WO2024238793A1 - Fused triazinones for use in the treatment of cancer - Google Patents

Fused triazinones for use in the treatment of cancer Download PDF

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Publication number
WO2024238793A1
WO2024238793A1 PCT/US2024/029691 US2024029691W WO2024238793A1 WO 2024238793 A1 WO2024238793 A1 WO 2024238793A1 US 2024029691 W US2024029691 W US 2024029691W WO 2024238793 A1 WO2024238793 A1 WO 2024238793A1
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Prior art keywords
heterocycloalkyl
cancer
7alkyl
mmol
optionally substituted
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PCT/US2024/029691
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French (fr)
Inventor
Hualin Simon XI
Travis T. Wager
Patricia Soulard
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Rgenta Therapeutics, Inc.
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Publication of WO2024238793A1 publication Critical patent/WO2024238793A1/en

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    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • MYB proto-oncogene protein is a transcription factor that regulates cell proliferation. It has been implicated in a variety of cancers. Accordingly, it may be a potential target for small-molecule inhibition. Small-molecule drugs have excellent pharmacokinetics, effective delivery, and bioavailability. Yet, the MYB inhbitior molecules come from a few limited chemical series.
  • SUMMARY [003] Provided herein are methods of treating diseases or disorders in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.
  • the present disclosure includes methods of treating diseases or disorders related to MYB.
  • the present disclosure provides a compound of Formula (I): I), or a pharmaceutically acceptable thereof, wherein: A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR 1 R 2 , wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R 1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R 2 is hydrogen, C 1-7 alkyl, or C 3-8 cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R 4 is optionally substituted with 1, 2, or 3 R7; each R 5
  • R 17 is H, halo, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl.
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described here (e.g., a method comprising one or more steps described in herein).
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described herein).
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides a method of preparing a compound of the present disclosure.
  • the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.
  • FIG.1 is a graph showing the change in tumor volume over time in a patient-derived adenoid cystic carcinoma xenograft model treated with vehicle or Compound 116.
  • DETAILED DESCRIPTION [021] Compounds described herein are generally designed to treat diseases and disorders disclosed herein. Definitions [022] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
  • alkyl As used herein, “alkyl”, “C1, C2, C3, C4, C5, C6, or C7 alkyl” or “C1-C7 alkyl” is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , or C 7 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, C6, or C7 branched saturated aliphatic hydrocarbon groups.
  • C 1 -C 7 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5, C 6, and C7 alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • alkenyl is intended to include straight-chain or branched hydrocarbon groups having from 2 to 6 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C2-C6alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2- C6alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2- butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • alkynyl is intended to include straight-chain or branched hydrocarbon groups having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds (“C2-C6 alkynyl”).
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C2-C4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • optionally substituted alkyl refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino), acylamino (including alky
  • optionally substituted moieties include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
  • substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.
  • heteroalkyl As used herein, “heteroalkyl”, “C1, C2, C3, C4, C5, C6, C7 or C8 heteroalkyl” or “C1- C 8 heteroalkyl” is intended to include C 1 , C 2 , C 3 , C 4 , C 5, C 6 , C 7 , or C 8 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, C6, C7, or C8 branched saturated aliphatic hydrocarbon groups, in which at least one of the carbons has been replaced with N, O, or S.
  • heteroatom will be bonded to any required hydrogens to complete the heteroatom’s valence (e.g., a CH 2 may be replaced with an “O” or a “NH”, a CH may be replaced with an N, etc.)).
  • substituents can include, for example, -O-CH(CH3)2, -CH2- N(CH 3 )-CH 2 CH 2 OCH 3 , -S-CH 2 CH 2 -O-CH 2 CH 3 , and so forth.
  • alkylene As used herein, “alkylene”, “C1, C2, C3, C4, C5, C6, or C7 alkylene” or “C1-C7 alkylene” is a bivalent branched or straight alkyl group which has two open valences to connect the alkylene with two other groups.
  • alkylene include -CH2-, -CH2CH2-, -CH 2 CH 2 CH 2 -, and -CH(CH 2 CH 3 )-CH 2 -. Where an alkylene connects its open valences to the same atom or to separate atoms which are already part of a chain or ring, the alkylene taken together with the atom or atoms to which it is attached will form a ring.
  • alkoxy refers to the group -OR where R is alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 7 carbon atoms.
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8).
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • polycyclic cycloalkyl only one of the rings in the cycloalkyl needs to be non- aromatic.
  • heterocycloalkyl refers to a saturated or partially unsaturated 3-8 membered monocyclic (e.g., 4-7 membered monocyclic), 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) (e.g., a mono- or bi-cyclic 4- to 9- membered heterocycloalkyl) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ⁇ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise.
  • heteroatoms such as O, N, S, P, or Se
  • heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-o
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system.
  • aryl groups include, but are not limited to, phenyl, naphthyl and the like.
  • an aryl is phenyl.
  • heteroaryl is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ⁇ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined).
  • heteroaryl groups examples include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).
  • aryl and heteroaryl include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
  • Bicyclic and tricyclic systems can be edge-fused, spiro-fused, or bridged systems.
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, IPTS/128571997.1 carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamin
  • Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).
  • substituted means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogen atoms on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [039] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring.
  • hydroxy or “hydroxyl” includes groups with an -OH or - O-.
  • cyano refers to the group -CN.
  • halo or “halogen” refers to fluoro, chloro, bromo and iodo.
  • haloalkyl refers to a branched or unbranched alkyl substituted with one or more halogens.
  • a C1-7haloalkyl is an alkyl group of from one to seven cabons wherein at least one H is substituted by a halogen.
  • haloalkyl include but are not limited to CFH2, CF2H, CF3, CH2CF3, CF2CF3, C(F)(CH3)2, CH 2 CH 2 Br, CH(I)CH 2 F, and CH 2 Cl.
  • haloalkoxy refers to alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and “fluoro alkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • amino refers to the radical -NH2.
  • one or both hydrogen atoms of -NH2 may be replaced with a different group, e.g., amino-C1-7alkyl.
  • optionally substituted haloalkyl refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates
  • the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.
  • the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
  • methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
  • order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models.
  • the terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the disclosure can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the term “treating” or “treat” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • pharmaceutical composition is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non- toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
  • the state of the disease condition e.g., a disease or disorder disclosed herein
  • the health of the subject should preferably be closely monitored during and for a reasonable period after treatment.
  • the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity of the subject, and the route of administration. [068] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes.
  • compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the appropriate formulation is dependent upon the route of administration chosen.
  • Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ⁇ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier.
  • compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebuliser.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. [076] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder.
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression.
  • the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalactur
  • the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.
  • salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4- toluenesulphonic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1- carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.
  • all references to pharmaceutically acceptable salts include solvent addition forms (solvates) as defined herein, of the same salt.
  • the compounds, or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compound is administered orally.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.
  • Suitable anions include chloride, bromide, iodide, sulphate, bisulphate, sulphamate, nitrate, phosphate, citrate, methanesulphonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulphonate, and acetate (e.g., trifluoroacetate).
  • pharmaceutically acceptable anion refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present disclosure for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative refers to compounds that have a common core structure and are substituted with various groups as described herein.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulphonamides, tetrazoles, sulphonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev.96, 3147-3176, 1996.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto/enol illustrated below
  • imine/enamine imine/enamine
  • amide/imino alcohol amidine/amidine
  • nitroso/oxime thioketone/enethiol
  • nitro/aci-nitro H O OH H + O- C C C C + C H isclosed herein containing an amine function may also form N-oxides.
  • a reference herein to a compound of Formula (I) and (II) that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn.
  • the compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
  • a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached.
  • prodrugs include derivatives containing in vivo cleavable alkyl or acyl substitutents at the ester or amide group in any one of the Formulae disclosed herein.
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers.
  • racemic mixture A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • chiral centre refers to a carbon atom bonded to four nonidentical substituents.
  • chiral isomer means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre.
  • the substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).
  • the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0100] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers.
  • Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached.
  • tautomerism The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (- CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the subject without undesirable pharmacological activities and without undue toxicity.
  • Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the subject to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1 -C 10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1- 4 alkylamine such as methylamine, a (C 1 -C 4 alkyl) 2 amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C 1 -C 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C1- 4 alkylamine such as methylamine
  • a (C 1 -C 4 alkyl) 2 amine such as dimethylamine, N-ethyl-N- methyl
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C 1 -C 10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4- (C 1 -C 4 alkyl)piperazin-1-ylmethyl.
  • the dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the subject; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • the present disclosure provides, inter alia, a compound of Formula (I): (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR 1 R 2 , wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R 1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R 2 is hydrogen, C 1-7 alkyl, or C 3-8 cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R 4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O,
  • R 17 is H, halo, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl.
  • A is saturated or part ially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl;
  • R 3 is H, halo, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl.
  • R17 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl.
  • A is saturated or parti ally unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR 1 R 2 , wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R 1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R 2 is hydrogen, C 1-7 alkyl, or C 3-8 cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R 4 is aryl or bicycl
  • R17 is H.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR 1 R 2 , wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6;
  • R 1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6;
  • R 2 is hydrogen, C 1-7 alkyl, or C 3-8 cycloalkyl;
  • R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl;
  • R 4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with
  • R17 is H, halo, C1-7alkyl, or OR5.
  • A is a nitrogen-containing heterocycloalkyl or NR1R2, wherein the nitrogen- containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl;
  • R 3 is H, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl;
  • R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R 4 can be optionally substituted
  • R 17 is H, halo, C 1-7 alkyl, OR 5 , or N(R 5 ) 2 .
  • A is a nitrogen-containing heterocycloalkyl or NR 1 R 2 , wherein the nitrogen- containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl;
  • R 3 is H, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl;
  • R4 is a bicyclic 9-membered heteroaryl comprising
  • R17 is H.
  • A is a nitrogen-contai ning heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6;
  • R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl;
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 can be optionally substituted with 1, 2, or 3 R7; each R 5 is independently H, C 1-7 alkyl, C 3-8 cycloalkyl, or heterocycloalkyl;
  • each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocyclo
  • R17 is H, halo, C1-7alkyl, or OR5.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl;
  • R 3 is H, halo, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl;
  • R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 hetero
  • the present disclosure provides, inter alia, a compound of Formula (II): (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: A is nitrogen-containing heterocycloalkyl or NR 1 R 2 , wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 ; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R 6 ; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R 3 is H, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R 4 is optionally substituted with 1, 2, or 3 R 7
  • the present disclosure provides, inter alia, a compound of Formula (II): or a pharmaceutically accept , wherein: A is nitrogen-contain ing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R 4 is optionally substituted with 1, 2, or 3 R 7 ; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R 6 is independently C 1-7 alkyl, amino, amino-C 1-7 alkyl, C 3-8 cycloalkyl, heterocycloalkyl, and C1-7alkoxy-
  • the present disclosure provides, inter alia, a compound of Formula (II): or a pharmaceutically acc ereof, wherein: A is nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 ; R 3 is H, C 1-7 alkyl, OR 5 , N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R 4 is optionally substituted with 1, 2, or 3 R 7 ; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R 6 is independently C 1-7 alkyl, amino, amino-C 1-7 alkyl, C 3-8 cycloalkyl, heterocycloalkyl, and
  • A, R 1 , R 2, R 3 , R 4 , R 5 , R 6 , and R7 can each be, where applicable, selected from the groups described herein, and any group described herein for any of A, R 1 , R 2, R 3 , R 4 , R 5 , R 6 , and R 7 can be combined, where applicable, with any group described herein for one or more of the remainder of A, R1, R2, R3, R 4 , R 5 , R 6 , and R 7 .
  • A is nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6, and is bonded to formula (I) or (II) by one of its nitrogen atoms wherein each R 6 is independently C 1-7 alkyl, amino, amino-C 1-7 alkyl, C 3-8 cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl or two R6 together form C1-7alkylene.
  • each R 6 is independently C 1-7 alkyl, heterocycloalkyl, or C 1- 7alkoxy-heterocycloalkyl or two R6 together form C1-.
  • each R6 is independently methyl, ethyl, isopropyl, methoxy-azetidinyl, or pyrrolidinyl, or two R 6 together form ethylene or propylene.
  • two R6 together form C1- 7alkylene.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is partially unsaturated mono- or bi-cyclic 4- to 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is partially unsaturated mono- or bi-cyclic 4- to 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is partially unsaturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is partially unsaturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is partially unsaturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is partially unsaturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bicyclic 4- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 5-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 5-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 7- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 7- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 7- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 7- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 8- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 8- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 7- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 7- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 6- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 5- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 1, 2, or 3 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 1 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 2 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 3 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 nitrogen ring atom.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 2 nitrogen ring atoms.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 nitrogen ring atom and is optionally substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 2 nitrogen ring atoms and is optionally substituted with 1, 2, or 3 R 6 .
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 nitrogen ring atom and is substituted with 1, 2, 3, or 4 R6.
  • A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 2 nitrogen ring atoms and is substituted with 1, 2, or 3 R 6 .
  • A is piperazinyl, diazepanyl, octahydropyrrolopyrazinyl, diazaspirooctanyl, pyrrolidinyl, octahydropyrrolopyrroyl, diazaspirononanyl, diazaspiroheptanyl, or diazabicyclooctanyl, each optionally substituted with 1, 2, 3, or 4 R6.
  • a n, Y is absent, N or CH;
  • R 9 is hydrogen, C 1-7 alkyl, or (CH 2 ) m -NR 14 R 15 ;
  • R10 is hydrogen or C1-7alkyl;
  • R 11 is hydrogen or C 1-7 alkyl;
  • R12 is hydrogen or C1-7alkyl;
  • R13 is hydrogen or C1-7alkyl;
  • each R14 and R15 are independently hydrogen, C1-7alkyl and C3-8cycloalkyl;
  • n is 0, 1 or 2;
  • m is 0, 1 or 2; or
  • R9 and R10 together form C1-7alkylene;
  • R 9 and R 12 together form C 1-7 alkylene;
  • R10 and R11 together form C2-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C 1-7 alkyl; or
  • R10 and R12 together form C1-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with
  • Y is N or CH. In some embodiments, Y is absent. In some embodiments, Y is N. In some embodiments, Y is CH. [0197] In some embodiments, R 9 is hydrogen, C 1-7 alkyl, or (CH 2 ) m -NR 14 R 15 . In some embodiments, R9 is hydrogen. In some embodiments, R9 is C1-7alkyl. In some embodiments, R 9 is (CH 2 ) m -NR 14 R 15 . [0198] In some embodiments, R10 is hydrogen or C1-7alkyl. In some embodiments, R10 is hydrogen. In some embodiments, C1-7alkyl.
  • R11 is hydrogen or C1-7alkyl. In some embodiments, R11 is hydrogen. In some embodiments, C 1-7 alkyl.
  • R12 is hydrogen or C1-7alkyl. In some embodiments, R12 is hydrogen. In some embodiments, C 1-7 alkyl.
  • R13 is hydrogen or C1-7alkyl. In some embodiments, R13 is hydrogen. In some embodiments, C 1-7 alkyl. [0202] In some embodiments, R14 is hydrogen, C1-7alkyl, or C3-8cycloalkyl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is C 1-7 alkyl.
  • R14 is C3-8cycloalkyl.
  • R 15 is hydrogen, C 1-7 alkyl, or C 3-8 cycloalkyl. In some embodiments, R15 is hydrogen. In some embodiments, R15 is C1-7alkyl. In some embodiments, R 15 is C 3-8 cycloalkyl.
  • n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • R9 and R10 together form C1-7alkylene.
  • R9 and R12 together form C1-7alkylene.
  • R 10 and R 11 together form C 2-7 alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl.
  • R10 and R11 together form C 2-7 alkylene.
  • R10 and R11 together form 4- to 6-membered heterocycloalkyl optionally substituted with C 1-7 alkyl.
  • R 10 and R 11 together form 4- membered heterocycloalkyl optionally substituted with C1-7alkyl.
  • R10 and R 11 together form 5-membered heterocycloalkyl optionally substituted with C 1-7 alkyl. In some embodiments, R10 and R11 together form 6-membered heterocycloalkyl optionally substituted with C 1-7 alkyl. [0210] In some embodiments, R10 and R11 together form 4- to 6-membered heterocycloalkyl substituted with C 1-7 alkyl. In some embodiments, R 10 and R 11 together form 4-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R11 together form 5-membered heterocycloalkyl substituted with C 1-7 alkyl.
  • R 10 and R 11 together form 6-membered heterocycloalkyl substituted with C1-7alkyl.
  • R10 and R12 together form C1-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C 1-7 alkyl.
  • R 10 and R 12 together form C1-7alkylene.
  • R 10 and R 12 together form 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl.
  • R10 and R12 together form 4- membered heterocycloalkyl optionally substituted with C 1-7 alkyl.
  • R 10 and R12 together form 5-membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R 10 and R 12 together form 6-membered heterocycloalkyl optionally substituted with C1-7alkyl. [0213] In some embodiments, R 10 and R 12 together form 4- to 6-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R12 together form 4-membered heterocycloalkyl substituted with C 1-7 alkyl. In some embodiments, R 10 and R 12 together form 5-membered heterocycloalkyl substituted with C1-7alkyl.
  • R10 and R12 together form 6-membered heterocycloalkyl substituted with C 1-7 alkyl.
  • R10 and R14 together form C1-7alkylene.
  • R12 and R13 together form C2-7alkylene.
  • R12 and R14 together form C1-7alkylene.
  • R14 and R15 together form C2-7alkylene.
  • R 14 and R 15 together form C 2-7 alkylene which is optionally substituted with C1-7alkoxy.
  • R 14 and R 15 together form C 2-7 alkylene which is substituted with C1-7alkoxy.
  • Y is CH and R 9 is (CH 2 ) m -NR 14 R 15 .
  • R9 is hydrogen, pyrrolidinyl, or methoxy-azetidinyl.
  • R 10 is hydrogen, methyl, ethyl or isopropyl.
  • R11 is hydrogen or methyl.
  • R 12 is hydrogen or methyl.
  • R9 and R10 together form propylene.
  • R 10 and R 11 together form ethylene.
  • R14 and R15 together form propylene or butylene.
  • A is hydrogen or C1-7alkyl.
  • R16 is hydrogen or C1-7alkyl.
  • R 16 is hydrogen.
  • R 16 is C 1-7 alkyl.
  • A is , [0233] In some embodiments A , , [0235] In some embodiments, A is NR 1 R 2 .
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom.
  • R 1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R6.
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 1, 2, 3, or 4 R 6 .
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 1, 2, or 3 R 6 .
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 1 R 6 .
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 2 R 6 .
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 3 R 6 .
  • R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 4 R 6 .
  • R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl.
  • R 2 is hydrogen or C 1-7 alkyl.
  • R2 is hydrogen.
  • R2 is C1-7alkyl.
  • R2 is methyl.
  • R2 is ethyl.
  • R2 is propyl.
  • R2 is butyl.
  • R2 is pentyl.
  • R2 is hexyl. In some embodiments, R 2 is heptyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is isobutyl. In some embodiments, R2 is isopentyl. In some embodiments, R2 is isohexyl. In some embodiments, R 2 is secbutyl. In some embodiments, R 2 is secpentyl. In some embodiments, R2 is sechexyl. In some embodiments, R2 is tertbutyl. [0248] In some embodiments, R 2 is C 3-8 cycloalkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • R 3 is H, halo, C 1-7 alkyl, -OR 5 , -N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl.
  • R 3 is H, C 1-7 alkyl, -OR 5 , -N(R 5 ) 2 , C 3-8 cycloalkyl, or heterocycloalkyl.
  • R 3 is H or C 1-7 alkyl.
  • R3 is H. [0253] In some embodiments, R 3 is halo. In some embodiments, R 3 is F, Cl, Br, or I. In some embodiments, R3 is F, Cl, or Br. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Br. In some embodiments, R 3 is I. [0254] In some embodiments, R3 is C1-7alkyl. In some embodiments, R3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl.
  • R3 is pentyl. In some embodiments, R3 is hexyl. In some embodiments, R 3 is heptyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is isobutyl. In some embodiments, R3 is isopentyl. In some embodiments, R3 is isohexyl. In some embodiments, R 3 is secbutyl. In some embodiments, R 3 is secpentyl. In some embodiments, R3 is sechexyl. In some embodiments, R3 is tertbutyl. [0255] In some embodiments, R 3 is -OR 5 or -N(R 5 ) 2 .
  • R 3 is -OR 5 . In some embodiments, R3 is -N(R5)2. [0256] In some embodiments, R 3 is C 3-8 cycloalkyl or heterocycloalkyl. [0257] In some embodiments, R3 is C3-8cycloalkyl. In some embodiments, R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. [0258] In some embodiments, R3 is heterocycloalkyl.
  • R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, or S.
  • R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N or O.
  • R4 is aryl.
  • R 4 is aryl optionally substituted with one, two, or three R 7 .
  • R4 is aryl substituted with one, two, or three R7. In some embodiments, R 4 is aryl substituted with one R 7 .
  • R 4 is aryl substituted with two R7. In some embodiments, R4 is aryl substituted with three R7. [0264] In some embodiments, R 4 is phenyl. [0265] In some embodiments, R4 is phenyl optionally substituted with one, two, or three R7. [0266] In some embodiments, R 4 is phenyl substituted with one, two, or three R 7 . In some embodiments, R4 is phenyl substituted with one R7. In some embodiments, R4 is phenyl substituted with two R 7 . In some embodiments, R 4 is phenyl substituted with three R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S.
  • R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O.
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N, O, and S.
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O.
  • R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R 4 is optionally substituted with 1, 2, or 3 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is optionally substituted 1, 2, or 3 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N, O, and S, wherein R 4 is optionally substituted with 1, 2, or 3 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7.
  • R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 1, 2, or 3 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R 4 is substituted with 1, 2, or 3 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 3 R7.
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R 4 is substituted with 3 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R 4 is optionally substituted with 1, 2, or 3 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising two heteroatoms independently selected from N and O, wherein R4 is substituted with 1, 2, or 3 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R 4 is substituted with 1 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R 4 is substituted with 2 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R 4 is substituted with 3 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7.
  • R4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R 4 is substituted with 1, 2, or 3 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 3 R7.
  • R 4 is a bicyclic 9-membered heteroaryl comprising four heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R 4 is substituted with 1, 2, or 3 R7.
  • R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R 4 is substituted with 1 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R 4 is substituted with 2 R 7 .
  • R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R 4 is substituted with 3 R 7 .
  • R4 is imidazo[1,2-a]pyrazine, benzo[d]oxazole, triazolo- pyridazinyl, or imidazo[1,2-a]pyrazine each optionally substituted with 1, 2, 3, or 4 R 7 .
  • R 4 [0300] In some embodiments, R4 is [0301] In some embodiments, R4 [0302] In some embodiments, R4 is ycloalkyl, or heterocycloalkyl.
  • each R 5 is independently C 1-7 alkyl. In some embodiments, each R5 is independently methyl. In some embodiments, each R5 is independently ethyl.
  • each R 5 is independently propyl. In some embodiments, each R 5 is independently butyl. In some embodiments, each R5 is independently pentyl. In some embodiments, each R 5 is independently hexyl. In some embodiments, each R 5 is independently heptyl. In some embodiments, each R5 is independently isopropyl. In some embodiments, each R 5 is independently isobutyl. In some embodiments, each R 5 is independently isopentyl. In some embodiments, each R5 is independently isohexyl. In some embodiments, each R 5 is independently secbutyl. In some embodiments, each R 5 is independently secpentyl. In some embodiments, each R5 is independently sechexyl.
  • each R 5 is independently tertbutyl. [0305] In some embodiments, each R5 is independently C3-8cycloalkyl or heterocycloalkyl. [0306] In some embodiments, each R 5 is independently C 3-8 cycloalkyl. In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. [0307] In some embodiments, each R5 is independently heterocycloalkyl.
  • each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl and C1-7alkoxy-heterocycloalkyl or two R6 together form C1- 7alkylene. [0309] In some embodiments, each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl and C1-7alkoxy-heterocycloalkyl. [0310] In some embodiments, each R 6 is independently C 1-7 alkyl. In some embodiments, each R6 is independently methyl. In some embodiments, each R6 is independently ethyl.
  • each R 6 is independently propyl. In some embodiments, each R 6 is independently butyl. In some embodiments, each R6 is independently pentyl. In some embodiments, each R 6 is independently hexyl. In some embodiments, each R 6 is independently heptyl. In some embodiments, each R6 is independently isopropyl. In some embodiments, each R 6 is independently isobutyl. In some embodiments, each R 6 is independently isopentyl. In some embodiments, each R6 is independently isohexyl. In some embodiments, each R 6 is independently secbutyl. In some embodiments, each R 6 is independently secpentyl. In some embodiments, each R6 is independently sechexyl.
