WO2022090938A1 - Dérivés de phtalazinone utiles en tant qu'inhibiteurs de parp - Google Patents

Dérivés de phtalazinone utiles en tant qu'inhibiteurs de parp Download PDF

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WO2022090938A1
WO2022090938A1 PCT/IB2021/059897 IB2021059897W WO2022090938A1 WO 2022090938 A1 WO2022090938 A1 WO 2022090938A1 IB 2021059897 W IB2021059897 W IB 2021059897W WO 2022090938 A1 WO2022090938 A1 WO 2022090938A1
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compound
disease
cancer
mmol
substituted
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PCT/IB2021/059897
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Debnath Bhuniya
Srikant Viswanadha
Swaroop Kumar Venkata Satya VAKKALANKA
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Rhizen Pharmaceuticals Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C07D403/10—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 carbon chain containing aromatic rings

Definitions

  • the present invention provides compounds of formula (I) as poly(ADP-ribose) polymerase (PARP) 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 PARP.
  • PARP poly(ADP-ribose) polymerase
  • Poly(ADP-ribose) polymerase defines a family of enzymes that cleaves NAD+ to nicotinamide and ADP-ribose to form long and branched (ADP-ribose) polymers on glutamic acid residues of a number of target proteins, including PARP itself.
  • the addition of negatively charged polymers profoundly alters the properties and functions of the acceptor proteins.
  • 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. These functions have been mainly attributed to PARP-1 that is regarded as the best characterized member of the PARP family.
  • the identification of novel genes encoding PARPs together with the characterization of their structure and subcellular localization have disclosed different roles for poly(ADP-ribosyl)ation in the cells, including telomere replication and cellular transport.
  • DNA damage checkpoint proteins such as: tumor suppressor p53, cyclin-dependent kinase inhibitor p21 Cipl/Wafl, DNA damage recognition factors (i.e. the nucleotide excision repair xeroderma pigmentosum group A complementing protein; the mismatch repair protein MSH6), base excision repair (BER) proteins (e.g., DNA ligase III, and X-ray repair cross complementing 1 (XRCC1)), DNA-dependent protein kinase (DNA-PK), cell death and survival regulators (i.e. NF-kB, inducible nitric oxide synthase, and telomerase).
  • DNA damage recognition factors i.e. the nucleotide excision repair xeroderma pigmentosum group A complementing protein; the mismatch repair protein MSH6
  • BER base excision repair
  • DNA-PK DNA-dependent protein kinase
  • cell death and survival regulators i.e. NF-kB, inducible n
  • NHEJ non-homologous end-joining
  • HR homologous recombination
  • DSB double strand breaks
  • NHEJ is initiated by the Ku heterodimer (consisting of Ku70 and Ku80) and DNA- PK complex binding to the DSB whilst HR results when an exonuclease creates a 3' single strand tail that is subsequently covered by RAD51.
  • Work from a group at the Mayo Clinic suggests that PARP inhibition may have direct effects on NHEJ.
  • Patel et al. Proc Natl Acad Set U SA., Feb. 22, 2011, 108(8) :3406— 3411
  • PARP inhibition results in NHEJ deregulation and that NHEJ mediated sensitivity of HR-deficient cells to PARP inhibitors. This implies that PARP -mediated genomic instability may be secondary to error- prone NHEJ in addition to BER inhibition.
  • PARP- 1 is a 116 kDa nuclear protein composed of four main regions : an
  • N-terminal DNA binding domain with two zinc finger motifs a nuclear location signal containing a caspase 3 cleavage site, an auto modification domain and a C-terminal catalytic domain.
  • This enzyme is activated in response to DNA damage such as that induced by alkylating agents, ionizing radiations or free radicals.
  • DNA damage such as that induced by alkylating agents, ionizing radiations or free radicals.
  • PARP-1 rapidly binds to DNA single or double strand breaks, undergoes auto ribosylation and adds ADP-ribose polymers to the acceptor proteins. Thereafter, the ribosylated PARP molecule is released from DNA and its catalytic activity is inactivated.
  • PARP-1 acts as a molecular nick-sensor and PARP-1 mediated post-translational modification of cellular proteins provides rapid signals to halt transcription and DNA replication, and to recruit DNA repair systems at the site of damage.
  • PARP-1 plays an important role both in necrosis and apoptosis.
