[go: up one dir, main page]

WO2016186453A1 - Dérivés de quinoléine à utiliser en tant qu'inhibiteurs de bromodomaine - Google Patents

Dérivés de quinoléine à utiliser en tant qu'inhibiteurs de bromodomaine Download PDF

Info

Publication number
WO2016186453A1
WO2016186453A1 PCT/KR2016/005274 KR2016005274W WO2016186453A1 WO 2016186453 A1 WO2016186453 A1 WO 2016186453A1 KR 2016005274 W KR2016005274 W KR 2016005274W WO 2016186453 A1 WO2016186453 A1 WO 2016186453A1
Authority
WO
WIPO (PCT)
Prior art keywords
methoxy
quinolin
imidazo
ethyl
pyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2016/005274
Other languages
English (en)
Inventor
MinJeong CHOI
Su-Sung OH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kainos Medicine Inc
Original Assignee
Kainos Medicine Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kainos Medicine Inc filed Critical Kainos Medicine Inc
Publication of WO2016186453A1 publication Critical patent/WO2016186453A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound inhibiting the bromodomain and extra terminal domain (BET) proteins; a method of preparation thereof; a pharmaceutical composition comprising the same; and a method for preventing or treating a precancerous transformation or a cancer using the compound.
  • BET bromodomain and extra terminal domain
  • Gene expression is regulated by a variety of different mechanisms at several different levels.
  • Epigenetic mechanisms regulate gene expression by modifying DNA without changing nucleotide sequences or modifying histones that wrap the DNA molecules and restrict access of DNA binding proteins such as transcription factors.
  • Histone modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and a few others. These modifications are called “writing” and the enzymes responsible for the "writing” are called “writers.” And these histone modifications are reversible, and the enzymes that carry out the reverse mechanisms, such as histone deacetylases and histone demethylases, are called “erasers.”
  • Bromodomain (BRD)-containing proteins bind to the acetylated histones through the BRDs, which are about 1 10 amino acids-long in length (P. Filippakopoulos, et al, Cell, 2012, 149:214-231).
  • This highly conserved bromodomain comprised of four antiparallel alpha-helices and two connecting loops, is found in a number of different classes of proteins including histone acetylases, eukaryotic transcription factors and co-regulators, DNA helicases, chromatin-remodeling complexes and others.
  • Bromodomain and extra terminal domain (BET) proteins are a subfamily of bromodomain-containing proteins that have two bromodomains and one extra-terminal domain (ET).
  • the subfamily is comprised of four members including BRD2, BRD3, BRD4, and BRDT (bromodomain testis-specific protein), which contain tandem bromodomains (BDl and BD2) capable of binding to two acetylated lysine residues in close proximity, thereby increasing the specificity of the interaction.
  • BET proteins play an important role in several transcriptional programs, and implicate in aberrant transcriptional events that are responsible for several types of human diseases including inflammation and cancer (A. C. Belkina, et al, Nature Reviews Cancer, 2012, 12 (7):465-477).
  • BRD2 Deregulated expression of BRD2, BRD3 and BRD4 is oncogenic in humans. Reciprocal chromosomal translocations between human BRD3 (9q34.2) or BRD4 (19pl3.1) genes and the NUT gene (15ql4) produce a fused oncoprotein causing an NUT midline carcinoma (NMC), and an aggressive cancer with high mortality (C. A. French, et al., Cancer Research, 2003, 63(2):304-307). BRD4 is often up-regulated in melanoma (M. F. Segura, et al, Cancer Research, 2013, 73(20):6264-6276). BRDT is uniquely expressed in the testis and ovary.
  • BRD inhibitors inhibited the expression of the oncogene c-myc, which had a critical effect on cell proliferation in many different types of cancers.
  • BRD inhibitors or BET protein inhibitors potentially represent a new class of therapeutics to prevent or treat precancerous transformation or a cancer.
  • It is another object of the present invention to provide a pharmaceutical composition comprising said compounds as an active ingredient.
  • A is a group selected from the following (i) and (ii):
  • Q is A A or ⁇ ⁇ .
  • Z is -O- or -NH-
  • Rx is H or C 1-7 alkyl
  • R 2 is H or Ci -5 alkyl
  • R 3 is C 1-7 alkyl, -(CH 2 ) m -C 1-7 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heterocyclyl, wherein the aryl and the heterocyclyl are each independently non-substituted or substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, oxido, C 1-4 alkyl, C ⁇ alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, C 1-4 alkoxyCi -4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, d. 4 alkylsulfonyloxy, C 1-4 alkylsulfonylC 1- alkyl and C 1-4 alkylsulfonamido;
  • R 5 is H or C 1-7 alkyl
  • each m is independently 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • p 0,1 or 2;
  • heterocyclyl moieties are, each independently, aromatic or non-aromatic and comprise at least one heteroatom selected from the group consisting of N, S and O.
  • a pharmaceutical composition for preventing or treating a precancerous transformation or a cancer which comprises the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a solvate or a stereoisomer thereof as an active ingredient, and a pharmaceutically acceptable carrier.
  • a method for preventing or treating a precancerous transformation or a cancer in a mammal which comprises administering the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a solvate or a stereoisomer thereof to the mammal in need thereof.