  • each R 6 is independently tertbutyl. [0311] In some embodiments, each R6 is independently amino or amino-C1-7alkyl. [0312] In some embodiments, each R 6 is independently amino. In some embodiments, R 6 is independently amino-C1-7alkyl. [0313] In some embodiments, each R 6 is independently C 3-8 cycloalkyl, heterocycloalkyl and C1-7alkoxy-heterocycloalkyl. [0314] In some embodiments, each R 6 is independently C 3-8 cycloalkyl. [0315] In some embodiments, each R6 is independently heterocycloalkyl and C1-7alkoxy- heterocycloalkyl.
  • each R6 is independently heterocycloalkyl. In some embodiments, each R6 is independently C1-7alkoxy-heterocycloalkyl. [0317] In some embodiments, two R6 together form C1-7alkylene. [0318] In some embodiments, each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C 1-7 alkoxy C 1-7 haloalkoxy, or C 3-8 cycloalkyl. [0319] In some embodiments, each R7 is independently halo or cyano. [0320] In some embodiments, each R 7 is independently halo.
  • each R7 is independently from F, Cl, Br, and I. In some embodiments, each R7 is independently from F, Cl, or Br. In some embodiments, each R 7 is independently F. In some embodiments, each R7 is independently Cl. In some embodiments, each R7 is independently Br. In some embodiments, each R 7 is independently I. [0321] In some embodiments, each R7 is independently cyano. [0322] In some embodiments, each R 7 is independently from C 1-7 alkyl, C 1-7 haloalkyl, C 1- 7alkoxy C1-7haloalkoxy, or C3-8cycloalkyl.
  • each R 7 is independently from C 1-7 alkyl, C 1-7 haloalkyl, C 1- 7alkoxy, or C1-7haloalkoxy. [0324] In some embodiments, each R 7 is independently C 1-7 alkyl. In some embodiments, each R7 is independently methyl. In some embodiments, each R7 is independently ethyl. In some embodiments, each R 7 is independently propyl. In some embodiments, each R 7 is independently butyl. In some embodiments, each R7 is independently pentyl. In some embodiments, each R 7 is independently hexyl. In some embodiments, each R 7 is independently heptyl. In some embodiments, each R7 is independently isopropyl.
  • each R 7 is independently isobutyl. In some embodiments, each R 7 is independently isopentyl. In some embodiments, each R7 is independently isohexyl. In some embodiments, each R 7 is independently secbutyl. In some embodiments, each R 7 is independently secpentyl. In some embodiments, each R7 is independently sechexyl. In some embodiments, each R 7 is independently tertbutyl. [0325] In some embodiments, each R7 is independently C1-7alkyl optionally substituted with OH. [0326] In some embodiments, each R7 is independently C1-7alkyl substituted with OH. In some embodiments, each R 7 is independently methyl substituted with OH.
  • each R7 is independently ethyl substituted with OH. In some embodiments, each R 7 is independently propyl substituted with OH. In some embodiments, each R 7 is independently butyl substituted with OH. In some embodiments, each R7 is independently pentyl substituted with OH. In some embodiments, each R7 is independently hexyl substituted with OH. In some embodiments, each R7 is independently heptyl substituted with OH. In some embodiments, each R7 is independently isopropyl substituted with OH. In some embodiments, each R 7 is independently isobutyl substituted with OH. In some embodiments, each R7 is independently isopentyl substituted with OH.
  • each R7 is independently isohexyl substituted with OH. In some embiments, each R 7 is independently secbutyl substituted with OH. In some embodiments, each R7 is independently secpentyl substituted with OH. In some embodiments, each R 7 is independently sechexyl substituted with OH. In some embodiments, each R7 is independently tertbutyl substituted with OH. [0327] In some embodiments, each R 7 is independently C 1-7 haloalkyl, C 1-7 alkoxy, or C 1- 7haloalkoxy. [0328] In some embodiments, each R 7 is independently C 1-7 haloalkyl.
  • each R7 is independently C1-7alkoxy. [0330] In some embodiments, each R 7 is independently C 1-7 haloalkoxy. [0331] In some embodiments, each R7 is independently C3-8cycloalkyl. [0332] To clarify, in all embodiments where two variable groups together form an alkylene, those groups along with the atoms they are attached to and possible intervening atoms, form a ring. This ring can be cycloalkyl or heterocyclyl depending on the attachment point of the variables, but the variable groups themselves are alkylene and thus contain no heteroatoms of their own.
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, solvates, or prodrugs thereof.
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the prodrugs of compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds described in Table 1, or from the disclosure.
  • the compound is selected from the compounds described in Table 1.
  • the compound is a therapeutically active substance.
  • the compound is a small molecule splicing modulator.
  • the compound is a small molecule splicing modulator of MYB. In some embodiments, the compound is a MYB inhibitor.
  • the compounds provided herein are also disclosed in PCT Publication No. WO 2023/086959 A1, the entire contents of which are incorpated by reference herein. [0340] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.
  • the various functional groups and substituents making up the compounds of the Formula (I) or (II) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons.
  • the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 daltons or less.
  • the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof comprise stereoisomers and mixtures of stereoisomers of all isomeric forms of said compounds.
  • the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
  • the in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). [0345] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Methods of Synthesis [0346] By way of example only, provided is a scheme for preparing a small molecule described herein.
  • a scheme for preparing a compound of the present disclosure is described herein in Scheme 1: of the present disclosure.
  • the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein.
  • the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.
  • the compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
  • protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons).
  • Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of Formula (I) into another compound of Formula (I) or (II); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.
  • the resultant compounds of Formula (I) or (II) can be isolated and purified using techniques well known in the art.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone,
  • reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.
  • Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.
  • additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples.
  • the skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure.
  • some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person.
  • the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • Cell proliferation assay [0367] Various cancer cell lines including K562, HL60, COLO201, COLO205 can be treated with the compounds of the present disclosure to assess their effect on inhibiting cell proliferation. [0368] Test compounds may be diluted in duplicates and dispensed into an assay plate. Positive and negative controls may be used (e.g. staurosporine). Frozen cell line stock is prepared and the cell suspension is dispensed into the assay plate.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1, or from the disclosure. .
  • the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • any suitable solubility enhancing agent can be used.
  • a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, randomly methylated- ⁇ -cyclodextrin, ethylated- ⁇ -cyclodextrin, triacetyl- ⁇ -cyclodextrin, peracetylated- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, sulphated ⁇ -cyclodextrin (S- ⁇ -CD), maltosyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin sulphobutyl ether,
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. Any suitable preservative can be used.
  • Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethon
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the aqueous vehicle may also contain a viscosity/suspending agent.
  • Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose
  • polyethylene glycols such as polyethylene glycol 300, polyethylene glycol 400
  • carboxymethyl cellulose such as polyethylene glycol 300, polyethylene glycol 400
  • carboxymethyl cellulose such as polyethylene
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the aqueous vehicle may also contain a buffering agent to stabilise the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ⁇ -aminocaproic acid, and mixtures thereof.
  • the formulation may further comprise a wetting agent.
  • Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene- polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a disease or disorder referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a disease or disorder referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a disease or disorder is a MYB-related disease or disorder.
  • the present disclosure includes a method of inhibiting MYB comprising contacting a cell with a compound disclosed herein.
  • the present disclosure provides compounds of the present disclosure or their pharmaceutically acceptable salts for the use in the treatment or prevention of cancer.
  • the present disclosure includes treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed here.
  • a disease or disorder is a proliferative disease or disorder.
  • a disease or disorder is cancer.
  • cancer is selected from the group consisting of adenoid cystic carcinoma (ACC), hepatocellular carcinoma (HCC), breast cancer, prostate cancer, pancreatic cancer, lung cancer, adenocarcinoma, osteosarcoma, colorectal cancer, and blood cancer.
  • ACC adenoid cystic carcinoma
  • HCC hepatocellular carcinoma
  • breast cancer prostate cancer
  • pancreatic cancer lung cancer
  • lung cancer adenocarcinoma
  • osteosarcoma colorectal cancer
  • lung cancer is small cell lung cancer.
  • lunch caner is non-small cell lung cancer.
  • cancer is a blood cancer.
  • a blood cancer is leukemia.
  • leukemia is acute myeloid leukemia.
  • leukemia is acute promyelocytic leukemia.
  • blood cancer is lymphoma.
  • lymphoma is selected from the group consisting of non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt lymphoma, B-cell lymphoma, and T-cell lymphoma.
  • cancer is adenoid cystic carcinoma (ACC). In some embodiments, cancer is hepatocellular carcinoma (HCC). In some embodiments, cancer is breast cancer. In some embodiments, cancer is prostate cancer. In some embodiments, cancer is pancreatic cancer. In some embodiments, cancer is adenocarcinoma. In some embodiments, cancer is osteosarcoma. In some embodiments, cancer is colorectal cancer. [0392] In one aspect, the present disclosure provides a method for the treatment or prevention of cancer in a subject in need thereof, which method comprises administering to the subject a pharmaceutically effective amount of a compound or pharmaceutical composition of the present disclosure. In some embodiments, the cancer is a liquid cancer.
  • the cancer is a leukemic cancer. In some embodiments, the cancer is a leukemia or lymphoma. In some embodiments, the cancer is colorectal cancer, breast cancer, or prostate cancer. In some embodiments, the cancer is a leukemia, acute myeloid leukemia, colon cancer, gastric cancer, acute monocytic leukemia, breast cancer, hepatocellular carcinoma, alveolar soft part sarcoma, myeloma, skin melanoma, pancreatic cancer, adenocarcinoma, adenoiditis, adenoid cystic carcinoma, gastrointestinal stromal tumor, sarcoma, prostate adenocarcinoma, Hodgkin's lymphoma, ovarian cancer, non-Hodgkin's lymphoma, multiple myeloma, chronic myeloid leukemia, acute lymphoblastic leukemia, renal cell carcinoma, transitional cell carcinoma, colorectal cancer, chronic lympho
  • the cancer is a solid cancer or solid tumor.
  • the tumor is selected from the group consisting of adenocarcinoma, melanoma (e.g., metastatic melanoma), liver cancer ⁇ e.g., hepatocellular carcinoma, hepatoblastoma, liver carcinoma), prostate cancer (e.g., prostate adenocarcinoma, androgen-independent prostate cancer, androgen-dependent prostate cancer, prostate carcinoma), sarcoma (e.g., leiomyosarcoma, rhabdomyosarcoma), brain cancer (e.g., glioma, a malignant glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, men
  • squamous cell carcinoma basal cancer
  • pharynx cancer e.g., squamous cell cancer, verrucous pharynx cancer
  • cancer of the head cancer of the neck, cancer of the throat, cancer of the chest, cancer of the spleen, cancer of skeletal muscle, cancer of subcutaneous tissue, adrenal cancer, pheochromocytoma, adrenocortical carcinoma, pituitary cancer, Cushing's disease, prolactin-secreting tumor, acromegaly, diabetes insipidus, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, ependyoma, optic nerve glioma,
  • a method of treating, preventing, or delaying cancer can comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject with basal cell carcinoma, goblet cell metaplasia, or a malignant glioma.
  • a method of treating, preventing, or delaying cancer can comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject with a cancer of the liver, breast, lung, prostate, cervix, uterus, colon, pancreas, kidney, stomach, bladder, ovary, or brain.
  • a method of treating, preventing, or delaying cancer can comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject with a cancer of the head, neck, eye, mouth, throat, esophagus, esophagus, chest, bone, lung, kidney, colon, rectum or other gastrointestinal tract organs, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.
  • the compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g.
  • transdermal including, e.g., by a patch, plaster, etc.
  • transmucosal including, e.g., by a patch, plaster, etc.
  • intranasal e.g., by nasal spray
  • ocular e.g., by eye drops
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose
  • rectal e.g., by suppository or enema
  • vaginal e.g., by pessary
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of
  • neutral compounds of Formula (I) or (II) are synthesized and tested in the examples. It is understood that the neutral compounds of Formula (I) or (II) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt).
  • NMR Nuclear magnetic resonance
  • LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as C182.1 x 30 mm, unless otherwise stated. Injection volumes were 0.7 – 8.0 ⁇ l and the flow rates were typically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionisation. MS range was 100 - 1000 Da.
  • DAD diode array
  • ELSD evaporative light scattering
  • Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid or ammonium carbonate.
  • a modifier typically 0.01 – 0.04 % such as trifluoroacetic acid or ammonium carbonate.
  • ACN Acetonitrile BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl CDCl 3 Chloroform-d DCM Dichloromethane DMF N,N-dimethylformamide DMSO dimethylsulphoxide DMSO-d6 Hexadeuterodimethylsulphoxide DP desired product eq.
  • Step 2 Synthesis of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile [0403] To a 230 mg, 1.01 mmol) in DMF (10 mL) was added Zn (CN)2 (230 mg, 2.02 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), and the reaction mixture was stirred for 2 h at 120 °C. After cooling to rt, the mixture was diluted with water (80 mL) and 100 mL of EA. The EA layer was separated, washed with brine and water once (100 mL x1), dried over Na 2 SO 4 , concentrated to dryness.
  • Zn (CN)2 230 mg, 2.02 mmol
  • Pd(PPh3)4 115 mg, 0.1 mmol
  • Step 3 Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate [0404]
  • NMP 80 mL
  • TEA 7.5 g, 75.0 mmol
  • the reaction mixture was stirred for 3 h at 120 °C.
  • the mixture was extracted with EA.
  • the combined organics were washed with brine and water, dried over Na2SO4 and concentrated to dryness.
  • the crude was purified by silica gel column (10 ⁇ 100% EA in PE). The product was obtained as off-white solid (5 g, Y: 68 %).
  • Step 5 Synthesis of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)piperazine-1-carboxylate [ 0 mg, 1.0 mmol) in THF was added LDA (1 mL, 2.0 mmol, 2M in THF) at –78 °C.
  • Step 6 Synthesis of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate carboximidamido)pyridin-3-yl)piperazine-1-carboxylate (45 mg, 0.1 mmol) in THF (5 mL) was added triphosgene (59 mg, 0.2 mmol) and pyridine (1 mL). The reaction mixture was stirred for 1 h at rt, After concentration, the residue was purified by silica gel column (1 ⁇ 10% MeOH in DCM).
  • Step 7 Synthesis of 2- ⁇ 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl ⁇ -7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (20 mg, 0.042 mmol) in DCM (3 mL) was added TFA (0.5 ml) at 0 °C. The reaction mixture was warmed to rt and stirred for 1 h.
  • Step 2 tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
  • tert-butyl 3-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate 1.25 mmol
  • Pd/C 300 mg
  • the reaction mixture was stirred for 16 h at rt under hydrogen atmosphere (balloon pressure).
  • the solvent was filtered and the filter cake was washed with MeOH (50 mL).
  • Step 2 tert-butyl 3-(6-aminopyridin-3-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate
  • tert-butyl 3-(6-nitropyridin-3-yl)-3,9-diazabicyclo [3.3.1]nonane-9- carboxylate 350 mg, 1.00 mmol
  • MeOH/THF 20 mL/10 mL
  • Pd/C 50 mg
  • the reaction mixture was stirred for 2 h at rt under hydrogen atmosphere (balloon pressure).
  • the solvent was filtered and the filter cake was washed with MeOH (50 mL).
  • Step 2 tert-butyl 5-(6-aminopyridin-3-yl)hexahydropyrrolo[3,4-c] pyrrole-2(1H)- carboxylate
  • tert-butyl 5-(6-nitropyridin-3-yl)hexahydropyrrolo [3,4-c]pyrrole- 2(1H)-carboxylate 700 mg, 2.09 mmol
  • Pd/C 70 mg, 10%
  • Step 2 tert-butyl 4-(6-((diphenylmethylene)amino)-4-methylpyridin-3-yl) piperazine-1- carboxylate
  • Step 3 tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperazine -1-carboxylate [0419] To a solution of tert-butyl 4-(6-((diphenylmethylene)amino)- 4-methylpyridin-3- yl)piperazine-1-carboxylate (1.64 g, 3.6 mmol) in MeOH (10 mL) was added NaOAc (887 mg, 10.8 mmol) and NH 2 OH.HCl (1.3 g, 18 mmol).
  • Example 7 Synthesis of tert-butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2- methylpiperazine-1-carboxylate St [0 420] To a solution of 5-bromo-2-chloro-3-fluoropyridine (4.0 g, 19.2 mmol) in toluene (20 mL) were added t-BuONa (2.4 g, 2.5 mmol), Xantphos (463 mg, 0.8 mmol), Pd2(dba)3 (528 mg, 0.56 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.6 g, 23.04 mmol).
  • Step 2 tert-butyl (S)-4-(6-((diphenylmethylene)amino)-5-fluoropyridin- 3-yl)-2- methylpiperazine-1-carboxylate
  • Pd(OAc) 2 134 mg, 0.6 mmol
  • Cs2CO3 3.9 g, 12.0 mmol
  • BINAP 747 mg, 1.2 mmol
  • diphenylmethanimine 1.2 g, 6.4 mmol.
  • Step 3 tert-butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2- methylpiperazine-1-carboxylate
  • tert-butyl (S)-4-(6-((diphenylmethylene) amino)-5-fluoropyridin-3- yl)-2-methylpiperazine-1-carboxylate 1.326 g, 2.8 mmol
  • MeOH MeOH
  • NaOAc 688 mg, 8.4 mmol
  • NH2OH.HCl 966 mg, 14 mmol
  • Step 2 tert-butyl (S)-4-(6-((diphenylmethylene)amino)-5-methyl pyridin-3-yl)-2- methylpiperazine-1-carboxylate
  • diphenylmethanimine (15.2 g, 0.08 mol) in 1,4-dioxane (350 mL) was added Cs2CO3 (52 g, 0.16 mol), BINAP (9.9 g, 0.016 mol) and Pd(OAc) 2 (1.79 g, 0.008 mol)
  • the mixture was charged with N 2 for three times and stirred at 100 oC for 16 h.
  • Example 9 Synthesis of tert-butyl 4-(6-amino-2-methylpyridin-3-yl) piperazine-1- carboxylate [0426] A mixture of 3-bromo-6-chloro-2-methylpyridine (6.63 g, 32.1 mmol), tert-butyl piperazine-1-carboxylate (8.57 g, 38.5 mmol), Pd 2 (dba) 3 (2.94 g, 3.2 mmol), Xantphos (3.7 g, 6.4 mmol) and t-BuONa (4.6 g, 48.2 mmol) in toluene (140 mL) was stirred at 80 o C for 16 h under Ar.
  • Step 2 tert-butyl 4-(6-((diphenylmethylene)amino)-2-methylpyridin-3-yl)piperazine -1- carboxylate
  • Step 3 tert-butyl 4-(6-amino-2-methylpyridin-3-yl)piperazine-1-carboxylate
  • a mixture of tert-butyl 4-(6-((diphenylmethylene)amino)-2-methylpyridin-3-yl) piperazine-1-carboxylate (548 mg, 1.2 mmol), NaOAc (296 mg, 3.6 mmol) and NH 2 OH ⁇ HCl (417 mg, 6.0 mmol) in MeOH (15 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), extracted with EtOAc (30 mL x 2).
  • Step 2 tert-butyl 4-(6-chloro-2-methoxypyridin-3-yl)piperazine-1-carboxylate
  • Step 3 tert-butyl 4-(6-((diphenylmethylene)amino)-2-methoxypyridin-3-yl) piperazine-1- carboxylate
  • Step 4 tert-butyl 4-(6-amino-2-methoxypyridin-3-yl)piperazine-1-carboxylate
  • a mixture of tert-butyl 4-(6-((diphenylmethylene)amino)-2-methoxypyridin-3- yl)piperazine- 1-carboxylate (577 mg, 1.2 mmol), NaOAc (296 mg, 3.6 mmol) and NH2OH ⁇ HCl (417 mg, 6.0 mmol) in MeOH (15 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), extracted with EtOAc (30 mL x 2).
  • Example 11 Synthesis of tert-butyl 4-(6-amino-5-fluoropyridin-3-yl) piperazine -1- carboxylate S [0433] To a mixture of 5-bromo-2-chloro-3-fluoropyridine (15 g, 71.5 mmol), tert-butyl piperazine-1-carboxylate (13.3 g, 71.5 mmol) in toluene (250 mL) was added t-BuONa (8.8 g, 92.2 mmol), Xantphos (1.65 g, 2.85 mmol) and Pd2(dba)3 (1.95 g, 2.3 mmol), the mixture was charged with N 2 for three times and stirred at 100 °C for 16 h.
  • Step 2 tert-butyl 4-(6-((diphenylmethylene)amino)-5- fluoropyridin-3-yl)piperazine-1- carboxylate
  • diphenylmethanimine (6.27 g, 36 mmol) in 1,4-dioxane (150 mL) was added Cs 2 CO 3 (21.5 g, 66 mol), BINAP (3.0 g, 5.0mmol) and Pd(OAc) 2 (370 mg, 1.65 mmol)
  • the mixture was charged with N2 for three times and stirred at 100 °C for 24 h.
  • Step 3 tert-butyl 4-(6-amino-5-fluoropyridin-3-yl) piperazine-1-carboxylate
  • tert-butyl 4-(6-((diphenylmethylene) amino)-5-fluoropyridin-3- yl)piperazine-1-carboxylate 20.4 g, 44.3 mmol
  • MeOH 300 mL
  • NaOAc 10.9 mg, 133 mmol
  • hydroxylamine hydrochloride (15.2 g, 221mmol
  • Step 3 tert-butyl 4-(6-amino-4-methoxypyridin-3-yl)piperazine-1- carboxylate
  • tert-butyl 4-(6-((diphenylmethylene)amino)-4-methoxypyridin- 3- yl)piperazine-1-carboxylate 800 mg, 1.67 mmol
  • MeOH MeOH
  • NaOAc 412 mg, 5.02 mmol
  • hydroxylamine hydrochloride 578 mg, 8.37 mmol
  • Step 2 tert-butyl 4-(6-((diphenylmethylene)amino)-5- methylpyridin-3-yl)-2,2- dimethylpiperazine-1-carboxylate
  • diphenylmethanimine (2.52 g, 13.93 mmol) in 1,4- dioxane (100 mL) was added Cs2CO3 (8.62 g, 26.54 mol), BINAP (1.65 g, 2.65 mmol) and Pd(OAc)2 (297 mg, 1.32 mmol).
  • Step 3 tert-butyl 4-(6-amino-5-methylpyridin-3-yl)-2,2- dimethylpiperazine-1-carboxylate
  • tert-butyl 4-(6-((diphenylmethylene) amino)-5-methylpyridin-3-yl)- 2,2-dimethylpiperazine-1-carboxylate 4 g, 8.26 mmol
  • MeOH 100 mL
  • NaOAc 2 g, 24.79 mmol
  • hydroxylamine hydrochloride 2.8 g, 41.32 mmol
  • Step 2 tert-butyl 4-(6-amino-5-methoxypyridin-3-yl)piperazine- 1-carboxylate
  • tert-butyl 5-(6-nitropyridin-3-yl)hexahydropyrrolo[3,4-c] pyrrole - 2(1H) -carboxylate 600 mg, 1.77 mmol
  • Pd/C 60 mg, 10%
  • the mixture was charged with H2 for three times and stirred at r.t. overnight under H2 balloon.
  • the mixture was filtered and the filtrate was concentrated to afford the title compound (470 mg, 86% yield) as a grey solid.
  • Step 2 Preparation of (Z)-1-(4-bromo-6-methylpyridin-2-yl)propan-2-one oxime
  • NH2OH.HCl 12.8 g, 185.7 mmol
  • NaOH 7.4 g, 185.7 mmol
  • Step 3 Preparation of 5-bromo-2,7-dimethylpyrazolo[1,5-a]pyridine
  • (Z)-1-(4-bromo-6-methylpyridin-2-yl)propan-2-one oxime (4.0 g, 16.5 mmol) and N1,N1,N6,N6-tetramethylhexane-1,6-diamine (4 mL, 19.8 mmol) in DCM (140 mL) was added TsCl (4.0 g, 19.8 mmol) in DCM (20 mL) dropwise at 0 oC, the reaction mixture was allowed to warmed to rt and stirred at rt for 16 h.
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H- pyrido[1,2- a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0451] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a] pyridine-6- carboximidamido) pyridin-3-yl)piperazine -1-carboxylate (600 mg, 1.32 mmol) in THF (60 mL) and pyridine (6 mL) was added triphosgene (1.18 g, 3.97 mmol).
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H- pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride
  • Step 2 tert-butyl (S)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate
  • tert-butyl (S)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate 120 mg, 0.26 mmol
  • tert-butyl (R)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1- carboxylate (293 mg, 1.0 mmol) was added and the resulting mixture was stirred for 1 h at rt.
  • 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile 100 mg, 0.57 mmol was added, the mixture was allowed to warm to rt and stirred for another 16 h.. After diluting with water (20 mL), the mixture was extracted with EA (50 ml x 2). The combined organics was washed with brine, dried over Na 2 SO 4 .
  • Example 20 Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 103) [0461] To a solution of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (20 mg, 0.048mmol), HCHO (0.5 mL) and HOAc (0.1 mL) was added NaBH3CN (10 mg, 0.144 mmol) in MeOH (5 mL) at rt.