  • PARP-2 Among the members of the PARP gene family characterized so far,
  • PARP-2 shows the highest homology with the catalytic domain of PARP-1 and contributes to the formation of ADP-ribose polymers in response to DNA damage observed in PARP-1 cells.
  • the genomic sequence of PARP-2 promoter indicates that the expression pattern of this gene is different from that of PARP-1, suggesting independent regulation and complementary roles for the two enzymes.
  • the PARP-2 gene encoding a 62 kDa protein, is located in a region of chromosome 14 that contains a number of genes involved in apoptosis, chromosome end maintenance and the immune system. Interestingly, this portion of chromosome 14 is frequently subjected to translocations in a variety of germ cell tumors, adenocarcinoma, leukemia and lymphoma.
  • PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA mutation cancer cell lines over normal cells.
  • PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as a single agent in BRCA1- or BRCA2- associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. See A. Chen, Chin J Cancer, 2011, 30(7): 463-471.
  • Poly(ADP-ribosyl)ation is an essential post-translational modification catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes.
  • PARP1 poly(ADP-ribose) polymerase 1
  • PARP1 plays a crucial role in multiple biological processes and PARP1 activation contributes to the development of various inflammatory and malignant disorders, including lung inflammatory disorders, cardiovascular disease, ovarian cancer, breast cancer, and diabetes.
  • the molecular mechanisms and signalling pathways that PARP1 is associated with in the regulation of pathogenesis. Recently, increasing evidence suggests that PARP inhibition is a promising strategy for intervention of some diseases.
  • Patent literature related to PARP inhibitors includes International Publication Nos. WO 2000/42040, WO 2001/016136, WO 2002/036576, WO 2002/090334, WO 2003/093261, WO 2003/106430, WO 2004/080976, WO 2004/087713, WO 2005/012305, WO 2005/012524, WO 2005/012305, WO 2005/012524, WO 2005/053662, WO 2006/033003, WO 2006/033007, WO 2006/033006, WO 2006/021801, WO 2006/067472, WO 2007/144637, WO 2007/144639, WO 2007/144652, WO 2008/047082, WO 2008/114114, WO 2009/050469, WO 2011/098971, WO 2015/108986, WO 2016/028689, WO 2016/165650, WO 2017/153958, WO 2017/191562, WO 2017/123156, WO 2017/140
  • 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 PARP.
  • the present invention relates to a compound of formula (I): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, wherein
  • R a , R b , R c and R d are each independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;
  • X is CR x or N;
  • Y is CR y or N
  • Z is CR z orN
  • R x , R y and R z may be same or different and are each independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CR xl and N; each occurrence of R xl is independently selected from hydrogen, halogen and substituted or unsubstituted alkyl; one of R e and R f is selected from -NR 5 R 6 and the other is independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, and haloalkyl, or both R e and R f directly bound to a common atom may be joined to form a cycloalkyl or heterocyclyl;
  • R 7 and R 8 are each independently selected from hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and p is 1 or 2.
  • One embodiment is a compound of formula (I), wherein at least one of R a , R b , R c and R d is halogen.
  • One embodiment is a compound of formula (I), wherein at least one of R a , R b , R c and R d is hydrogen.
  • One embodiment is a compound of formula (I), wherein R a , R c and R d are hydrogen and R b is halogen.
  • One embodiment is a compound of formula (I), wherein R b is fluorine or chlorine.
  • One embodiment is a compound of formula (I), wherein R a , R b and R d are hydrogen and R c is halogen.
  • One embodiment is a compound of formula (I), wherein R c is fluorine.
  • One embodiment is a compound of formula (I), wherein X, Y and Z are CH.
  • One embodiment is a compound of formula (I), wherein X is CH or N.
  • One embodiment is a compound of formula (I), wherein Y is CH or N.
  • One embodiment is a compound of formula (I), wherein Z is CH or N.
  • One embodiment is a compound of formula (I), wherein X is N.
  • One embodiment is a compound of formula (I), wherein Y is N.
  • One embodiment is a compound of formula (I), wherein Z is N.
  • One embodiment is a compound of formula (I), wherein Y and Z are CH and X is N [33] One embodiment is a compound of formula (I), wherein X and Z are CH and Y is N
  • One embodiment is a compound of formula (I), wherein X and Y are CH and Z is N
  • One embodiment is a compound of formula (I), wherein X and Y are CH and Z is CR Z .
