WO2017039318A1 - Dérivés de benzimidazole pour des inhibiteurs de méthylation de l'adn - Google Patents

Dérivés de benzimidazole pour des inhibiteurs de méthylation de l'adn Download PDF

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Publication number
WO2017039318A1
WO2017039318A1 PCT/KR2016/009722 KR2016009722W WO2017039318A1 WO 2017039318 A1 WO2017039318 A1 WO 2017039318A1 KR 2016009722 W KR2016009722 W KR 2016009722W WO 2017039318 A1 WO2017039318 A1 WO 2017039318A1
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alkyl
phenyl
benzo
alkoxy
imidazol
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PCT/KR2016/009722
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English (en)
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MinJeong CHOI
Nakcheol Jeong
Hak Joong Kim
Jiaojie LI
Sunmi SHIN
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Kainos Medicine, Inc.
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Publication of WO2017039318A1 publication Critical patent/WO2017039318A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to certain compounds which can modulate the hypermethylation of DNA sequences containing CpG sites that are associated with disease; and relates to processes for their preparation, as well as pharmaceutical compositions containing them as an active ingredient, and their use as medicaments.
  • DNA methylation is the most stable epigenetic mark and means by which gene expression is modulated inside a cell. It occurs most frequently at CpG islands, used to designate "-C-phosphate-G-" or cytosine and guanine separated by only one phosphate and with cytosine being 5 prime to the guanine base, as distinguished from base-pairing of cytosine and guanine. Cytosine methylation in CpG islands is associated with gene silencing and gene transcription regulation.
  • DNA hypermethylation is observed at a specific CpG islands and in relation to specific genes in a number of diseases, as compared to the same regions of DNA or in relation to the same gene or genes in healthy subjects (e.g., where no methylation or less methylation is observed).
  • Hypermethylation is also used to refer to a plurality of CpG dinucleotides in a specific or defined region of nucleic acid where DNA sequence is methylated. In that regard, such methylation is known to cause transcriptional inactivation of genes, and this methylation and transcriptional inactivation have been associated with, or thought to contribute to, the disease process.
  • telomeres For example, in cancer cells showing hypermethylation at selected CpG islands, there is transcriptional inactivation of genes involved in main cellular pathways including, but not limited to, DNA repair (e.g., hMLHl, MGMT, BRAC1), vitamin response (e.g., CRBP1, RARB2), Ras signaling, cell cycle control (e.g., RASSF1A), p53 network, and apoptosis (e.g., DAPK1).
  • DNA repair e.g., hMLHl, MGMT, BRAC1
  • vitamin response e.g., CRBP1, RARB2
  • Ras signaling e.g., Ras signaling
  • cell cycle control e.g., RASSF1A
  • p53 network e.g., p53 network
  • apoptosis e.g., DAPK1
  • DNA hypermethylation has been observed in several tumor types including, but not limited to, colon cancer, endometrial cancer, stomach cancer, esophageal cancer, head and neck cancer, breast cancer, ovarian cancer, non-Hodgkins lymphoma, lung cancer, thyroid cancer, prostate cancer, renal cancer, brain cancer, leukemia, and lymphoma.
  • CpG hypermethylation is observed in Alzheimer's disease, resulting in transcriptional inactivation of a number of genes.
  • the frontal cortex of subjects with Alzheimer's disease showed disease-specific hypermethylation in the promoter region of cAMP response element-binding protein (CREB).
  • CREB cAMP response element-binding protein
  • the result may be exacerbation of reduced levels of brain-derived neurotrophic factor, along with in reduced neuronal plasticity and long-term memory formation, as observed in brains of subjects with Alzheimer's disease.
  • Hypermethylation in the promoter region of the gene for synaptophysin has also been observed, and the reduced level of that protein is associated with altered synaptic plasticity in subjects with Alzheimer's disease.
  • CpG hypermethylation is observed in rheumatoid arthritis, resulting in transcriptional inactivation of a number of genes.
  • the CpG island containing the death receptor (DR3) gene promoter was specifically methylated. The result is reduced expression of DR3 protein, which may provide resistance to apoptosis. Increased proliferation and decreased apoptosis of synovial cells results in hyperplasia of the lining layer of the synovial tissue, an important feature of rheumatoid arthritis. Hypermethylation was also observed for genes including Transforming growth factor ⁇ receptor 2 (TGFBR2) and FOXOl.
  • TGFBR2 Transforming growth factor ⁇ receptor 2
  • FOXOl Transforming growth factor ⁇ receptor 2
  • TGFBR2 affects the function of B cells, and changes in B cells in rheumatoid arthritis are evident by the pathogenic autoantibodies produced in the disease process.
  • FOXOl transcript levels appear to be down-regulated in peripheral blood mononuclear cells in subjects with rheumatoid arthritis, suggesting the possibility that the down-regulation of FOXOl expression may contribute to the development of lymphocyte over-activation in rheumatoid arthritis.
  • DNA methylation inhibitors may be used to reactivate antiproliferative, apoptotic, and regulating genes in cells involved in diseases such as cancer, neurological diseases, and autoimmune diseases, with a resultant decrease in disease severity.
  • DNMTs C5-DNA methyltransferases
  • DNMTl is mainly involved in the maintenance of the methylation pattern and is active on hemimethylated DNA
  • DNMT 3 A and 3B are active both on unmethylated and hemimetnylated substrates, are responsible of de novo DNA methylation, and include DNMT3A, DNMT3B, and the catalytically inactive DNMT3L (Jurkowska, R. Z., et al, Chembiochem 2011, 12:206-222).