  • the compounds of the present invention can exhibit a high potency against BRD4 enzyme and cancer cells. Further, the compound of the present invention can exhibit excellent in vivo pharmacokinetic properties.
  • Fig. 1 Pharmacokinetics of the compound obtained in Example 13 in mouse via PO and IV administration routes. DETAILED DESCRIPTION OF THE INVENTION
  • 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- or 6-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 16- membered tricyclic ring system.
  • cycloalkyl is used herein to refer to monocyclic or polycyclic ⁇ 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 in which 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 aromatic (e.g., “heteroaryl) ring system, which have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a solvate or a stereoisomer thereof:
  • Z is -O- or -NH-
  • R a and R b are, each independently, H, C 1-5 alkyl, or 5- to 10-membered heterocyclyl, or R a and R b together with the N to which they are attached form a 5- or 6-membered heterocyclyl;
  • Rx is H or C 1-7 alkyl
  • R 2 is H or C 1-5 alkyl
  • R 3 is C 1-7 alkyl, -(CH 2 ) m -Ci -7 alkoxy, C 3-6 cycloalkyl, C 6-1 oaryl, or 5- to 10-membered heterocyclyl, wherein the aryl and the heterocyclyl are each independently non-substituted or substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, oxido, C 1-4 alkyl, C 1- alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, C ⁇ . 4 alkylsulfonyloxy, C 1-4 alkylsulfonylC 1-4 alkyl and C 1-4 alkylsulfonamido;
  • t is H, halogen, C 1-7 alkyl, cyano, -CF 3 , -CHF 2 , -CH 2 F, or -(CH 2 ) m -C 1-7 alkoxy;
  • R 5 is H or C 1-7 alkyl;
  • each m is independently 0, 1 , 2 or 3;
  • n 0, 1 or 2;
  • p 0,1 or 2;
  • heterocyclyl moieties are, each independently, aromatic or non-aromatic and comprise at least one heteroatom selected from the group consisting of N, S and O.
  • the present invention provides compounds of formula (I), wherein A is the group (i).
  • the present invention provides compounds of formula (I), wherein A is the group (i); R 2 is C 1-5 alkyl; R 3 is -(CH 2 ) m -C 1-5 alkoxy, C 6- ioaryl, or 5- or 6-membered heteroaryl which is non-substituted or substituted with oxido or C 1-3 alkyl; m is 1 or 2; and said heteroaryl moiety comprises at least one heteroatom selected from the group consisting of N, S and O.
  • the invention provides compounds of formula
  • the present invention provides compounds of formula
  • the present invention provides compounds of formula (I), wherein A is the group (i); and Z is -0-.
  • the present invention provides compounds of formula (I), wherein A is the group (ii).
  • the present invention provides compounds of formula
  • the present invention provides compounds of formula (I), wherein A is the group (ii); R 2 is C 1-5 alkyl; R 3 is -(CH 2 ) m -C 1-5 alkoxy, C 6-10 aryl, or 5- or 6-membered heteroaryl which is non-substituted or substituted with oxido or C 1-3 alkyl; m is 1 or 2; and said heteroaryl moiety comprises at least one heteroatom selected from the group consisting of N, S and O.
  • the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is the group (ii); and Q is N In a preferred embodiment, the present invention provides compounds of formula (I), wherein A is
  • the present invention provides compounds of formula (I), wherein A is the group (ii); and Z is -0-.
  • the present invention provides compounds of formula
  • the present invention provides a
  • the present invention provides compounds of formula
  • the present invention provides a compound of formula (I), wherein A is the group (ii) and Q is 0 .
  • A is the group (ii) and Q is 0 .
  • Such compound can be depicted by formula (Id) below:
  • the compound of the present invention comprises quinoline derivatives that inhibit BRD-containing proteins such as BRD2, BRD3 and BRD4.
  • BRD-containing proteins such as BRD2, BRD3 and BRD4.
  • the compound of the present invention was evaluated for in vitro potency using the BRD binding and cancer cell antiproliferative activity assay.
  • the compound of the present invention exhibited a significant inhibition of BRD binding activity to acetylated histone peptides, and excellent pharmacokinetic properties in mouse.
  • the compounds of formula (I) can form salts, and salts of the compounds are included within the scope of the invention.
  • salts or “pharmaceutically acceptable salt”, as used herein, refer to inorganic or organic salts of a compound. These salts can be prepared, for example, by reacting the compound of formula (I) with an equivalent amount of acid or base in a medium such as one in which the salt formed then precipitates, or in an aqueous medium followed by lyophilization.
  • Representative salts include bisulfate, sulfate, benzene sulfonate, camphorsulfonate, laurylsulfonate, methanesulfonate, naphthalenesulfonate, toluenesulfonate, acetate, trifluoroacetate, benzoate, borate, butyrate, citrate, formate, fumarate, hydrobromide, hydrochloride, hydroiodide, lactate, laurate, maleate, malonate, mesylate, nitrate, oxalate, phosphate, hexafluorophosphate, 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) may exist in a solvated form or unsolvated form.
  • Solvates of the compound of the present invention may be formed in a synthetic process in which the compound becomes physically associated with one or more solvent molecules (e.g., by ionic and/or covalent bonding).
  • it may be converted to a solvate by dissolving the compound in desired amounts of a solvent of choice (e.g., organic solvent, water, or mixtures thereof) to form a solution, heating the solution at 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 in the art.
  • suitable solvents include methanolates, ethanolates, hydrates (where the solvent molecule is water), and the like.