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-1,4-diazepane-1-carboxylate [0463] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-1,4-diazepane-1-carboxylate (135 mg, 0.29 mmol) was dissolved in THF (15 mL) and pyridine(1 mL) was added triphosgene (301 mg, 1.02 mmol) at 0°C, the mixture was stirred for 2h at r.t.
  • Step 3 7-(1,4-diazepan-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride
  • Example 22 Synthesis of 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(8-fluoro-2- methylimidazo [1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 105) F F N N Step 1: tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0465] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 o C.
  • Step 2 tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0466] To a solution of tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a] pyridine-6- carboximidamido)pyridine-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.35 mmol) in THF (16 mL) and pyridine (2 mL) was added triphosgene (315 mg, 1.05 mmol).
  • Step 3 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0467] To a solution of tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 4- oxo-4H-pyrido[1,2-a][1,3,5] triazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (90 mg, 0.18 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (2 ml) at room temperature.
  • Step 2 tert-butyl 5-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [0469] To a solution of tert-butyl 5-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido) pyridine -3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (120 mg, 0.25 mmol) in THF (8 mL) and pyridine(1 mL) was added triphosgene (222 mg, 0.75 mmol), the mixture was stirred at rt for 1 h.
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- (hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0470] A solution of tert-butyl 5-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50 mg, 0.099 mmol) in 4M HCl/EA (2 mL) was stirred for 1 h at RT.
  • Example 24 Synthesis of 7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-(8-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 107) carboximidamido)pyridin-3-yl)-2,6-dimethylpiperazine-1-carboxylate [0471] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 o C.
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7-(piperazin-1-yl) -4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate
  • tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido) pyridin-3-yl) -2,2-dimethylpiperazine-1-carboxylate (220 mg, 0.46 mmol) in THF (6 mL) and pyridine (1 mL) was added triphosgene (407 mg, 1.37 mmol).
  • Step 3 7-(3,3-dimethylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one
  • Step 2 tert-butyl 4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1carboxylate
  • tert-butyl 4-(5-fluoro-6- (8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridine-3-yl)piperazine-1-carboxylate 300 mg, 0.64 mmol
  • THF 15 mL
  • pyridine(1.5 mL) triphosgene
  • Step 3 9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride
  • Example 28 Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6- tetrahydropyridin- 4-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 111) a][1,3,5]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate [0482] A mixture of 7-bromo-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H- pyrido[1,2-a] [1,3,5]triazin-4-one (100 mg, 0.268 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (124 mg, 0.4
  • Step 2 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin- 4-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0483] To a solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (30 mg, 0.063 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (2 mL) at room temperature.
  • Example 29 Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin- 3-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 112) Step pyridine-3-yl)pyrrolidine-1-carboxylate [0484] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (20 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 o C. The mixture was stirred at this temperature for 1 hour.
  • tert-butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (512 mg, 2 mmol) in dry THF (7 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (175 mg, 1 mmol) in dry THF (10 mL) was added to the mixture at -65 o C and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (20 mL), extracted with EtOAc (15 mL x 2).
  • Step 2 tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido [1,2- a][1,3,5]triazin-7-yl)pyrrolidine-1-carboxylate [0485] To a solution of tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)pyrrolidine-1-carboxylate (60 mg, 0.14 mmol) in THF (5 mL) and pyridine (1 mL) was added triphosgene (125 mg, 0.42 mmol).
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin-3-yl)-4H- pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0486] To a solution of tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)pyrrolidine-1-carboxylate (4 mg, 0.009 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (3 mL) at room temperature.
  • Step 3 (2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H- pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0489] To a solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperidine-1-carboxylate (60 mg, 0.125 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (5 ml) at room temperature.
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 9-methoxy-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0491] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-5-methoxy pyridin-3-yl)piperazine-1-carboxylate (45 mg, 0.09 mmol) in THF (8 mL) and pyridine (1 mL) was added triphosgene (83 mg, 0.75 mmol), the mixture was stirred at r.t.
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methoxy-7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride
  • a solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methoxy-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (15 mg, 0.029 mmol) in 3M HCl/EA (2 mL) was stirred for 1h at rt.
  • tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperazine-1- carboxylate (438 mg, 1.5 mmol) was added, the mixture was allowed to warm to rt and stirred for 1.5 h at rt. The mixture was cooling down to -60 o C again. Then 8-fluoro-2- methylimidazo[1,2-a] pyridine-6-carbonitrile (175 mg, 1.0 mmol) in THF (5 mL) was added, the mixture was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3).
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-8-methyl-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate
  • tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido) -4-methylpyridin-3-yl)piperazine-1-carboxylate 70 mg, 0.15 mmol
  • THF 15 mL
  • pyridine pyridine
  • triphosgene 134 mg, 0.45 mmol
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-8- methyl-7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride
  • Step 2 tert-butyl (S)-4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate
  • tert-butyl (S)-4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2- a]pyridine-6- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate 1.0 g, 2.06 mmol
  • THF 100 mL
  • pyridine(10 mL) triphosgene
  • Step 3 (S)-9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridine -6-yl)-7-(3-methylpiperazin- 1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one.
  • Step 3 (S)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7- (3-methylpiperazin- 1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0501] To a solution of tert-butyl (S)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.157 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (5 ml) at room temperature.
  • Step 2 tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido [1,2- a][1,3,5]triazin-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate [0503] To a solution of tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a] pyridine-6- carboximidamido)pyridin-3-yl) -3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (20 mg, 0.041 mmol) in THF (4 mL) and pyridine (0.4 mL) was added triphosgene (36 mg, 0.122 mmol).
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 8-methoxy-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate
  • tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-4-methoxypyridin-3-yl)piperazine-1-carboxylate 70 mg, 0.15 mmol
  • THF 8 mL
  • pyridine pyridine
  • triphosgene 1.2 g, 2.22 mmol
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methoxy-4-oxo -4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate
  • tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-2-methoxypyridin-3-yl)piperazine-1-carboxylate 150 mg, 0.31 mmol
  • THF 10 mL
  • pyridine 2 pyridine
  • the reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was mixed with MeOH (40 mL), stirred for 1 hour at rt. The precipitate was filtered and dried in vacuo to give title product as a white solid (20 mg, 12.6%).
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methoxy-7-(piperazin-1-yl)- 4H- pyrido[1,2-a][1,3,5]triazin-4-one formic acid.
  • Step 2 tert-butyl (S)-4-(2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9- fluoro-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate
  • tert-butyl (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyridine -6- carboximidamido) -5-fluoropyridin-3-yl)-2-methylpiperazine-1-carboxylate 400 mg, 0.83 mmol
  • THF 40 mL
  • pyridine 4 mL
  • Step 3 (S)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9-fluoro-7-(3-methyl piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0513] To a solution of tert-butyl (S)-4-(2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9- fluoro-4-oxo-4H –pyrido [1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.39 mmol) in EtOAc (10 mL) was added 3M HCl/EtOAc (10 mL) at room temperature.
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methyl-4-oxo- 4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0515] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-2-methylpyridin-3-yl) piperazine-1-carboxylate (100 mg, 0.21 mmol) in THF (10 mL) and pyridine (2 mL) was added triphosgene (187 mg, 0.63 mmol).
  • the reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (40 mL) and stirred for 1 hour at rt. The precipitate was filtered and the solid was dried in vacuo to give title product as a yellow solid (60 mg, 57.9%).
  • Step 3 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methyl-7-(piperazin-1-yl)- 4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride
  • Step 2 tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate
  • the tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboximidamido)-5- methylpyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate 400 mg, 0.808 mmol
  • THF 20 mL
  • pyridine 2 mL
  • triphosgene 1.2 g, 2.22 mmol
  • Step 3 7-(3,3-dimethylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-9- methyl-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride
  • Example 43 Synthesis of 2-2,8-dimethylimidazo[1,2-a]pyridin-6-yl-7-(piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 126) Step 1 [0524] 5-Chloro-2-nitropyridine (150.0 g, 946.12 mmol), tert-butyl piperazine-1-carboxylate (185.03 g, 993.43 mmol) and potassium carbonate (326.9 g, 2.37 mol) were mixed in DMF (1000 mL) The reaction mixture was stirred for 12 h at 75 o C.
  • Step 2 tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate
  • tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 9.5 g, 30.81 mmol
  • MeOH 200mL
  • 10% Pd/C 10% Pd/C
  • the reaction mixture was stirred for 16h at rt under hydrogen atmosphere (balloon pressure).
  • the solvent was filtered and the filter cake was washed with MeOH (50 mL).
  • the filtrate was concentrated to give title product (8 g; 93% yield).
  • Step 3 methyl 2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylate
  • 2,8-Dimethylimidazo[1,2-a]pyridine-6-carboxylic acid hydrochloride (10.0 g, 44.11 mmol) was dissolved in MeOH (100 mL) and thionyl chloride (15.74 g, 132.34 mmol, 9.6 ml, 3.0 equiv) was added dropwise and the resulting mixture was stirred 18h at room temperature. The mixture was then concentrated and DCM (250 mL) was added. Saturated NaHCO 3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes.
  • Step 4 2,8-dimethylimidazo[1,2-a]pyridine-6-carboxamide
  • MeOH 60 mL
  • methanolic ammonia solution 80 mL
  • the mixture was concentrated in vacuo to give the product (5 g, 93% yield).
  • TFAA (8.33 g, 39.66 mmol, 5.56 ml, 1.5 equiv) was added dropwise at 0C. The mixture was stirred at this temperature for 20 min and allowed to warm to room temperature and stirred for 16h. The mixture was diluted with water (150 mL), extracted with DCM (2x50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo The residue was purified by column chromatography (CHCl3/ACN) to give title product (2.5 g, 55% yield). ESI-MS: 172.1 [M+H].
  • Step 6 tert-butyl 4-(6-2,8-dimethylimidazo[1,2-a]pyridine-6-imidamidopyridin-3-yl) piperazine-1-carboxylate
  • tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 1.5 g, 5.39 mmol
  • dry THF 25 mL
  • lithium bis(trimethylsilyl)amide (1.08 g, 6.47 mmol, 5.39 ml, 1.2 equiv
  • Step 7 tert-butyl 4-(2-2,8-dimethylimidazo[1,2-a]pyridin-6-yl-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0530] To a mixture of tert-butyl 4-(6-2,8-dimethylimidazo[1,2-a]pyridine-6- imidamidopyridin-3-yl) piperazine-1-carboxylate (502.92 mg, 1.12 mmol) and triethylamine (566.28 mg, 5.6 mmol, 780.0 ⁇ l, 5.0 equiv) in THF (15 mL) was added ditrichloromethyl carbonate (331.98 mg, 1.12 mmol).
  • Step 8 2-2,8-dimethylimidazo[1,2-a]pyridin-6-yl-7-(piperazin-1-yl)-4H-pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride
  • 2-,8-dimethylimidazo[1,2-a]pyridin-6-yl-4-oxo-4H -pyrido[1,2- a][1,3,5]triazin-7-yl piperazine-1-carboxylate (99.98 mg, 210.25 ⁇ mol) in MeOH (10 mL) was added HCl in dioxane( 1mL) at 0 C.
  • Example 44 Synthesis of 7-2,6-diazaspiro[3.3]heptan-2-yl-2-8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl-4H-pyrido[1,2-a][1,3,5]triazin-4-one trifluoroacetic acid (Compound 127) [0532] To a solution of methyl 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylate (8.0 g, 38.43 mmol) in MeOH (60 mL) 25% methanolic ammonia solution (100 mL) was added and the mixture was sealed in autoclave and heated at 80 °C for 12 hours.
  • TFAA (9.62 g, 45.79 mmol, 6.42 ml, 1.5 equiv) was added dropwise at 0°C. The mixture was stirred at this temperature for 20 min and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (150 mL), extracted with DCM (2x50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (CHCl3/ACN) to give title product (3g, 56% yield).
  • Step 3 N-(5-bromopyridin-2-yl)-8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamide
  • 5-bromopyridin-2-amine (2.96 g, 17.13 mmol) in THF (30 ml) sodium bis(trimethylsilyl)amide (3.74 g, 20.38 mmol, 8.77 ml, 1.19 equiv) was added dropwise while the reaction mixture was magnetically stirred under Ar at ice-bath temperature.
  • Step 4 7-bromo-2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4H-pyrido[1,2- a][1,3,5]triazin-4-one
  • N-(5-bromopyridin-2-yl)-8-fluoro-2-methylimidazo[1,2-a]pyridine- 6-carboximidamide 4.5 g, 12.92 mmol
  • triethylamine (6.54 g, 64.62 mmol, 9.01 ml, 5.0 equiv) was added ditrichloromethyl carbonate (3.84 g, 12.92 mmol).
  • Step 5 tert-butyl 6-(2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
  • Step 6 7-2,6-diazaspiro[3.3]heptan-2-yl-2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4H- pyrido[1,2-a][1,3,5]triazin-4-one trifluoroacetic acid [0537]
  • tert-butyl 6-(2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 20.0 mg, 40.69 ⁇ mol
  • TFA 232.37 mg, 2.04 mmol, 160.0 ⁇ l, 50.0 equiv
  • Step 2 Preparation of tert-butyl (S)-2-ethyl-4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0539] To a solution of tert-butyl (S)-2-ethyl-4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2- a]pyridine-6-carboximidamido)pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in THF (50 mL) and pyridine (1.0 mL) was added triphosgene (178 mg, 0.60 mmol) at r.t, the mixture was stirred for 15 min at rt.
  • Step 3 Preparation of (S)-7-(3-ethylpiperazin-1-yl)-9-fluoro-2-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one [0540] To a solution of tert-butyl (S)-2-ethyl-4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (50 mg, 0.095 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (2 mL) at room temperature.
  • Step 2 Preparation of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0542] To a solution of tert-butyl (S)-4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5- carboximidamido)-5-methylpyridin-3-yl)-2-methylpiperazine-1-carboxylate (130 mg, 0.273 mmol) in THF (60 mL) and pyridine (1.5 mL) was added triphosgene (242 mg, 0.819 mmol) at r.t, the mixture was stirred for 15 min at rt.
  • Step 3 Preparation of (S)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-methyl-7-(3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one [0543] To a solution of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (75 mg, 0.15 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (3 ml) at room temperature.
  • Step 2 Preparation of tert-butyl 4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate [0545] To a solution of tert-butyl 4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate (170 mg, 0.339 mmol) in THF (18 mL) and pyridine (1.8 mL) was added triphosgene ( 322 mg, 1.08 mmol).
  • Step 3 7-(3,3-dimethylpiperazin-1-yl)-9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0546] To a solution of tert-butyl 4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (3 mL) at room temperature.
  • Step 2 Preparation of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl) -9- fluoro-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0548] To a solution of tert-butyl (S)-4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5- carboximidamido)-5- fluoropyridin-3-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.312 mmol) in THF (60 mL) and pyridine(1.5 mL) was added triphosgene (277 mg, 0.936 mmol) at rt, the mixture was stirred for 15 min at rt.
  • Step 3 Preparation of (S)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro-7- (3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one [0549] To a solution of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9- fluoro-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (180 mg, 0.35 mmol) in EtOAc (10 mL) was added 3M HCl/EtOAc (15 ml) at room temperature.
  • Step 3 Preparation of tert-butyl 7-(6-amino-5-methylpyridin-3-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate [0552] To a solution of tert-butyl 7-(6-((diphenylmethylene)amino)-5-methylpyridin-3-yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate.
  • Step 4 Preparation of tert-butyl 7-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-5-methylpyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate
  • Fresh prepared LDA was added to a solution of 6-amino-5-methylpyridin-3-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (1 g, 3 mmol) in THF(5 mL) dropwised at -60 °C, the mixture was stirred for 1.5 at RT. The mixture was cool down to -60 °C.
  • Step 5 Preparation of tert-butyl 7-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate [0554] To a solution of t-butyl 7-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-5-methylpyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (130 mg, 0.15 mmol) in THF (30 mL) and pyridine(3 mL) was added triphosgene (234 mg, 0.791 mmol), the mixture was stirred at rt for 15 min.
  • Step 6 Preparation of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7-(4,7- diazaspiro[2.5]octan-7-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one HCl salt
  • the reaction mixture was stirred for 15 min at rt.
  • the mixture was diluted with water (25 mL) and extracted with EtOAc (50 mL*2).
  • the combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo.
  • the residue was diluted with MeOH (40 mL) and stirred for 1 hour at rt.
  • Step 3 (S)-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(3-methylpiperazin-1-yl)-4H-pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0558] To a solution of tert-butyl (S)-4-(2-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (30 mg, 0.061 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (5 ml) at room temperature.
  • Step 2 tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0560] To a solution of tert-butyl (S)-4-(6-(7-fluoro-2-methyl-2H-indazole-5- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.259 mmol) in THF (10 mL) and pyridine (1.5 mL) was added triphosgene ( 231 mg, 0.778 mmol).
  • Step 3 (S)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-7-(3-methylpiperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one [0561] To a solution of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (65 mg, 0.133 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (3 ml) at room temperature.
  • Example 51 Synthesis of 7-(3,3-dimethylpiperazin-1-yl)-2-(2,7-dimethylpyrazolo[1,5- a]pyridin-5-yl)-9-fluoro-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 135)
  • Step 1 tert-butyl 4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5-carboximidamido)-5- fluoropyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate
  • Step 2 tert-butyl 4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate [0563] To a solution of tert-butyl 4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5- carboximidamido)-5-fluoropyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate (90 mg, 0.182 mmol) in THF (10 mL) and pyridine (1.5 mL) was added triphosgene ( 162 mg, 0.545 mmol).
  • Step 3 7-(3,3-dimethylpiperazin-1-yl)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro- 4H-pyrido[1,2-a][1,3,5]triazin-4-one [0564] To a solution of tert-butyl 4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro-4- oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate (60 mg, 0.115 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (3 ml) at room temperature.
  • test compounds were diluted in duplicates from 10 mM stocks in 11-points 1:3 serial dilutions in DMSO. Then 100 nL test compounds at the serial dilutions were dispensed into 384-well assay plate using Echo dispenser. Staurosporine (5 ⁇ M final concentration) and DMSO (0.5% final concentration) were used as the positive (HPE) and negative (ZPE) controls respectively.
  • each frozen cell line stock was resuspended and grown in proper growth medium to a density of ⁇ 100,000 cells/mL.
  • 20 ⁇ L of cell suspension were dispensed into the assay plate to give seed cell density at 1,000 cells/well, compounds at 50 ⁇ M top concentration with 11-point serial dilutions, and 0.5% DMSO final concentration.
  • Assay plates were then centrifuged at 300 rpm for 1 minute.
  • Microclime plate lids were filled with ⁇ 8 mL sterile water and used to cover the cell plates. The plates were incubated at 37 °C, 95% humidity, 5% CO 2 for 72 hours.
  • the assay plate and its contents were equilibrated at room temperature for approximately 30 minutes.20 ⁇ L of CellTiterGlo reagent was added to the assay plate and the plates were centrifuged at 500 rpm for 1 minute and equilibrated for 5 min. The luminescence (RLU) signals in each well were recorded using Envision plate reader, then converted to percentage inhibition values using the signals in HPE and ZPE treated wells as the references. IC50 values were determined by curve fitting in Levenberg– Marquardt algorithm.
  • % Inhibition (Value – ZPE)/(HPE – ZPE) x 100% [0571]
  • A indicates a IC 50 ( ⁇ M) ⁇ 1 ⁇ M
  • B indicates a IC 50 ( ⁇ M) 1 ⁇ M to ⁇ 10 ⁇ M
  • C indicates a IC50 ( ⁇ M) ⁇ 10 ⁇ M.
  • Table 3 – CTG Assay Data – COLO205, HL60, MOLM13, and MV4-11 Compound IC 50 ( ⁇ M) IC 50 ( ⁇ M) IC 50 ( ⁇ M) IC 50 ( ⁇ M) No.
  • Mini-gene reporter constructs for each target site can be constructed by first PCR amplifying the region-of-interest including the sequence of the alternatively skipped sequences of the immediate upstream and downstream introns, and sequences of the immediate upstream and downstream exons. Then the 3’end of the amplified sequence can be ligated to a firefly luciferase reporter gene and cloned into the pcDNA3.1 vector backbone.
  • the final reporter construct can be transiently transfected into HEK293 cells using Lipofectamine 3000 transfection reagents. Compounds that can induce the inclusion of the skipped exon in the reporter construct would increase the reporter firefly luciferase activity.
  • DMEM medium Gibco #12100-046 ⁇ FBS Fetal Bovine Serum: Gibco #10091-148 ⁇ Culture medium: DMEM + 10% FBS + 1% P/S ⁇ ONE-Glo Luciferase Assay System: Promega # E6130 ⁇ HPE compound: Branaplam (CAS# 1562338-42-4) ⁇ White, 384-well assay plate: Corning #3570 [0573]
  • test compounds were diluted in duplicates from 10mM stocks in 11-points 1:3 serial dilutions in DMSO. Then 100 nL test compounds at the serial dilutions were dispensed into 384-well assay plate using Echo dispenser.
  • Assay plates were then centrifuged at 300 rpm for 1 minute and then incubated at 37 °C, 95% humidity, 5% CO 2 for 16 hours. After incubation, the assay plate and its contents were equilibrated at room temperature for approximately 20 minutes.20 ⁇ L of One-Glo reagent was added to the assay plate and the plates were centrifuged at 500 rpm for 1 minute and equilibrated for 5 min. The luminescence (RLU) signals in each well were recorded using Envision plate reader, then converted to percentage inhibition values using the signals in HPE and ZPE treated wells as the references. EC50 values were determined by curve fitting in Levenberg–Marquardt algorithm.
  • % Inhibition (Value – ZPE)/(HPE – ZPE) x 100% [0576]
  • A indicates a EC50 ( ⁇ M) ⁇ 1 ⁇ M
  • B indicates a EC50 ( ⁇ M) 1 ⁇ M to ⁇ 10 ⁇ M
  • C indicates a EC50 ( ⁇ M) ⁇ 10 ⁇ M.
  • test compounds were diluted in duplicates from 10 mM stocks in 11-points 1:3 serial dilutions in DMSO. Then 100 nL test compounds at the serial dilutions were dispensed into 384-well assay plate using Echo dispenser.
  • HPE positive control
  • ZPE negative control
  • DMSO negative control
  • K562/MYB-HiBiT cells were transferred to a 15 ml tube and centrifuged at 1000 rpm for 5 min to pellet the cells. The cells were resuspended to 20,0000 cells/mL in the IMDM medium. Then 20 ⁇ L of cell suspension were dispensed into the assay plate containing compounds to give seed cell density at 4,000 cells/well. Assay plates were then centrifuged at 300 rpm for 1 minute and then incubated at 37 °C, 5% CO 2 for 24 hours.
  • A indicates a IC50 ( ⁇ M) ⁇ 1 ⁇ M
  • B indicates a IC50 ( ⁇ M) 1 ⁇ M to ⁇ 10 ⁇ M
  • C indicates a IC 50 ( ⁇ M) ⁇ 10 ⁇ M.
  • Table 5 MYB HiBiT assay activity C ompound No. IC 50 ( ⁇ M) 100 A Example 55.
  • mice Female athymic nude (Crl:NU(NCr)-Foxn1nu) mice, between 6-12 weeks of age, weighing an approximate minimum of 20 grams on Day 0, were acclimated for a minimum of 24 hours and housed on irradiated corncob bedding (Teklad) in individual HEPA ventilated cages (Sealsafe® Plus, Techniplast USA) on a 12-hour light-dark cycle at 70-74°F (21-23°C) and 40-60% humidity.
  • Tumor models Patient-Derived Xenograft (XPDX) models were established from viable human tumor tissue or fluid that had been serially passaged in animals a limited number of times to maintain tumor heterogeneity.
  • XPDX Patient-Derived Xenograft
  • athymic nude (Crl:NU(NCr)-Foxn1nu) mice were implanted unilaterally on the flank with tumor fragments harvested from host animals each implanted from a specific passage lot.
  • Pre-study tumor volumes were recorded for each experiment beginning approximately one week prior to its estimated start date.
  • TKI Tumor Volume Initiation
  • animals were assigned to treatment and control groups so that groups had equal mean starting volume and dosing initiated (Day 0); animals in all studies were followed individually, via ear notch, throughout each experiment.
  • Protocol methodology Animals were ear notched and sorted by mean tumor volume into treatment and control groups, all with similar mean tumor volumes of approximately 150-300 mm 3 and treatment initiated on Day 0.
  • the mean tumor volume in the Vehicle and Compound 116 treatment groups from Day 0 to Day 24 are provided in Table 6 and Table 7, respectively.
  • the mean changes in tumor volume from Day 0 to Day 24 for the Vehicle and Compound 116 treatment groups are depicted in FIG.1.
