Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/14—Ortho-condensed systems
• • 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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D495/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems

Definitions

• the genomes of eukaryotic organisms are highly organized within the nucleus of the cell.
• the long strands of duplex DNA are wrapped around an octamer of histone proteins (usually comprising two copies of histones H2A, H2B, H3, and H4) to form a nucleosome, which then is further compressed to form a highly condensed chromatin structure.
• a range of different condensation states are possible, and the tightness of this structure varies during the cell cycle.
• the chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin.
• the chromatin structure is controlled by a series of post translational modifications to histone proteins, notably histones H3 and H4. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation.
• Histone acetylation usually is associated with the activation of gene transcription, as the modification loosens the interaction of the DNA and the histone octamer by changing the electrostatics.
• specific proteins bind to acetylated lysine residues within histones to read the epigenetic code.
• Bromodomains are small (about 110 amino acid) distinct domains within proteins that bind to acetylated lysine resides commonly, but not exclusively, in the context of histones. There is a family of about 50 proteins known to contain bromodomains, which have a range of functions within the cell.
• BET bromodomains The BET family of bromodomain-containing proteins (“BET bromodomains”) includes four proteins, i.e., BRD2, BRD3, BRD4, and BRD-t, which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, thereby increasing the specificity of the interaction.
• BRD2 and BRD3 associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation, while BRD4 may be involved in the recruitment of the pTEF- ⁇ complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output.
• the present disclosure provides a Compound of the Disclosure for use in treatment of a disease or condition of interest, e.g., cancer.
• R 6a and R 6b taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
• R 17b is selected from the group consisting of hydrogen and halo.
• Z is heteroarylenyl
• R 2c is selected from the group consisting of hydrogen and Ci_ 3 alkyl
• R 18 is selected from the group consisting of -C ⁇ CH, -CHO, -C0 2 H, -OH, and halo;
• Compounds of the Disclosure are compounds represented by Formula XII, and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R 18 is -CHO.
• Compounds of the Disclosure are compounds represented by Formula XII, and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R 18 is -C ⁇ CH.
• Compounds of the Disclosure are compounds represented by Formula XII, and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein Q is -0-.
• Compounds of the Disclosure are compounds represented by Formula XII, and the pharmaceutically accepta ble salts, hydrates, and solvates thereof, wherein Q is -N(H)-.
• Compounds of the Disclosure inhibit BET bromodomains and are useful in the treatment of a variety of diseases and conditions.
• Compounds of the Disclosure are useful in methods of treating a disease or condition wherein inhibition of BET bromodomains provides a benefit, for example, cancers and proliferative diseases.
• Methods of the disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need thereof.
• the present methods also encompass administering a second therapeutic agent to the individual in addition to the Compound of the Disclosure.
• the second therapeutic agent is selected from drugs known as useful in treating the disease or condition afflicting the individual in need thereof, e.g., a chemo therapeutic agent and/or radiation known as useful in treating a particular cancer.
• Salts, hydrates, and solvates of the Compounds of the Disclosure can also be used in the methods disclosed herein.
• the present disclosure further includes all possible stereoisomers and geometric isomers of Compounds of the Disclosure to include both racemic compounds and optically active isomers.
• a Compound of the Disclosure When a Compound of the Disclosure is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883-888 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of the Compounds of the Disclosure are possible, the present disclosure is intended to include all tautomeric forms of the compounds.
• Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pi
• solvate encompasses both solution-phase and isolatable solvates.
• Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.
• a pharmaceutically acceptable solvent such as water, methanol, and ethanol
• One type of solvate is a hydrate.
• a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
• Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut.
• a typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration.
• Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
• the methods of the present disclosure can be accomplished by administering a
• the second therapeutic agent is administered in an amount to provide its desired therapeutic effect.
• the effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.
• the cancer is a leukaemia, for example a leukaemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukaemia (MLL).
• the cancer is NUT-midline carcinoma.
• the cancer is multiple myeloma.
• the cancer is a lung cancer such as small cell lung cancer (SCLC).
• SCLC small cell lung cancer
• the cancer is a neuroblastoma.
• the cancer is Burkitt's lymphoma.
• the cancer is cervical cancer.
• the cancer is esophageal cancer.
• the cancer is ovarian cancer.
• the cancer is colorectal cancer.
• the cancer is prostate cancer.
• the cancer is breast cancer.
• the present disclosure provides a method of treating a benign proliferative disorder, such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
• a benign proliferative disorder such as, but are not limited to,
• Compounds of the Disclosure can also treat infectious and noninfectious inflammatory events and autoimmune and other inflammatory diseases by administration of an effective amount of a present compound to a mammal, in particular a human in need of such treatment.
• autoimmune and inflammatory diseases, disorders, and syndromes treated using the compounds and methods described herein include inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendictitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhin
• the present disclosure provides a method of treating systemic inflammatory response syndromes, such as LPS -induced endotoxic shock and/or bacteria-induced sepsis by administration of an effective amount of a Compound of the Disclosure to a mammal, in particular a human in need of such treatment.
• systemic inflammatory response syndromes such as LPS -induced endotoxic shock and/or bacteria-induced sepsis
• the present disclosure provides a method for treating viral infections and diseases.
• viral infections and diseases treated using the compounds and methods described herein include episome-based DNA viruses including, but not limited to, human papillomavirus, Herpesvirus, Epstein-Barr virus, human immunodeficiency virus, hepatis B virus, and hepatitis C virus.
• compositions include those wherein a Compound of the
• Disclosure is administered in an effective amount to achieve its intended purpose.
• the exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a Compound of the Disclosure that is sufficient to maintain therapeutic effects.
• Toxicity and therapeutic efficacy of the Compounds of the Disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals.
• MTD maximum tolerated dose
• the dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index.
• the dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
• a therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the BET bromodomain inhibitor that are sufficient to maintain the desired therapeutic effects.
• the desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required.
• a Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
• a Compound of the Disclosure can be administered, per dose, in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 milligrams, including all doses between 0.005 and 500 milligrams.
• the dosage of a composition containing a Compound of the Disclosure can be from about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.
• the dosage of a composition can be at any dosage including, but not limited to, about 1 ⁇ g/kg.
• Nonlimiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
• steroids such as atamestane, exemestane, and formestane
• non-steroids such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.
• Nonlimiting anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride.
• Anti-androgens include, but are not limited to, bicalutamide.
• Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
• Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
• taxanes such as paclitaxel and docetaxel
• vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine
• discodermolides such as cochicine and epothilones and derivatives thereof.
• Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.
• Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.
• mTOR mammalian target of rapamycin
• Exemplary nonlimiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.
• 5-fluorouracil 5-FU
• capecitabine gemcitabine
• gemcitabine DNA demethylating compounds, such as 5-azacytidine and decitabine
• methotrexate and edatrexate methotrexate and edatrexate
• folic acid antagonists such as pemetrexed.
• Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.
• Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.
• telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
• Patent No. 5,093,330 such as midostaurin
• examples of further compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521 ; LY333531/LY379196; a isochinoline compound; a farnesyl transferase inhibitor; PD 184352 or QAN697, or AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein- tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG- 50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494
• Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
• Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP-470.
• Additional, nonlimiting, exemplary chemotherapeutic compounds include: daunorubicin, adriamycin, Ara-C, VP- 16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-lH-isoindole-l,3-dione derivatives, l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4- chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate,
• a liquid carrier such as water, petroleum, or oils of animal or plant origin
• the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
• the composition When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a Compound of the Disclosure.
• composition When a therapeutically effective amount of a Compound of the Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
• parenterally acceptable aqueous solution having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
• a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
• Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
• Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
• the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
• excipients such as starch or lactose
• capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
• Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
• Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
• the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
• a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
• second therapeutic agent refers to a therapeutic agent different from a Compound of the Disclosure and that is known to treat the disease or condition of interest.
• the second therapeutic agent can be a known chemotherapeutic drug, like taxol, or radiation, for example.
• disease or "condition” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
• a Compound of the Disclosure is a potent inhibitor of BET bromodomains and can be used in treating diseases and conditions wherein inhibition of BET bromodomains provides a benefit.
• the terms “treat,” “treating,” “treatment,” refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
• the terms “treat,” “treating,” “treatment,” may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
• the term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
• treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
• the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
• the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; reduce BET bromodomain signaling in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
• the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
• Constant administration means that two or more agents are administered concurrently to the subject being treated.
• concurrently it is meant that each agent is administered either simultaneously or sequentially in any order at different points in time. However, if not administered simultaneously, it is meant that they are administered to an individual in a sequence and sufficiently close in time so as to provide the desired therapeutic effect and can act in concert.
• a Compound of the Disclosure can be administered at the same time or sequentially in any order at different points in time as a second therapeutic agent.
• a Compound of the Disclosure and the second therapeutic agent can be administered separately, in any appropriate form and by any suitable route.
• a Compound of the Disclosure and the second therapeutic agent are not administered concurrently, it is understood that they can be administered in any order to a subject in need thereof.
• a Compound of the Disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent treatment modality (e.g., radiotherapy), to an individual in need thereof.