  • DNMT3A, DNMT3B the catalytically inactive DNMT3L
  • promoter CpG islands are methylated, the corresponding gene is repressed due to poor recognitions by transcription factors and recruitment of proteins involved in the chromatin remodeling such as methyl-binding proteins.
  • the enzyme required for maintenance methylation the aberrant methylation of the tumor suppressor genes can be prevented.
  • cytidine analogs such as azacitidine(vidaza®) and decitabine (Dacogen®), antimetabolites that have been found to inhibit the activity of DNA methyltransferases by incorporating into newly synthesized DNA, in the place of cytidine, causing covalent complex formation between DNA methyltransferases and azacitidine or decitabine containing DNA.
  • Covalent complex formation results in the trapping of the enzyme (suicide enzyme inhibitor), preventing turnover even at other sites, and thus leads to DNA demethylation.
  • suicide enzyme inhibitor myelodysplasia syndromes
  • lymphoproliferative diseases myelodysplasia syndromes
  • DNA methylation appears to be a particularly interesting target from a therapeutic point of view.
  • these two clinically approved DNMT inhibitors, azacitidine and decitabine are not selective toward the different DNMTs, are chemically instable (degradatde by cytidine deaminase: CDA), and have strong secondary effects, for example, renal toxicity or myelotoxicity (Boumber Y, et al., Oncology, 2011, 25(3), 220-6). Therefore, there is a need to identify novel, more specific and selective inhibitors.
  • the present invention includes compounds that selectively inhibit the activity of mammalian DNA methyltransferases DNMTl and DNMT3s (DNMT 3 A, 3B and 3L).
  • the compounds of the present invention comprising DNA methylation inhibitors, surprisingly may provide improved metabolic stability, drug permeability, absorption, and increase in the DNMT binding when a compound of the invention inhibits the catalytic domain, transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) as compared to deoxycytidine, strong decrease in the dissociation rate, better toxicity profile.
  • AdoMet S-adenosyl-L-methionine
  • the compounds and compositions herein are useful in treatment or modulation of disease (one or more of pathology, symptoms, disorders, or conditions) in a subject, wherein the disease is treated or modulated by inhibition of DNA methylation of one or more genes which is transcriptionally inactivated by DNA methylation.
  • the compounds are useful to inhibit DNA methyltransferase activity (and methods therefor).
  • the compounds, compositions, and methods are useful in treatment or modulation of a disease in which one or more genes whose transcriptional inactivation is due to methylation and contributes to the disease.
  • Diseases in which one or more genes whose transcriptional inactivation contributes to the disease include, but are not limited to, cancer, neurological disease, autoimmune disease, and symptoms or conditions thereof in a subject having the disease.
  • Z is selected from NH, O or S
  • Y is a phenyl group optionally substituted by C ⁇ 4 alkyl, CF 3 , halogen, hydroxyl, C ⁇ alkoxy, cyano, nitro, halo C ⁇ 4 alkyl, halo C1-4 alkoxy, hydroxyl C 1--4 alkyl, C M alkoxy C ⁇ 4 alkyl, or C 1--4 alkoxycarbonyl ; a 5- to 6- membered heteroaromatic group optionally substituted by C ⁇ 4 alkyl, CF 3 , halogen, hydroxyl, Ci ⁇ 4 alkoxy, cyano, nitro, halo C ⁇ alkyl, halo Ci ⁇ 4 alkoxy, hydroxyl alkyl, or C 1-4 alkoxycarbonyl ; a 5- to 6-membered heterocarbocyclic group optionally substituted by C1- alkyl, CF 3 , halogen, hydroxyl, C ⁇ alkoxy, cyano, nitro, halo C ⁇ 4 alkyl,
  • Ri and R 2 are each independently selected from the following groups Ql to Q5;
  • A is a 5-membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered aryl or fused heteroaryl ring having 2 to 3 nitrogen atoms;
  • R4 and e are each independently R', halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 , -
  • B] and B 2 are each independently selected from CH or N;
  • n 1 or 2;
  • w is an integer of 1 to 4.
  • Ci, C 2 and C 3 are each independently selected from CH or N;
  • R 5 and R 5 ' are each independently R', halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 ,
  • Di, D 2 , D 3 and D 4 are each independently selected from CH, N, or SH;
  • Ei, E 2 , E 3 and E 4 are each independently selected from CH 2 , NH, S, SH 2 , or O; p is an integer of 1 to 3; and
  • R' is hydrogen, Ci 6 aliphatic, Ci ⁇ 6 alkoxy, Ci ⁇ 6 alkyl, phenyl, CF 3 , halogen, hydroxyl, Ci ⁇ 4 alkoxy, cyano, nitro, halo C w alkyl, halo C1-4 alkoxy, hydroxyl C ⁇ alkyl, Ci ⁇ 4 alkoxycarbonyl, Ci ⁇ 6 alkyl substituted with amino or hydroxyl, or 5- to 6-membered heterocyclic having one or more oxygen, sulfur or nitrogen.
  • R 3 is selected from R ⁇ halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 , -NO 2 , -C(O)R', - C(S)R', -C0 2 R', -C(O)N(R') 2 , -C(O)SR', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(S)N(R') 2 , - C(S)OR ⁇ -S(0)R', -SO 2 R', -SO 2 N(R') 2 , -N(R')C(O)R', -N(R')C(O)N(R') 2 , - N(R')C(S)N(R') 2 , -N(R')SO 2 R', -N(R')SO 2 R', -N(R'
  • R and R 2 are each independently selected from the following groups Ql to Q5;
  • A is a 5 -membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered aryl or fused heteroaryl ring having 2 to 3 nitrogen atoms;
  • R 4 and 3 ⁇ 4 are each independently R', halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 , -
  • B t and B 2 are each independently selected from CH or N;
  • n 1 or 2;
  • w is an integer of 1 to 4.