  • Tumor volume of Compound 116 treatment group Day 0-24, n 7 Day: -8 0 3 6 11 13 17 20 24

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Abstract

The present disclosure relates to methods of treating diseases or disorders comprising administering compounds of Formula (I) or (II) or subformulas thereof: (I) and pharmaceutically acceptable salts thereof.

Description

METHODS OF USING FUSED TRIAZINONES CROSS REFERENCE TO RELATED APPLICATIONS [001] This application claims the benefit of and priority to U.S. Provisional Patent Application No.63/467,266, filed on May 17, 2023, the disclosure of which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND [002] MYB proto-oncogene protein is a transcription factor that regulates cell proliferation. It has been implicated in a variety of cancers. Accordingly, it may be a potential target for small-molecule inhibition. Small-molecule drugs have excellent pharmacokinetics, effective delivery, and bioavailability. Yet, the MYB inhbitior molecules come from a few limited chemical series. Thus, there is a great need to develop additional methods of treated MYB- related diseases and disorders, particularly cancer. SUMMARY [003] Provided herein are methods of treating diseases or disorders in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the present disclosure includes methods of treating diseases or disorders related to MYB. [004] In some aspects, the present disclosure provides a compound of Formula (I): I), or a pharmaceutically acceptable
Figure imgf000003_0001
thereof, wherein: A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6alkyl, -C(O)O-C1-C6alkyl, C1-C7alkyl, C1-C8heteroalkyl, C1- 7alkoxy-heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(CH2)0-2-C3- C8cycloalkyl, 4-7-membered monocyclic heterocycloalkyl, NH2, NH(C1-C6alkyl), N(C1- C6alkyl)2, -NHC(O)-C1-C6alkyl, -N(C1-C6alkyl)-C(O)-C1-C6alkyl, -C(O)-NH2, -C(O)-NH(C1- C6alkyl), and -C(O)-N(C1-C6alkyl)2, wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl or NH2, and wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, or NH2; or two R6 on the same carbon can be taken together as keto (=O); or two R6 together form C1-7alkylene; each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH; R16 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; and. R17 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl. [005] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described here (e.g., a method comprising one or more steps described in herein). [006] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier. [007] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described herein). [008] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure. [009] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.
[010] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for use in treating or preventing a disease or disorder disclosed herein.
[Oil] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for use in treating a disease or disorder disclosed herein.
[012] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for treating or preventing a disease or disorder disclosed herein.
[013] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof for treating a disease or disorder disclosed herein.
[014] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
[015] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
[016] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.
[017] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.
[018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. [019] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS [020] FIG.1 is a graph showing the change in tumor volume over time in a patient-derived adenoid cystic carcinoma xenograft model treated with vehicle or Compound 116. DETAILED DESCRIPTION [021] Compounds described herein are generally designed to treat diseases and disorders disclosed herein. Definitions [022] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [023] As used herein, “alkyl”, “C1, C2, C3, C4, C5, C6, or C7 alkyl” or “C1-C7 alkyl” is intended to include C1, C2, C3, C4, C5, C6, or C7 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, C6, or C7 branched saturated aliphatic hydrocarbon groups. For example, C 1 -C 7 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5, C 6, and C7 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. [024] As used herein, “alkenyl” is intended to include straight-chain or branched hydrocarbon groups having from 2 to 6 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C6alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2- C6alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2- butenyl (C4), butadienyl (C4), and the like. [025] As used herein, “alkynyl” is intended to include straight-chain or branched hydrocarbon groups having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C2-C6 alkynyl"). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-C4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. [026] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkylaryl, or an aromatic or heteroaromatic moiety. [027] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl. [028] As used herein, “heteroalkyl”, “C1, C2, C3, C4, C5, C6, C7 or C8 heteroalkyl” or “C1- C8 heteroalkyl” is intended to include C1, C2, C3, C4, C5, C6, C7, or C8 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, C6, C7, or C8 branched saturated aliphatic hydrocarbon groups, in which at least one of the carbons has been replaced with N, O, or S. The heteroatom will be bonded to any required hydrogens to complete the heteroatom’s valence (e.g., a CH2 may be replaced with an “O” or a “NH”, a CH may be replaced with an N, etc.)). Such substituents can include, for example, -O-CH(CH3)2, -CH2- N(CH3)-CH2CH2OCH3, -S-CH2CH2-O-CH2CH3, and so forth. [029] As used herein, “alkylene”, “C1, C2, C3, C4, C5, C6, or C7 alkylene” or “C1-C7 alkylene” is a bivalent branched or straight alkyl group which has two open valences to connect the alkylene with two other groups. Examples of alkylene include -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH(CH2CH3)-CH2-. Where an alkylene connects its open valences to the same atom or to separate atoms which are already part of a chain or ring, the alkylene taken together with the atom or atoms to which it is attached will form a ring. [030] As used herein, the term “alkoxy” refers to the group -OR where R is alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 7 carbon atoms. [031] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non- aromatic. [032] As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic (e.g., 4-7 membered monocyclic), 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) (e.g., a mono- or bi-cyclic 4- to 9- membered heterocycloalkyl) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4- c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl- 2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). [033] As used herein, the term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and the like. Conveniently, an aryl is phenyl. [034] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised (i.e., N ^O and S(O)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). [035] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine. [036] Bicyclic and tricyclic systems can be edge-fused, spiro-fused, or bridged systems. [037] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, IPTS/128571997.1 carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). [038] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [039] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [040] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [041] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or - O-. [042] As used herein, the term “cyano” refers to the group -CN. [043] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. [044] As used herein, the term “haloalkyl” refers to a branched or unbranched alkyl substituted with one or more halogens. For example, a C1-7haloalkyl is an alkyl group of from one to seven cabons wherein at least one H is substituted by a halogen. Examples of haloalkyl include but are not limited to CFH2, CF2H, CF3, CH2CF3, CF2CF3, C(F)(CH3)2, CH2CH2Br, CH(I)CH2F, and CH2Cl. [045] As used herein, the term “haloalkoxy” refers to alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoro alkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine. [046] As used herein, the term “amino” refers to the radical -NH2. In certain embodiments as specified herein, one or both hydrogen atoms of -NH2 may be replaced with a different group, e.g., amino-C1-7alkyl. [047] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkylaryl, or an aromatic or heteroaromatic moiety. [048] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise. [049] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples. [050] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [051] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. [052] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art [053] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999. [054] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. [055] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). [056] As used herein, the term “treating” or “treat” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like. [057] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. [058] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. [059] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. [060] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier. [061] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the subject. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. [062] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [063] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non- toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. [064] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. [065] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the subject should preferably be closely monitored during and for a reasonable period after treatment. [066] As used herein, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Altneratively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. [067] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the subject, and the route of administration. [068] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. [069] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. [070] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. [071] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [072] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [073] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser. [074] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. [075] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. [076] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. [077] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell. [078] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. [079] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure. [080] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. [081] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt. [082] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4- toluenesulphonic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1- carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. [083] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) as defined herein, of the same salt. [084] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration. [085] A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulphate, bisulphate, sulphamate, nitrate, phosphate, citrate, methanesulphonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulphonate, and acetate (e.g., trifluoroacetate). [086] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms. [087] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. [088] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. [089] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound. [090] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. [091] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulphonamides, tetrazoles, sulphonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev.96, 3147-3176, 1996. [092] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. [093] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) and (II) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I) and (II). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. H O OH H+ O- C C C C + C C H isclosed herein containing an amine
Figure imgf000022_0001
function may also form N-oxides. A reference herein to a compound of Formula (I) and (II) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N- oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. [095] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substitutents at the ester or amide group in any one of the Formulae disclosed herein. [096] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” [097] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents. [098] As used herein, the term “chiral isomer” means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116). [099] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0100] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. [0101] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity. [0102] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. [0103] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (- CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. [0104] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. [0105] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0106] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). [0107] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound. [0108] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the subject without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987. [0109] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the subject to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0110] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1- 4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0111] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl. [0112] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the subject; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition. [0113] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. [0114] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. [0115] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. [0116] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The present disclosure having now been described by way of written description, those of skill in the art will recognize that the present disclosure can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. [0117] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Compounds of the Present Disclosure [0118] In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6alkyl, -C(O)O-C1-C6alkyl, C1-C7alkyl, C1-C8heteroalkyl, C1- 7alkoxy-heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(CH2)0-2-C3- C8cycloalkyl, 4-7-membered monocyclic heterocycloalkyl, NH2, NH(C1-C6alkyl), N(C1- C6alkyl)2, -NHC(O)-C1-C6alkyl, -N(C1-C6alkyl)-C(O)-C1-C6alkyl, -C(O)-NH2, -C(O)-NH(C1- C6alkyl), and -C(O)-N(C1-C6alkyl)2, wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl or NH2, and wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, or NH2; or two R6 on the same carbon can be taken together as keto (=O); or two R6 together form C1-7alkylene; each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH; R16 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; and. R17 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl. [0119] In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): or a pharmaceutically accept of, wherein: A is saturated or part
Figure imgf000029_0001
ially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH; R16 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; and. R17 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl. [0120] In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): or a pharmaceutically accepta eof, wherein: A is saturated or parti
Figure imgf000030_0001
ally unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH; R16 is H; and. R17 is H. [0121] In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): or a pharmaceutically a f, wherein:
Figure imgf000030_0002
A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH; R16 is H, halo, C1-7alkyl, or OR5; and. R17 is H, halo, C1-7alkyl, or OR5. [0122] In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): or a pharmaceutically acceptab of, wherein:
Figure imgf000031_0001
A is a nitrogen-containing heterocycloalkyl or NR1R2, wherein the nitrogen- containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 can be optionally substituted with 1, 2, or 3 R7; each R5 is independently H, C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, or C1-7haloalkoxy; R16 is H, halo, C1-7alkyl, OR5, or N(R5)2; and. R17 is H, halo, C1-7alkyl, OR5, or N(R5)2. [0123] In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: A is a nitrogen-containing heterocycloalkyl or NR1R2, wherein the nitrogen- containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 can be optionally substituted with 1, 2, or 3 R7; each R5 is independently H, C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, or C1-7haloalkoxy; R16 is H; and. R17 is H. [0124] In some aspects, the present disclosure provides, inter alia, a compound of Formula (I): or a pharmaceutically accept ereof, wherein: A is a nitrogen-contai
Figure imgf000033_0001
ning heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 can be optionally substituted with 1, 2, or 3 R7; each R5 is independently H, C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, or C1-7haloalkoxy; R16 is H, halo, C1-7alkyl, or OR5; and. R17 is H, halo, C1-7alkyl, or OR5. [0125] In some aspects, the present disclosure provides, inter alia, a compound of Formula (II): or a pharmaceutically accep of, wherein:
Figure imgf000033_0002
A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; and each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH. [0126] In some aspects, the present disclosure provides, inter alia, a compound of Formula (II): (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: A is nitrogen-containing heterocycloalkyl or NR1R2, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; and each R7 is independently halo, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, or C1-7haloalkoxy. [0127] In some aspects, the present disclosure provides, inter alia, a compound of Formula (II): or a pharmaceutically accept , wherein: A is nitrogen-contain
Figure imgf000035_0001
ing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; and each R7 is independently halo or C1-7alkyl. [0128] In some aspects, the present disclosure provides, inter alia, a compound of Formula (II): or a pharmaceutically acc ereof, wherein:
Figure imgf000035_0002
A is nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; and each R7 is independently halo or C1-7alkyl. [0129] It is understood that, for a compound of Formula (I) or (II), A, R1, R2, R3, R4, R5, R6, and R7 can each be, where applicable, selected from the groups described herein, and any group described herein for any of A, R1, R2, R3, R4, R5, R6, and R7 can be combined, where applicable, with any group described herein for one or more of the remainder of A, R1, R2, R3, R4, R5, R6, and R7. [0130] In some embodiments, A is nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6, and is bonded to formula (I) or (II) by one of its nitrogen atoms wherein each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl or two R6 together form C1-7alkylene. [0131] In some embodiments each R6 is independently C1-7 alkyl, heterocycloalkyl, or C1- 7alkoxy-heterocycloalkyl or two R6 together form C1-. In some embodiments each R6 is independently methyl, ethyl, isopropyl, methoxy-azetidinyl, or pyrrolidinyl, or two R6 together form ethylene or propylene. In some embodiments, two R6 together form C1- 7alkylene. [0132] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0133] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0134] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0135] In some embodiments, A is saturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0136] In some embodiments, A is saturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0137] In some embodiments, A is partially unsaturated mono- or bi-cyclic 4- to 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0138] In some embodiments, A is partially unsaturated mono- or bi-cyclic 4- to 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0139] In some embodiments, A is saturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0140] In some embodiments, A is saturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0141] In some embodiments, A is partially unsaturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0142] In some embodiments, A is partially unsaturated monocyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0143] In some embodiments, A is saturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0144] In some embodiments, A is saturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0145] In some embodiments, A is partially unsaturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0146] In some embodiments, A is partially unsaturated bicyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0147] In some embodiments, A is saturated or partially unsaturated mono- or bicyclic 4- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0148] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0149] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0150] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0151] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0152] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0153] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 5-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0154] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 5-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0155] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0156] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0157] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0158] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0159] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0160] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0161] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0162] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0163] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0164] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0165] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0166] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0167] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 7- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0168] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 7- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0169] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 7- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0170] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 7- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0171] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0172] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 9- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0173] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 8- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0174] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 8- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0175] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 7- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0176] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 7- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0177] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0178] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 6- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0179] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0180] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 5- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0181] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6. [0182] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms. [0183] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 1, 2, 3, or 4 R6. [0184] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 1, 2, or 3 R6. [0185] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 1 R6. [0186] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 2 R6. [0187] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is substituted with 3 R6. [0188] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 nitrogen ring atom. [0189] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 2 nitrogen ring atoms. [0190] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 nitrogen ring atom and is optionally substituted with 1, 2, 3, or 4 R6. [0191] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 2 nitrogen ring atoms and is optionally substituted with 1, 2, or 3 R6. [0192] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 1 nitrogen ring atom and is substituted with 1, 2, 3, or 4 R6. [0193] In some embodiments, A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl, wherein the heterocycloalkyl comprises 2 nitrogen ring atoms and is substituted with 1, 2, or 3 R6. [0194] In some embodiments, A is piperazinyl, diazepanyl, octahydropyrrolopyrazinyl, diazaspirooctanyl, pyrrolidinyl, octahydropyrrolopyrroyl, diazaspirononanyl, diazaspiroheptanyl, or diazabicyclooctanyl, each optionally substituted with 1, 2, 3, or 4 R6. [0195] In some embodiments, A n, Y is absent, N or CH;
Figure imgf000042_0001