  • the compounds of the present invention may also include a hydrate of the compound of formula (I).
  • the hydrate may be prepared using a known method, and they are preferred to be non-toxic, and in particular, they may be preferably a hydrate having 1 - 5 molecules of water bound thereto.
  • the compounds of formula (I) or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the individual stereoisomers (enantiomers and diastereomers) and their mixtures are included within the scope of the present invention.
  • a compound or salt of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined herein above.
  • the present invention provides a pharmaceutical composition for preventing or treating a precancerous transformation or a cancer, which comprises the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a solvate or a stereoisomer thereof as an active ingredient, and a pharmaceutically acceptable carrier.
  • the precancerous transformation or the cancer is selected from the group consisting of autoimmune diseases, epithelial tumors, melanoma, leukemia such as acute promyelocytic leukemia, lymphoma, solid or non-lymphoid tumors such as osteogenic sarcoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, ovarian cancer, brain cancer, cervical cancer, and lung cancer.
  • the pharmaceutical composition according to the present 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, disorder, or condition by inhibiting BRD in an individual receiving the composition.
  • a medically effective amount of the composition e.g., an amount effective to mediate modulation of a disease, disorder, or condition by inhibiting BRD in an individual receiving the composition.
  • 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.
  • a medically effective amount of the pharmaceutical composition comprising the compound of the present invention may be an amount that enters into cells which are contacted with the compound, and which results in inhibiting BRD within the cells.
  • Such a medically effective amount of the pharmaceutical 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 individual to receive such a composition, and other factors which can be taken into consideration by a medical practitioner skilled in the art.
  • the pharmaceutical composition or the compound of formula (I) may be administered in an amount ranging from 0.01 mg to about 1,000 mg, and more specifically from about 1 mg per day to about 200 mg per day for a 70 kg adult mammal. This amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • 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 a compound of the invention.
  • the pharmaceutically acceptable carriers include, but are not limited to, a binder (e.g., syrup, sorbitol, gum, corn starch, gelatin and acacia), a filler (e.g., lactose, sugar, starch and calcium phosphate), an excipient (e.g., dicalcium phosphate), a disintegrating agent (e.g., vegetable starch and alginic acid), a lubricant (e.g., magnesium stearate), a flavoring agent (e.g., sweetening agent, natural and artificial flavors), and the like as known in the art.
  • a binder e.g., syrup, sorbitol, gum, corn starch, gelatin and acacia
  • a filler e.g., lactose, sugar, starch and calcium phosphate
  • an excipient e.g., dicalcium phosphate
  • a disintegrating agent e.g., vegetable starch and alginic
  • the pharmaceutically acceptable carrier may be at least one selected from the group consisting of a diluent, water, saline, a suitable vehicle, 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, and a flavor agent.
  • a diluent water, saline, a suitable vehicle, 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,
  • the pharmaceutically acceptable carrier 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, a powder or solid form.
  • the carrier may be in a semi-solid, gel, or liquid formula, so that the pharmaceutical composition may be ingested, injected, applied, or otherwise administered.
  • the carrier may be gaseous, so that the pharmaceutical 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 present invention may be present in a predetermined amount as a powder, granules, solution, or suspension as the sole active ingredient, or in combination with an additional one or more pharmaceutical agents.
  • Such oral formulations may be coated or uncoated to modify their disintegration and/or absorption. Coating may be performed using conventional coating agents and methods known in the art.
  • the mode of administration of the compound or pharmaceutical composition of the present invention to an individual in need thereof may be any mode known in the art to be suitable for delivering a pharmaceutical composition, and particularly suitable for treating a disease, disorder or condition by inhibiting BRD.
  • the pharmaceutical composition may be administered intravenously, intraperitoneally, orally, subcutaneously, intramuscularly, intranasally, transdermally, by perfusion, and by peristaltic techniques.
  • the pharmaceutical composition according to the present invention may further comprise at least one additional pharmaceutical agent.
  • the pharmaceutical composition may also be combined with other therapies, such as one or more additional pharmaceutical agents, to treat a disease, disorder or condition, i.e., a precancerous transformation or a cancer.
  • additional pharmaceutical agents such as one or more additional pharmaceutical agents, to treat a disease, disorder or condition, i.e., a precancerous transformation or a cancer.
  • Such combination therapy may be administered concurrently, sequentially, or in regimen alternating between the composition of the invention and the other therapy.