  • Ci, C 2 and C 3 are each independently selected from CH or N;
  • R 5 and R 5 ' are each independently R ⁇ halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 , -NO 2 , -C(O)R', -C(S)R', -CO 2 R', -C(O)N(R') 2 , -C(O)SR', -C(O)C(O)R ⁇ -C(O)CH 2 C(O)R', -C(S)N(R') 2 , -C(S)OR ⁇ -S(O)R', -SO 2 R', -SO 2 N(R') 2 , -N(R')C(O)R', -N(R')C(O)N(R') 2 , - N(R')C(S)N(R') 2 , -N(R')
  • Di, D 2 , D 3 and D 4 are each independently selected from CH, N, or SH;
  • Ei, E 2 , E 3 and E 4 are each independently selected from CH 2 , ⁇ , S, SH 2 , or O; p is an integer of 1 to 3; and
  • R' is hydrogen, C ⁇ 6 aliphatic, C ⁇ 6 alkoxy, alkyl, phenyl, CF 3 , halogen, hydroxyl, C ⁇ alkoxy, cyano, nitro, halo C ⁇ 4 alkyl, halo alkoxy, hydroxyl Ci ⁇ alkyl, C ⁇ alkoxycarbonyl, alkyl substituted with amino or hydroxyl, or 5- to 6-membered heterocyclic having one or more oxygen, sulfur or nitrogen.
  • a pharmaceutical composition for preventing or treating precancerous transformation or a cancer which comprises the compound of formula (I) or a pharmaceutically acceptable salt, a hydrate, a solvate or an isomer thereof as an active ingredient, and a pharmaceutically acceptable carrier.
  • a method for preventing or treating precancerous transformation or a cancer in a subject which comprises administering the compound of formula (I) or a pharmaceutically acceptable salt, a hydrate, a solvate, or an isomer thereof to the subject in need thereof.
  • the compounds of the present invention may be more potent, more metabolically stable and more effective in cancer treatment than other DNMT inhibitors that do not have the benzimidazole core derivatives. Further, the compound of the present invention may exhibit excellent enzyme activity and in vitro DMPK properties.
  • alkyl is used herein to refer to a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms (e.g., linear saturated aliphatic hydrocarbon groups, branched saturated aliphatic hydrocarbon groups, or a saturated or unsaturated non- aromatic hydrocarbon mono or multi-ring system (e.g., cycloalkyl)).
  • alkyl is used without reference to a number of carbon atoms, it is to be understood to refer to a l o alkyl.
  • aryl is used herein to refer to cyclic, aromatic hydrocarbon groups which have 1 to 3 aromatic rings.
  • the aryl group may have fused thereto a second or third ring which is a heterocyclo, cycloalkyl, or heteroaryl ring, provided in that case the point of attachment will be to the aryl portion of the ring system.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, indanyl, anthracyl or phenanthryl, as well as substituted derivatives thereof.
  • heteroaryl is used herein to refer to an aryl group in which at least one of the carbon atoms in the aromatic ring has been replaced by a heteroatom selected from oxygen, nitrogen and sulfur.
  • the nitrogen and/or sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heteroaryl group may be a 5- to 6-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 16- membered tricyclic ring system.
  • alkenyl is used herein to refer to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • alkynyl is used herein to refer to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • alkoxy is used herein to refer to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • aralkyl is used herein to refer to an aryl-alkyl group in which the aryl and alkyl are as defined herein. Preferred aralkyls comprise a lower alkyl group.
  • aryloxy is used herein to refer to an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • carbocyclyl (alone or in combination with another term(s)) is used herein to refer to a saturated cyclic (i.e., “cycloalkyl"), partially saturated cyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., "aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms” being the atoms bound together to form the ring or rings of a cyclic substituent).
  • a carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms.
  • cycloalkyl is used herein to refer to monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds but does not amount to an aromatic group.
  • cyano is used herein to refer to a -CN group.
  • halo or halogen is used herein to refer to -CI, -Br, -I, or -F.
  • haloalkyl is used herein to refer to an alkyl, as defined herein, wherein at least one hydrogen atom is replaced with halogen atoms.
  • heterocyclyl is used herein to include a saturated (e.g., “heterocycloalkyl”), partially unsaturated (e.g., “heterocycloalkenyl” or “hetercycloalkynyl”) or completely unsaturated (e.g., “heteroaryl) ring system, which have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • first and second are used herein for the purpose of distinguishing between two compounds, or between two compositions, as will be clearer from the description.
  • medically effective amount means an amount of a composition or compound that treats the particular disease, condition or disorder; ameliorates, relieves, or decreases one or more symptoms associated with the particular disease, condition or disorder; and/or delays or prevents the onset of symptoms of, or a pathological process associated with the particular disease, condition or disorder described herein in more detail.
  • pharmaceutically acceptable carrier is used herein to mean any compound or composition or carrier medium useful in any one or more of administration, delivery, storage, stability of a composition or compound described herein.
  • the pharmaceutically acceptable carriers include, but are not limited to, a diluent, water, saline, a suitable vehicle (e.g., liposome, microparticle, nanoparticle, emulsion, and capsule), a buffer, a medical parenteral vehicle, an excipient, an aqueous solution, a suspension, a solvent, an emulsion, a detergent, a chelating agent, a solubilizing agent, a salt, a colorant, a polymer, a hydrogel, a surfactant, an emulsifier, an adjuvant, a filler, a preservative, a stabilizer, an oil, a binder, a disintegrant, an absorbant, a flavor agent, and the like as broadly known in the art.
