (2), using a coupling agent such as, e.g., HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate), T 3 P (propylphosphonic anhydride) (PPAA), or EDC-HCl (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride).
  • a coupling agent such as, e.g., HATU (1-[bis(dimethylamino)
  • Illustration 5 Scheme-2 A compound of formula (I) can be synthesized as shown in Scheme-2 by Wittig reaction of a compound of formula (3) with a compound of formula (4) to form a compound of formula (5), which is then reacted with hydrazine. This scheme is illustrated below as Illustration 6. Illustration 6:
  • a compound of formula (I) can be synthesized by N-arylation, N-alkylation, N- acylation/sulfonylation or Buchwald coupling reaction of a compound of formula (6) with a compound of formula (7), where Lg is halogen or other leaving group, or a boronate functional group, in a suitable solvent, such as DMF, THF, DMSO, n-BuOH, i-prOH, toluene or N- methylpyrrolidone, in the presence of a suitable base, such as potassium carbonate, cesium carbonate, sodium tert-butoxide or DIPEA and a suitable palladium catalyst, such as Pd(Ph 3 P) 4 or Pd2dba3.
  • a suitable solvent such as DMF, THF, DMSO, n-BuOH, i-prOH, toluene or N- methylpyrrolidone
  • a suitable base such as potassium carbonate, cesium carbonate, sodium ter
  • the organic layer is washed with water, dried using anhydrous Na2SO4 and distilled in vacuo using a rotavapor to obtain a crude product.
  • the crude product is purified by combi-flash using a suitable mixture of ethyl acetate and petroleum ether or a mixture of methanol and dichloromethane.
  • N-Arylation reactions are also performed by Buckwald reaction in suitable solvents like DMF, DMSO, Toluene or N-methylpyrrolidone, suitable bases like potassium carbonate, caesium carbonate, sodium tert-butoxide or DIPEA and suitable palladium catalysts like Pd(Ph3P)4 or Pd2dba3.
  • reaction mixture is then diluted with water and extracted using a suitable solvent (such as ethyl acetate, dichloromethane or a mixture of methanol and dichloromethane).
  • a suitable solvent such as ethyl acetate, dichloromethane or a mixture of methanol and dichloromethane.
  • the organic layer is washed with saturated sodium bicarbonate solution, water, brine solution, then dried using anhydrous Na2SO4 and distilled in vacuo using a rotavapor to obtain a crude product.
  • the crude product is purified by combi-flash using a suitable mixture of ethyl acetate and petroleum ether or a mixture of methanol and dichloromethane.
  • reaction mixture cooled to 100°C and water was added to the reaction mixture. Continued the reaction at 100°C for 18 h. After 18 h, reaction mixture cooled to room temperature and diluted with ethyl acetate (250 ml). Reaction mixture filtered on a plug of celite and celite bed washed with ethyl acetate (100 ml). Combined ethyl acetate filtrates were washed with water (200 ml), brine solution (200 ml) and saturated aqueous lithium chloride solution (200 ml). Organic layer dried on anhydrous Na2SO4 and evaporated to obtain a crude.
  • reaction mixture was heated to 80°C and stirred for 16h. After 16h the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (15:85) as eluent to obtain the title compound as a pale-brown solid (300 mg). Yield: 32%.
  • Tetrakis triphenylphosphine palladium (0) 160 mg, 0.14 mmol were added and purged under nitrogen for 20 min.
  • the reaction mixture was heated to 110°C and stirred for 20h. After 20h, the reaction mixture was filtered through cealite bed and washed with ethyl acetate (100 ml). The organic layer was distilled under reduced pressure using rotavap to obtain a crude. Crude product was purified by combi-flash using ethyl acetate and Petroleum ether (4:96) as eluent to obtain the title compound as a off-white solid (550 mg). Yield: 61%.
  • Example 1 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)phthalazin-1(2H)- one [370] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (4 ml), intermediate 11 (131 mg, 0.43 mmol), pyridine (204 mg, 2.58 mmol) and T3P (Propylphosphonic anhydride) (411 mg, 1.29 mmol; 0.82 ml of 50% solution in ethyl acetate). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent.
  • Example 3 4-(4-(4-(methylsulfonyl)piperazin-1-yl)-4-oxobutyl)phthalazin-1(2H)-one [372] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (4 ml), intermediate 15 (135 mg, 0.51 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (5:95) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 49. M.P.: 225-228 o C.