  • the compounds having BRD inhibitory activity of the present invention when used to treat a precancerous transformation or a cancer, may be used in combination with one or more chemotherapeutic agents, with the potential for synergistically enhancing apoptosis and/or growth inhibition of cancer cells by the combination.
  • chemotherapeutic agents include, but are not limited to, LSD1 blockers, peroxisome proliferating-activator receptor (PPAR) ligands (e.g., rosiglitazone); alkylating agents (e.g., nitrogen mustards, such as mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, and melphalan; nitrosoureas, such as streptozocin, carmustine, and lomustine; alkyl sulfonates, such as busulfan; triazines, such as dacarbazine and temozolomide; ethylenimines, such as thiotepa and altretamine; and platinum-based drugs, such as cisplatin, carboplatin, and oxalaplatin); antimetabolites (e.g., 5-fluorouracil, 6-mercaptopurine, capecitabine, cladribine, clofara
  • the present invention provides a method for preventing or treating a precancerous transformation or a cancer in a mammal, which comprises administering the compound of formula (I), or a pharmaceutically acceptable salt, a hydrate, a solvate or a stereoisomer thereof to the mammal in need thereof.
  • the mammal may be a human.
  • one or more compounds of the present invention may be administered in a medically effective amount as the sole pharmaceutical agent, or may be administered in combination therapy wherein a medically effective amount of the compound of the present invention is administered with a medically effective amount of at least one additional pharmaceutical agent.
  • the method for preventing or treating a precancerous transformation or a cancer may comprise the steps of: (i) administering to the mammal in need thereof a first composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier; and (ii) administering to the mammal in need thereof a second composition comprising at least one additional pharmaceutical agent comprising a chemotherapeutic agent.
  • the first and second compositions are administered simultaneously or sequentially and in any order.
  • the present invention provides a use of the compound of the present invention for the manufacture of a medicament for preventing or treating a precancerous transformation or a cancer.
  • the present invention also provides a kit comprising the compounds or the pharmaceutical composition of the present invention and instructions for its use.
  • Scheme A shows the synthesis of the intermediate I- 10 through the common route that utilizes well-established chemistry.
  • the 5- and 6-membered ring compounds can be prepared by reacting the intermediate I- 10 with sulfamide, chloroacetyl chloride or (thio)carbonyldiimidazole in a solvent at appropriate temperature.
  • Scheme C shows that the 5- and 6-membered ring compounds can be prepared by reacting the intermediate I- 10 with sulfamide, chloroacetyl chloride or (thio)carbonyldiimidazole in a solvent at appropriate temperature.
  • R 1 ⁇ R 2 , R 3 and R4 are the same as defined in formula (I)
  • the quinoline derivatives having oxygen linker can be prepared by formation of methyl sulfonyl group as a good leaving group in the presence of mCPBA at 0°C.
  • the final compound can be obtained by reacting the intermediate 1-15 and the conjugate base of R ⁇ in a solvent as DMF at room temperature.
  • the one of the alternative route for the quinoline derivatives having oxygen linker is the formation of chloroimidazole compound (the intermediate 1-18) followed by the reaction with alcohol in the presence of NaH at the high temperature.
  • NMR spectra were recorded in CDC1 3 and DIVISOR 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.
  • NIS N-iodosuccinimide - Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium(0)
  • Example 1 7-(3,5-dimethylisoxazol-4-yI)-8-fluoro-l-((R)-l-(pyridin-2- yl)ethyl)-lH-imidazo[4,5-c]quinolin-2(3H)-one
  • Example 7 4-(8-methoxy-2-(methylsulfonyl)-l-((R)-l-(pyridin-2-yl)ethyl)-lH- imidaz -c] quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 8 4-(2-isopropoxy-8-methoxy-l-((R)-l-(pyridin-2-yl)ethyl)-lH- imidaz -c] quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 10 4-(2-(4-fluorophenoxy)-8-methoxy-l-((R)-l-(pyridin-2-yI)ethyl)- lH-imidazo [4,5-c] quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 13 2-(((7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((R)-l-(pyridin-2- yl)ethy -lH-iim ⁇ azo[4,5-c]quinolin-2-yl)oxy)methyl)-5-methyl-l,3,4-oxadiazole
  • Example 14 8-chloro-7-(3,5-dimethylisoxazol-4-yl)-l-((R)-l-(pyridin-2- yl)ethy -lH-imidazo[4,5-c]quinolin-2(3H)-one
  • Example 15 4-(8-chloro-2-(methylsulfonyl)-l-((R)-l-(pyridin-2-yl)ethyl)-lH- imidaz -c] quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 16 2-(((8-chloro-7-(3,5-dimethylisoxazol-4-yl)-l-((R)-l-(pyridin-2- yl)ethy -lH-imidazo[4,5-c]quinolin-2-yl)oxy)methyl)-5-methyl-l,3,4-oxadiazole
  • Example 17 2-(((7-(3,5-dimethylisoxazol-4-yl)-8-fluoro-l-((R)-l-(pyridin-2- yl)ethy -lH-imidazo[4,5-c]quinolin-2-yl)oxy)methyl)-5-methyl-l,3,4-oxadiazole
  • Example 18 4-(8-methoxy-2-((5-methylthiazol-2-yl)thio)-l-((R)-l-(pyridin yl)ethyl)-lH-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 21 4-(8-methoxy-l-((R)-l-methoxypropan-2-yl)-2-(methylthio)-lH- imidaz -c] quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 23 4-(2-(ethylsulfinyl)-8-methoxy-l-((R)-l-(pyridin-2-yl)ethyl)-lH- imidaz -c] quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 25 4-(2-(isopropylsulfinyl)-8-methoxy-l-((R)-l-(pyridiii-2-yl)ethyl)- 1 H-imidazo [4,5-c] quinoIin-7-yl)-3,5-dimethylisoxazole
  • Example 26 4-(2-(isopropylsulfonyl)-8-methoxy-l-((R)-l-(pyridin-2-yl)ethyl)- lH-imidazo [4,5-c] quinoIin-7-yI)-3,5-dimethylisoxazole