• a second therapeutic agent treatment modality e.g., radiotherapy
• a Compound of the Disclosure and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
• the components of the combination therapies are administered at about 1 minute to about 24 hours apart.
• the term "leaving group” refers to an atom or group of atoms that becomes detached from an atom or group of atoms in what is considered to be the residual or main part of the molecule in a specified reaction.
• Non-limiting exemplary leaving groups include -CI, -I, -Br, -OTf, -OMs, and -OTs.
• the alkyl group is a straight chain C 1-6 alkyl. In another embodiment, the alkyl group is a branched chain C 3 _ 6 alkyl. In another embodiment, the alkyl group is a straight chain Ci_ 4 alkyl. In another embodiment, the alkyl group is a branched chain C 3 _ 4 alkyl group. In another embodiment, the alkyl group is a straight or branched chain C 3 _ 4 alkyl group.
• Non-limiting exemplary CM O alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ie/t-butyl, wo-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
• Non-limiting exemplary Ci_ 4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, se -butyl, tert-butyl, and wo-butyl.
• the term "optionally substituted alkyl” as used by itself or as part of another group refers to an alkyl that is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, and cycloalkyl.
• the optionally substituted alkyl is substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, and -CHO.
• the optionally substituted alkyl is substituted with two substituents.
• the optionally substituted alkyl is substituted with one substituent.
• Non-limiting exemplary substituted alkyl groups include -CH 2 CH 2 N0 2 , -CH 2 S0 2 CH 3 CH 2 CH 2 C0 2 H, -CH 2 CH 2 S0 2 CH 3 , -CH 2 CH 2 COPh, and -CH 2 C 6 Hn.
• Non-limiting exemplary substituted alkyl groups also include -CH 2 CH 2 CHO, -CH 2 CH 2 CH 2 CHO, and -CH 2 CH 2 CH 2 CH 2 CHO.
• the cycloalkyl group is a C 3 _ 8 cycloalkyl group. In another embodiment, the cycloalkyl group is a C 3 _ 7 cycloalkyl group. In another embodiment, the cycloalkyl group is a Cs_ 7 cycloalkyl group. In another embodiment, the cycloalkyl group is a C 3 _ 6 cycloalkyl group.
• Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl, cyclohexenyl, and cyclopentanone.
• the term "optionally substituted cycloalkyl” as used by itself or as part of another group refers to a cycloalkyl that is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl,
• the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In another embodiment, the optionally substituted cycloalkyl is substituted with one optionally susbstituted phenyl, e.g.,
• optionally substituted cycloalkyl includes cycloalkyl groups having a fused optionally substituted aryl, e.g., phenyl, or fused optionally substituted heteroaryl, e.g., pyridyl.
• An optionally substituted cycloalkyl having a fused optionally substituted aryl or fused optionally substituted heteroaryl group may be attached to the remainder of the molecule at any available carbon atom on the cycloalkyl ring.
• the optionally substituted cycloalkyl group is a 5-, 6-, or 7-membered cycloalkyl group having a fused phenyl group, wherein the the phenyl optionally substituted with one, two, or three substituents.
• Non-limiting examples include:
• the term "optionally substituted alkenyl” as used herein by itself or as part of another group refers to an alkenyl that is either unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, heteroaryl, and optionally substituted heterocyclo.
• alkynyl refers to an alkynyl that is either unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, heterocyclo, and -Si(R) 3 , wherein
• Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
• hydroxyalkyl as used by itself or as part of another group refers to an alkyl substituted with one two, or three, hydroxy groups.
• the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups, e.g.,
• the hydroxyalkyl group is a C 1-4 hydroxyalkyl group.
• Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1 -hydroxyethyl, 2-hydroxyethyl, 1,2- dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-l-methylpropyl, and l,3-dihydroxyprop-2-yl.
• the term "(cycloalkyl)alkyl,” as used by itself or as part of another group refers to an alkyl substituted with an optionally substituted cycloalkyl group.
• the (cycloalkyl) alkyl is a "(C 3 -6 cycloalkyl)Ci_ 4 alkyl,” i.e., a C 1-4 alkyl substituted with an unsubstituted or substituted C 3 -6 c cloalkyl.
• Non-limiting exemplary (cycloalk l) alkyl groups include