  • One embodiment is a compound of formula (I), wherein X and Y are CH and Z is CR Z wherein R z is halogen.
  • One embodiment is a compound of formula (I), wherein X and Y is CH and Z is CR Z where in R z is fluorine.
  • One embodiment is a compound of formula (I), wherein Z is CH.
  • One embodiment is a compound of formula (I), wherein R e is -NR 5 R 6 and R f is substituted or unsubstituted Ci-3 alkyl.
  • One embodiment is a compound of formula (I), wherein R e and R f are independently selected from hydrogen, -NH2 and substituted or unsubstituted C1-3 alkyl.
  • One embodiment is a compound of formula (I), wherein R e is -NH2.
  • One embodiment is a compound of formula (I), wherein R f is substituted or unsubstituted C1-3 alkyl.
  • One embodiment is a compound of formula (I), wherein R e is -NH2 and R f is substituted or unsubstituted C1-3 alkyl.
  • One embodiment is a compound of formula (I), wherein wherein one of R e and R f is selected from -NR 5 R 6 and the other is independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, and haloalkyl, or both R e and R f directly bound to a common atom, may be joined to form a cycloalkyl or heterocyclyl; and R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen and substituted or unsubstituted C1-3 alkyl; and the squiggly line represents the point of attachment to the rest of the molecule.
  • the compound of formula from (a), (b), (c), (d) and (e), as shown above.
  • One embodiment is a compound of formula (I), wherein at least one of R 1 , R 2 , R 3 and R 4 is selected from hydrogen and halogen.
  • One embodiment is a compound of formula (I), wherein at least one of R 1 , R 2 , R 3 and R 4 is hydrogen.
  • One embodiment is a compound of formula (I), wherein at least one of R 1 , R 2 , R 3 and R 4 is halogen.
  • One embodiment is a compound of formula (I), wherein at least one of R 1 , R 2 , R 3 and R 4 is fluorine or chlorine.
  • One embodiment is a compound of formula (I), wherein R 1 , R 3 and R 4 are hydrogen and R 2 is halogen.
  • One embodiment is a compound of formula (I), wherein R 1 , R 3 and R 4 are hydrogen and R 2 is fluorine.
  • One embodiment is a compound of formula (I), wherein R 1 , R 2 and R 4 are hydrogen and R 3 is halogen.
  • One embodiment is a compound of formula (I), wherein from
  • Representative compounds of the present invention include those recited below, and pharmaceutically acceptable salts thereof.
  • the present invention should not be construed to be limited to the compounds recited below.
  • Yet another aspect of the present invention is a method for inhibiting PARP in a patient by administering to the patient (e.g., a patient in need thereof) an effective amount of at least one compound of the present invention (for example, a compound of formula (I), as defined above).
  • the patient e.g., a patient in need thereof
  • 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) 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 PARP1 and/or PARP2 (i.e., an effective amount of the compound is administered to inhibit PARP1 and/or PARP2).
  • Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune or proliferative disease (e.g., via inhibition of PARP) 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.
  • 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, in particular the amelioration of diseases or disorders mediated by PARP, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, and cancer and other proliferative diseases or disorders.
  • the compounds of the present invention are useful in the treatment of a variety of cancers, including, but not limited to:
  • 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;
  • lymphoid lineage • 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 Glioblastoma, Astrocytoma, Neuroglioma;
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas;
  • tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the compounds of the present invention as modulators of apoptosis are useful in the treatment of cancer (including, but not limited to, those types mentioned herein above), 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, stroke and reperfusion
  • 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, or a renal disease or disorder.
  • the method includes administering to a patient in need thereof an effective amount of one or more compounds of the present invention.
  • 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 inhibitor
  • 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
  • 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 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-Hodgkins 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 by 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.
  • 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).
  • Ci-ealkyl refers to an alkyl group as defined above having up to 6 carbon atoms.
  • C2-4alkyl refers to an alkyl group as defined above having 2 to 4 carbon atoms.
  • Ci-salkyl refers to an alkyl group as defined above having up 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.
  • multicyclic cycloalkyl groups include, for example, perhydronaphthyl, adamantyl and norbomyl groups, bridged cyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • Cs-6 cycloalkyl refers to a cycloalkyl group as defined above having 3 to 6 carbon atoms.