  • Example 28 4-(2-(2,2-difluoroethoxy)-8-methoxy-l-((R)-l-(pyridin-2-yl)ethyI)- lH-imidazo [4,5-c] quinolin-7-yl)-3,5-dimethylisoxazoIe
  • Example 29 l-((7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((R)-l-(pyridin yl)ethyl)-lH-imidazo[4,5-c]quinolin-2-yl)oxy)-2-methylpropaii-2-ol
  • Example 30 4-(2-(2-ethoxyethoxy)-8-methoxy-l-((R)-l-(pyridin-2-yI)ethyl)- lH-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 36 4-(8-methoxy-2-(methylsulfonyI)-l-((R)-l-phenylethyI)-lH- imidaz -c] quinolin-7-yl)-3,5-dimethylisoxazole
  • Example 37 2-(((7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((R)-l- phenylethyl)-lH-iinidazo[4,5-c]quinolin-2-yl)oxy)methyl)-5-methyl-l,3,4-oxadiazole
  • Example 38 2-(((7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((R)-l-(6- methylpyridm-2-yl)ethyl)-lH-imidazo[4,5-c]qumolin-2-yl)oxy)methyl)-5-methyl-l,3,4- oxadiazole
  • Example 40 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-l-((R)-l-(pyridin-2- yl)ethy -l,3-dihydro-[l,2,5]thiadiazolo[3,4-c]quinoline 2,2-dioxide
  • Example 46 7-(3,5-dimethylisoxazol-4-yl)-8-ethyl-l-((R)-l-(pyridin-2- yl)ethy -lH-imidazo[4,5-c]quinolin-2(3H)-one
  • Test 1 Bromodomain binding assay (IC 50 measurement for inhibitors using BKD4 Alpha-screen)
  • Bromodomain binding assays were carried out in Reaction Biology (PA, USA) to test the degrees of the inventive compound in inhibiting the human BPJD4 bromodomain 1 by Alpha-screen assay method.
  • Recombinant human BRD4 bromodomain 1 expressed in E. coli with N-terminal His-tag was used as the enzyme target.
  • a synthetic peptide containing 1 st to 21 th amino acids of histone H4 acetylated at lysine 5, 8, 12 and 16 and conjugated to biotin was purchased from Millipore.
  • BRD4-1 (44 to 170 th amino acids; Genbank Accession # NM_058243) was expressed in E. coli with N-terminal His-tag (see Ni-NTA spin Kit Handbook (Qiagen), second edition, January, 2008).
  • Nickel-chelate ALPHA acceptor beads (Perkin Elmer) were used to specifically bind BRD4-1, and ALPHA streptavidin donor beads (Perkin Elmer) were used because they specifically recognized the biotinylated H4 peptide. Binding of BRD4-1 to the synthetic peptide resulted in proximity of the donor and acceptor beads, which leads to an increase in ALPHA signal whereas in a decrease in ALPHA signal.
  • BRD binding assay was performed in a mixture comprising 50 mM Hepes (pH 7.5),
  • IC 50 ( ⁇ ) of the inventive compound against hematological cancer cells and solid tumors was measured for identifying anti-proliferative activities.
  • a human prostatic adenocarcinoma cell line, LnCAP (ATCC ® , CRL-1740) and human leukemia cell line MV4-11 (ATCC ® , CRL-9591) were used to test the degrees of the inventive compound in inhibiting the cancer cell growth.
  • the testing cell concentration was adjusted to 6.7x10 cells/mL with a culture medium supplemented with 10 % FBS, at the temperature of 37 °C, 5 % C0 2 and 95% humidity.
  • Culture media and FBS were purchased from GIBCO. 90 ⁇ . of cell suspensions thus obtained was added to two 96-well plates with the final cell density of 600 cells/well, followed by addition of 10 of culture medium to each well of plate. The plates were incubated overnight in a humidified incubator at 37°C with 5% C0 2 .
  • Test compound was dissolved with dimethylsulfoxide (DMSO) or phosphate buffer solution (PBS) as a stock solution, and 200 x solutions of the test compound (2 mM) using DMSO were prepared. Then, the DMSO solution thus obtained was diluted 20-fold with culture medium or PBS to obtain 10 x working solution. 10 ⁇ L of 10 x working solution (drug solution) was dispensed to each well (triplicate for each concentration). The final concentration of DMSO in culture medium was 0.5% [v/v].
  • DMSO dimethylsulfoxide
  • PBS phosphate buffer solution
  • Cell viability was determined using CellTiter-Glo ® (CTG) assay. 100 of CellTiter-Glo ® was added to the equal volume of the cultured cells to read luminescence in En Vision Multi Label Reader. The results are shown in Table 1. Test 3: Human/mouse/dog liver microsomal stability
  • Human, mouse, and dog liver microsomal clearance assays were carried out in CROWN Biosciences (Taicang, China).
  • the human liver microsomes (Cat No. X008067, Lot No. KQB), mouse liver microsomes (Cat No. M1000, Lot No. 1210302), and dog liver microsomes (Cat. No. D1000, Lot No. 0810342) were purchased from Celsis and Xenotech, respectively.
  • test compound stock solution was diluted with 495 iL of 1 :1 methanol/water (final concentration: 100 ⁇ , 50% MeOH) and combined with 534 ⁇ i 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 (incubation of the test compound with the liver microsomal solution and NADPH for 60 min at 37°C), T30 (incubation under the same condition for 30 min), and T10 (incubation under the same condition for 10 min).
  • 300 ⁇ . of a cold (4°C) stop solution acetonitrile (ACN) including 500 nM of tolbutamide as internal standard
  • ACN acetonitrile
  • NADPH co-factor solution was added to starting plate (TO: 100% of the test compound without any reaction).
  • the reaction was stopped by adding 300 ⁇ , of the cold (4°C) stop solution to the other plates in the following order: T10 first, then T30 and T60.
  • the sample was centrifuged at 4,000 rpm for 20 min and transferred to
  • Example 40 0.055 >10/>10 6/3.6/-
  • the compounds of Examples 1 to 46 exhibited good enzyme binding activity, and cancer cell anti-proliferative activity on LnCAP (human prostatic adenocarcinoma) and MV4-11 (human leukemia). Furthermore, the compounds of Examples 1 to 46 were stable in human, mouse and dog liver microsomes.
  • LLOQ Lower limit of quantification
  • the inventive compounds exhibited an excellent mouse PK, both in rV and PO routes.