  • the present invention provides a compound of Formula I and Formula II, or a pharmaceutically acceptable salt, a hydrate, a solvate, or an isomer thereof:
  • Z is selected from NH, O or S
  • Y is a phenyl group optionally substituted by C ⁇ 4 alkyl, CF 3 , halogen, hydroxyl, Ci-4 alkoxy, cyano, nitro, halo C ⁇ alkyl, halo C ⁇ alkoxy, hydroxyl C w alkyl, C ⁇ 4 alkoxy C ⁇ 4 alkyl, or Ci_4 alkoxycarbonyl ; a 5- to 6- membered heteroaromatic group optionally substituted by C 1--4 alkyl, CF 3 , halogen, hydroxyl, C 1--4 alkoxy, cyano, nitro, halo C 1--4 alkyl, halo C ⁇ alkoxy, hydroxyl C ⁇ alkyl, C ⁇ alkoxyC ⁇ alkyl, or C w alkoxycarbonyl ; a 5- to 6-membered heterocarbocyclic group optionally substituted by C ⁇ alkyl, CF 3 , halogen, hydroxyl, C ⁇ 4 alkoxy, cyano,
  • Ri and R 2 are each independently selected from the following groups Ql to Q5;
  • A is a 5-membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered aryl or fused heteroaryl ring having 2 to 3 nitrogen atoms;
  • R4 and Re are each independently R ⁇ halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 , - NO 2 , -C(O)R', -C(S)R', -CO 2 R', -C(O)N(R') 2 , -C(O)SR', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(S)N(R') 2 , -C(S)OR', -S(O)R', -SO 2 R', -SO 2 N(R') 2 , -N(R')C(O)R', -N(R')C(O)N(R') 2 , - N(R')C(S)N(R') 2 , -N(R')SO 2 R', -N(R')SO 2 R', -
  • B ⁇ and B 2 are each independently selected from CH or N;
  • n 1 or 2;
  • w is an integer of 1 to 4.
  • Ci, C 2 and C 3 are each independently selected from CH or N;
  • R 5 and R 5 ' are each independently R', halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 ,
  • Di, D 2 , D 3 and D 4 are each independently selected from CH, N, or SH;
  • Ei, E 2 , E 3 and E 4 are each independently selected from CH 2 , NH, S, SH 2 , or O; p is an integer of 1 to 3; and
  • R' is hydrogen, Ci ⁇ 6 aliphatic, Ci_ 6 alkoxy, C ⁇ 6 alkyl, phenyl, CF 3 , halogen, hydroxyl, C ⁇ alkoxy, cyano, nitro, halo Ci ⁇ alkyl, halo Ci ⁇ 4 alkoxy, hydroxyl Ci_4 alkyl, Ci ⁇ 4 alkoxycarbonyl, C ⁇ alkyl substituted with amino or hydroxyl, or 5- to 6-membered heterocyclic having one or more oxygen, sulfur or nitrogen. Also, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, a hydrate, a solvate, or an isomer thereof:
  • Y is a phenyl group optionally substituted by C ⁇ alkyl, CF 3 , halogen, hydroxyl, C ⁇ alkoxy, cyano, nitro, halo Ci_4 alkyl, halo C ⁇ alkoxy, hydroxyl C ⁇ 4 alkyl, C ⁇ 4 alkoxy C 1--4 alkyl, or alkoxycarbonyl ; a 5- to 6- membered heteroaromatic group optionally substituted by C 1--4 alkyl, CF 3 , halogen, hydroxyl, C 1 - alkoxy, cyano, nitro, halo C ⁇ 4 alkyl, halo C ⁇ alkoxy, hydroxyl C 1--4 alkyl, C ⁇ 4 alkoxyC ⁇ alkyl, or C 1--4 alkoxycarbonyl ; a 5- to 6-membered heterocarbocyclic group optionally substituted by alkyl, CF 3 , halogen, hydroxyl, C 1--4 alkoxy, cyano, nitro
  • R 3 is selected from R', halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 , -NO 2 , -C(0)R', - C(S)R', -CO 2 R', -C(O)N(R') 2 , -C(O)SR', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(S)N(R') 2 , - C(S)OR', -S(O)R', -SO 2 R', -SO 2 N(R') 2 , -N(R')C(O)R', -N(R')C(O)N(R') 2 , - N(R')C(S)N(R') 2 , -N(R')SO 2 R', -N(R')SO 2 R', -N(R
  • Ri and R 2 are each independently selected from the following groups Ql to Q5;
  • A is a 5-membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered aryl or fused heteroaryl ring having 2 to 3 nitrogen atoms;
  • R4 and Re are each independently R', halogen, -OR', -SR ⁇ -N(R') 2 , -CN, -CF 3 , - NO 2 , -C(O)R', -C(S)R', -CO 2 R', -C(O)N(R') 2 , -C(O)SR', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(S)N(R') 2 , -C(S)OR', -S(O)R', -SO 2 R', -SO 2 N(R') 2 , -N(R')C(O)R ⁇ -N(R')C(O)N(R') 2 , - N(R')C(S)N(R') 2 , -N(R')SO 2 R', -N(R')SO 2 R', -N
  • Bi and B 2 are each independently selected from CH or N;
  • n 1 or 2;
  • w is an integer of 1 to 4.