  • Example 4 4-(4-oxo-4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)phthalazin-1(2H)-one [373] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 17 (112 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4.1:95.9) as eluent. Appearance: Pale brown solid. Yield: 100 mg. % Yield: 61. M.P.: 198-201 o C.
  • Example 6 7-fluoro-4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1- yl)butyl)phthalazin-1(2H)-one [375] Following the general procedure 6, the titled compound was synthesized from intermediate 22 (100 mg, 0.40 mmol), DMF (3 ml), intermediate 11 (134 mg, 0.40 mmol), DIPEA (258 mg, 2.0/0 mmol) and HBTU (182 mg, 0.48 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 43.
  • Example 7 4-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)phthalazin-1(2H)-one [376] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2 ml), intermediate 24 (121 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (4:96) as eluent. Appearance: Pale brown solid. Yield: 80 mg. % Yield: 47.
  • Example 16 4-(3-hydroxy-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1- yl)butyl)phthalazin-1(2H)-one [385] To intermediate 52 (150 mg, 0.27 mmol) in dichloromethane (10 ml) cooled to 0 o C, BCl 3 (1M in dichloromethane, 5.5 ml) was added and stirred for 1h. After 1h, the reaction mixture was quenched with saturated sodium bicarbonate solution (5 ml), extracted with dichloromethane (3 x 50 ml) and distilled under reduced pressure using rotavap to obtain a crude.
  • Example 17 4-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pentan-2-yl)phthalazin- 1(2H)-one [386] Following the general procedure 6, the titled compound was synthesized from intermediate 55 (60 mg, 0.24 mmol), DMF (2.5 ml), intermediate 11 (82 mg, 0.27 mmol DIPEA (160 mg, 1.2 mmol) and HBTU (110 mg, 0.29 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Pale-brown solid. Yield: 50 mg. % Yield: 45.
  • Example 18 4-(4-(4-(5-(difluoromethoxy)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)phthalazin-1(2H)- one [387] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2.5 ml), intermediate 57 (143 mg, 0.47 mmol DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0519 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2:98) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 52.
  • Example 20 4-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-1-yl)butyl)phthalazin-1(2H)- one [389] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2.5 ml), intermediate 63 (127 mg, 0.47 mmol DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.519 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 90 mg. % Yield: 47.
  • Example 22 4-(4-(4-(5-(difluoromethoxy)pyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)phthalazin- 1(2H)-one [391] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (3 ml), intermediate 67 (144 mg, 0.38 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid. Yield: 80 mg. % Yield: 42.
  • Example 27 4-(4-oxo-3,4-dihydrophthalazin-1-yl)butyl 4-(5-(trifluoromethyl)pyrimidin-2- yl)piperazine-1-carboxylate [396] Following the general procedure 2, the titled compound was synthesized from Intermediate 80 (0.35 g, 0.76 mmol), 2-propanol (10 ml), and hydrazine hydrate (57 mg, 1.1 mmol). Purification: Combi-Flash. Eluent: ethyl acetate and petroleum ether (88:12) as eluent. Appearance: Off-white solid. Yield: 135 mg. % Yield: 37. M.P.: 165-168 o C.
  • Example 28 4-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)phthalazin-1(2H)- one [397]
  • the titled compound was synthesized from intermediate 69 (1.0 g, 2.67 mmol), n-butanol (5 ml), 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (411 mg, 2.67 mmol) and DIPEA (1.73 g, 13.39 mmol).
  • Purification Combi-Flash.
  • Eluent methanol and dichloromethane (4:96) as eluent. Appearance: Pale-brown solid.
  • Example 33 4-(4-(4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)-4-oxobutyl)phthalazin-1(2H)-one [402] Following the general procedure 4, the titled compound was synthesized from intermediate 92 (200 mg, 0.57 mmol), N-methylpyrrolidone (5 ml), 2,5-dichloropyrimidine (93.2 mg, 0.62 mmol) and DIPEA (221 mg, 1.71 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3.5:96.5) as eluent. Appearance: Off-white solid. Yield: 35 mg. % Yield: 14.