Landscapes

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

Abstract

L'invention concerne un nouveau dérivé de quinoléine inhibant les protéines à bromodomaine et domaine extra-terminal (BET), ainsi qu'une composition pharmaceutique comprenant ledit dérivé qui peut être utile pour prévenir ou traiter une transformation précancéreuse ou un cancer.
PCT/KR2016/005274 2015-05-20 2016-05-18 Dérivés de quinoléine à utiliser en tant qu'inhibiteurs de bromodomaine Ceased WO2016186453A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562164186P 2015-05-20 2015-05-20
US62/164,186 2015-05-20

Publications (1)

Publication Number Publication Date
WO2016186453A1 true WO2016186453A1 (fr) 2016-11-24

Family

ID=57320589

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2016/005274 Ceased WO2016186453A1 (fr) 2015-05-20 2016-05-18 Dérivés de quinoléine à utiliser en tant qu'inhibiteurs de bromodomaine

Country Status (1)

Country Link
WO (1) WO2016186453A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9737516B2 (en) 2013-11-26 2017-08-22 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US9777003B2 (en) 2013-12-19 2017-10-03 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US9834565B2 (en) 2014-09-15 2017-12-05 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US9850257B2 (en) 2013-07-08 2017-12-26 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9918990B2 (en) 2013-11-26 2018-03-20 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
US9957268B2 (en) 2014-04-23 2018-05-01 Incyte Corporation 1H-pyrrolo[2,3,c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
CN108033957A (zh) * 2018-01-09 2018-05-15 中国药科大学 一种喹啉类BET bromodomain抑制剂及其制备方法和用途
US10189832B2 (en) 2016-06-20 2019-01-29 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10329305B2 (en) 2015-10-29 2019-06-25 Incyte Corporation Amorphous solid form of a BET protein inhibitor
WO2019201283A1 (fr) * 2018-04-20 2019-10-24 Xrad Therapeutics, Inc. Inhibiteurs doubles d'atm et d'adn-pk pour une utilisation en thérapie antitumorale
CN111909147A (zh) * 2019-05-10 2020-11-10 山东轩竹医药科技有限公司 Dna-pk抑制剂
US10919912B2 (en) 2013-03-15 2021-02-16 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
CN112469720A (zh) * 2018-04-20 2021-03-09 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
WO2025036241A1 (fr) * 2023-08-15 2025-02-20 Ribopeutic Inc. Composés et procédés de modulation de l'épissage de l'arn
WO2025183591A1 (fr) * 2024-02-29 2025-09-04 Федеральное государственное унитарное предприятие "Всероссийский научно-исследовательский институт автоматики им. Н.Л. Духова" (ФГУП "ВНИИА") Dérivés de 2н-[1,4]oxazino- et 2h-[1, 4]thiazino[3,2-c]quinoléine-3(4h)-ones en qualité d'inhibiteurs d'atm et d'adn-pk kinase
RU2848373C1 (ru) * 2024-12-25 2025-10-17 Федеральное Государственное Унитарное Предприятие "Всероссийский Научно-Исследовательский Институт Автоматики Им.Н.Л.Духова" (Фгуп "Внииа") Производные 2H-[1,4]оксазино- и 2H-[1,4]тиазино[3,2-c]хинолин-3(4H)-онов в качестве ингибиторов ATM и DNA-PK киназ для лечения и/или профилактики онкологических заболеваний