  • Ci, C 2 and C 3 are each independently selected from CH or N;
  • R 5 and R 5 ' are each independently R ⁇ halogen, -OR', -SR', -N(R') 2 , -CN, -CF 3 , -N0 2 , -C(O)R', -C(S)R', -CO 2 R', -C(O)N(R') 2 , -C(O)SR', -C(O)C(O)R', -C(O)CH 2 C(O)R', -C(S)N(R') 2 , -C(S)OR', -S(O)R', -SO 2 R', -SO 2 N(R') 2 , -N(R')C(O)R', -N(R')C(O)N(R') 2 , - N(R')C(S)N(R') 2 , -N(R')SO 2 R', -N(R')SO 2 R
  • Di, D 2 , D 3 and D 4 are each independently selected from CH, N, or SH;
  • Ei, E 2 , E3 and E 4 are each independently selected from CH 2 , NH, S, SH 2 , or O; p is an integer of 1 to 3; and
  • R' is hydrogen, Ci ⁇ 6 aliphatic, Ci_ 6 alkoxy, Ci_ 6 alkyl, phenyl, CF 3 , halogen, hydroxyl, C ⁇ 4 alkoxy, cyano, nitro, halo Ci ⁇ alkyl, halo Ci_4 alkoxy, hydroxyl C 1--4 alkyl, C 1-4 alkoxycarbonyl, Ci ⁇ 6 alkyl substituted with amino or hydroxyl, or 5- to 6-membered heterocyclic having one or more oxygen, sulfur or nitrogen.
  • the present invention provides compounds of formula I, wherein,
  • Z is selected from NH or O
  • R] and R 2 are each independently selected from the following groups Ql to Q5;
  • A is a 5-membered fused heteroaryl ring having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered aryl or fused heteroaryl ring having 2 to 3 nitrogen atoms;
  • B 2 are each independently selected from CH or N;
  • n 1 or 2;
  • w is an integer of 1 to 4.
  • C-i, C 2 and C 3 are each independently selected from CH or N;
  • R 5 and R 5 ' are each independently R ⁇ halogen, -OR', -N(R') 2 , -CN, -CF 3 , -NO 2 ,
  • Di, D 2 , D 3 and D 4 are each independently selected from CH, N, or SH; Ei, E 2 , E 3 and E 4 are each independently selected from CH 2 , NH, or O; p is an integer of 0 to 3; and
  • R' is hydrogen, or an optionally substituted group selected from C w aliphatic,
  • the present invention provides compounds of formula I, wherein,
  • Z is NH
  • X] and X 2 are each independently -NR' or -O- ;
  • Y is a 5- to 6-membered heteroaromatic group optionally substituted by alkyl, CF 3 , halogen, hydroxy 1, C 1--4 alkoxy, cyano, nitro, halo C 1-4 alkyl, halo C 1--4 alkoxy, hydroxyl Ci ⁇ alkyl, C ⁇ alkoxy, Ci ⁇ 4 alkyl or C ⁇ alkoxycarbonyl ;
  • R and R 2 are each independently selected from the following groups Ql to Q5;
  • A is a 6-membered aryl or fused heteroaryl ring having 2 to 3 nitrogen atoms
  • R 4 and R6 are each independently R', -N(R') 2 or -CN;
  • i and B 2 are each independently selected from CH or N;
  • n 1 or 2;
  • w is an integer of 1 to 4.
  • Ci, C 2 and C 3 are each independently selected from CH or N;
  • R 5 and R 5 ' are each independently R' or -N(R') 2 ;
  • D 2 , D 3 and D 4 are each independently selected from CH or N;
  • Ei, E 2 , E 3 and E 4 are each independently selected from CH 2 or NH; p is an integer of 0 to 3; and
  • R' is hydrogen, C ⁇ 6 alkyl, cyano, nitro, or a C ⁇ 6 alkyl substituted with amino.
  • Example 1 6-methyl-N4-(2-(4-(quinolin-4-ylamino)phenyl)-lH-benzo[d]imidazol-5- yl)pyrimidine-2,4-diamine
  • Example 2 6-methyl-N4-(2-(4-(quinolin-4-ylamino)phenyl)-lH-benzo[d]imidazol-5- yl)pyrimidine-2,4-diamine tri-hydrogen chloride
  • Example 12 4-methyl-N2-(2-(4-(pyridin-4-ylamino)phenyl)-lH-benzo[d]imidazol- 5 -yl)pyridine-2,6-diamine trihydrochloride
  • Example 14 6-methyl-N4-(2-(4-((3-methylpyridin-4-yl)amino)phenyl)-lH- benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine trihydrochloride
  • Example 15 N-(4-(5-(quinolin-4-ylamino)-lH-benzo[d]imidazol-2- yl)phenyl)quinolin-4-amine trihydrochloride
  • Example 27 N4-(2-(4-((lH-tetrazol-5-yl)amino)phenyl)-lH-benzo[d]imidazol-5- yl)pyrimidine-2,4-diamine tris(2,2,2-trifluoroacetate). While the terms used in the description of the invention are believed to be well understood by one of ordinary skill in the pharmaceutical arts, definitions, where provided herein, are set forth to facilitate description of the invention, and to provide illustrative examples for use of the terms.
  • purified or isolated for a compound according to Formula I refers to the physical state of the compound following isolation from a synthetic process or purification step described herein or well known to those in the art, and in sufficient purity to be characterizable by standard analytical methods described herein or well known in the art.
  • treat embrace one or more of preventative (prophylactically) or therapeutically (palliative).
  • the compounds of Formula I or Formula II can form salts, and salts of the compounds are included within the scope of the invention.