  • aryl refers to an aromatic radical having in the range of 6 up 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 sulfur.
  • 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 quatemized.
  • the 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 to 14 member 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, benzofiiranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofiiranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,
  • heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.
  • R‘, R u and R v in each of the above groups can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted heterocyclic ring, or substituted heterocyclically ring, or any two of R‘, R u and R v may be joined to form
  • 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 that are substituted with one or more halo groups or with combinations thereof.
  • 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-fluorenylmethylenoxy carbonyl (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, -CH2CH2SO2PI1, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • 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. Where tautomerization is possible (e.g.
  • tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • phenol-keto tautomerization is a specific example of phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
  • a "leaving group or atom” is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.
  • 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). A thorough discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bio reversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
  • 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 13C - or 14C -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). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • Pharmaceutically acceptable salts forming part of this invention include 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, ornithine, lysine, arginine, and serine; quaternary ammonium salts of the compounds of invention with alkyl
  • 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.
  • AIDS Acquired Immuno Deficiency Syndrome
  • HIV Human Immunodeficiency Virus
  • Abbreviations used herein have their conventional meaning within the chemical and biological arts.
  • cell proliferation refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
  • co-administration encompasses administration of two or more active agents to an animal so that 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.
  • the term "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 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.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the 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 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.
  • 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 conversion electron emitters
  • high-energy radiation including without limitation x-rays, gamma rays, and neutrons.
  • compositions include, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, fdlers, 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 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.
  • 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 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 fdlers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions 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 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, fdlers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.
  • the compounds or 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 or infusion), topical administration (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • routes such as oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • the compounds and compositions can also be administered intraadiposally or intrathecally.
  • compositions can be administered in solid, semi-solid, liquid or gaseous form, or may be in dried powder, 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.
  • 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.
  • the 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.
  • 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 treatment methods of the invention are useful in the fields of human medicine and veterinary medicine.
  • the individual to be treated may be a mammal, preferably human, or other 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 invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • said 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. lymphoma and Kaposi's sarcoma) or viral-induced cancer.
  • 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,
  • said 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)).
  • the invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention.
  • said 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.
  • 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 duct
  • the invention further provides methods of inhibiting PARP by contacting a PARP with an amount of a compound of the invention sufficient to inhibit the activity of the PARP enzyme .
  • the invention provides methods of inhibiting PARP enzyme activity by contacting a PARP enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the PARP enzyme.
  • the invention provides methods of inhibiting PARP enzyme activity. Such inhibition can take place in solution, in a cell expressing one or more PARP enzyme, in a tissue comprising a cell expressing the PARP, or in an organism expressing PARP.
  • the invention provides methods of inhibiting PARP activity in an animal (including mammal such as humans) by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of the PARP enzyme in said animal.
  • the compounds of the present invention may be prepared by the following processes. Unless otherwise indicated, the variables (e.g. X, Y, Z, G, R a , R b , R c , R d , R e , R f , R 1 , R 2 , R 3 and R 4 ) when used in the below formulae are to be understood to represent those groups described above in relation to compounds of formula (I). These methods can similarly be applied to other compounds as provided herein above with or without modification.
  • a compound of formula (1) which is an aldehyde can be protected to obtain acetal (2).
  • a compound of formula (3) can be N-arylated with acetal (2) using Buchwald reaction conditions to obtain a compound of formula (4).
  • the acetal of formula (4) can be deprotected to form an aldehyde of formula (5) using a suitable acid, such as hydrochloric acid.
  • the aldehyde of formula (5) can react with a Wittig salt of formula (6) to give an olefin of formula (7).
  • the olefin of formula (7) can react with hydrazine hydrate to form a compound of formula (8).
  • the compound of formula (8) can be halogenated to form a compound of formula (9).
  • the compound of formula (9) can then be converted to the desired compound of formula (I).
  • This scheme is illustrated below as Illustration 1.
  • the compound of formula (7) can be halogenated by treatment with a reagent such as SOCh, POCh, or oxalyl chloride in a suitable solvent to form a compound of formula (8a).
  • the compound of formula (8a) can be converted into a compound of formula (9a) by treatment with an azide compound such as NaNs in the presence of suitable solvent such as DMF.
  • the compound of formula (9a) can be converted to a compound of formula (10) by treatment with a reagent such as triphenylphosphine (PPhi). e.g., in a mixture of THF and water.