R9 is hydrogen, C1-7alkyl, or (CH2)m-NR14R15; R10 is hydrogen or C1-7alkyl; R11 is hydrogen or C1-7alkyl; R12 is hydrogen or C1-7alkyl; R13 is hydrogen or C1-7alkyl; each R14 and R15 are independently hydrogen, C1-7alkyl and C3-8cycloalkyl; n is 0, 1 or 2; m is 0, 1 or 2; or R9 and R10 together form C1-7alkylene; or R9 and R12 together form C1-7alkylene; or R10 and R11 together form C2-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl; or R10 and R12 together form C1-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl; or R10 and R14 together form C1-7alkylene; or R12 and R13 together form C2-7alkylene; or R12 and R14 together form C1-7alkylene; or R14 and R15 together form C2-7alkylene which is optionally substituted with C1- 7alkoxy. [0196] In some embodiments, Y is N or CH. In some embodiments, Y is absent. In some embodiments, Y is N. In some embodiments, Y is CH. [0197] In some embodiments, R9 is hydrogen, C1-7alkyl, or (CH2)m-NR14R15. In some embodiments, R9 is hydrogen. In some embodiments, R9 is C1-7alkyl. In some embodiments, R9 is (CH2)m-NR14R15. [0198] In some embodiments, R10 is hydrogen or C1-7alkyl. In some embodiments, R10 is hydrogen. In some embodiments, C1-7alkyl. [0199] In some embodiments, R11 is hydrogen or C1-7alkyl. In some embodiments, R11 is hydrogen. In some embodiments, C1-7alkyl. [0200] In some embodiments, R12 is hydrogen or C1-7alkyl. In some embodiments, R12 is hydrogen. In some embodiments, C1-7alkyl. [0201] In some embodiments, R13 is hydrogen or C1-7alkyl. In some embodiments, R13 is hydrogen. In some embodiments, C1-7alkyl. [0202] In some embodiments, R14 is hydrogen, C1-7alkyl, or C3-8cycloalkyl. In some embodiments, R14 is hydrogen. In some embodiments, R14 is C1-7alkyl. In some embodiments, R14 is C3-8cycloalkyl. [0203] In some embodiments, R15 is hydrogen, C1-7alkyl, or C3-8cycloalkyl. In some embodiments, R15 is hydrogen. In some embodiments, R15 is C1-7alkyl. In some embodiments, R15 is C3-8cycloalkyl. [0204] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. [0205] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0206] In some embodiments, R9 and R10 together form C1-7alkylene. [0207] In some embodiments, R9 and R12 together form C1-7alkylene. [0208] In some embodiments, R10 and R11 together form C2-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R11 together form C2-7alkylene. [0209] In some embodiments, R10 and R11 together form 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R11 together form 4- membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R11 together form 5-membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R11 together form 6-membered heterocycloalkyl optionally substituted with C1-7alkyl. [0210] In some embodiments, R10 and R11 together form 4- to 6-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R11 together form 4-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R11 together form 5-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R11 together form 6-membered heterocycloalkyl substituted with C1-7alkyl. [0211] In some embodiments, R10 and R12 together form C1-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R12 together form C1-7alkylene. [0212] In some embodiments, R10 and R12 together form 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R12 together form 4- membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R12 together form 5-membered heterocycloalkyl optionally substituted with C1-7alkyl. In some embodiments, R10 and R12 together form 6-membered heterocycloalkyl optionally substituted with C1-7alkyl. [0213] In some embodiments, R10 and R12 together form 4- to 6-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R12 together form 4-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R12 together form 5-membered heterocycloalkyl substituted with C1-7alkyl. In some embodiments, R10 and R12 together form 6-membered heterocycloalkyl substituted with C1-7alkyl. [0214] In some embodiments, R10 and R14 together form C1-7alkylene. [0215] In some embodiments, R12 and R13 together form C2-7alkylene. [0216] In some embodiments, R12 and R14 together form C1-7alkylene. [0217] In some embodiments, R14 and R15 together form C2-7alkylene. [0218] In some embodiments, R14 and R15 together form C2-7alkylene which is optionally substituted with C1-7alkoxy. [0219] In some embodiments, R14 and R15 together form C2-7alkylene which is substituted with C1-7alkoxy. [0220] In some embodiments, Y is CH and R9 is (CH2)m-NR14R15. [0221] In some embodiments, R9 is hydrogen, pyrrolidinyl, or methoxy-azetidinyl. [0222] In some embodiments, R10 is hydrogen, methyl, ethyl or isopropyl. [0223] In some embodiments, R11 is hydrogen or methyl. [0224] In some embodiments, R12 is hydrogen or methyl. [0225] In some embodiments, R9 and R10 together form propylene. [0226] In some embodiments, R10 and R11 together form ethylene. [0227] In some embodiments, R14 and R15 together form propylene or butylene. [0228] In some embodiments, A
Figure imgf000045_0001
Figure imgf000045_0002
is hydrogen or C1-7alkyl. [0229] [0230] In some embodiments, A i
Figure imgf000045_0003
Figure imgf000045_0004
wee 9, 10, 11, 12, ad 13 ae as de ed ay oe o te peced g ca s, ad 16 is hydrogen or C1-7alkyl. [0231] In some embodiments, R16 is hydrogen or C1-7alkyl. In some embodiments, R16 is hydrogen. In some embodiments, R16 is C1-7alkyl. [0232] In some embodiments A is ,
Figure imgf000046_0001
Figure imgf000046_0002
[0233] In some embodiments A
Figure imgf000046_0003
, ,
Figure imgf000046_0004
[0235] In some embodiments, A is NR1R2. [0236] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom. [0237] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R6. [0238] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 1, 2, 3, or 4 R6. [0239] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 1, 2, or 3 R6. [0240] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 1 R6. [0241] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 2 R6. [0242] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 3 R6. [0243] In some embodiments, R1 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein the heterocycloalkyl is substituted with 4 R6. [0244] In some embodiments, R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl. [0245] In some embodiments, R2 is hydrogen or C1-7alkyl. [0246] In some embodiments, R2 is hydrogen. [0247] In some embodiments, R2 is C1-7alkyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is butyl. In some embodiments, R2 is pentyl. In some embodiments, R2 is hexyl. In some embodiments, R2 is heptyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is isobutyl. In some embodiments, R2 is isopentyl. In some embodiments, R2 is isohexyl. In some embodiments, R2 is secbutyl. In some embodiments, R2 is secpentyl. In some embodiments, R2 is sechexyl. In some embodiments, R2 is tertbutyl. [0248] In some embodiments, R2 is C3-8cycloalkyl. In some embodiments, R2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. [0249] In some embodiments, R3 is H, halo, C1-7alkyl, -OR5, -N(R5)2, C3-8cycloalkyl, or heterocycloalkyl. [0250] In some embodiments, R3 is H, C1-7alkyl, -OR5, -N(R5)2, C3-8cycloalkyl, or heterocycloalkyl. [0251] In some embodiments, R3 is H or C1-7alkyl. [0252] In some embodiments, R3 is H. [0253] In some embodiments, R3 is halo. In some embodiments, R3 is F, Cl, Br, or I. In some embodiments, R3 is F, Cl, or Br. In some embodiments, R3 is F or Cl. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Br. In some embodiments, R3 is I. [0254] In some embodiments, R3 is C1-7alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is butyl. In some embodiments, R3 is pentyl. In some embodiments, R3 is hexyl. In some embodiments, R3 is heptyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is isobutyl. In some embodiments, R3 is isopentyl. In some embodiments, R3 is isohexyl. In some embodiments, R3 is secbutyl. In some embodiments, R3 is secpentyl. In some embodiments, R3 is sechexyl. In some embodiments, R3 is tertbutyl. [0255] In some embodiments, R3 is -OR5 or -N(R5)2. In some embodiments, R3 is -OR5. In some embodiments, R3 is -N(R5)2. [0256] In some embodiments, R3 is C3-8cycloalkyl or heterocycloalkyl. [0257] In some embodiments, R3 is C3-8cycloalkyl. In some embodiments, R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. [0258] In some embodiments, R3 is heterocycloalkyl. [0259] In some embodiments, R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, or S. [0260] In some embodiments, R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N or O. [0261] In some embodiments, R4 is aryl. [0262] In some embodiments, R4 is aryl optionally substituted with one, two, or three R7. [0263] In some embodiments, R4 is aryl substituted with one, two, or three R7. In some embodiments, R4 is aryl substituted with one R7. In some embodiments, R4 is aryl substituted with two R7. In some embodiments, R4 is aryl substituted with three R7. [0264] In some embodiments, R4 is phenyl. [0265] In some embodiments, R4 is phenyl optionally substituted with one, two, or three R7. [0266] In some embodiments, R4 is phenyl substituted with one, two, or three R7. In some embodiments, R4 is phenyl substituted with one R7. In some embodiments, R4 is phenyl substituted with two R7. In some embodiments, R4 is phenyl substituted with three R7. [0267] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S. [0268] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O. [0269] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N, O, and S. [0270] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O. [0271] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7. [0272] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is optionally substituted 1, 2, or 3 R7. [0273] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7. [0274] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7. [0275] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 1, 2, or 3 R7. [0276] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 1, 2, or 3 R7. [0277] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7. [0278] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7. [0279] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7. [0280] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7. [0281] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 3 R7. [0282] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 or 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 3 R7. [0283] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7. [0284] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising two heteroatoms independently selected from N and O, wherein R4 is substituted with 1, 2, or 3 R7. [0285] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7. [0286] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7. [0287] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, wherein R4 is substituted with 3 R7. [0288] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7. [0289] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 1, 2, or 3 R7. [0290] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7. [0291] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7. [0292] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 3 heteroatoms independently selected from N and O, wherein R4 is substituted with 3 R7. [0293] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising four heteroatoms independently selected from N and O, wherein R4 is optionally substituted with 1, 2, or 3 R7. [0294] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 1, 2, or 3 R7. [0295] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 1 R7. [0296] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 2 R7. [0297] In some embodiments, R4 is a bicyclic 9-membered heteroaryl comprising 4 heteroatoms independently selected from N and O, wherein R4 is substituted with 3 R7. [0298] In some embodiments, R4 is imidazo[1,2-a]pyrazine, benzo[d]oxazole, triazolo- pyridazinyl, or imidazo[1,2-a]pyrazine each optionally substituted with 1, 2, 3, or 4 R7. [0299] In some embodiments, R4
Figure imgf000051_0001
Figure imgf000051_0002
[0300] In some embodiments, R4 is
Figure imgf000051_0003
[0301] In some embodiments, R4
Figure imgf000051_0004
Figure imgf000051_0005
[0302] In some embodiments, R4 is ycloalkyl, or
Figure imgf000052_0001
heterocycloalkyl. [0304] In some embodiments, each R5 is independently C1-7alkyl. In some embodiments, each R5 is independently methyl. In some embodiments, each R5 is independently ethyl. In some embodiments, each R5 is independently propyl. In some embodiments, each R5 is independently butyl. In some embodiments, each R5 is independently pentyl. In some embodiments, each R5 is independently hexyl. In some embodiments, each R5 is independently heptyl. In some embodiments, each R5 is independently isopropyl. In some embodiments, each R5 is independently isobutyl. In some embodiments, each R5 is independently isopentyl. In some embodiments, each R5 is independently isohexyl. In some embodiments, each R5 is independently secbutyl. In some embodiments, each R5 is independently secpentyl. In some embodiments, each R5 is independently sechexyl. In some embodiments, each R5 is independently tertbutyl. [0305] In some embodiments, each R5 is independently C3-8cycloalkyl or heterocycloalkyl. [0306] In some embodiments, each R5 is independently C3-8cycloalkyl. In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. [0307] In some embodiments, each R5 is independently heterocycloalkyl. [0308] In some embodiments, each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl and C1-7alkoxy-heterocycloalkyl or two R6 together form C1- 7alkylene. [0309] In some embodiments, each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl and C1-7alkoxy-heterocycloalkyl. [0310] In some embodiments, each R6 is independently C1-7alkyl. In some embodiments, each R6 is independently methyl. In some embodiments, each R6 is independently ethyl. In some embodiments, each R6 is independently propyl. In some embodiments, each R6 is independently butyl. In some embodiments, each R6 is independently pentyl. In some embodiments, each R6 is independently hexyl. In some embodiments, each R6 is independently heptyl. In some embodiments, each R6 is independently isopropyl. In some embodiments, each R6 is independently isobutyl. In some embodiments, each R6 is independently isopentyl. In some embodiments, each R6 is independently isohexyl. In some embodiments, each R6 is independently secbutyl. In some embodiments, each R6 is independently secpentyl. In some embodiments, each R6 is independently sechexyl. In some embodiments, each R6 is independently tertbutyl. [0311] In some embodiments, each R6 is independently amino or amino-C1-7alkyl. [0312] In some embodiments, each R6 is independently amino. In some embodiments, R6 is independently amino-C1-7alkyl. [0313] In some embodiments, each R6 is independently C3-8cycloalkyl, heterocycloalkyl and C1-7alkoxy-heterocycloalkyl. [0314] In some embodiments, each R6 is independently C3-8cycloalkyl. [0315] In some embodiments, each R6 is independently heterocycloalkyl and C1-7alkoxy- heterocycloalkyl. [0316] In some embodiments, each R6 is independently heterocycloalkyl. In some embodiments, each R6 is independently C1-7alkoxy-heterocycloalkyl. [0317] In some embodiments, two R6 together form C1-7alkylene. [0318] In some embodiments, each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy C1-7haloalkoxy, or C3-8cycloalkyl. [0319] In some embodiments, each R7 is independently halo or cyano. [0320] In some embodiments, each R7 is independently halo. In some embodiments, each R7 is independently from F, Cl, Br, and I. In some embodiments, each R7 is independently from F, Cl, or Br. In some embodiments, each R7 is independently F. In some embodiments, each R7 is independently Cl. In some embodiments, each R7 is independently Br. In some embodiments, each R7 is independently I. [0321] In some embodiments, each R7 is independently cyano. [0322] In some embodiments, each R7 is independently from C1-7alkyl, C1-7haloalkyl, C1- 7alkoxy C1-7haloalkoxy, or C3-8cycloalkyl. [0323] In some embodiments, each R7 is independently from C1-7alkyl, C1-7haloalkyl, C1- 7alkoxy, or C1-7haloalkoxy. [0324] In some embodiments, each R7 is independently C1-7alkyl. In some embodiments, each R7 is independently methyl. In some embodiments, each R7 is independently ethyl. In some embodiments, each R7 is independently propyl. In some embodiments, each R7 is independently butyl. In some embodiments, each R7 is independently pentyl. In some embodiments, each R7 is independently hexyl. In some embodiments, each R7 is independently heptyl. In some embodiments, each R7 is independently isopropyl. In some embodiments, each R7 is independently isobutyl. In some embodiments, each R7 is independently isopentyl. In some embodiments, each R7 is independently isohexyl. In some embodiments, each R7 is independently secbutyl. In some embodiments, each R7 is independently secpentyl. In some embodiments, each R7 is independently sechexyl. In some embodiments, each R7 is independently tertbutyl. [0325] In some embodiments, each R7 is independently C1-7alkyl optionally substituted with OH. [0326] In some embodiments, each R7 is independently C1-7alkyl substituted with OH. In some embodiments, each R7 is independently methyl substituted with OH. In some embodiments, each R7 is independently ethyl substituted with OH. In some embodiments, each R7 is independently propyl substituted with OH. In some embodiments, each R7 is independently butyl substituted with OH. In some embodiments, each R7 is independently pentyl substituted with OH. In some embodiments, each R7 is independently hexyl substituted with OH. In some embodiments, each R7 is independently heptyl substituted with OH. In some embodiments, each R7 is independently isopropyl substituted with OH. In some embodiments, each R7 is independently isobutyl substituted with OH. In some embodiments, each R7 is independently isopentyl substituted with OH. In some embodiments, each R7 is independently isohexyl substituted with OH. In some embiments, each R7 is independently secbutyl substituted with OH. In some embodiments, each R7 is independently secpentyl substituted with OH. In some embodiments, each R7 is independently sechexyl substituted with OH. In some embodiments, each R7 is independently tertbutyl substituted with OH. [0327] In some embodiments, each R7 is independently C1-7haloalkyl, C1-7alkoxy, or C1- 7haloalkoxy. [0328] In some embodiments, each R7 is independently C1-7haloalkyl. [0329] In some embodiments, each R7 is independently C1-7alkoxy. [0330] In some embodiments, each R7 is independently C1-7haloalkoxy. [0331] In some embodiments, each R7 is independently C3-8cycloalkyl. [0332] To clarify, in all embodiments where two variable groups together form an alkylene, those groups along with the atoms they are attached to and possible intervening atoms, form a ring. This ring can be cycloalkyl or heterocyclyl depending on the attachment point of the variables, but the variable groups themselves are alkylene and thus contain no heteroatoms of their own. [0333] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, solvates, or prodrugs thereof. [0334] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0335] In some embodiments, the compound is selected from the prodrugs of compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0336] In some embodiments, the compound is selected from the compounds described in Table 1, or from the disclosure. [0337] In some embodiments, the compound is selected from the compounds described in Table 1. [0338] In some embodiments, the compound is a therapeutically active substance. In some embodiments, the compound is a small molecule splicing modulator. In some embodiments, the compound is a small molecule splicing modulator of MYB. In some embodiments, the compound is a MYB inhibitor. [0339] The compounds provided herein are also disclosed in PCT Publication No. WO 2023/086959 A1, the entire contents of which are incorpated by reference herein. [0340] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group. [0341] The various functional groups and substituents making up the compounds of the Formula (I) or (II) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 daltons or less. [0342] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers and mixtures of stereoisomers of all isomeric forms of said compounds. [0343] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. [0344] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). [0345] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Methods of Synthesis [0346] By way of example only, provided is a scheme for preparing a small molecule described herein. [0347] In some embodiments, a scheme for preparing a compound of the present disclosure is described herein in Scheme 1:
Figure imgf000056_0001
of the present disclosure. [0349] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein. [0350] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein. [0351] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein. [0352] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. [0353] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [0354] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized. [0355] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [0356] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. [0357] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0358] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0359] Once a compound of Formula (I) or (II)has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of Formula (I) into another compound of Formula (I) or (II); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof. [0360] The resultant compounds of Formula (I) or (II) can be isolated and purified using techniques well known in the art. [0361] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulphoxides, such as dimethyl sulphoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. [0362] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. [0363] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. [0364] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). [0365] General routes for the preparation of a compound of the application are described herein. Biological Assays [0366] Compounds designed, selected and/or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. Cell proliferation assay [0367] Various cancer cell lines including K562, HL60, COLO201, COLO205 can be treated with the compounds of the present disclosure to assess their effect on inhibiting cell proliferation. [0368] Test compounds may be diluted in duplicates and dispensed into an assay plate. Positive and negative controls may be used (e.g. staurosporine). Frozen cell line stock is prepared and the cell suspension is dispensed into the assay plate. After incubation, the luminescence (RLU) signals in each well may be recorded and converted to percentage inhibition values using the signals in negative and positive control standards. IC50 values may be determined by curve fitting in Levenberg–Marquardt algorithm. Pharmaceutical Compositions [0369] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1, or from the disclosure. . In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. [0370] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts. [0371] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. [0372] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulphated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulphobutyl ether, branched-β- cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof. [0373] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof. [0374] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. [0375] The aqueous vehicle may also contain a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. [0376] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range. [0377] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof. [0378] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene- polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. [0379] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [0380] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). [0381] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. [0382] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a disease or disorder referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0383] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a disease or disorder referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0384] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) or (II) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine. Methods of Use [0385] In some embodiments, a disease or disorder is a MYB-related disease or disorder. In some embodiments, the present disclosure includes a method of inhibiting MYB comprising contacting a cell with a compound disclosed herein. [0386] In one aspect, the present disclosure provides compounds of the present disclosure or their pharmaceutically acceptable salts for the use in the treatment or prevention of cancer. [0387] In some embodiments, the present disclosure includes treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed here. In some embodiments, a disease or disorder is a proliferative disease or disorder. In some emobdiments, a disease or disorder is cancer. [0388] In some emobodiments, cancer is selected from the group consisting of adenoid cystic carcinoma (ACC), hepatocellular carcinoma (HCC), breast cancer, prostate cancer, pancreatic cancer, lung cancer, adenocarcinoma, osteosarcoma, colorectal cancer, and blood cancer. [0389] In some embodiments, cancer is lung cancer. In some embodiments, lung cancer is small cell lung cancer. In some embodiments, lunch caner is non-small cell lung cancer. [0390] In some embodiments, cancer is a blood cancer. In some embodiments, a blood cancer is leukemia. In some embodiments, leukemia is acute myeloid leukemia. In some embodiments, leukemia is acute promyelocytic leukemia. In some embodiments, blood cancer is lymphoma. In some embodiments, lymphoma is selected from the group consisting of non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt lymphoma, B-cell lymphoma, and T-cell lymphoma. [0391] In some embodiments, cancer is adenoid cystic carcinoma (ACC). In some embodiments, cancer is hepatocellular carcinoma (HCC). In some embodiments, cancer is breast cancer. In some embodiments, cancer is prostate cancer. In some embodiments, cancer is pancreatic cancer. In some embodiments, cancer is adenocarcinoma. In some embodiments, cancer is osteosarcoma. In some embodiments, cancer is colorectal cancer. [0392] In one aspect, the present disclosure provides a method for the treatment or prevention of cancer in a subject in need thereof, which method comprises administering to the subject a pharmaceutically effective amount of a compound or pharmaceutical composition of the present disclosure. In some embodiments, the cancer is a liquid cancer. In some embodiments, the cancer is a leukemic cancer. In some embodiments, the cancer is a leukemia or lymphoma. In some embodiments, the cancer is colorectal cancer, breast cancer, or prostate cancer. In some embodiments, the cancer is a leukemia, acute myeloid leukemia, colon cancer, gastric cancer, acute monocytic leukemia, breast cancer, hepatocellular carcinoma, alveolar soft part sarcoma, myeloma, skin melanoma, pancreatic cancer, adenocarcinoma, adenoiditis, adenoid cystic carcinoma, gastrointestinal stromal tumor, sarcoma, prostate adenocarcinoma, Hodgkin's lymphoma, ovarian cancer, non-Hodgkin's lymphoma, multiple myeloma, chronic myeloid leukemia, acute lymphoblastic leukemia, renal cell carcinoma, transitional cell carcinoma, colorectal cancer, chronic lymphocytic leukemia, anaplastic large cell lymphoma, kidney cancer, breast cancer, or cervical cancer. [0393] In some embodiments, the cancer is a solid cancer or solid tumor. In some embodiments, the tumor is selected from the group consisting of adenocarcinoma, melanoma (e.g., metastatic melanoma), liver cancer {e.g., hepatocellular carcinoma, hepatoblastoma, liver carcinoma), prostate cancer (e.g., prostate adenocarcinoma, androgen-independent prostate cancer, androgen-dependent prostate cancer, prostate carcinoma), sarcoma (e.g., leiomyosarcoma, rhabdomyosarcoma), brain cancer (e.g., glioma, a malignant glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary brain lymphoma, anaplastic astrocytoma, juvenile pilocytic astrocytoma, a mixture of oligodendroglioma and astrocytoma elements), breast cancer (e.g., triple negative breast cancer, metastatic breast cancer, breast carcinoma, breast sarcoma, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, inflammatory breast cancer), Paget's disease, juvenile Paget's disease, lung cancer (e.g., KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, small cell lung cancer, lung carcinoma), pancreatic cancer (e.g., insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin- secreting tumor, carcinoid tumor, islet cell tumor, pancreas carcinoma), skin cancer (e.g., skin melanoma, basal cell carcinoma, squamous cell carcinoma, melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acrallentiginous melanoma, skin carcinoma), cervical cancer (e.g., squamous cell carcinoma, adenocarcinoma, cervical carcinoma), ovarian cancer (e.g., ovarian epithelial carcinoma, borderline tumor, germ cell tumor, stromal tumor, ovarian carcinoma), cancer of the mouth, cancer of the nervous system (e.g., cancer of the central nervous system, a CNS germ cell tumor), goblet cell metaplasia, kidney cancer (e.g., renal cell cancer, adenocarcinoma, hypernephroma, Wilms' tumor, fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer), renal cell carcinoma, renal carcinoma), bladder cancer (e.g., transitional cell carcinoma, squamous cell cancer, carcinosarcoma), stomach cancer (e.g., fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, liposarcoma, fibrosarcoma, carcinosarcoma), uterine cancer (e.g., endometrial cancer, endometrial carcinoma, uterine sarcoma), cancer of the esophagus (e.g., squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma, esophageal carcinomas), colon cancer (e.g., colon carcinoma), cancer of the rectum (e.g., rectal cancers), colorectal cancer (e.g., colorectal carcinoma, metastatic colorectal cancer, hereditary nonpolyposis colorectal cancer, KRAS mutated colorectal