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Derives d'imidazo [4, 5-c] quinoline comme inhibiteurs de bromodomaine
WO2012143416A2 (fr) * 2011-04-21 2012-10-26 Glaxosmithkline Llc Nouveaux composés
WO2013024104A1 (fr) * 2011-08-17 2013-02-21 Glaxosmithkline Llc 4-(8-méthoxy-1-((1-méthoxypropan-2-yl)-2-(tétrahydro-2h-pyran-4-yl)-1 h-imidazo[4,5-c]quinolin-7-yl)-3,5-diméthylisoxazole et utilisation de ce dernier en tant qu'inhibiteur de bromodomaines
WO2014128655A1 (fr) * 2013-02-25 2014-08-28 Aurigene Discovery Technologies Limited Dérivés d'imidazo[4,5-c]quinoléine substituée utilisés comme inhibiteurs de bromodomaines
WO2015049629A1 (fr) * 2013-10-01 2015-04-09 Piramal Enterprises Limited Composés d'imidazoquinoline à utiliser en tant qu'inhibiteurs de bromodomaine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054846A1 (fr) * 2009-11-05 2011-05-12 Glaxosmithkline Llc Derives d'imidazo [4, 5-c] quinoline comme inhibiteurs de bromodomaine
WO2012143416A2 (fr) * 2011-04-21 2012-10-26 Glaxosmithkline Llc Nouveaux composés
WO2013024104A1 (fr) * 2011-08-17 2013-02-21 Glaxosmithkline Llc 4-(8-méthoxy-1-((1-méthoxypropan-2-yl)-2-(tétrahydro-2h-pyran-4-yl)-1 h-imidazo[4,5-c]quinolin-7-yl)-3,5-diméthylisoxazole et utilisation de ce dernier en tant qu'inhibiteur de bromodomaines
WO2014128655A1 (fr) * 2013-02-25 2014-08-28 Aurigene Discovery Technologies Limited Dérivés d'imidazo[4,5-c]quinoléine substituée utilisés comme inhibiteurs de bromodomaines
WO2015049629A1 (fr) * 2013-10-01 2015-04-09 Piramal Enterprises Limited Composés d'imidazoquinoline à utiliser en tant qu'inhibiteurs de bromodomaine