  • salt or pharmaceutically acceptable salt
  • Representative salts include bisulfate, sulfate, benzene sulfonate, camphorsulfonate, laurylsulphonate, methanesulfonate, toluenesulfonate, naphthalenesulformate, acetate, trifluoracetate, benzoate, borate, butyrate, citrate, formate, fumarate, hydorbromide, hydrochloride, hydroiodide, lactate, laurate, maleate, malonate, mesylate, nitrate, oxalate, phosphate, hexafiuorophosphate, propionate, salicylate, stearate, succinate, tartrate, thiocyanate, and the like.
  • the salts may include base salts based on the alkali and alkaline earth metals, such as calcium, sodium, lithium, magnesium, and potassium; or with organic bases such as with organic amines (e.g., dicyclohexylamine, t- butyl amine, methylamine, dimethylamine, triethylamine, ethylamine, procaine, morpholine, N-methylpiperidine, dibenzylamine, and the like); or as an ammonium salt.
  • organic amines e.g., dicyclohexylamine, t- butyl amine, methylamine, dimethylamine, triethylamine, ethylamine, procaine, morpholine, N-methylpiperidine, dibenzylamine, and the like
  • ammonium salt e.g., dicyclohexylamine, t- butyl amine, methylamine, dimethylamine, triethylamine, ethyl
  • the compounds of Formula I or Formula II may exist in a solvated form or unsolvated form.
  • Solvates of a compound of the invention may be formed in the synthetic process in which the compound becomes physically associated with one or more solvent molecules (e.g., such as by ionic and/or covalent bonding) or, optionally, may be converted to a solvate such as by dissolving the compound in desired amounts of a solvent of choice (e.g., organic solvent, water, or mixtures thereof) in forming a solution, heating the solution to a temperature higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals of the solvate, which may then be further isolated using methods known the art.
  • suitable solvents include methanolates, ethanolates, hydrates (where the solvent molecule is water), and the like.
  • the compounds of Formula I may contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. All stereoisomers (e.g., geometric isomers, optical isomers, and the like), enantiomeric forms, diastereomeric forms, tautomeric forms, positional isomers, of the compounds of the invention are embraced within the scope of the invention.
  • a first conformational form of a compound can be separated from a second and different conformational form of the compound using methods well known in the chemical arts such as by chromatography, crystallization, and methods of synthesis which selectively result in a particular desired conformational form.
  • the invention further provides a composition, preferably a pharmaceutical composition or medicament, containing a medically effective amount of a compound of Formula I or Formula II (or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof) and a pharmaceutically acceptable carrier.
  • a composition according to the invention may be administered once, or multiple times, as needed, to deliver a medically effective amount of the composition, e.g., an amount effective to mediate modulation of a disease by inhibiting DNA methyltransferase activity in cells in the subject receiving the composition.
  • a medically effective amount of a composition comprising the compound of the invention may be an amount that enters into cells which are contacted with the compound, and which results in inhibiting DNA methylation in the cells.
  • Such a medically effective amount of the composition will depend on such factors as the mode of administration, the formulation for administration, disease to be modulated, the size and health of the subject to receive such a composition, and other factors which can be taken into consideration by a medical practitioner who is skilled in the art of determining appropriate dosages for treatment.
  • An amount of the compound of the invention in a composition to be administered may vary from 0.01 milligrams to about 500 milligrams, and more typically from about 1 milligram per day to about 200 milligram per day.
  • One skilled in the art can apply known principles and models of drug delivery and pharmacokinetics to ascertain a likely range of dosages to be tested in preclinical and clinical studies for determining a medically effective amount of the compound of the invention.
  • a pharmaceutically acceptable carrier used in a composition of the invention, may facilitate one or more of storage, stability, administration, and delivery, of the composition.
  • the carrier may be particulate, so that the composition may be in, for example, powder or solid form.
  • the carrier may be in a semi-solid, gel, or liquid formula, so that the composition may be ingested, injected, applied, or otherwise administered.
  • the carrier may be gaseous, so that the composition may be inhaled.
  • suitable formulations may be presented in the form of tablets, caplets, capsules, and the like, in which typically the compound of the invention may be present in a predetermined amount as a powder, granules, solution, or suspension as the sole active agent, or in combination with an additional one or more pharmaceutical agents.
  • such oral formulations typically involve one or more of a binder (e.g., syrup, sorbitol, gum, corn starch, gelatin, acacia), a filler (e.g., lactose, sugar, starch, calcium phosphate), an excipient (e.g., dicalcium phosphate), a disintegrating agent (e.g., vegetable starch, alginic acid), a lubricant (e.g., magnesium stearate), a flavoring agent (sweetening agent, natural or artificial flavors).
  • a binder e.g., syrup, sorbitol, gum, corn starch, gelatin, acacia
  • a filler e.g., lactose, sugar, starch, calcium phosphate
  • an excipient e.g., dicalcium phosphate
  • a disintegrating agent e.g., vegetable starch, alginic acid
  • a lubricant e.g., magnesium
  • the mode of administration of a compound or composition of the invention to a subject (such as a human) in need of such composition or compound may be any mode known in the art to be suitable for delivering a pharmaceutical composition, and particularly suitable for treating a disease by inhibiting DNA methyltransferase activity in cells, and may include but is not limited to, intravenously, intraperitoneally, orally, subcutaneously, intramuscularly, intranasally, transdermally, by perfusion, and by peristaltic techniques.
  • the compositions of the invention may also be combined with other therapies, such as one or more additional pharmaceutical agents, to treat a disease in which hypermethylation of CpG islands is observd.