cancer), gallbladder cancer (e.g., adenocarcinoma, cholangiocarcinoma, papillary cholangiocarcinoma, nodular cholangiocarcinoma, diffuse cholangiocarcinoma), testicular cancer (e.g., germinal tumor, seminoma, anaplastic testicular cancer, classic (typical) testicular cancer, spermatocyte testicular cancer, nonseminoma testicular cancer), embryonal carcinoma (e.g., teratoma carcinoma, choriocarcinoma (yolk- sac tumor)), gastric cancer (e.g., gastrointestinal stromal tumor, cancer of other gastrointestinal tract organs, gastric carcinomas), bone cancer (e.g., connective tissue sarcoma, bone sarcoma, cholesteatoma-induced bone osteosarcoma, Paget's disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcoma, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, alveolar soft part sarcoma), liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, synovial sarcoma, cancer of the lymph node (e.g., lymphangioendotheliosarcoma), adenoid cystic carcinoma, vaginal cancer (e.g., squamous cell carcinoma, adenocarcinoma, melanoma), vulvar cancer (e.g., squamous cell carcinoma, melanoma, adenocarcinoma, sarcoma, Paget' s disease), cancer of other reproductive organs, thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, thyroid carcinoma), salivary gland cancer (e.g., adenocarcinoma, mucoepidermoid carcinoma), eye cancer (e.g., ocular melanoma, iris melanoma, choroidal melanoma, cilliary body melanoma, retinoblastoma), penal cancers, oral cancer (e.g. squamous cell carcinoma, basal cancer), pharynx cancer (e.g., squamous cell cancer, verrucous pharynx cancer), cancer of the head, cancer of the neck, cancer of the throat, cancer of the chest, cancer of the spleen, cancer of skeletal muscle, cancer of subcutaneous tissue, adrenal cancer, pheochromocytoma, adrenocortical carcinoma, pituitary cancer, Cushing's disease, prolactin-secreting tumor, acromegaly, diabetes insipidus, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, ependyoma, optic nerve glioma, primitive neuroectodermal tumor, rhabdoid tumor, renal cancer, glioblastoma multiforme, neurofibroma, neurofibromatosis, pediatric cancer, neuroblastoma, malignant melanoma, carcinoma of the epidermis, polycythemia vera, Waldenstrom's macroglobulinemia, monoclonal gammopathy of undetermined significance, benign monoclonal gammopathy, heavy chain disease, pediatric solid tumor, Ewing's sarcoma, Wilms tumor, carcinoma of the epidermis, HIV-related Kaposi's sarcoma, rhabdomyosarcoma, thecomas, arrhenoblastomas, endometrial carcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, nasopharyngeal carcinoma, laryngeal carcinoma, hepatoblastoma, Kaposi's sarcoma, hemangioma, cavernous hemangioma, hemangioblastoma, retinoblastoma, glioblastoma, Schwannoma, neuroblastoma, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, urinary tract carcinoma, abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs' syndrome, pituitary adenoma, primitive neuroectodermal tumor, medullblastoma, and acoustic neuroma. [0394] A method of treating, preventing, or delaying cancer can comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject with basal cell carcinoma, goblet cell metaplasia, or a malignant glioma. A method of treating, preventing, or delaying cancer can comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject with a cancer of the liver, breast, lung, prostate, cervix, uterus, colon, pancreas, kidney, stomach, bladder, ovary, or brain. [0395] A method of treating, preventing, or delaying cancer can comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a subject with a cancer of the head, neck, eye, mouth, throat, esophagus, esophagus, chest, bone, lung, kidney, colon, rectum or other gastrointestinal tract organs, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system. Routes of Administration [0396] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action). [0397] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES [0398] For exemplary purpose, neutral compounds of Formula (I) or (II) are synthesized and tested in the examples. It is understood that the neutral compounds of Formula (I) or (II) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt). [0399] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated; the chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker or Varian instrument with 8, 16 or 32 scans. [0400] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as C182.1 x 30 mm, unless otherwise stated. Injection volumes were 0.7 – 8.0 µl and the flow rates were typically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionisation. MS range was 100 - 1000 Da. Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid or ammonium carbonate. [0401] Abbreviations: ACN Acetonitrile BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl CDCl3 Chloroform-d DCM Dichloromethane DMF N,N-dimethylformamide DMSO dimethylsulphoxide DMSO-d6 Hexadeuterodimethylsulphoxide DP desired product eq. Equivalents ESI Electrospray ionisation EA ethyl acetate FCC flash column chromatography h hour(s) 1H NMR Proton nuclear magnetic resonance spectroscopy HPLC high performance liquid chromatography LC-MS Liquid chromatography-mass spectrometry MeOD Methanol-d4 MeOH Methanol min minute(s) NaOAc Sodium acetate NMP N-Methyl-2-Pyrrolidone PE petroleum ether ppm parts per million RM reaction mixture rt room temperature SM starting material TEA Triethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography Y Yield
Example 1. Synthesis of 2-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}-7-(piperazin-1- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 99) Step 1: Synthesis of 6-br
Figure imgf000070_0001
[0402] A mix l) and 1- bromopropan-
Figure imgf000070_0002
2-one (17.9 g, 131.6 mmol) in EtOH (80 mL) was heated to 80 °C for 16 h. LCMS showed 15% of SM was left and 50% of DP was formed. The reaction was stopped and cooled to rt. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (PE/EA=4:1) to give 6-bromo-8-fluoro-2- methylimidazo[1,2-a]pyridine (5.0 g, Y: 41.7%) as light pink solid. ESI-MS (M+H)+: 229.1, 231.1.1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 1.4 Hz, 1H), 6.97 (dd, J = 9.6, 1.5 Hz, 1H), 2.47 (s, 3H). Step 2: Synthesis of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile [0403] To a 230 mg, 1.01
Figure imgf000070_0003
mmol) in DMF (10 mL) was added Zn (CN)2 (230 mg, 2.02 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), and the reaction mixture was stirred for 2 h at 120 °C. After cooling to rt, the mixture was diluted with water (80 mL) and 100 mL of EA. The EA layer was separated, washed with brine and water once (100 mL x1), dried over Na2SO4, concentrated to dryness. The crude was purified by silica gel column (10~60% EA in PE). The product was obtained as off-white solid (120 mg, Y: 68 %).1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 1.2 Hz, 1H), 7.52 (dd, J = 3.0, 0.7 Hz, 1H), 6.98 (dd, J = 9.6, 1.3 Hz, 1H), 2.51 (d, J = 0.8 Hz, 3H). Step 3: Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate [0404] To piperazine
Figure imgf000071_0001
-1-carboxylate (9.3 g, 50.0 mmol) in NMP (80 mL) was added TEA (7.5 g, 75.0 mmol), and the reaction mixture was stirred for 3 h at 120 °C. After cooling to rt and diluting with water, the mixture was extracted with EA. The combined organics were washed with brine and water, dried over Na2SO4 and concentrated to dryness. The crude was purified by silica gel column (10~100% EA in PE). The product was obtained as off-white solid (5 g, Y: 68 %).1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 3.0 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 9.3, 3.1 Hz, 1H), 3.55 – 3.46 (m, 8H), 1.43 (s, 9H). Step 4: Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate [0405] T ate (5.5 g,
Figure imgf000071_0002
17.86 mmol) in MeOH (100 mL) was added Pd/C (1.1 g). The reaction mixture was stirred for 16 h at rt under hydrogen atmosphere (balloon pressure). The solvent was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give desired product as a purple semi-solid (4.9 g, crude yield: 97 %), which was used in the next step without further purification. ESI-MS: [M+H] + 279.2. Step 5: Synthesis of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)piperazine-1-carboxylate [
Figure imgf000071_0003
0 mg, 1.0 mmol) in THF was added LDA (1 mL, 2.0 mmol, 2M in THF) at –78 °C. The mixture was stirred at this temperature for 30 min. Compound 8-fluoro-2-methylimidazo[1,2- a]pyridine-6-carbonitrile (150 mg, 0.9 mmol) was added. The mixture was allowed to warm to rt and stirred for 16 h. After concentration, the crude as purified by silica gel column (DCM/MeOH = 10:1) to give desired product (120 mg, Y: 29%) as a brown solid. ESI-MS: [M+H] + 454.1. Step 6: Synthesis of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate
Figure imgf000072_0001
carboximidamido)pyridin-3-yl)piperazine-1-carboxylate (45 mg, 0.1 mmol) in THF (5 mL) was added triphosgene (59 mg, 0.2 mmol) and pyridine (1 mL). The reaction mixture was stirred for 1 h at rt, After concentration, the residue was purified by silica gel column (1~10% MeOH in DCM). The product was obtained as a white solid (20 mg, yield: 41 %) ESI-MS: [M+H] + 480.1. Step 7: Synthesis of 2-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}-7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one oxo-
Figure imgf000072_0002
4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (20 mg, 0.042 mmol) in DCM (3 mL) was added TFA (0.5 ml) at 0 °C. The reaction mixture was warmed to rt and stirred for 1 h. After concentration, the residue was purified by prep-HPLC (MeCN/0.05 % NH3 ^H2O in water) to give 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one as white solid (2 mg, yield: 13%). ESI-MS: [M+H] + 380.2.1H NMR (400 MHz, CD3OD) δ 9.28 (d, J = 1.3 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.25 (dd, J = 9.4, 2.6 Hz, 1H), 7.94 (dd, J = 12.0, 1.3 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 9.6 Hz, 1H), 4.58 (br s, 4H), 3.07 – 3.01 (m, 4H), 2.45 (d, J = 0.7 Hz, 3H). Example 2. Synthesis of tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diaza bicyclo[3.2.1]octane-8- carboxylate
Figure imgf000073_0001
[0409] To a suspension of tert-butyl 3,8-diazabicyclo[3.2.1] octane-8-carboxylate (1.0 g, 4.69 mmol) and 5-bromo-2-nitropyridine (1.44 g, 7.04 mmol) in NMP (10 mL) was added TEA (947 mg, 9.38 mmol), and the reaction mixture was stirred for 10 h at 110 oC. After cooling to rt and diluting with water, the mixture was extracted with EA (40 mL x 2), the combined organics was washed with brine (60 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by silica gel column (10~100% EA in PE) to give title product (1.4 g, yield: 93.3 %) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 9.2 Hz, 1H), 8.08 (d, J = 3.2 Hz, 1H), 7.15 (dd, J = 9.2, 3.2 Hz, 1H), 3.59 – 3.55 (m, 2H), 3.40 – 3.36 (m, 1H), 3.30 – 3.24 (m, 2H), 2.37 (t, J = 8.0 Hz, 1H), 2.04 – 1.98 (m, 2H), 1.83 – 1.77 (m, 2H), 1.49 (s, 9H). Step 2: tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate [0410] To a mixture of tert-butyl 3-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.4 g, 4.19 mmol) in MeOH/THF/EtOAc (15 mL/15 mL/15 mL) was added Pd/C (300 mg). The reaction mixture was stirred for 16 h at rt under hydrogen atmosphere (balloon pressure). The solvent was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give title product (1.3 g, crude) as a brown solid.1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 2.8 Hz, 1H), 7.07 (dd, J = 8.8, 2.8 Hz, 1H), 6.48 (d, J = 8.8 Hz, 1H), 4.32 – 4.28 (m, 2H), 4.11 (s, 2H), 3.38 (t, J = 7.2 Hz, 1H), 3.18 (d, J = 10.4 Hz, 2H), 2.91-2.89 (m, 2H), 2.37 (t, J = 8.0 Hz, 1H), 2.06 - 1.96 (m, 2H), 1.47 (s, 9H). ESI- MS: [M+H] + 305.2. Example 3. Synthesis of tert-butyl 3-(6-aminopyridin-3-yl)-3,9-diaza bicyclo[3.3.1]nonane-9- carboxylate
Figure imgf000074_0001
[0411] To a suspension of tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (400 mg, 1.77 mmol) and 5-fluoro-2-nitropyridine (377 mg, 2.65 mmol) in NMP (10 mL) was added TEA (357 mg, 3.54 mmol), and the reaction mixture was stirred for 6 h at 110 oC. After cooling to rt and diluting with water, the mixture was extracted with EA (40 mL x 2), the combined organics was washed with brine (60 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by silica gel column (10~100% EA in PE) to give tert-butyl 3-(6-nitropyridin-3-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (350 mg, yield: 56.9 %) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 3.2 Hz, 1H), 7.19 (dd, J = 9.2, 3.2 Hz, 1H), 4.52 – 4.45 (m, 1H), 4.37 – 4.34 (m, 1H), 3.76 (d, J = 12.0 Hz, 2H), 3.31 – 3.30 (m, 2H), 2.09 – 2.01 (m, 1H), 1.95 – 1.87 (m, 2H), 1.81 – 1.77 (m, 2H), 1.64 – 1.61 (m, 1H), 1.50 (s, 9H). Step 2: tert-butyl 3-(6-aminopyridin-3-yl)-3,9-diazabicyclo[3.3.1]nonane-9- carboxylate [0412] To a mixture of tert-butyl 3-(6-nitropyridin-3-yl)-3,9-diazabicyclo [3.3.1]nonane-9- carboxylate (350 mg, 1.00 mmol) in MeOH/THF (20 mL/10 mL) was added Pd/C (50 mg). The reaction mixture was stirred for 2 h at rt under hydrogen atmosphere (balloon pressure). The solvent was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give tert-butyl 3-(6-aminopyridin-3-yl)-3,9-diazabicyclo[3.3.1]nonane- 9- carboxylate (280 mg, yield:87.7%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 2.8 Hz, 1H), 7.12 (dd, J = 8.8, 3.0 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.33 – 4.31 (m, 1H), 4.21 – 4.20 (m, 1H), 4.13 – 4.11 (m, 2H), 3.37 (t, J = 9.8 Hz, 2H), 3.03 – 2.98 (m, 2H), 1.94 – 1.83 (m, 2H), 1.80 – 1.75 (m, 2H), 1.48 (s, 9H). ESI-MS: [M+H] + 319.1. Example 4. Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-2,2- dimethylpiperazine-1- carboxylate
Figure imgf000075_0001
[0413] To a mixture of 5 bromo 2 nitropyridine (300 mg, 1.5 mmol) and tert butyl 2,2 dimethylpiperazine-1-carboxylate (214 mg, 1 mmol) in NMP (5 mL) was added TEA (303 mg, 3 mmol), the reaction mixture was stirred for 24 h at 120 oC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by silica gel column chromatography (PE/EA=6:1 to 1:1) to give title compound (210 mg, 62.3% yield) as a brown solid. ESI-MS (M+H)+: 337.3. Step 2: tert-butyl 4-(6-aminopyridin-3-yl)-2,2- dimethylpiperazine-1-carboxylate [0414] The compound tert-butyl 4-(6-aminopyridin-3-yl)-2,2- dimethylpiperazine-1- carboxylate (900 mg, 2.67 mmol) was dissolved in MeOH (15 mL) and Pd/C (180 mg, 20%) was added. The mixture was charged with H2 for three times and stirred at r.t. overnight under H2 balloon. The mixture was filtered and the filtrate was concentrated to afford the title compound (700 mg, 86% yield) as a grey solid. ESI-MS (M+H)+: 307.3. Example 5. Synthesis of tert-butyl 5-(6-nitropyridin-3-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate
Figure imgf000075_0002
Step : te t butyl 5 (6 n it opy idin 3 yl)hexahyd opy olo [3,4 c]py ole ( ) carboxylate [0415] To a mixture of 5-bromo-2-nitropyridine (1.28 g, 6.33 mmol) and tert-butyl hexahydropyrrolo [3,4-c]pyrrole-2(1H)-carboxylate (900 mg, 4.2 mmol) in toluene (30 mL) was added Pd2(dba)3 (396 mg, 0.42 mmol), Xantphos(495 mg, 0.85 mmol) and Cs2CO3 (2.7 g, 8.49 mmol), the reaction mixture was stirred for 16 h at 100 oC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by silica gel column chromatography (PE/EA=4:1 to 1:3) to give title compound (700 mg, 50% yield) as a brown solid. ESI-MS (M+H)+: 335.3. Step 2: tert-butyl 5-(6-aminopyridin-3-yl)hexahydropyrrolo[3,4-c] pyrrole-2(1H)- carboxylate [0416] To a solution of tert-butyl 5-(6-nitropyridin-3-yl)hexahydropyrrolo [3,4-c]pyrrole- 2(1H)-carboxylate (700 mg, 2.09 mmol) in MeOH (15 mL) was added Pd/C (70 mg, 10%), the mixture was charged with H2 for three times and stirred at r.t. overnight under H2 balloon. The mixture was filtered and the filtrate was concentrated to afford the title compound (600 mg, 94% yield) as a grey solid. ESI-MS (M+H)+: 305.2.1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.7 Hz, 1H), 6.87 – 6.79 (m, 1H), 6.49 (d, J = 8.7 Hz, 1H), 3.64 (br.s, 2H), 3.45 – 3.25 (m, 4H), 3.17 – 3.10 (m, 2H), 2.98 (br.s, 2H), 1.45 (s, 9H). Example 6. Synthesis of tert-butyl 4-(6-amino-4-methylpyridin-3-yl) piperazine-1- carboxylate
Figure imgf000076_0001
[0417] To a solution of 5-bromo-2-chloro-4-methylpyridine (3.0 g, 14.4 mmol) in toluene (20 mL) were added t-BuONa (1.8 g, 18.6 mmol), Xantphos (333 mg, 0.57 mmol), Pd2(dba)3 (394 mg, 0.45 mmol) and tert-butyl piperazine-1-carboxylate (3.3 g, 17.3 mmol), the mixture was stirred at 80 oC overnight. The reaction mixture was concentrated in vacuo, the residue was purified by column chromatography (PE/EA=5:1) to give title product (2.1 g, 52 %) as a light yellow solid. ESI-MS (M+H)+: 312.1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.07 (s, 1H), 3.52 – 3.49 (m, 4H), 2.84 – 2.82 (m, 4H), 2.23 (s, 3H), 1.42 (s, 9H). Step 2: tert-butyl 4-(6-((diphenylmethylene)amino)-4-methylpyridin-3-yl) piperazine-1- carboxylate [0418] A mixture of tert-butyl 4-(6-chloro-4-methylpyridin-3-yl) piperazine-1-carboxylate (1.7 g, 5.5 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)2 (123 mg, 0.55 mmol), Cs2CO3 (3.6 g, 11.0 mmol), BINAP (685 mg, 1.1 mmol) and diphenylmethanimine (1.04 g, 5.7 mmol) was stirred at 80 oC overnight. The reaction mixture was concentrated in vacuo, the residue was purified by column chromatography (PE/EA=5:1) to give title product (3.5 g, yield: 60%) as a light yellow solid. ESI-MS (M+H) +457.3. Step 3: tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperazine -1-carboxylate [0419] To a solution of tert-butyl 4-(6-((diphenylmethylene)amino)- 4-methylpyridin-3- yl)piperazine-1-carboxylate (1.64 g, 3.6 mmol) in MeOH (10 mL) was added NaOAc (887 mg, 10.8 mmol) and NH2OH.HCl (1.3 g, 18 mmol). The mixture was stirred at rt for 2 h. The mixture was diluted with water (20 mL), adjusted to pH=2 with 1M HCl, and extracted with EtOAc(50 mL x 2). The aqueous phase was adjusted to pH = 9 with NaHCO3 (aq) and extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was washed with tert-butyl methyl ether (10 mL) to give title product (770 mg, crude) as a yellow solid. ESI-MS (M+H)+293.1.1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 6.37 (s, 1H), 4.23 (s, 2H), 3.54 – 3.52 (m, 4H), 2.83 – 2.81 (m, 4H), 2.22 (s, 3H), 1.48 (s, 9H).
Example 7. Synthesis of tert-butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2- methylpiperazine-1-carboxylate St [0
Figure imgf000078_0001
420] To a solution of 5-bromo-2-chloro-3-fluoropyridine (4.0 g, 19.2 mmol) in toluene (20 mL) were added t-BuONa (2.4 g, 2.5 mmol), Xantphos (463 mg, 0.8 mmol), Pd2(dba)3 (528 mg, 0.56 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.6 g, 23.04 mmol). The mixture was stirred at 80 oC overnight. The reaction mixture was concentrated in vacuum, the residue was purified by column chromatography (PE/EA=5:1) to give title product (5 g, 79.4%) as a light yellow solid. ESI-MS (M+H)+ 330.2.1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 2.5, 0.8 Hz 1H), 4.30 (br.s, 1H), 3.90 (d, J = 13.5 Hz, 1H), 3.43 (d, J = 11.7 Hz, 1H), 3.31 – 3.15 (m, 2H), 3.03 – 3.01 (m, 1H), 2.81 – 2.79 (m, 1H), 1.42 (s, 9H), 1.20 (d, J = 6.8 Hz, 3H). Step 2: tert-butyl (S)-4-(6-((diphenylmethylene)amino)-5-fluoropyridin- 3-yl)-2- methylpiperazine-1-carboxylate [0421] To a solution of tert-butyl (S)-4-(6-chloro-5-fluoro pyridin-3-yl)-2-methylpiperazine- 1-carboxylate (2.0 g, 6 mmol) in 1,4-dioxane (20 mL) were added Pd(OAc)2 (134 mg, 0.6 mmol), Cs2CO3 (3.9 g, 12.0 mmol), BINAP (747 mg, 1.2 mmol) and diphenylmethanimine (1.2 g, 6.4 mmol). The mixture was stirred at 80 oC overnight. The reaction mixture was concentrated in vacuo, the residue was purified by column chromatography (PE/EA=5:1) to give title product (2.1 g yield: 55 %) as a light yellow solid. ESI-MS (M+H) +: 475.3. Step 3: tert-butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2- methylpiperazine-1-carboxylate [0422] To a solution of tert-butyl (S)-4-(6-((diphenylmethylene) amino)-5-fluoropyridin-3- yl)-2-methylpiperazine-1-carboxylate (1.326 g, 2.8 mmol) in MeOH (10 mL) was added NaOAc (688 mg, 8.4 mmol), NH2OH.HCl (966 mg, 14 mmol) and the mixture was stirred at rt overnight. The mixture was diluted with water (20 mL), adjusted to pH=2 with 1M HCl, and extracted with EtOAc(50 mL x 2). The aqueous phase was adjusted to pH = 9 with NaHCO3 (aq) and extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by C18 flash (0.1% NH3.H2O in water / CH3CN) to give title product (943 mg, yield: 40%) as a yellow solid. ESI-MS (M+H)+: 311.3.1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 2.1 Hz, 1H), 7.01 – 6.90 (m, 1H), 4.34 (s, 3H), 3.94 (d, J = 13.5 Hz, 1H), 3.29 – 3.17 (m, 2H), 3.10 (d, J = 11.6 Hz, 1H), 2.84 (dd, J = 11.6, 3.8 Hz, 1H), 2.72 – 2.59 (m, 1H), 1.48 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). Example 8. Synthesis of tert-butyl (S)-4-(6-amino-5-methylpyridin-3-yl)-2- methylpiperazine-1-carboxylate Step 1
Figure imgf000079_0001
late [0423] To a mixture of 5-bromo-2-chloro-3-methylpyridine (20 g, 0.097 mol), tert-butyl (S)- 2-methylpiperazine-1-carboxylate (19.4 g, 0.097 mol) in toluene (400 mL) was added t- BuONa (12.1 g, 0.126 mol), Xantphos (2.25 g, 3.88 mmol) and Pd2(dba)3 (2.37 g, 2.91 mmol), the mixture was charged with N2 for three times and stirred at 80 oC for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified by silica gel column chromatography (EtOAc: PE=1:5) to give title compound (26 g, 82.4 % yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 2.9 Hz, 1H), 7.03 (t, J = 10.2 Hz, 1H), 4.36 (br.s, 1H), 3.96 (d, J = 13.4 Hz, 1H), 3.51 – 3.41 (m, 1H), 3.34 – 3.21 (m, 2H), 2.98 – 2.95 (m, 1H), 2.83 – 2.75 (m, 1H), 2.33 (s, 3H), 1.48 (s, 9H), 1.29 (d, J = 6.8 Hz, 3H). ESI-MS (M+H)+: 326.0. Step 2: tert-butyl (S)-4-(6-((diphenylmethylene)amino)-5-methyl pyridin-3-yl)-2- methylpiperazine-1-carboxylate [0424] To a mixture of tert-butyl (S)-4-(6-chloro- 5-methylpyridin-3-yl)-2- methylpiperazine-1-carboxylate (26 g, 0.08 mol), diphenylmethanimine (15.2 g, 0.08 mol) in 1,4-dioxane (350 mL) was added Cs2CO3 (52 g, 0.16 mol), BINAP (9.9 g, 0.016 mol) and Pd(OAc)2 (1.79 g, 0.008 mol), the mixture was charged with N2 for three times and stirred at 100 oC for 16 h. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (400 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The residue was purified by silica gel column chromatography (EtOAc/PE=1:5) to give title compound (30 g, 80 %yield) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 7.73 – 7.65 (m, 3H), 7.56 – 7.53 (m, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.34 – 7.25 (m, 3H), 7.16 – 7.05 (m, 3H), 4.16 (br.s, 1H), 3.75 (d, J = 13.2 Hz, 1H), 3.46 (d, J = 11.9 Hz, 1H), 3.38 (d, J = 12.1 Hz, 1H), 3.17 – 3.05 (m, 1H), 2.71 – 2.68 (m, 1H), 2.56 – 2.51 (m, 1H), 2.06 (d, J = 8.0 Hz, 3H), 1.45 – 1.38 (m, 9H), 1.21 – 1.15 (m, 3H). ESI- MS (M+H)+: 471.2. Step 3: tert-butyl (S)-4-(6-amino-5-methylpyridin-3-yl)-2- methylpiperazine-1-carboxylate [0425] To a solution of tert-butyl (S)-4-(6-((diphenylmethylene)amino)-5- methylpyridin-3- yl)-2-methylpiperazine-1-carboxylate (30 g, 0.06 mol) in MeOH (400 mL) was added NaOAc (15.6 g, 0.19 mol) and hydroxylamine hydrochloride (22 g, 0.32 mol), the mixture was stirred for 2 h at RT. The mixture was filtered and the filtrate was concentrated. The crude was purified by C18 flash to give title compound (14 g, 72% yield) as a yellow solid. ESI-MS (M+H)+:307.3.1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 3.3 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 5.22 (s, 2H), 4.17 (br.s, 1H), 3.76 (d, J = 13.1 Hz, 1H), 3.29 – 3.20 (m, 1H), 3.17 – 3.04 (m, 2H), 2.61 (dd, J = 11.7, 3.8 Hz, 1H), 2.48 – 2.40 (m, 1H), 2.03 (s, 3H), 1.41 (s, 9H), 1.22 (d, J = 6.8 Hz, 3H).
Example 9. Synthesis of tert-butyl 4-(6-amino-2-methylpyridin-3-yl) piperazine-1- carboxylate
Figure imgf000081_0001
[0426] A mixture of 3-bromo-6-chloro-2-methylpyridine (6.63 g, 32.1 mmol), tert-butyl piperazine-1-carboxylate (8.57 g, 38.5 mmol), Pd2(dba)3 (2.94 g, 3.2 mmol), Xantphos (3.7 g, 6.4 mmol) and t-BuONa (4.6 g, 48.2 mmol) in toluene (140 mL) was stirred at 80 oC for 16 h under Ar. After cooling to rt, the mixture was diluted with EA (100 mL) and washed with brine and water, concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=10:1 to 5:1) to afford title product as a white solid (8.0 g, yield: 80.2%).1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 3.76 – 3.60 (m, 4H), 2.89 – 2.73 (m, 4H), 2.16 (s, 3H), 1.57 (s, 9H). Step 2: tert-butyl 4-(6-((diphenylmethylene)amino)-2-methylpyridin-3-yl)piperazine -1- carboxylate [0427] A mixture of tert-butyl 4-(6-chloro-2-methylpyridin-3-yl) piperazine-1-carboxylate (2.5 g, 8.0 mmol), diphenylmethanimine (1.6 g, 8.8 mmol), Pd(OAc)2 (180 mg, 0.8 mmol), BINAP (1.0 g, 1.6 mmol) and Cs2CO3 (5.2 g, 16.0 mmol) in dioxane (50 mL) was stirred at 100oC for 5 h under Ar. After cooling to rt, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=5:1 to 2:1) to afford title product (1.2 g, yield: 51.3%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.3 Hz, 2H), 7.46 – 7.29 (m, 3H), 7.26 – 7.18 (m, 3H), 7.17 – 7.12 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 3.62 – 3.33 (m, 4H), 2.84 – 2.60 (m, 4H), 2.44 (s, 3H), 1.47 (s, 9H). ESI-MS: 457.5[M+H]+. Step 3: tert-butyl 4-(6-amino-2-methylpyridin-3-yl)piperazine-1-carboxylate [0428] A mixture of tert-butyl 4-(6-((diphenylmethylene)amino)-2-methylpyridin-3-yl) piperazine-1-carboxylate (548 mg, 1.2 mmol), NaOAc (296 mg, 3.6 mmol) and NH2OH ^HCl (417 mg, 6.0 mmol) in MeOH (15 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=5:1 to 2:1) to give title product as a white solid (280 mg, yield: 83%).1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 3.63 – 3.48 (m, 4H), 2.82 – 2.66 (m, 4H), 2.41 (s, 3H), 1.48 (s, 9H). ESI-MS: 293.1[M+H]+. Example 10. Synthesis of tert-butyl 4-(6-amino-2-methoxypyridin-3-yl) piperazine-1- carboxylate
Figure imgf000082_0001
[0429] To a solution of 3-bromo-2,6- dichloropyridine (554 mg, 2.0 mmol) in MeOH (10 mL) was added sodium methylate (216 mg, 4.0 mmol). The mixture was stirred at 80 oC for 5 h. After cooling to rt, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and used for next step directly without any further purification.1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.02 (s, 3H). Step 2: tert-butyl 4-(6-chloro-2-methoxypyridin-3-yl)piperazine-1-carboxylate [0430] A mixture of 3-bromo-6-chloro-2-methoxypyridine (223 mg, 1.0 mmol), tert-butyl piperazine-1-carboxylate (224 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (116 mg, 0.2 mmol) and t-BuONa (145 mg, 1.5 mmol) in toluene (10 mL) was stirred at 80 oC for 16 h under Ar. After cooling to rt, the mixture was diluted with EA (80 mL) and washed with brine and water, concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=10:1 to 5:1) to afford title product as a white solid (100 mg, yield: 30.6%).1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 4.01 (s, 3H), 3.66 – 3.52 (m, 4H), 3.04 – 2.94 (m, 4H), 1.48 (s, 9H). ESI-MS [M+Na]+: 350.2. Step 3: tert-butyl 4-(6-((diphenylmethylene)amino)-2-methoxypyridin-3-yl) piperazine-1- carboxylate [0431] A mixture of tert-butyl 4-(6-chloro-2-methoxypyridin -3-yl)piperazine-1-carboxylate (100 mg, 0.3 mmol), diphenylmethanimine (58 mg, 0.32 mmol) Pd(OAc)2 (7 mg, 0.03 mmol), BINAP (38 mg, 0.06 mmol) and Cs2CO3 (196 mg, 0.6 mmol) in dioxane (5 mL) was stirred at 110 oC for 24 h under Ar. After cooling to rt, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=5:1 to 2:1) to afford title product as a white solid (100 mg, yield: 69.3%). ESI-MS: 473.2[M+H]+. Step 4: tert-butyl 4-(6-amino-2-methoxypyridin-3-yl)piperazine-1-carboxylate [0432] A mixture of tert-butyl 4-(6-((diphenylmethylene)amino)-2-methoxypyridin-3- yl)piperazine- 1-carboxylate (577 mg, 1.2 mmol), NaOAc (296 mg, 3.6 mmol) and NH2OH ^HCl (417 mg, 6.0 mmol) in MeOH (15 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=5:1 to 2:1) to give title product as a white solid (300 mg, yield: 83%).1H NMR (400 MHz, CDCl3) δ 7.19 – 6.94 (m, 1H), 6.21 – 5.93 (m, 1H), 4.36 (s, 2H), 3.91 (s, 3H), 3.64 – 3.47 (m, 4H), 2.97 – 2.79 (m, 4H), 1.47 (s, 9H). ESI-MS: [M+H] + 309.1.