• alkoxy refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl attached to a terminal oxygen atom.
• the alkoxy group is a C 1-6 alkyl attached to a terminal oxygen atom.
• the alkoxy group is chosen from a Ci_ 4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, ie/t-butoxy, -OCH 2 CH 2 C ⁇ CH, and -OCH 2 CH 2 CH 2 C ⁇ CH.
• haloalkoxy as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom.
• Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
• the term "optionally substituted aryl" as used herein by itself or as part of another group refers to an aryl that is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl,
• optionally substituted aryl includes phenyl groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings.
• An optionally substituted aryl having a fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo is attached to to the remainder of the molecule at any available carbon atom on the aryl ring.
• Non-limiting examples include:
• aryloxy as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom.
• a non-limiting exemplary aryloxy group is PhO-.
• aralkyloxy as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom.
• a non-limiting exemplary aralkyloxy group is PhCH 2 0-.
• heteroalkyl refers to stable straight or branched chain hydrocarbon radicals containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quatemized.
• the heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule.
• the heteroalkyl group contains two oxygen atoms.
• the heteroalkyl contains one oxygen and one nitrogen atom. In one embodiment, the heteroalkyl contains two nitrogen atoms.
• Non-limiting exemplary heteroalkyl groups include -CH 2 OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OCH 2 CH 2 OCH 3 , - CH 2 NHCH 2 CH 2 OCH 2 , -OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 N(H)CH 3 , -NHCH 2 CH 2 OCH 3 and -OCH 2 CH 2 OCH 3 .
• heteroaryl refers to unsubstituted monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms, i.e., a 5- to 14-membered heteroaryl, wherein at least one carbon atom of one of the rings is replaced with a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur.
• the heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur.
• the heteroaryl has three heteroatoms.
• the heteroaryl has two heteroatoms.
• the heteroaryl has one heteroatom.
• the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl is a 5- or 6-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom.
• Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H- pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ⁇ - carboliny
• the heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2- furyl and 3-furyl), pyrrolyl (e.g., lH-pyrrol-2-yl and lH-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., lH-pyrazol-3-yl, lH-pyrazol- 4-yl, and lH-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (
• heteroaryl also includes possible N-oxides.
• a non-limiting exemplary N-oxide is pyridyl N-oxide.
• the heteroaryl is a 5- or 6-membered heteroaryl.
• the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms wherein at least one carbon atom of the ring is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
• Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl.
• the heteroaryl is a 6-membered heteroaryl, e.g., the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms wherein at least one carbon atom of the ring is replaced with a nitrogen atom.
• Non-limiting exemplary 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.
• the term "optionally substituted heteroaryl” as used by itself or as part of another group refers to a heteroaryl that is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
• heteroarylenyl refers to a divalent form of an optionally substituted heteroaryl group.
• the heteroarylenyl is a 5-membered heteroarylenyl.
• Non-limiting examples of a 5-membered heteroarylenyl include:
• the heteroarylenyl is a 6-membered heteroarylenyl.
• Non-limiting examples of a 6-membered heteroarylenyl include:
• heterocycle or “heterocyclo” as used by itself or as part of another group refers to unsubstituted saturated and partially unsaturated, e.g., containing one or two double bonds, cyclic groups containing one, two, or three rings having from three to fourteen ring members, i.e., a 3- to 14-membered heterocyclo, wherein at least one carbon atom of one of the rings is replaced with a heteroatom.
• Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be oxidized or quaternized.
• cyclic ureido groups such as 2-imidazolidinone
• cyclic amide groups such as ⁇ -lactam, ⁇ -lactam, ⁇ -lactam, ⁇ - lactam, and piperazin-2-one.