  • Such combination therapy may be administered in concurrently, sequentially, or in regimen alternating between the composition of the invention and the other therapy.
  • Such combination therapies may include administering a compound of Formula I with one or more additional therapeutic agents, for treating one or more diseases selected from the group consisting of cancer, neurological disease (e.g., Alzheimer's disease), autoimmune or inflammatory disease (e.g., rheumatoid arthritis), and a myelodysplastic disorder.
  • the structure of the agents, for combination with a compound of Formula I or Formula II, identified herein, and their generic or trademark names, are readily available to those skilled in the art, such as from the standard compendium of drugs (e.g., The Merck Index) or from the applicable pharmaceutical company's web site, as well as dosages applicable for treatment (see also The Physician's Desk Reference).
  • the doses and dosage regimen of an additional pharmaceutical agent, used in conjunction with a compound of the invention in combination therapy can be determined by a physician, taking into account the medical literature, the health, age and sex of the patient, the disease to be treated, the mode of administration and dosing schedule of the pharmaceutical agent, and other relevant considerations.
  • dosages of such agents can range from about 0.1 mg to 1000 mg per day, with more specific dosages dependent on the aforementioned factors.
  • a pharmaceutical composition or medicament comprising a medically effective amount of a compound of one or more of Formula I or Formula II, in combination with a medically effective amount of one or more of a chemotherapeutic agent, anti-inflammatory drug, COX-2 inhibitor, immune modulator, cholinesterase inhibitor, NMDA receptor antagonist, or a combination thereof; and optionally further comprising a pharmaceutically acceptable carrier.
  • a pharmaceutical composition or medicament comprising a medically effective amount of a compound of one or more of Formula I or Formula II, and a pharmaceutically acceptable carrier.
  • Example 1 illustrated is the use of a compound of the invention, a compound of Formula I or Formula II, (or a pharmaceutical composition comprising such compound) in a medically effective amount to treat a disease modulated by inhibiting DNA methyltransferase activity in cells.
  • a method for treating a disease modulated by inhibiting DNA methyltransferase activity in cells of a subject in need of inhibition of DNA methylation comprising the step of administering to the subject(a subject, such as a human) in need of such treatment a medically effective amount of one or more compounds having Formula I or Formula II, wherein the disease modulated by inhibiting DNA methyltransferase activity in cells is selected from the group consisting of an atherosclerosis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, liver cirrhosis, cancer (e.g., lymphoma; leukemia; and solid, non- lymphoid tumors), rheumatoid arthritis, Alzheimer's disease, and myelodysplastic disorders.
  • an atherosclerosis psoriasis, idiopathic pulmonary fibrosis, scleroderma, liver cirrhosis
  • cancer e.g., lymphoma;
  • a pharmaceutical composition comprising one or more compounds having Formula I or Formula II, and a pharmaceutically acceptable carrier
  • the disease modulated by inhibiting DNA methyltransferase activity is selected from the group
  • the pharmaceutical composition may further comprise one or more chemotherapeutic agents.
  • a compound having Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease modulated by inhibiting DNA methyltransferase activity in cells may be selected from the group consisting of an atherosclerosis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, liver cirrhosis, cancer (e.g., lymphoma; leukemia; and solid, non-lymphoid tumors), rheumatoid arthritis, Alzheimer's disease, and myelodysplastic disorders.
  • NMR spectra were recorded in CDC1 3 and OMSO-d 6 solution in 5-mm o.d. tubes (Norell, Inc. 507-HP) at 30 °C and were collected on Varian VNMRS-400 at 400 MHz for 1H.
  • Scheme 1 shows the synthesis of Example 1 and Example 2.
  • Schemel shows the synthesis of Example 1 and Example 2.
  • Test Example 1 DNMT1 Inhibitory Assay (IC 50 measurement)
  • Reaction buffer was prepared with 50 mM Tris-HCl (pH 7.5), 50 mM NaCl, 5 mM EDTA, 5 mM DTT, 0.1 mM PMSF, 5% glycerol, and 1% DMSO.
  • Human and mouse liver microsomal clearance assays were carried out in CROWN Biosciences (Taicang, China).
  • the human liver microsomes (Cat No. X008067, Lot No. KQB) and mouse liver microsomes (Cat No. Ml 000, Lot No. 1210302) were purchased from Celsis and Xenotech, respectively.
  • test compound stock solution was diluted with 495 uL of 1 : 1 Methanol/Water (final concentration: 100 ⁇ , 50% MeOH) and combined with 534 ⁇ of the respective liver microsome solution (final concentration: 1.111 ⁇ , 0.555% MeOH).
  • the final concentration of the liver microsome solution was 0.7 mg protein /mL.
  • liver microsome solutions were performed in a 96 well plate at 37°C. 90 ⁇ of the liver microsome solutions were added to Blank, and 90 ⁇ of working solution of the test compound was added to all plates except the Blank.
  • the resulting plates were incubated at 37°C in the following order: T60 (The test compound was incubated with the liver microsomal solution and NADPH for 60 min at 37°C), T30 (such as for 30 min.), and T10 (such as for 10 min.).
  • 300 uL of a cold (4°C) stop solution acetonitrile (ACN) including 500 nM of tolbutamide as internal standard
  • 10 uL of NADPH co-factor solution to starting plate TO: 100% of the parent compound without any reaction
  • the reaction was stopped by adding 300 ⁇ L of the cold (4°C) stop solution to the other plates in the following order: T10 first, then T30 and T60.