Example 11. Synthesis of tert-butyl 4-(6-amino-5-fluoropyridin-3-yl) piperazine -1- carboxylate S
Figure imgf000084_0001
[0433] To a mixture of 5-bromo-2-chloro-3-fluoropyridine (15 g, 71.5 mmol), tert-butyl piperazine-1-carboxylate (13.3 g, 71.5 mmol) in toluene (250 mL) was added t-BuONa (8.8 g, 92.2 mmol), Xantphos (1.65 g, 2.85 mmol) and Pd2(dba)3 (1.95 g, 2.3 mmol), the mixture was charged with N2 for three times and stirred at 100 ℃ for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified silica gel column chromatography eluted with (EtOAc: PE=3:1) to give title compound (14.7 g, 65.8% yield) as a grey solid, ESI-MS (M+H) +:316.0. Step 2: tert-butyl 4-(6-((diphenylmethylene)amino)-5- fluoropyridin-3-yl)piperazine-1- carboxylate [0434] To a mixture of tert-butyl 4-(6-chloro-5-fluoropyridin-3-yl)piperazine-1-carboxylate (10.4 g, 33 mmol), diphenylmethanimine (6.27 g, 36 mmol) in 1,4-dioxane (150 mL) was added Cs2CO3 (21.5 g, 66 mol), BINAP (3.0 g, 5.0mmol) and Pd(OAc)2 (370 mg, 1.65 mmol), the mixture was charged with N2 for three times and stirred at 100 ℃ for 24 h. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (400 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified by silica gel column chromatography eluted with (EtOAc/PE=3:1) to give title compound (10.2 g, 67% yield) as a brown solid, ESI-MS (M+H) +:461.2. Step 3: tert-butyl 4-(6-amino-5-fluoropyridin-3-yl) piperazine-1-carboxylate [0435] To a solution of tert-butyl 4-(6-((diphenylmethylene) amino)-5-fluoropyridin-3- yl)piperazine-1-carboxylate (20.4 g, 44.3 mmol) in MeOH (300 mL) was added NaOAc (10.9 mg, 133 mmol) and hydroxylamine hydrochloride (15.2 g, 221mmol) at RT, the mixture was stirred for 2h at RT. The mixture was filtered and the filtrate was concentrated. The crude was purified by silica gel column chromatography (EtOAc/PE=3:1) to give title compound (8.4 g, 65.2%yield) as a grey solid, ESI-MS (M+H) +:297.1.1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 1.7 Hz, 1H), 7.22 (dd, J = 13.4, 2.4 Hz, 1H), 5.63 (s, 2H), 3.48 – 3.38 (m, 4H), 2.96 – 2.84 (m, 4H), 1.41 (s, 9H). Example 12. Synthesis of tert-butyl 4-(6-amino-4-methoxypyridin-3-yl) piperazine-1- carboxylate
Figure imgf000085_0001
[0436] To a mixture of 5-bromo-2-chloro-4-methoxypyridine (6 g, 27.1 mmol), tert-butyl piperazine-1-carboxylate (6 g, 32.5 mmol) in toluene (100 mL) was added t-BuONa (5.2 g, 54.2 mmol), Xantphos (3.1 g, 5.42 mmol) and Pd2(dba)3 (2.5 g, 2.71 mmol), the mixture was charged with N2 for three times and stirred at 100℃ for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified by silica gel column chromatography (EtOAc: PE=3:1) to give title compound (1.4 g, 16% yield) as a grey solid, ESI-MS (M+H) +:328.0 Step 2: tert-butyl 4-(6-((diphenylmethylene)amino)-4- methoxypyridin-3-yl)piperazine-1- carboxylate [0437] To a mixture of tert-butyl 4-(6-chloro-5- fluoropyridin-3-yl)piperazine-1-carboxylate (1.4 g, 4.28 mmol), diphenylmethanimine (800 mg, 4.50 mmol) in 1,4-dioxane (40 mL) was added Cs2CO3 (2.78 g, 8.56 mol), BINAP (532 mg, 0.856 mmol) and Pd(OAc)2 (96 mg, 0.428 mmol). The mixture was charged with N2 for three times and stirred at 100℃ for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified by silica gel column chromatography eluted with (EtOAc/PE=4:1) to give title compound (800 mg, 40% yield) as a brown solid, ESI-MS (M+H) +:473.1. Step 3: tert-butyl 4-(6-amino-4-methoxypyridin-3-yl)piperazine-1- carboxylate [0438] To a solution of tert-butyl 4-(6-((diphenylmethylene)amino)-4-methoxypyridin- 3- yl)piperazine-1-carboxylate (800 mg, 1.67 mmol) in MeOH (20 mL) was added NaOAc (412 mg, 5.02 mmol) and hydroxylamine hydrochloride (578 mg, 8.37 mmol) at RT, the mixture was stirred for 1h at RT. The mixture was diluted with water (20 mL), adjusted to pH=2 with 1M HCl, and extracted with EtOAc (50 mL x 2). The aqueous phase was adjusted to pH = 9 with NaHCO3 (aq) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered filtrate were concentrated to afford title compound (400 mg, 77.8% yield) as a grey solid, ESI-MS (M+H) +: 309.1.1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 6.02 (s, 1H), 4.35 (s, 2H), 3.85 (s, 3H), 3.59 – 3.56 (m, 4H), 2.94 – 2.90 (m, 4H), 1.48 (s, 9H). Example 13. Synthesis of tert-butyl 4-(6-amino-5-methylpyridin-3-yl)-2,2- dimethylpiperazine-1-carboxylate
Figure imgf000086_0001
Step : te t butyl 4 (6 chlo o 5 methylpy idin 3 yl) , dimethylpipe a ine ca boxylate [0439] To a mixture of 5-bromo-2-chloro-3-methylpyridine (5 g, 25.9 mmol), tert-butyl 2,2- dimethylpiperazine-1-carboxylate (5.32 g, 23.3 mmol) in toluene (100 mL) was added t- BuONa (5 g, 51.8 mmol), Xantphos (3 g, 5.18 mmol) and Pd2(dba)3 (2.38 g, 2.5 mmol), the mixture was charged with N2 for three times and stirred at 80℃ for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified silica gel column chromatography eluted with (EtOAc: PE=6:1) to give title compound (4.5 g, 51 % yield) as a grey solid, ESI-MS (M+H) +:340.2. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 3.0 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 3.87 – 3.75 (m, 2H), 3.42 – 3.33 (m, 2H), 3.30 (s, 2H), 2.33 (s, 3H), 1.49 (s, 9H), 1.42 (s, 6H). Step 2: tert-butyl 4-(6-((diphenylmethylene)amino)-5- methylpyridin-3-yl)-2,2- dimethylpiperazine-1-carboxylate [0440] To a mixture of tert-butyl 4-(6-chloro-5-methylpyridin-3-yl)-2,2-dimethylpiperazine -1-carboxylate (4.5 g, 13.27mmol), diphenylmethanimine (2.52 g, 13.93 mmol) in 1,4- dioxane (100 mL) was added Cs2CO3 (8.62 g, 26.54 mol), BINAP (1.65 g, 2.65 mmol) and Pd(OAc)2 (297 mg, 1.32 mmol). The mixture was charged with N2 for three times and stirred at 100℃ for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified by silica gel column chromatography (EtOAc/PE=6:1) to give title compound (4 g, 62% yield) as a brown solid, ESI-MS (M+H)+:473.1. Step 3: tert-butyl 4-(6-amino-5-methylpyridin-3-yl)-2,2- dimethylpiperazine-1-carboxylate [0441] To a solution of tert-butyl 4-(6-((diphenylmethylene) amino)-5-methylpyridin-3-yl)- 2,2-dimethylpiperazine-1-carboxylate (4 g, 8.26 mmol) in MeOH (100 mL) was added NaOAc (2 g, 24.79 mmol) and hydroxylamine hydrochloride (2.8 g, 41.32 mmol) at RT, the mixture was stirred for 1h at RT. The mixture was diluted with water (20 mL), adjusted to pH=2 with 1M HCl, and extracted with EtOAc(50 mL x 2). The aqueous phase was adjusted to pH = 9 with NaHCO3 (aq) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford title compound (1.5 g, 57.7% yield) as a grey solid, ESI-MS (M+H) +: 321.0.1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 2.6 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 4.09 (s, 2H), 3.69 – 3.65 (m, 2H), 3.18 – 3.13 (m, 2H), 2.97 (s, 2H), 2.13 (s, 3H), 1.49 (s, 9H), 1.44 (s, 6H). Example 14. Synthesis of tert-butyl 4-(6-amino-5-methoxypyridin-3-yl) piperazine- 1- carboxylate O O NH O NH2 BocN NO2 St [0
Figure imgf000088_0001
442] To a mixture of 5-bromo-3-methoxy-2-nitropyridine (3 g, 12.93 mmol) and tert-butyl piperazine-1-carboxylate (3.61 g, 19.39 mmol) in toluene (30 mL) was added Pd2(dba)3 (1.18 g, 1.29 mmol), Xantphos (1.50 g，2.58 mmol) and Cs2CO3 (8.43 g, 25.86 mmol). The reaction mixture was stirred for 4 h at 100 oC. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by silica gel column chromatography (PE/EA=3:1 to 1:1) to give title compound (600 mg, 13.7% yield) as a brown solid. ESI-MS (M+H)+: 339.1.1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H), 3.66 – 3.63 (m, 4H), 3.44 – 3.41 (m, 4H), 1.49 (s, 9H). Step 2: tert-butyl 4-(6-amino-5-methoxypyridin-3-yl)piperazine- 1-carboxylate [0443] To a solution of tert-butyl 5-(6-nitropyridin-3-yl)hexahydropyrrolo[3,4-c] pyrrole - 2(1H) -carboxylate (600 mg, 1.77 mmol) in MeOH (15 mL) was added Pd/C (60 mg, 10%). The mixture was charged with H2 for three times and stirred at r.t. overnight under H2 balloon. The mixture was filtered and the filtrate was concentrated to afford the title compound (470 mg, 86% yield) as a grey solid. ESI-MS (M+H)+: 309.1.1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 4.43 (s, 2H), 3.84 (s, 3H), 3.60 – 3.56 (m, 4H), 3.01 – 2.94 (m, 4H), 1.48 (s, 9H). Example 15. Synthesis of 2,7-dimethylpyrazolo[1,5-a]pyridine -5- carbonitrile
Figure imgf000088_0002
[0444] To a solution of 4-bromo-2,6-dimethylpyridine (25 g, 135 mmol) in dry. THF (400 mL) was added LDA (1.0 M, 162 mL, 162 mmol) dropwise at – 65 oC, the reaction mixture was stirred at this temperature for 4 hours. N-methoxy-N-methylacetamide (6.95 g, 67.5 mmol) in dry. THF (100 mL) was added dropwise at - 65 oC, the reaction mixture was stirred at this temperature for 1 hour. TLC (PE/EA=5:1) showed the reaction was completed. The mixture was diluted with water (30 mL), extracted with EtOAc (100 mL x 2). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by column chromatography (PE/EA=5:1) to afford 1-(4- bromo-6-methylpyridin-2-yl)propan-2-one (16 g, Y:95%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.21 (s, 1H), 3.86 (s, 2H), 2.51 (s, 3H), 2.24 (s, 3H). Step 2: Preparation of (Z)-1-(4-bromo-6-methylpyridin-2-yl)propan-2-one oxime [0445] To a solution of 1-(4-bromo-6-methylpyridin-2-yl)propan-2-one (14 g, 61.9 mmol) in MeOH (350 mL) were added NH2OH.HCl (12.8 g, 185.7 mmol) and NaOH (7.4 g, 185.7 mmol), the mixture was stirred 60 oC for 16 h. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was diluted with water (100 mL), extracted with EtOAc (100 mL x 2). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by column chromatography (PE/EA=5:1) to afford (Z)-1-(4-bromo-6-methylpyridin-2-yl)propan-2-one oxime (12.5 g, 83.3% yield) as a yellow solid. ESI-MS (M+H) +:245.0. Step 3: Preparation of 5-bromo-2,7-dimethylpyrazolo[1,5-a]pyridine [0446] To a solution of (Z)-1-(4-bromo-6-methylpyridin-2-yl)propan-2-one oxime (4.0 g, 16.5 mmol) and N1,N1,N6,N6-tetramethylhexane-1,6-diamine (4 mL, 19.8 mmol) in DCM (140 mL) was added TsCl (4.0 g, 19.8 mmol) in DCM (20 mL) dropwise at 0 oC, the reaction mixture was allowed to warmed to rt and stirred at rt for 16 h. TLC (PE/EA=5:1) showed the reaction was completed. The mixture was diluted with water (100 mL), extracted with DCM (100 mL x 2). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by column chromatography (PE/EA=5:1) to 5-bromo-2,7-dimethylpyrazolo[1,5-a]pyridine (1.8 g, 48.6% yield) as a yellow solid. ESI-MS (M+H) +:225.2.1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 1.4 Hz, 1H), 6.90 (d, J = 1.4 Hz, 1H), 6.41 (s, 1H), 2.62 (s, 3H), 2.41 (s, 3H). Step 4: Preparation of 2,7-dimethylpyrazolo[1,5-a]pyridine-5-carbonitrile [0447] To a solution of 5-bromo-2,7-dimethylpyrazolo[1,5-a]pyridine (2.0 g, 8.93 mmol) and Zn(CN)2 (2.61 g, 22.32 mmol) in dry.DMF (50 mL) was added Pd(PPh3)4 (1.03 g, 0.89 mmol), the mixture was charged with Ar for three times and stirred at 130 oC for 2 hours. TLC (PE/EA=5:1) showed the reaction was completed. The mixture was added water (40 mL), extracted with EA (50 mL *2), the combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo, the residue was purified by column chromatography (PE/EA=5:1) to 2,7-dimethylpyrazolo[1,5-a]pyridine-5- carbonitrile (1.4 g, 91.5% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 6.67 (s, 1H), 6.55 (s, 1H), 2.75 (s, 3H), 2.55 (s, 3H). Example 16. Synthesis of tert-butyl (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1- carboxylate
Figure imgf000090_0001
carboxylate [0448] To a mixture of tert-butyl (S)-2-methylpiperazine-1-carboxylate (5 g, 0.025 mol), 5- bromo-2-nitropyridine (7.6 g, 0.038 mol) in NMP (40 mL) was added TEA (7.57 g, 0.075 mol), the mixture was stirred at 120 ℃ for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified silica gel column chromatography eluted with (EtOAc: PE=1:1) to give title compound (6 g, 74.5 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 3.0 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.46 – 7.38 (m, 1H), 4.22 – 4.12 (m, 1H), 3.93 – 3.75 (m, 3H), 3.42 – 3.41 (m, 1H), 3.33 – 3.21 (m, 1H), 3.18 – 3.10 (m, 1H), 1.42 (s, 9H), 1.11 (d, J = 6.6 Hz, 3H). ESI-MS (M+H) +:323.0 Step 2: Preparation of tert-butyl (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1- carboxylate [0449] To a mixture of tert-butyl (S)-2-methyl-4-(6-nitropyridin-3-yl)piperazine-1- carboxylate (4 g, 0.012mol) in THF (200 mL) was added Pd/C (400 mg, 10 %), the mixture was charged with H2 for three times and stirred at r.t. overnight. The mixture was filtered and the filtrate was concentrated to afford the title compound (3.5 g, 96.4 % yield) as a yellow solid. ESI-MS: (M+H)+:293.1.1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 8.8, 2.6 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 5.43 (s, 2H), 4.17 – 4,16 (m, 1H), 3.77 – 3.76 (m, 1H), 3.24 – 3.23 (m, 1H), 3.16 – 3.06 (m, 2H), 2.62 – 2.61 (m, 1H), 2.49 – 2.40 (m, 1H), 1.41 (s, 9H), 1.22 (d, J = 6.6 Hz, 3H). Example 17. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin- 1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 100)
Figure imgf000091_0001
carboximidamido)pyridin-3-yl)piperazine-1-carboxylate [0450] To a mixture of diisopropylamine (0.6 mL, 4.4 mmol) in dry THF (15 mL) was added n-BuLi (3 mL, 4.8 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (1.12 g, 4.0 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (350 mg, 2.0 mmol) in dry THF (10 mL) was added to the mixture at -40 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1:1 to 0:1), then slurried with MeOH (30 mL) to give title product (600 mg, yield: 44.4%, three batches) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.21 (d, J = 8.8 Hz, 1H), 3.62 – 3.58 (m, 4H), 3.15 – 3.12 (m, 4H), 2.50 (s, 3H), 1.49 (s, 9H). ESI-MS: [M+H]+: 454.3. Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H- pyrido[1,2- a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0451] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a] pyridine-6- carboximidamido) pyridin-3-yl)piperazine -1-carboxylate (600 mg, 1.32 mmol) in THF (60 mL) and pyridine (6 mL) was added triphosgene (1.18 g, 3.97 mmol). The reaction mixture was stirred for 1 h at rt. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (40 mL) and stirred for 1 hour at rt. The precipitate was filtered and dried in vacuo to give title product (600 mg, yield: 97%).1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.95 – 7.90 (m, 2H), 7.66 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 3.67 – 3.63 (m, 4H), 3.29 – 3.26 (m, 4H), 2.50 (s, 3H), 1.50 (s, 9H). ESI-MS: [M+H] +: 480.0. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H- pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0452] To a solution of tert-butyl 4-(2-(8-fluoro -2-methylimidazo[1,2-a]pyridin-6-yl)-4- oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (1.25 g, 2.61 mmol) in EtOAc (15 mL) was added 3M HCl in EtOAc (15 ml) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and lyophilized to give title product as HCl salt (1.0 g, yield: 86.2%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.66 (s, 1H), 8.66 (d, J = 11.2 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 9.6, 2.8 Hz, 1H), 8.25 (s, 1H), 7.91 (d, J = 9.6 Hz, 1H), 3.71 – 3.67 (m, 4H), 3.49 – 3.46 (m, 4H), 2.62 (s, 3H). ESI- MS: [M+H] + 380.2. Example 18. Synthesis of (S)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one HCl (Compound 101)
Figure imgf000092_0001
p y ( ) ( ( f y [ , ]py carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate [0453] To a mixture of tert-butyl (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1- carboxylate (700 mg, 2.40 mmol) in THF (15 mL) was added LDA (2.8 mL, 1M in THF) at - 78 oC under N2. The resulting mixture was stirred for 1 h at 0 oC, The mixture was allowed to cool down to -78 oC and 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (140 mg, 0.80 mmol) was added. The mixture was stirred overnight at room temperature. After diluting with water, the mixture was extracted with EtOAc (40 mL x 3). The organic layers was washed with brine and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give title product (130 mg, yield: 35%) as a yellow solid. ESI-MS (M+H)+: 468.11H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.97 (d, J = 2.9 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.38 – 7.33 (m, 1H), 7.29 (dd, J = 8.9, 3.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.38 (br s, 1H), 3.98 (d, J = 13.0 Hz, 1H), 3.47 (d, J = 11.4 Hz, 1H), 3.36 – 3.22 (m, 2H), 2.97 (dd, J = 11.9, 3.7 Hz, 1H), 2.79 – 2.76 (m, 1H), 2.49 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). Step 2: tert-butyl (S)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0454] To a mixture of tert-butyl (S)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.26 mmol) in THF (5 mL) was added triphosgene (193 mg, 0.65 mmol) and pyridine (1 mL). The resulting mixture was stirred for 1 h at room temperature. The mixture was quenched with water and extracted with EtOAc (40 mL x 3). The organic layers and washed with brine. The organic layer was concentrated and purified by silica gel column chromatography (DCM:MeOH=20:1) to give title product (120 mg, yield: 94%) as a yellow solid. ESI-MS (M+H)+: 494.1 Step 3: (S)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(3-methylpiperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one HCl [0455] To a solution of tert-butyl (S)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (110 mg, 0.22 mmol) in DCM (10 mL) was added HCl in dioxane (1 mL) at 0 oC. The mixture was stirred for 1 h at rt. After concentration, the residue was stirred with EtOAc. The precipitate was filtered and the solid was dried to give title product (55.68 mg, yield: 64%) as a yellow solid. ESI-MS (M+H)+: 394.41H NMR (400 MHz, MeOD) δ 9.66 (s, 1H), 8.66 (d, J = 11.0 Hz, 1H), 8.60 (d, J = 2.7 Hz, 1H), 8.43 (dd, J = 9.6, 2.8 Hz, 1H), 8.25 (s, 1H), 7.91 (d, J = 9.5 Hz, 1H), 4.06 (dd, J = 17.7, 14.2 Hz, 2H), 3.64 – 3.57 (m, 2H), 3.46 – 3.32 (m, 2H), 3.09 (dd, J = 13.3, 10.7 Hz, 1H), 2.63 (s, 3H), 1.47 (d, J = 6.6 Hz, 1H). Example 19. Synthesis of (R)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one formic acid (Compound 102)
Figure imgf000094_0001
[0456] To a suspension of 5-bromo-2-nitropyridine (2.0 g, 10.0 mmol) and tert-butyl (R)-2- methylpiperazine-1-carboxylate (2.4 g, 12.0 mmol) in NMP (50 mL) was added TEA (3.0 g, 30.0 mmol), and the reaction mixture was stirred for 16 h at 120 oC. After cooling to rt, the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated. The crude was purified by silica gel column (10~100% EA in PE). The product was obtained as off-white solid (2.5 g, yield: 77 %). ESI- MS: [M+H] + 323.1 Step 2: tert-butyl (R)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1-carboxylate [0457] To a mixture of tert-butyl (R)-2-methyl-4-(6-nitropyridin-3-yl)piperazine-1- carboxylate (2.5 g, 7.76 mmol) in MeOH (100 mL) was added Pd/C (250 mg). The reaction mixture was stirred for 16 h at rt under hydrogen (balloon pressure). The mixture was filtered and washed with MeOH (50 mL). The filtrate was concentrated to give the desired product as purple semi-solid (2 g, crude yield: 89 %), which was used to next step without further purification. ESI-MS: [M+H] + 293.3 Step 3: tert-butyl (R)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate [0458] To a mixture of N, N-Diisopropylamine (0.15 mL, 1 mmol) in dry THF (5 mL) was added n-BuLi (0.7 mL, 1.6 M in hexane, 1.1 mmol) at -78 oC, and the mixture was stirred for 40 min at -70 oC. Then tert-butyl (R)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1- carboxylate (293 mg, 1.0 mmol) was added and the resulting mixture was stirred for 1 h at rt. After cooling to -78 oC, 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (100 mg, 0.57 mmol) was added, the mixture was allowed to warm to rt and stirred for another 16 h.. After diluting with water (20 mL), the mixture was extracted with EA (50 ml x 2). The combined organics was washed with brine, dried over Na2SO4. After concentration, the crude was purified with silica gel (PE: EA=1:2) to give product (70 mg, yield: 26%). ESI-MS: [M+H] + 468.4 Step 4: tert-butyl (R)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0459] To a solution of tert-butyl (R)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (70 mg, 0.15 mmol) in THF (8 mL) was added triphosgene (120 mg, 0.75 mmol), the reaction mixture was stirred for 5 min, and pyridine (1.0 mL) was added. The mixture was stirred for 1 h. After concentrated under reduced pressure, the residue was purified by silica gel column (1~10% MeOH in DCM). The product was obtained as a white solid (40 mg, yield: 53 %). ESI-MS: [M+H] + 494.4 Step 5: (R)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(3-methylpiperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one formic acid [0460] To a solution of tert-butyl (R)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4- oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.08 mmol) in DCM (3 mL) was added TFA (0.5 ml) at 0 oC. The reaction mixture was warmed to rt and stirred for 1 h. After concentration, the residue was purified by pre-HPLC (MeCN/0.05 % formic acid in water) to give title product as white solid (3.1 mg, yield: 10%). ESI-MS: [M+H] + 394.3.1H NMR (400 MHz, MeOD) δ 9.28 (d, J = 1.0 Hz, 1H), 8.50 (s, 2H), 8.41 (d, J = 2.6 Hz, 1H), 8.27 (dd, J = 9.6, 2.7 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 3.97 – 3.84 (m, 2H), 3.53 – 3.43 (m, 2H), 3.26 – 3.24 (m, 1H), 3.13 – 3.10 (m, 1H), 2.92 – 2.84 (m, 1H), 2.45 (s, 3H), 1.40 (d, J = 6.5 Hz, 3H). Example 20. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 103)
Figure imgf000095_0001
[0461] To a solution of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (20 mg, 0.048mmol), HCHO (0.5 mL) and HOAc (0.1 mL) was added NaBH3CN (10 mg, 0.144 mmol) in MeOH (5 mL) at rt. The reaction mixture was stirred for 1 h at rt. After concentration, the residue was purified by pre- HPLC (MeCN/0.05 % NH3H2O in water) to give title product (4.8 mg, yield: 25 %) as a yellow solid. ESI-MS (M+H)+: 394.3.1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 1.3 Hz, 1H), 8.35 (dd, J = 9.6, 2.9 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 12.4, 1.3 Hz, 1H), 7.72 (d, J = 9.5 Hz, 1H), 3.29 (s, 8H), 2.38 (s, 3H), 2.25 (s, 3H). Example 21. Synthesis of 7-(1,4-diazepan-1-yl)-2-(8-fluoro-2-methylimidazo [1,2- a]pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 104)
Figure imgf000096_0001
carboximidamido)pyridin-3-yl)-1,4-diazepane-1-carboxylate [0462] To three-neck flask were added added DIPA(220 mg, 2.2 mmol) and THF(6 mL), the mixture was cooling down to -60 oC, then 1.6 M n-BuLi (1.5mL, 2.4 mmol) was dropwise added under N2 and stirred for 1h at this temperature. Tert-butyl 4-(6-aminopyridin-3-yl)-1,4- diazepane-1-carboxylate (584 mg, 2 mmol) in THF (2 mL) was added at -60 oC, the mixture was stirred for 1.5 h at RT. The mixture was cooling down to -60 oC again. Then 8-fluoro-2- methylimidazo[1,2-a]pyridine-6-carbonitrile (175 mg, 1 mmol) in THF (5 mL) was added slowly. The mixture was stirred at RT overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (160 mg, 34% yield) as a grey solid. ESI-MS (M+H)+: 468.3. Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-1,4-diazepane-1-carboxylate [0463] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-1,4-diazepane-1-carboxylate (135 mg, 0.29 mmol) was dissolved in THF (15 mL) and pyridine(1 mL) was added triphosgene (301 mg, 1.02 mmol) at 0℃, the mixture was stirred for 2h at r.t. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (80 mg; 56% yield) as a yellow solid. ESI- MS (M+H)+: 494.3. Step 3: 7-(1,4-diazepan-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0464] A solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H- pyrido[1,2-a] [1,3,5]triazin-7-yl)-1,4-diazepane-1-carboxylate (80 mg, 0.62 mmol) in HCl/EA (3 mL) was stirred for 2 h at RT. The mixture was filtered and the filter cake was washed with EtOAc (1 mL) and dried to afford title compound (50 mg, 78.3% yield) as a yellow solid. ESI-MS (M+H)+:394.3.1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 2H), 9.24 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 10.6 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 3.85 (br.s, 2H), 3.63 (br.s, 2H), 3.26 (br.s, 2H), 3.15 (br.s, 2H), 2.38 (s, 3H), 2.14 (br s, 2H). Example 22. Synthesis of 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(8-fluoro-2- methylimidazo [1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 105) F F N N
Figure imgf000097_0001