• heterocyclo also include a groups having fused optionally substituted aryl groups, e.g., indolinyl, chroman-4-yl.
• the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms.
• amino refers to -NR a R , wherein R a and R are each independently hydrogen, optionally substituted alkyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, or optionally substituted heteroaryl, or R 7a and R 7b are taken together to form a 3- to 8-membered optionally substituted heterocyclo.
• Non-limiting exemplary amino groups include -NH 2 and -N(H)(CH 3 ).
• R 9a and R 9b are each independently hydrogen or optionally substituted alkyl.
• R 9a and R 9b are taken together to taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group.
• Non-limiting exemplary carboxamido groups include, but are
• Non-limiting exemplary sulfonamido groups include -S0 2 NH 2 , -S0 2 N(H)CH 3 , and -S0 2 N(H)Ph.
• a non-limiting exemplary alkylcarbonyl group is -COCH 3 .
• a non-limiting exemplary arylcarbonyl group is -COPh.
• (alkoxycarbonyl)alkyl refers to an alkyl group substituted by an alkoxycarbonyl group.
• mercaptoalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a -SH group.
• carboxy as used by itself or as part of another group refers to a radical of the formula -COOH.
• carboxyalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a - COOH.
• a non-limiting exemplary carboxyalkyl group is -CH 2 C0 2 H.
• the terms "aralkyl” or “arylalkyl” as used by themselves or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups.
• the optionally substituted aralkyl group is a C 1-4 alkyl substituted with one optionally substituted C5 or C 6 aryl group.
• the optionally substituted aralkyl group is a Ci or C 2 alkyl substituted with one optionally substituted aryl group.
• the optionally substituted aralkyl group is a Ci or C 2 alkyl substituted with one optionally substituted phenyl group.
• the terms "(heterocyclo)alkyl” as used by itself or part of another group refers to an alkyl substituted with an optionally substituted heterocyclo group.
• the (heterocyclo)alkyl is a Ci_ 4 alkyl substituted with one optionally substituted heterocyclo group.
• Non-limiting exemplary (heterocyclo)alkyl groups include:
• the term "(carboxamido)alkyl” as used by itself or as part of another group refers to an alkyl substituted with one or two carboxamido groups.
• the (carboxamido)alkyl is a C 1-4 alkyl substituted with one carboxamido group, i.e., a (carboxamido)Ci_ 4 alkyl.
• the (carboxamido)alkyl is a Ci_ 4 alkyl substituted with two carboxamido groups.
• Non-limiting exemplary (carboxamido)alkyl groups include -CH 2 CONH 2 , -C(H)CH 3 -CONH 2 , -CH 2 CON(H)CH 3 , and -CH(C0 2 NH 2 )CH- 2CH 2 C0 2 NH 2 .
• Step 2 A round bottom flask containing a solution of 2-amino-5-methyl thiophene-3-carboxylic acid (12.8 g, 82 mmol, 1 equiv.) in dry THF (100 mL) was immersed into an oil bath. Triphosgene (8.2 g, 28 mmol, 0.34 equiv.) was added portionwise (exothermic reaction) and the reaction was heated at 40 - 50 °C for 3 hr. After cooling, hexanes (200 mL) was added. The precipitate was filtered to give the isatoic anhydride product (14.5 g, 97%).
• Step 3 To a solution of N,0-dimethylhydroxylamine hydrochloride (11.5 g, 119 mmol) in 90% aqueous ethanol (40 mL) was added triethylamine (16.5 mL, 119 mmol). after 10 min of stirring at 25 °C , isatoic anhydride product (14.5 g, 79 mmol) was added in portions. The reaction was then heated at reflux for 1.5 h and poured into an equal volume of ice and saturated sodium bicarbonate.
• Boc 2 0 (7.3 g, 33.6 mmol, 1.6 eq) and DMAP (2.56 g, 21 mmol, 1 eq) and the mixture was stirred for 10 min during which time yellow precipitate was observed. Then tert- butanol (3.2 mL, 33.6 mmol, 1.6 eq) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to 40 °C, ⁇ 2 ⁇ 4 ⁇ 2 0 (1 mL, 21 mmol, 1.0 eq) was added to the mixture and continued to stir at 40 °C for 3 h.
• Step 1 A solution of 33% HBr in acetic acid (7.3 mL) was cooled to 0 °C. A cold solution of HYB-107 (1 g, 4 mmol) in DCM (1 mL) was added and the reaction mixture turned red immediately. The reaction mixture was immediately poured into ice- water (50 g each) and was taken up in ethyl acetate. The organic layer was separated, washed successively with 10% NaOH (40 mL), NaHCO 3 (40 mL), and brine (40 mL). After drying, the organic solution was passed through a short pad of silica gel, then concentrated. The residue was dissolved in dichloromethane for next step. [0304] Step 2: The solution prepared above was cooled to 0 °C, and 2-chloroacetic acid
• Step 1 A solution of HYB-125 (600 mg, 2.8 mmol) in methanol was cooled to