  • Example 35 4-(3-(4-(5-chloropyrimidin-2-yl)-2-oxopiperazin-1-yl)propyl)phthalazin-1(2H)-one [404] Following the general procedure 2, the titled compound was synthesized from Intermediate 100 (0.280 g, 0.72 mmol), 2-propanol (10 ml), and hydrazine hydrate (146 mg, 2.9 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.9:97.1) as eluent. Appearance: Off-white solid. Yield: 110 mg. % Yield: 37. M.P.: 228-232 o C.
  • Example 36 4-(4-(4-(5-chloro-4-methylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)phthalazin-1(2H)- one [405] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (2.5 ml), intermediate 102 (135 mg, 0.39 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.51 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (3:97) as eluent. Appearance: Off-white solid. Yield: 65 mg. % Yield: 35.
  • Example 38 4-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropyl)phthalazin-1(2H)-one [407] Following the general procedure 6, the titled compound was synthesized from intermediate 107 (100 mg, 0.45 mmol), DMF (5 ml), intermediate 28 (137 mg, 0.50 mmol), DIPEA (296 mg, 2.29 mmol) and HBTU (209 mg, 0.55 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.5:97.5) as eluent. Appearance: Off-white solid.
  • Example 40 4-((3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)phthalazin- 1(2H)-one [409] To TFA (980 mg, 8.6 mmol) and trifluoromethanesulfonic acid (27 mg, 0.18 mmol) cooled to 0°C, intermediate 112 (100 mg, 0.18 mmol) was added and stirred at room temperature for 1h.
  • Example 41 4-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1- yl)propoxy)methyl)phthalazin-1(2H)-one [410] To TFA (1.50 g, 13.0 mmol) and trifluoromethanesulfonic acid (41 mg, 0.27 mmol) cooled to 0°C, intermediate 114 (160 mg, 0.27 mmol) was added and stirred at room temperature for 1h.
  • Example 42 4-((2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1- yl)ethoxy)methyl)phthalazin-1(2H)-one [411] To TFA (1.4 g, 12.0 mmol) and trifluoromethanesulfonic acid (52.0 mg, 0.35 mmol) cooled to 0°C, intermediate 117 (200 mg, 0.35 mmol) was added and stirred at room temperature for 1h.
  • Example 43 4-(4-(4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)phthalazin- 1(2H)-one [412] Following the general procedure 6, the titled compound was synthesized from intermediate 119 (230 mg, 0.71 mmol), DMF (5 ml), intermediate 11 (150 mg, 0.65 mmol), DIPEA (500 mg, 3.9 mmol) and HBTU (290 mg, 0.78 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (1:99) as eluent. Appearance: Off-white solid. Yield: 150 mg. % Yield: 50.
  • Example 44 4-(5-(4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-5- oxopentyl)phthalazin-1(2H)-one [413] Following the general procedure 6, the titled compound was synthesized from intermediate 119 (200 mg, 0.63 mmol), DMF (5 ml), intermediate 45 (140 mg, 0.57 mmol), DIPEA (440 mg, 3.4 mmol) and HBTU (260 mg, 0.68 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (1:99) as eluent. Appearance: Off-white solid. Yield: 100 mg. % Yield: 37.
  • Example 45 4-(4-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)phthalazin- 1(2H)-one [414] Following the general procedure 6, the titled compound was synthesized from intermediate 121 (240 mg, 0.71 mmol), DMF (5 ml), intermediate 11 (150 mg, 0.65 mmol), DIPEA (500 mg, 3.9 mmol) and HBTU (290 mg, 0.78 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (2.3:97.7) as eluent. Appearance: Pale-brown solid. Yield: 150 mg.
  • Example 48 8-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)pyrido[2,3- d]pyridazin-5(6H)-one [417] Following the general procedure 6, the titled compound was synthesized from intermediate 132 (110 mg, 0.47 mmol), DMF (5 ml), intermediate 11 (170 mg, 0.57 mmol), DIPEA (300 mg, 2.4 mmol) and HBTU (210 mg, 0.57 mmol). Purification: Combi-Flash. Eluent: methanol and dichloromethane (0.7:99.3) as eluent. Appearance: Off-white solid.
  • Example 61 4-(4-oxo-4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6- yl)butyl)phthalazin-1(2H)-one [430] Following the general procedure 6, the titled compound was synthesized from intermediate 9(100 mg, 0.43 mmol), DMF (5 ml), intermediate 161 (150 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash.