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10919912B2 (en) 2013-03-15 2021-02-16 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors
US11498926B2 (en) 2013-03-15 2022-11-15 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9850257B2 (en) 2013-07-08 2017-12-26 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9737516B2 (en) 2013-11-26 2017-08-22 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US9918990B2 (en) 2013-11-26 2018-03-20 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
US9777003B2 (en) 2013-12-19 2017-10-03 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US11091484B2 (en) 2013-12-19 2021-08-17 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US10442803B2 (en) 2013-12-19 2019-10-15 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US10472358B2 (en) 2014-04-23 2019-11-12 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US11702416B2 (en) 2014-04-23 2023-07-18 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US12227502B2 (en) 2014-04-23 2025-02-18 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c] pyridin-7(6H)-ones as inhibitors of BET proteins
US9957268B2 (en) 2014-04-23 2018-05-01 Incyte Corporation 1H-pyrrolo[2,3,c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US10781209B2 (en) 2014-04-23 2020-09-22 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US11059821B2 (en) 2014-04-23 2021-07-13 Incyte Corporation 1H-pyrrolo[2,3-c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US10227359B2 (en) 2014-09-15 2019-03-12 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US10618910B2 (en) 2014-09-15 2020-04-14 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9834565B2 (en) 2014-09-15 2017-12-05 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US10329305B2 (en) 2015-10-29 2019-06-25 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US10858372B2 (en) 2015-10-29 2020-12-08 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US11377446B2 (en) 2016-06-20 2022-07-05 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10189832B2 (en) 2016-06-20 2019-01-29 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10626114B2 (en) 2016-06-20 2020-04-21 Incyte Corporation Crystalline solid forms of a BET inhibitor
US11091480B2 (en) 2016-06-20 2021-08-17 Incyte Corporation Crystalline solid forms of a BET inhibitor
US12459943B2 (en) 2016-06-20 2025-11-04 Incyte Corporation Crystalline solid forms of a BET inhibitor
US12030882B2 (en) 2016-06-20 2024-07-09 Incyte Corporation Crystalline solid forms of a bet inhibitor
CN108033957A (zh) * 2018-01-09 2018-05-15 中国药科大学 一种喹啉类BET bromodomain抑制剂及其制备方法和用途
JP2021522316A (ja) * 2018-04-20 2021-08-30 エクスラッド セラピューティクス，インコーポレーテッド 抗腫瘍療法で使用するためのデュアルａｔｍ及びｄｎａ−ｐｋ阻害剤
JP7366996B2 (ja) 2018-04-20 2023-10-23 エクスラッド セラピューティクス，インコーポレーテッド 抗腫瘍療法で使用するためのデュアルａｔｍ及びｄｎａ－ｐｋ阻害剤
CN112469720A (zh) * 2018-04-20 2021-03-09 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
CN112469720B (zh) * 2018-04-20 2024-03-29 艾科思莱德制药公司 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂
WO2019201283A1 (fr) * 2018-04-20 2019-10-24 Xrad Therapeutics, Inc. Inhibiteurs doubles d'atm et d'adn-pk pour une utilisation en thérapie antitumorale
US12187742B2 (en) 2018-04-20 2025-01-07 Xrad Therapeutics, Inc. Dual ATM and DNA-PK inhibitors for use in anti-tumor therapy
CN111909147A (zh) * 2019-05-10 2020-11-10 山东轩竹医药科技有限公司 Dna-pk抑制剂
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
US12440495B2 (en) 2020-06-03 2025-10-14 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
WO2025036241A1 (fr) * 2023-08-15 2025-02-20 Ribopeutic Inc. Composés et procédés de modulation de l'épissage de l'arn
WO2025183591A1 (fr) * 2024-02-29 2025-09-04 Федеральное государственное унитарное предприятие "Всероссийский научно-исследовательский институт автоматики им. Н.Л. Духова" (ФГУП "ВНИИА") Dérivés de 2н-[1,4]oxazino- et 2h-[1, 4]thiazino[3,2-c]quinoléine-3(4h)-ones en qualité d'inhibiteurs d'atm et d'adn-pk kinase
RU2848373C1 (ru) * 2024-12-25 2025-10-17 Федеральное Государственное Унитарное Предприятие "Всероссийский Научно-Исследовательский Институт Автоматики Им.Н.Л.Духова" (Фгуп "Внииа") Производные 2H-[1,4]оксазино- и 2H-[1,4]тиазино[3,2-c]хинолин-3(4H)-онов в качестве ингибиторов ATM и DNA-PK киназ для лечения и/или профилактики онкологических заболеваний

Similar Documents

Publication Publication Date Title
WO2016186453A1 (fr) Dérivés de quinoléine à utiliser en tant qu'inhibiteurs de bromodomaine
CN114981268B (zh) 嘧啶-4(3h)-酮类杂环化合物、其制备方法及其在医药学上的应用
EP4031547B1 (fr) Inhibiteurs de la kallicréine plasmatique et leurs utilisations
EP3600287B1 (fr) Inhibiteurs de réseaux de kinase et leurs utilisations
CN114394966A (zh) 吡啶并嘧啶酮cdk2/4/6抑制剂
JP2015520186A (ja) 増殖性疾患の治療にキナーゼ阻害剤として有用なジヒドロナフチリジン及び関連化合物
US9884874B2 (en) Bromodomain-inhibiting compounds and pharmaceutical composition comprising same for preventing or treating a cancer
CN112292374B (zh) 一种新型磷酸肌醇3-激酶抑制剂及其制备方法和用途
CN111909157A (zh) Ezh2抑制剂及其用途
TW201136939A (en) Tricyclic compounds and PBK inhibitors containing the same
RU2579513C2 (ru) Ингибиторы активности акт
KR20220051226A (ko) 아자헤테로아릴 화합물 및 이의 용도
WO2019080723A1 (fr) Dérivé de pyridone polysubstitué, son procédé de préparation et son utilisation médicale
TW202204351A (zh) 具有大環結構的化合物及其用途
CN103936762A (zh) 吗啉并喹啉类化合物，其制备方法和用途
CN117412967A (zh) 蛋氨酸腺苷转移酶2a抑制剂
CN103626783B (zh) 双环稠杂环化合物及其用途和药物组合物
CN114763360A (zh) 手性大环化合物作为蛋白激酶抑制剂及其用途
TWI546304B (zh) Protein tyrosine kinase inhibitors and their use
CN104418867B (zh) 作为PI3K/mTOR抑制剂的化合物，其制备方法和用途
WO2016171470A1 (fr) Composés inhibiteurs de bromodomaine et méthodes pour prévenir ou traiter un cancer
CN108456214A (zh) 含噁唑或咪唑结构的喹唑啉类化合物及其应用
CN101857594A (zh) 一种四氢吡啶并吲哚类化合物及其制备方法和应用
WO2022121788A1 (fr) Pyrazoloazépine, inhibiteur d'akt
WO2022121967A1 (fr) Inhibiteur de la tyrosine kinase de l'egfr et ses utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16796780

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16796780

Country of ref document: EP

Kind code of ref document: A1