  • the Caco-2 cells (Passage 48) were diluted with culture medium into cell concentration of 6.86x105 cells/mL. This cell concentration can be used to seed 2.40x105 cells/cm2 and dispense 50 uL into the filter well of the 96-well HTS Transwell plate. Cells were cultivated in a cell culture incubator set at 37 °C, 5% CO2, 95% relative humidity. Incubate the plate for 14-18 days and replaced the medium every other day, beginning no sooner than 48 hours after initial plating. The standard transport buffer in the study was HBSS at pH 7.4. Before and after the transport studies, the monolayer integrity was evaluated by measuring transepithelial electrical resistance (TEER).
  • TEER transepithelial electrical resistance
  • the pre-transport and post-transport TEER were required to be no less than 200 ⁇ -cm 2 .
  • the stock solutions of test compound and control compounds were prepared in DMSO and dilute with HBSS (10 mM HEPES, pH 7.4). The final concentration of the test compounds and control compounds was 5 ⁇ .
  • the Papp value has the dimension of a rate (10-6cm/s).
  • C Rec is the compound concentration in the receiver chamber at the measurement time t;
  • V Rec is the volume of the receiver chamber
  • A is the area of the permeability barrier, which corresponds to the surface area of the filter (0.143 cm2 for HTS Transwell-96 Well Permeable Supports);
  • Co is the initial concentration in the donor chamber ( ⁇ ).
  • a compound is considered as likely Pgp substrate when the efflux ratio is more than
  • V d and V rec are the volume of donor and receiver chambers
  • C d and C rec are the final concentrations of test compound in donor and receiver chambers at time t;
  • Co is the initial concentration in the donor chamber at time Zero.
  • Test Example 4 Thermodynamic solubility assay
  • phosphate buffer pH 7.0
  • the sample vials were incubated at room temperature (25 °C), 600rpm for 24 hours. All samples were centrifuged at 14000 rpm, 25°C for 4 minutes.
  • a standard solution was prepared by dissolving the weighed powders of the same test compound in pure DMSO (1 mg/ml), then diluted the lmg/ml standard solution to 200 ⁇ g/ml, 40 ⁇ g/ml and 8 ⁇ g/ml standard solutions with 100% DMSO.
  • 20 ⁇ working and standard solution were transferred to a new plate which contain 580 ⁇ / ⁇ ACN:H2O 20:80 (including 40ng/ml Tolbutamide as internal standard), mixed.
  • 20 ⁇ , ⁇ step 5 solutions were transferred to a new plate which contain 580 ⁇ _ ⁇ 11 ACN:H2O 20:80 (including 40ng/ml Tolbutamide as internal standard), mixed.
  • 20 ⁇ ⁇ step 6 solutions were transferred to a new plate which contain 580 uL/well ACN:H 2 O 20:80 (including 40ng/ml Tolbutamide as internal standard), mixed. This sample of step above was transferred for LC-MS/MS analysis.

Abstract

L'invention concerne des inhibiteurs de méthylation de l'ADN, ainsi que des procédés et l'utilisation des composés de l'invention, seuls ou en combinaison avec d'autres thérapies, pour le traitement d'une maladie dans laquelle une hyperméthylation de l'ADN est trouvée.
PCT/KR2016/009722 2015-09-01 2016-08-31 Dérivés de benzimidazole pour des inhibiteurs de méthylation de l'adn WO2017039318A1 (fr)

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CN109020957A (zh) * 2017-06-12 2018-12-18 南京天印健华医药科技有限公司 作为mnk抑制剂的杂环化合物
CN109734661A (zh) * 2018-09-10 2019-05-10 江苏工程职业技术学院 一种乐伐替尼的合成方法
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
CN112390791A (zh) * 2019-08-14 2021-02-23 复旦大学 一类dna甲基转移酶1荧光探针及其用途
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2021242790A1 (fr) * 2020-05-26 2021-12-02 Baylor College Of Medicine Nouveaux inhibiteurs d'époxyde hydrolase soluble et leur procédé d'utilisation
US11548867B2 (en) 2017-07-19 2023-01-10 Idea Ya Biosciences, Inc. Amido compounds as AhR modulators
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2
US11897871B1 (en) 2021-06-14 2024-02-13 Scorpion Therapeutics, Inc. Methods for treating cancer

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WO2008141731A2 (fr) * 2007-05-18 2008-11-27 Bayer Healthcare Ag Dérivés pyrazoles à substitution hétéroaryle utiles pour le traitement de troubles hyperprolifératifs et de maladies associées à l'angiogenèse
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
CN109020957A (zh) * 2017-06-12 2018-12-18 南京天印健华医药科技有限公司 作为mnk抑制剂的杂环化合物
US11548867B2 (en) 2017-07-19 2023-01-10 Idea Ya Biosciences, Inc. Amido compounds as AhR modulators
CN109734661A (zh) * 2018-09-10 2019-05-10 江苏工程职业技术学院 一种乐伐替尼的合成方法
CN109734661B (zh) * 2018-09-10 2021-12-21 江苏工程职业技术学院 一种乐伐替尼的合成方法
CN112390791A (zh) * 2019-08-14 2021-02-23 复旦大学 一类dna甲基转移酶1荧光探针及其用途
CN112390791B (zh) * 2019-08-14 2023-08-01 复旦大学 一类dna甲基转移酶1荧光探针及其用途
WO2021242790A1 (fr) * 2020-05-26 2021-12-02 Baylor College Of Medicine Nouveaux inhibiteurs d'époxyde hydrolase soluble et leur procédé d'utilisation
US11897871B1 (en) 2021-06-14 2024-02-13 Scorpion Therapeutics, Inc. Methods for treating cancer
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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