  • the compound of formula (10) can then be reacted with hydrazine hydrate to form the desired compound of formula (I).
  • This scheme is illustrated below as Illustration 2.
  • the compound of formula (4) can be halogenated by treatment with a reagent such as SOCh, POCh, or oxalyl chloride in a suitable solvent to form a compound of formula (5b).
  • a reagent such as SOCh, POCh, or oxalyl chloride in a suitable solvent to form a compound of formula (5b).
  • the compound of formula (5b) can be converted into a compound of formula (6b) by treatment with an azide compound such as NaNs in the presence of suitable solvent such as dimethylformamide (DMF).
  • DMF dimethylformamide
  • the compound of formula (6b) can be converted to a compound of formula (7b) by treating with a reagent such as triphenylphosphine (PPhs) in a mixture of THF and water.
  • PPhs triphenylphosphine
  • the compound of formula (7b) can be treated with concentrated hydrochloric acid in the presence of a suitable solvent such as THF to form an aldehyde compound of formula (8b).
  • a suitable solvent such as THF
  • the compound of formula (8b) and the compound of formula (6) can be coupled under Witting reaction conditions in the presence of triethylamine (TEA) and a suitable solvent such as dichloromethane (DCM) to form a compound of formula (9b).
  • TAA triethylamine
  • DCM dichloromethane
  • the compound of formula (9b) can be reacted with hydrazine hydrate to form the desired compound of formula (I).
  • the compound of formula (3) is treated with a reagent such as SOCh, POCh, or oxalyl chloride in a suitable solvent such as DCM to obtain a compound of formula (4c).
  • Compound (4c) can be converted to a compound of formula (5c) by reaction with a suitable amine base such as NH4OH.
  • the compound of formula (5c) can be treated with protecting group- 1 (PG1) and protecting group-2 (PG2) to form a compound of formula (6c).
  • the compound of formula (6c) can be coupled with a compound of formula (2) to form a compound of formula (7c) in the presence of a suitable solvent such as DMSO and suitable reagents such as K2CO3, trans-4-hydroxy-L-proline and Cui.
  • the compound of formula (7c) can be treated with concentrated hydrochloric acid and THF to form an aldehyde compound of formula (8c).
  • the compound of formula (8c) can be coupled with the compound of formula (6) to form a compound of formula (9c) in the presence of a suitable solvent and a reagent TEA.
  • the compound of formula (9c) can react with hydrazine hydrate to form a compound of formula (10c).
  • the compound of formula (10c) is deprotected to form the desired compound of formula (I).
  • Example 1 is also prepared from Intermediate 45 as follows:
  • Example 1 400 mg, 1.0 mmol was dissolved in dichloromethane (10ml). Triethylamine (200 mg, 2.0 mmol) was added and cooled to 0°C. Methane sulfonyl chloride (230 mg, 2.0 mmol) was added and stirred for 2h at room temperature. The reaction mass was quenched with water (50 ml), extracted with dichloromethane (2 x 50 ml). The organic layer was dried with anhydrous sodium sulphate and concentrated under vacuum. The crude obtained was purified by combi-flash using MeOH and DCM (4.5:95.5) as eluent. Combined pure fractions from combi-flash were distilled to obtain the titled compound as an off-white solid.
  • the pharmacological properties of the compounds of the present invention may be confirmed by a number of pharmacological assays. Exemplary pharmacological assays which can be carried out with the compounds of the present invention and/or their pharmaceutically acceptable salts are provided below.
  • Block the wells by adding 100 pL of Blocking buffer 3 to every well. Incubate at room temperature for 1 hour and 15 minutes.
  • N wells x ( 1.25 pL 1 Ox PARP buffer + 1.25 pL 1 OX PARP Assay mixture + 2.5 pL Activated DNA + 7.5 pL distilled water). Add 12.5 pL to every well.
  • Step 3 Detection:

Abstract

La présente invention concerne des composés de formule (I) utilisés en tant qu'inhibiteurs de poly(ADP-ribose) polymérase (PARP), leurs procédés de préparation, 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 la PARP. (I)
PCT/IB2021/059897 2020-10-31 2021-10-26 Dérivés de phtalazinone utiles en tant qu'inhibiteurs de parp WO2022090938A1 (fr)

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