• Step 2 A suspension of NaO'Bu (5.5 mmol, 3 eq) in T3uOH (10 mL) was heated at 80 °C until it turns into a clear solution. Then the solid prepared above (400 mg, 1.8 mmol) was added in one portion and the reaction is finished in 5 min. The reaction mixture was cooled and poured into ice-water, extracted with ethyl acetate.
• Cpd. No. 1 14 was synthesized following the same synthetic procedures as compound Cpd. No. 109 except for starting from chiral (R)-2-((tert- butyldiphenylsilyl)oxy)propanoic acid.
• ESI M+H 326.08.
• Step 2 To a solution of methyl (S)-2-(4-(tert-butoxy)-2-((tert- butyldimethylsilyl)oxy)-4-oxobutanethioamido)-5-methylthiophene-3-carboxylate (510 mg, 1.1 mmol) in THF (4 mL) was added hydrazine monohydrate (0.12 mL, 2.4 mmol, 2 eq) at 0 °C and the reaction mixture was allowed to warm to r.t. The reaction mixture was stirred for 1 h prior to being concentrated in vacuum. The residue was taken up in DCM and washed with water and brine. The organic layer was separated, dried and concentrated.
• Step 3 The residue was taken up in ethanol (4 mL) and triethyl orthoacetate
• Step 4 All volatiles were removed under vacuum and the residue was dissolved in AcOH (4 mL). The solution was heated at reflux for lh prior to the removal of the solvent under vacuum. The residue was taken up in EtOAc and washed with 2 M Na 2 C0 3 . The organic layer was washed with brine, dried and concentrated.
• Step 2 The residue was dissolved in DCM and cooled to 0 °C. Thionyl chloride (0.13 mL, 1.8 mmol, 3 eq) was added and the reaction mixture was allowed to warm to r.t. After 1 h, all the volatiles were removed and the residue was taken up in EtOAc and washed with 2 M Na 2 C0 3 . The organic layer was washed with brine, dried and concentrated. The residue was chromatographed on silica gel (ethyl acetate) to give HYC-247 as a mixture of diastereoisomers: (229 mg, 64%).
• Step 1 To a solution of methyl l-(thiopher!-3-ylrnethoxy)cyclopropane-l- carboxylate (1.65 g, 7.8 mmol) in DCM (5 mL) and AcOH (5 mL) was added NBS (1.38 g, 7.8 mmol) and the reaction mixture was stirred overnight. The reaction mixture was poured into mixture of ice-water and extracted with Et 2 0 (3x20 mL). The combined organic layer was washed with 1 M NaOH (2x10 mL), saturated NaHC0 3 (2x20mL), and brine, dried, filtered and then concentrated The oil was used directly in the next step without further purification.
• Step 3 The above crude was dissolved in DCM and cooled to 0 °C. Oxallyl chloride (0.87 mL, 10 mmol, 1.3 eq) was added slowly followed by several drops of DMF. The reaction mixture was allowed to warm to rt. and stirred for 1 h prior to being concentrated under vacuum. The residue was dissolved in DCM and added slowly at 0 °C to a solution of NH 3 in methanol (7 M, 5 mL) . The reaction mixture was stirred overnight prior to being filtered over Celite. The filtrate was concentrated and the residue was chromatographed on silica gel (ethyl acetate) to give HYC-276 as a solid. (1.38 g, 64%.).
• Step 2 To a solution of 7'-bromo- ,5'-dihydro-2'H-spiro[cyclopropane-l,3'- thieno[2,3-e][l,4]oxazepine]-2'-thione in THF (2 mL) was added hydrazine monohydrate (0.038 mL, 0.8 mmol, 2 eq) at 0 °C and the reaction mixture was allowed to warm to r.t. The reaction mixture was stirred for 1 h prior to being concentrated in vacuum. The residue was taken up in DCM and washed with water and brine. The organic layer was separated, dried and concentrated.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Oncology (AREA)
• Immunology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Communicable Diseases (AREA)
• Epidemiology (AREA)
• Hematology (AREA)
• Transplantation (AREA)
• Virology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Priority Applications (7)

Applications Claiming Priority (4)

Publications (1)

Family

ID=58191613

Family Applications (1)

Country Status (8)

Cited By (16)

Families Citing this family (2)

Citations (34)

Family Cites Families (11)

• 2017
  • 2017-02-15 EP EP17708046.2A patent/EP3416969B1/en active Active
  • 2017-02-15 US US16/077,844 patent/US11548899B2/en active Active
  • 2017-02-15 AU AU2017219627A patent/AU2017219627B2/en not_active Ceased
  • 2017-02-15 ES ES17708046T patent/ES2882066T3/es active Active
  • 2017-02-15 WO PCT/US2017/017848 patent/WO2017142881A1/en not_active Ceased
  • 2017-02-15 CN CN201780023735.8A patent/CN109071562B/zh not_active Expired - Fee Related
  • 2017-02-15 CA CA3014644A patent/CA3014644A1/en active Pending
  • 2017-02-15 JP JP2018543139A patent/JP6967522B2/ja not_active Expired - Fee Related

Patent Citations (51)

Non-Patent Citations (11)

Also Published As

Similar Documents

Legal Events