  • Example 62 4-(4-oxo-4-(6-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)butyl)phthalazin-1(2H)-one [431] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (100 mg, 0.43 mmol), DMF (5 ml), intermediate 163 (150 mg, 0.47 mmol), DIPEA (278 mg, 2.15 mmol) and HBTU (196 mg, 0.52 mmol). Purification: Combi-Flash.
  • Example 66 4-(4-(3-(5-(methylsulfinyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [435] Following the general procedure 4, the titled compound was synthesized from intermediate 174 (100 mg, 0.30 mmol), intermediate 172 (59.5 mg, 0.33 mmol), N- Methylpyrrolidone (3 ml) and DIPEA (119 mg, 0.92 mmol). Purification: Combi-Flash.
  • Example 70 4-(4-(3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4-oxobutyl)-8- fluorophthalazin-1(2H)-one [439] Following the general procedure 6, the titled compound was synthesized from intermediate 184 (150 mg, 0.59 mmol), DMF (5 ml), intermediate 151 (196 mg, 0.66 mmol), DIPEA (387 mg, 3.00 mmol) and HBTU (296 mg, 0.77 mmol). Purification: Combi-Flash.
  • Example 71 4-(4-(3-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4- oxobutyl)phthalazin-1(2H)-one [440] Following the general procedure 6, the titled compound was synthesized from intermediate 9 (120 mg, 0.52 mmol), DMF (3 ml), intermediate 186 (145 mg, 0.52 mmol), DIPEA (334 mg, 2.58 mmol) and HBTU (225 mg, 0.62 mmol). Purification: Combi-Flash.
  • Example 74 4-(4-(8-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4- oxobutyl)phthalazin-1(2H)-one [443] Following the general procedure 4, the titled compound was synthesized from intermediate 190 (500 mg 125 mmol), 2,5-dichloropyrimidine (205 mg, 1.37 mmol), N- Methylpyrrolidone (7.5 ml) and K2CO3 (519 mg, 3.75 mmol). Purification: Not done. Appearance: Pale-brown solid. Yield: 180 mg.
  • Example 76 4-(5-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5- oxopentyl)phthalazin-1(2H)-one [445] Following the general procedure 6, the titled compound was synthesized from intermediate 45 (110 mg, 0.45 mmol), DMF 43 ml), intermediate 192 (180 mg, 0.49 mmol), DIPEA (350 mg, 2.7 mmol) and HBTU (200 mg, 0.54 mmol). Purification: Combi-Flash.
  • Example 82 4-(((3-oxo-3-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)propyl)amino)methyl)phthalazin-1(2H)-one [451] To TFA (1.77 g, 15.5 mmol) and trifluoromethanesulfonic acid (420 mg, 2.8 mmol) cooled to 0°C, intermediate 196 (200 mg, 0.28 mmol) was added and stirred at room temperature.
  • Example 83 4-(((3-oxo-3-(3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)propyl)amino)methyl)phthalazin-1(2H)-one [452] To TFA (2.66 g, 23.3 mmol) and trifluoromethanesulfonic acid (63.7 mg, 0.42 mmol) cooled to 0°C, intermediate 197 (300 mg, 0.42 mmol) was added and stirred at room temperature.
  • PARP7 enzyme was prepared in 1X PARP buffer, and the reaction was initiated by adding 10 ⁇ L of diluted PARP7 enzyme to the designated wells. To the wells designated as "Blank,” 10 ⁇ L of 1X PARP buffer was added. The plate was centrifuged for 30 seconds and incubated at room temperature for 60 minutes. The reaction mixture was discarded after 1 hour, and the plate was washed three times with 100 ⁇ L phosphate buffer saline (1 x PBS containing 0.05 % Tween-20 (PBST)) buffer. 25 ⁇ L of diluted (1:50 in blocking buffer) Streptavidin-Horseradish Peroxide (HRP) was added to each well. The plate was incubated for 30 minutes at room temperature.
  • PBST 0.05 % Tween-20
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • GI50 values for select compounds described herein are provided in Table 4. TABLE-4 [459] GI50 values of ⁇ 1 ⁇ M and in the range of > 1 ⁇ M to 10 ⁇ M are categorised as “##” and “###” respectively. [460] All references, patents, and patent applications cited herein are hereby incorporated by reference.

Abstract

La présente invention concerne des composés de formule (I) utilisés comme inhibiteurs de poly(ADP-ribose) polymérase 7 (PARP7), des méthodes de préparation de ceux-ci, des compositions pharmaceutiques les contenant et leur utilisation dans des méthodes de traitement, de prévention et/ou d'atténuation de maladies ou de troubles impliquant PARP7.
PCT/IB2023/050507 2022-01-24 2023-01-20 Composés (4-pipérazin-1yl)-4-alkyl-phtalazin-1(2h)-one en tant qu'inhibiteurs de parp7 WO2023139536A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003063874A1 (fr) * 2002-01-29 2003-08-07 Fujisawa Pharmaceutical Co., Ltd. Composés hétérocycliques condensés
WO2016116602A1 (fr) * 2015-01-23 2016-07-28 Astrazeneca Ab Traitement du cancer
CN110698411A (zh) * 2018-07-09 2020-01-17 四川大学 一类4-(胺烷基)酞嗪-1-酮类化合物、其制备方法和用途
CN115490671A (zh) * 2022-10-21 2022-12-20 水木未来(北京)科技有限公司 Parp7抑制剂及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003063874A1 (fr) * 2002-01-29 2003-08-07 Fujisawa Pharmaceutical Co., Ltd. Composés hétérocycliques condensés
WO2016116602A1 (fr) * 2015-01-23 2016-07-28 Astrazeneca Ab Traitement du cancer
CN110698411A (zh) * 2018-07-09 2020-01-17 四川大学 一类4-(胺烷基)酞嗪-1-酮类化合物、其制备方法和用途
CN115490671A (zh) * 2022-10-21 2022-12-20 水木未来(北京)科技有限公司 Parp7抑制剂及其制备方法

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
"Basic and Clinical Pharmacology", 2003, MCGRAW HILL
"Bio reversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION
"Goodman and Gilman's The Pharmacological Basis of Therapeutics", 1996, pages: 11 - 16
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
"Remingtons Pharmaceutical Sciences", 2000, LIPPINCOTT WILLIAMS & WILKINS.
"The Pharmacological Basis of Therapeutics", 2001, MCGRAW HILL
BOCK, BIOCHEM. PHARMACOL., vol. 112, 2016, pages 1 - 5
DENISON, TOXICOL. SCI., vol. 124, 2011, pages 1 - 22
GOZGIT JOSEPH M ET AL: "PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity", CANCER CELL, CELL PRESS, US, vol. 39, no. 9, 22 July 2021 (2021-07-22), pages 1214, XP086777352, ISSN: 1535-6108, [retrieved on 20210722], DOI: 10.1016/J.CCELL.2021.06.018 *
HIGUCHI ET AL.: "ASCD Symposium Series", vol. 14, article "Prodrugs as Novel Delivery Systems"
M.GOZGIT ET AL., CANCER CELL, vol. 39, no. 9, 2021, pages 1214 - 1226
MA ET AL., BIOCHEM., vol. 289, 2001, pages 499 - 506
MACPHERSON ET AL., INT. J. MOL. SCI., vol. 15, 2014, pages 7939 - 7957
MARTINDALE: "The Extra Pharmacopoeia", 1999, THE PHARMACEUTICAL PRESS
OPITZ ET AL., NATURE, vol. 478, 2011, pages 197 - 203
REGISTRY ET AL: "Pyrido-pyridazin-5(1H)-one derivative", 10 June 2008 (2008-06-10), pages 1, XP093039676, Retrieved from the Internet <URL:www.stn.org> [retrieved on 20230418] *
REGISTRY ET AL: "Pyrido-pyridazin-5(1H)-one derivative", 8 June 2008 (2008-06-08), pages 1, XP093039677, Retrieved from the Internet <URL:www.stn.org> [retrieved on 20230418] *
T. W. GREENE: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS
YE CHANYUAN ET AL: "Design, synthesis, and in vitro evaluation of 4-aminoalkyl-1(2H)-phthalazinones as potential multifunctional anti-Alzheimer's disease agents", BIOORGANIC CHEMISTRY, vol. 111, 1 June 2021 (2021-06-01), US, pages 104895, XP093039473, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2021.104895 *

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