Step 1: tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0465] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Tert-butyl 3-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (608 m, 2.0 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine -6- carbonitrile (175 mg, 1.0 mmol) in dry THF (5 mL) was added to the mixture at -40 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1:1 to 0:1) to give title product (170 mg, yield: 35.5%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.07 (s, 1H), 7.75 (s, 2H), 7.16 (s, 2H), 7.06 (d, J = 10.9 Hz, 1H), 4.47 – 4.34 (m, 2H), 3.43 (d, J = 10.4 Hz, 2H), 3.11 – 3.02 (m, 2H), 2.50 (s, 3H), 2.04 – 1.99 (m, 2H), 1.87 (m, 2H), 1.49 (s, 9H). Step 2: tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0466] To a solution of tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a] pyridine-6- carboximidamido)pyridine-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.35 mmol) in THF (16 mL) and pyridine (2 mL) was added triphosgene (315 mg, 1.05 mmol). The reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1:1 to 0:1) to give title product as a brown solid (90 mg, yield:50 %).1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.07 (d, J = 2.8 Hz, 1H), 8.00 (dd, J = 11.2, 5.2 Hz, 2H), 7.28 (s, 1H), 6.82 (d, J = 9.2 Hz, 1H), 4.44 – 4.42 (m, 2H), 3.48 (d, J = 10.4 Hz, 2H), 3.15 – 3.12 (m, 2H), 2.47 (s, 3H), 2.03 – 2.01 (m, 2H), 1.85 – 1.83 (m, 2H), 1.49 (s, 9H). ESI-MS: [M+H] + 506.2. Step 3: 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0467] To a solution of tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 4- oxo-4H-pyrido[1,2-a][1,3,5] triazin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (90 mg, 0.18 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (2 ml) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and the solid was dried by lyophilization to give title product (40 mg, yield: 51.3%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.61 – 9.52 (m, 2H), 9.22 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.76 (dd, J = 9.0, 2.8 Hz, 1H), 7.57 (dd, J = 9.1, 2.8 Hz, 1H), 7.45 – 7.41 (m, 1H), 4.18 (br.s, 2H), 3.81 (d, J = 12.0 Hz, 2H), 3.30 – 3.26 (m, 2H), 2.38 (s, 3H), 2.04 – 1.95 (m, 4H). ESI-MS: [M+H] +: 406.1. Example 23. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 106)
Figure imgf000099_0001
carboximidamido)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [0468] To a solution of DIPA (220 mg, 2.2 mmol) and THF (6 mL) was added n-BuLi (2.4 mmol, 1.5mL, 1.6M) at -60oC under N2. The mixture was stirred for 1 h, then tert-butyl 5-(6- aminopyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (608 mg, 2 mmol) in THF (5 mL) was added. The mixture was allowed to warn to rt and stirred for 1.5 h at RT. The mixture was cooling down to -60℃ again.8-fluoro-2-methylimidazo[1,2-a] pyridine-6- carbonitrile(175 mg, 1 mmol) in THF (5 mL) was added slowly. The mixture was stirred at RT overnight. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (120 mg, 25% yield) as a grey solid. ESI-MS (M+H)+: 480.2. Step 2: tert-butyl 5-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [0469] To a solution of tert-butyl 5-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido) pyridine -3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (120 mg, 0.25 mmol) in THF (8 mL) and pyridine(1 mL) was added triphosgene (222 mg, 0.75 mmol), the mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by pre-TLC (EtOAc: PE=1:3) to give title compound (50 mg, 47.6% yield) as a yellow solid. ESI-MS (M+H)+:506.3. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7- (hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0470] A solution of tert-butyl 5-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50 mg, 0.099 mmol) in 4M HCl/EA (2 mL) was stirred for 1 h at RT. The precipitate was filtered, washed with EtOAc (1 mL) and dried under vacuum to afford title compound (30 mg, 24.4% yield) as a yellow solid. ESI-MS (M+H)+:406.1.1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 2H), 9.26 (s, 1H), 8.10 (s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 10.5 Hz, 1H), 7.27 – 7.20 (m, 1H), 3.57 (br.s, 2H), 3.48 – 3.46 (m, 6H), 3.18 (d, J = 2.9 Hz, 2H), 3.14 – 3.06 (m, 2H), 2.38 (s, 3H). Example 24. Synthesis of 7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-(8-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 107)
Figure imgf000100_0001
carboximidamido)pyridin-3-yl)-2,6-dimethylpiperazine-1-carboxylate [0471] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Then cis tert-butyl -4-(6-aminopyridin-3-yl)-2,6-dimethylpiperazine- 1-carboxylate (612 mg, 2.0 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carbonitrile (175 mg, 1.0 mmol) in dry THF (5 mL) was added in at -40 oC and the mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (10 mL), extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column C18 column to give title product (100 mg, yield: 20.8%) as a yellow solid. ESI-MS: [M+H]+ 482.3 Step 2: tert-butyl (2S,6R)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2,6-dimethylpiperazine-1-carboxylate [0472] To a solution of cis tert-butyl-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido) pyridin-3-yl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 0.208 mmol) in THF (18 mL) and pyridine (0.8 mL) was added triphosgene (185 mg, 0.624 mmol). The reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (10 mL), extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.05% FA in water / CH3CN) to give title product as a yellow solid (50 mg, 47.6%).1H NMR (400 MHz, CDCl3) δ 9.22 (d, J = 1.3 Hz, 1H), 8.51 (d, J = 2.7 Hz, 1H), 7.95 (dd, J = 11.6, 1.3 Hz, 1H), 7.90 (dd, J = 9.6, 2.9 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 7.48 (d, J = 2.9 Hz, 1H), 4.38 – 4.33 (m, 2H), 3.47 (d, J = 12.1 Hz, 2H), 3.08 (dd, J = 12.1, 4.5 Hz, 2H), 2.50 (s, 3H), 1.51 (s, 9H), 1.38 (d, J = 6.4 Hz, 6H). ESI-MS: [M+H] +: 508.1 Step 3: 7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0473] To a solution of tert-butyl (2S,6R)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4-oxo-4H- pyrido [1,2-a][1,3,5]triazin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (50 mg, 0.099 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (3 ml) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and the solid was dried via lyophilization to give title product (25 mg, yield: 57.3%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.66 (s, 1H), 8.67 (d, J = 11.0 Hz, 1H), 8.58 (s, 1H), 8.42 (d, J = 11.8 Hz, 1H), 8.23 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 4.12 (d, J = 11.5 Hz, 2H), 3.65 – 3.57 (m, 2H), 2.96 (t, J = 12.3 Hz, 2H), 2.62 (s, 3H), 1.47 (d, J = 6.4 Hz, 6H). ESI-MS: [M+H] + 408.2. Example 25. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7- (piperazin-1-yl) -4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 108)
Figure imgf000102_0001
methylpyridin-3-yl)piperazine-1-carboxylate [0474] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Then tert-butyl 4-(6-amino-5-methylpyridin-3-yl)piperazine-1- carboxylate (600 mg, 2.0 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carbonitrile (175 mg, 1.0 mmol) in dry THF (5 mL) was added to the mixture at -40 oC and the mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1:1 to 0:1) to give title product (60 mg, yield: 22.5%) as a yellow solid. ESI-MS: [M+H]+: 468.3 Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-4- oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0475] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-5-methyl pyridin-3-yl)piperazine-1-carboxylate (60 mg, 0.121 mmol) in THF (6 mL) and pyridine (0.6 mL) was added triphosgene (108 mg, 0.363 mmol). The reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (10 mL), extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.05% FA in water / CH3CN) to give title product (30 mg, 47.6%).1H NMR (400 MHz, CDCl3) δ 9.22 (d, J = 1.3 Hz, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.97 (dd, J = 11.6, 1.3 Hz, 1H), 7.76 (dd, J = 2.7, 0.9 Hz, 1H), 7.48 s, 1H), 3.66 – 3.61 (m, 4H), 3.28 – 3.22 (m, 4H), 2.69 (s, 3H), 2.51 (s, 3H), 1.50 (s, 9H). ESI-MS: [M+H] +: 494.3. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7-(piperazin-1-yl) -4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0476] To a solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (30 mg, 0.061 mmol) in EtOAc (0.5 mL) was added 3M HCl/EtOAc (1 mL) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and dried via lyophilization to give title product (18 mg, yield: 69.2%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.68 (s, 1H), 8.66 (d, J = 10.8 Hz, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.31 – 8.27 (m, 2H), 3.69 – 3.65 (m, 4H), 3.49 – 3.45 (m, 4H), 2.75 (s, 3H), 2.63 (s, 3H). ESI-MS: [M+H] +: 394.2. Example 26. Synthesis of 7-(3,3-dimethylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 109) St
Figure imgf000103_0001
carboximidamido)pyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate [0477] To a solution of diisopropyl amine (220 mg, 2.2 mmol) in THF (6 mL) was added n- BuLi (1.5 mL, 1.6M) at -60o C under N2. The mixture was stirred for 1h, then tert-butyl 4-(6- aminopyridin-3-yl)-2,2-dimethylpiperazine -1-carboxylate (612 mg, 2 mmol) in THF(5 mL) was added at -60oC. The mixture was allowed to warm to rt and stirred for 1.5 h at RT. The mixture was cooling down to -60 ℃ again. Then 8-fluoro-2-methylimidazo[1,2-a] pyridine- 6-carbonitrile (175 mg, 1 mmol) in THF (5 mL) was added. The mixture was stirred overnight at RT. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (220 mg, 45.7% yield) as a grey solid. ESI-MS (M+H)+: 482.3.1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.83 (s, 1H), 7.47 (s, 1H), 7.36 (d, J = 10.9 Hz, 1H), 7.23 (s, 1H), 7.16 – 7.05 (m, 1H), 3.81 (d, J = 4.9 Hz, 2H), 3.49 (s, 2H), 3.40 (br s, 2H), 2.48 (s, 3H), 1.50 (s, 9H), 1.44 (s, 6H). Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate [0478] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido) pyridin-3-yl) -2,2-dimethylpiperazine-1-carboxylate (220 mg, 0.46 mmol) in THF (6 mL) and pyridine (1 mL) was added triphosgene (407 mg, 1.37 mmol). The mixture was stirred at r.t. for 1 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (150 mg, 64.6% yield) as a yellow solid. ESI-MS (M+H)+:508.7.1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 8.36 (s, 1H), 7.93 (d, J = 11.7 Hz, 1H), 7.77 (d, J = 9.3 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 7.47 (s, 1H), 3.90 (br.s, 2H), 3.52 (br.s, 2H), 3.45 (s, 2H), 2.50 (s, 3H), 1.47 (s, 15H). Step 3: 7-(3,3-dimethylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one [0479] A solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate(140 mg) in 4M HCl/EA (5 mL) was stirred for 1h at RT. The precipitate was filtered and the filter cake was further purified by pre-HPLC to afford title compound (30 mg, 24.4% yield) as a yellow solid. ESI-MS (M+H)+:408.1.1H NMR (400 MHz, CDCl3): δ 9.22 (s, 1H), 8.46 (s, 1H), 7.95 – 7.89 (m, 2H), 7.64 (d, J = 9.6 Hz, 1H), 7.48 (s, 1H), 3.25 – 3.17 (m, 2H), 3.17 – 3.10 (m, 2H), 3.02 (s, 2H), 2.50 (s, 3H), 1.26 (s, 6H). Example 27. Synthesis of 9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -7- (piperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 110)
Figure imgf000105_0001
carboximidamido)pyridin-3-yl)piperazine-1-carboxylate [0480] To a solution of diisopropylamine (606 mg, 6 mmol) and THF (10 mL) was added n- BuLi (6.4 mmol, 1.6M, 4 mL) at -60 oC under N2 and the mixture was stirred for 1 h. Tert- butyl 4-(6-amino-5-fluoropyridin-3-yl)piperazine-1-carboxylate (1.34 g, 4.5 mmol) in THF (10 mL) was added at -60 oC, the mixture was allowed to warm to rt and stirred for 1.5 h. The mixture was cooling down to -60 ℃ again. Then 8-fluoro-2-methylimidazo[1,2-a] pyridine- 6-carbonitrile (525 mg, 3 mmol) in THF (15 mL) was added slowly. The mixture was stirred overnight at RT. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (300 mg, 21.2% yield) as a grey solid. ESI-MS (M+H)+:472.1. Step 2: tert-butyl 4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1carboxylate To a solution of tert-butyl 4-(5-fluoro-6- (8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridine-3-yl)piperazine-1-carboxylate (300 mg, 0.64 mmol) in THF (15 mL) and pyridine(1.5 mL) was added triphosgene (1.2 g, 2.22 mmol). The mixture was stirred at r.t. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The residue was purified by pre-HPLC (0.05% FA in water / CH3CN) to give title compound (130 mg, 41.1% yield) as a yellow solid. ESI-MS (M+H)+ :498.1. Step 3: 9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0481] A solution of tert-butyl 4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 4-oxo-4H-pyrido [1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (130 mg, 0.26 mmol) in 3M HCl/EtOAc (5 mL) was stirred for 1 h at RT. The mixture was filtered. The solid was washed with EtOAc (1 mL) and dried under vacuum to afford title compound (105 mg, 94.6% yield) as a yellow solid, ESI-MS (M+H)+:398.1.1H NMR (400 MHz, MeOD-d4) δ 9.67 (d, J = 0.9 Hz, 1H), 8.65 (dd, J = 10.9, 1.1 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.35 (dd, J = 11.3, 2.6 Hz, 1H), 8.24 (dd, J = 2.1, 1.1 Hz, 1H), 3.72 – 3.65 (m, 4H), 3.50 – 3.43 (m, 4H), 2.62 (d, J = 0.9 Hz, 3H). Example 28. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6- tetrahydropyridin- 4-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 111)
Figure imgf000106_0001
a][1,3,5]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate [0482] A mixture of 7-bromo-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H- pyrido[1,2-a] [1,3,5]triazin-4-one (100 mg, 0.268 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (124 mg, 0.402 mol), K2CO3 (111 mg, 0.804 mol) and Pd(dppf)Cl2 (22 mg, 0.027 mmol) in 1,4-dioxane/H2O(15 mL/3mL) was stirred at 95 oC for 3 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purification by Prep- HPLC (0.05%FA in water / CH3CN) to give title compound (40 mg, 31.3 % yield) as a yellow solid. ESI-MS (M+H)+: 477.1. Step 2: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin- 4-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0483] To a solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (30 mg, 0.063 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (2 mL) at room temperature. The reaction mixture was stirred for 1 h. The precipitate was filtered and dried under vacuum to give title product (6 mg, yield: 25.3 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.70 – 9.65 (m, 1H), 9.36 (s, 2H), 8.89 (s, 1H), 8.60 (d, J = 9.2 Hz, 1H), 8.26 – 8.15 (m, 2H), 7.83 (d, J = 9.0 Hz, 1H), 6.61 (s, 1H), 3.85 (s, 2H), 3.40 – 3.33 (m, 2H), 2.79 (br.s, 2H), 2.48 (s, 3H). ESI-MS: [M+H]+ =377.1. Example 29. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin- 3-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 112) Step
Figure imgf000107_0001
pyridine-3-yl)pyrrolidine-1-carboxylate [0484] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (20 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. tert-butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (512 mg, 2 mmol) in dry THF (7 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (175 mg, 1 mmol) in dry THF (10 mL) was added to the mixture at -65 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (20 mL), extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18- flash (0.05%NH3.H2O in water/CH3CN) to give title product (60 mg, yield:13.7 %) as a yellow solid. ESI-MS: [M+H]+ =439.1. Step 2: tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido [1,2- a][1,3,5]triazin-7-yl)pyrrolidine-1-carboxylate [0485] To a solution of tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)pyrrolidine-1-carboxylate (60 mg, 0.14 mmol) in THF (5 mL) and pyridine (1 mL) was added triphosgene (125 mg, 0.42 mmol). The reaction mixture was stirred for 1 h at rt. The mixture was diluted with water (15 mL), extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.05%NH3.H2O in water / CH3CN) to give title product (4 mg, yield: 6.3 %). ESI-MS: [M+H] + =465.1. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin-3-yl)-4H- pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0486] To a solution of tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)pyrrolidine-1-carboxylate (4 mg, 0.009 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (3 mL) at room temperature. The reaction mixture was stirred for 1 h. The precipitate was filtered and dried under vacuum to title product (0.9 mg, yield: 29 %) as a white solid.1H NMR (400 MHz, MeOD-d4) δ 9.72 (s, 1H), 9.12 (s, 1H), 8.69 (d, J = 10.8 Hz, 1H), 8.46 (d, J = 7.0 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J = 7.4 Hz, 1H), 3.86 (br.s, 2H), 3.66 (br.s, 1H), 3.40 – 3.35 (m, 3H), 2.63 (s, 3H), 1.34 – 1.27 (m, 1H).. ESI- MS: [M+H] +365.1. Example 30. Synthesis of (2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin- 4-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 113) Step
Figure imgf000108_0001
: e - u y - - - uo o- -me y n o ne- -ca ox m am o py n- -y piperidine-1-carboxylate [0487] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (20 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1- carboxylate (556 mg, 2 mmol) in dry THF (7 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a] pyridine-6-carbonitrile (175 mg, 1 mmol) in dry THF (10 mL) was added to the mixture at -65 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (20 mL), extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18- flash to give title product (150 mg, yield: 33.3%) as a yellow solid.1H NMR (400 MHz, DMSO-D6) δ 9.04 (d, J = 1.1 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.70 – 7.62 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 4.14 – 4.02 (m, 2H), 2.89 – 2.65 (m, 3H), 2.37 (s, 3H), 1.77 – 1.74 (m, 2H), 1.57 – 1.51 (m, 2H), 1.41 (s, 9H). ESI-MS: [M+H]+ =453.2. Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido [1,2- a][1,3,5]triazin-7-yl)piperidine-1-carboxylate [0488] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylindolizine-6- carboximidamido)pyridin-3-yl)piperidine-1-carboxylate (150 mg, 0.33 mmol) in THF (5 mL) and pyridine (1 mL) was added triphosgene (294 mg, 0.99 mmol). The reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (15 mL), extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo, the residue was purified by prep-HPLC to give title product (60 mg, yield: 38%) as a yellow solid. ESI-MS: [M+H] + =479.1. Step 3: (2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H- pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0489] To a solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperidine-1-carboxylate (60 mg, 0.125 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (5 ml) at room temperature. The reaction mixture was stirred for 1 h. The precipitate was filtered and the solid was dried under vacuum to give title product (15 mg, yield: 32 %) as a white solid. H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.17 (s, 2H), 8.85 (s, 1H), 8.32 – 8.29 (m, 3H), 7.86 (d, J = 9.0 Hz, 1H), 3.41 – 3.39 (m, 2H), 3.19 (br.s, 1H), 3.02 (br.s, 2H), 2.10 – 1.94 (m, 4H). ESI-MS: [M+H] + 379.2. Example 31. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methoxy-7- (piperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 114) Step 1 do)-5-
Figure imgf000110_0001
methoxypyridin-3-yl)piperazine-1-carboxylate [0490] To a solution of diisopropylamine (110 mg, 1.1 mmol) in THF (6 mL) was added n- BuLi (0.75 mL, 1.6M) at -60 oC under N2 and the mixture was stirred for 1 h. Tert-butyl 4-(6- amino-5-methoxypyridin-3-yl)piperazine-1-carboxylate (308 mg, 1 mmol) in THF (5 mL) was added, the mixture was allowed to warm to rt and stirred for 1.5 h. The mixture was cooling down to -60℃ again.8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (88 mg, 0.5 mmol) in THF (5 mL) was added slowly. The mixture was stirred overnight at RT. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (45 mg, 21.3 yield) as a grey solid. ESI-MS (M+H)+: 484.3. Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 9-methoxy-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0491] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-5-methoxy pyridin-3-yl)piperazine-1-carboxylate (45 mg, 0.09 mmol) in THF (8 mL) and pyridine (1 mL) was added triphosgene (83 mg, 0.75 mmol), the mixture was stirred at r.t. for 1 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was suspended in MeOH, and stirred for 1 h，the precipitate was filtered to give title compound (15 mg, 32% yield) as a yellow solid. ESI-MS (M+H)+:510.1. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methoxy-7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0492] A solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methoxy-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (15 mg, 0.029 mmol) in 3M HCl/EA (2 mL) was stirred for 1h at rt. The precipitate was filtered and the solid was dried to afford title compound (9 mg, 81.8% yield) as a yellow solid. ESI-MS (M+H)+: 410.2.1H NMR (400 MHz, MeOD-d4) δ 9.66 (s, 1H), 8.68 (d, J = 10.8 Hz, 1H), 8.24 (s, 2H), 7.77 (d, J = 2.1 Hz, 1H), 4.17 (s, 3H), 3.69 – 3.65 (m, 4H), 3.49 – 3.46 (m, 4H), 2.62 (s, 3H). Example 32. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-8- methyl-7- (piperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 115) Ste 4-
Figure imgf000111_0001
methylpyridin-3-yl)piperazine-1-carboxylate [0493] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Then tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperazine-1- carboxylate (438 mg, 1.5 mmol) was added, the mixture was allowed to warm to rt and stirred for 1.5 h at rt. The mixture was cooling down to -60 oC again. Then 8-fluoro-2- methylimidazo[1,2-a] pyridine-6-carbonitrile (175 mg, 1.0 mmol) in THF (5 mL) was added, the mixture was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (150 mg, yield: 51.2 %) as a grey solid. ESI-MS (M+H)+: 468.2. Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-8-methyl-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0494] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido) -4-methylpyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.15 mmol) in THF (15 mL) and pyridine (1 mL) was added triphosgene (134 mg, 0.45 mmol) at 0 ℃, the mixture was stirred for 20 min at r.t. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (18 mg, yield: 24.3%) as a yellow solid. ESI- MS (M+H)+: 494.1. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-8- methyl-7-(piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0495] A solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-8- methyl-4- oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (18 mg, 0.04 mmol) in HCl/EA (3 mL) was stirred for 1 h at rt. The mixture was filtered and the solid was dried under vacuum to afford title compound (10 mg, 62.5%) as a yellow solid. ESI-MS (M+H)+:394.2.1H NMR (400 MHz, MeOD-d4) δ 9.64 (s, 1H), 8.73 (s, 1H), 8.63 (d, J = 11.0 Hz, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 3.51 – 3.47 (m, 4H), 3.39 – 3.36 (m, 4H), 2.66 (s, 3H), 2.61 (s, 3H). Example 33. Synthesis of (S)-9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridine -6-yl)- 7-(3-methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 116) F F F NH2 F N F N H
Figure imgf000112_0001
carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate [0496] To a mixture of diisopropylamine (0.3 mL, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour, then tert-butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2- methylpiperazine-1-carboxylate (465 mg, 1.56 mmol) in THF (2 mL) was added, the mixture was allowed to warm to rt and stirred for 1.5 h. The mixture was cooling down to -60 oC again. Then 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (175 mg, 1 mmol) in THF (5 mL) was added slowly, the mixture was stirred overnight at rt. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (150 mg, yield: 30%) as a grey solid. ESI-MS (M+H)+: 486.3.1H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 1.3 Hz, 1H), 7.78 (d, J = 2.6 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 11.1, 1.3 Hz, 1H), 7.04 (dd, J = 12.4, 2.6 Hz, 1H), 4.44 – 4.34 (m, 1H), 3.98 (d, J = 13.8 Hz, 1H), 3.48 (d, J = 11.9 Hz, 1H), 3.38 – 3.21 (m, 2H), 3.02 – 3.00 (m, 1H), 2.83 – 2.80 (m, 1H), 2.50 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). Step 2: tert-butyl (S)-4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a] pyridin-6-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0497] To a solution of tert-butyl (S)-4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2- a]pyridine-6- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (1.0 g, 2.06 mmol) in THF (100 mL) and pyridine(10 mL) was added triphosgene (1.83 g, 6.18 mmol) at 0 ℃, the mixture was stirred for 20 min at 0 ℃. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by prep-HPLC (0.05% HCl in water / CH3CN) to give title compound (550 mg yield: 52.6%) as a yellow solid. ESI-MS (M+H)+:512.0.1H NMR (400 MHz, CDCl3) δ 9.22 (d, J = 1.2 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 11.6, 1.2 Hz, 1H), 7.63 (dd, J = 10.5, 2.6 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 4.44 – 4.40 (m, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.59 (d, J = 12.0 Hz, 1H), 3.44 – 3.40 (m, 1H), 3.36 – 3.29 (m, 1H), 3.21 – 3.16 (m, 1H), 3.03 – 2.96 (m, 1H), 2.51 (s, 3H), 1.50 (s, 9H), 1.30 (d, J = 6.8 Hz, 3H). Step 3: (S)-9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridine -6-yl)-7-(3-methylpiperazin- 1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one. [0498] To a solution of tert-butyl (S)-4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-4-oxo- 4H-pyrido [1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1- carboxylate (1.1 g, 2.15 mmol) in EtOAc (10 mL) was added 3M HCl/EtOAc (15 ml) at room temperature. The reaction mixture was stirred for 1 h. The mixture was concentrated in vacuo, the residue was purified by prep-HPLC (0.05 % NH4OH in water / CH3CN) to afford title compound (520 mg, 58%) as a yellow solid. ESI-MS (M+H)+:412.1.1H NMR (400 MHz, DMSO-d6 ) δ 9.43 (d, J = 1.1 Hz, 1H), 8.43 (dd, J = 12.4, 2.5 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 12.3, 1.0 Hz, 1H), 3.70 – 3.65 (m, 2H), 3.02 – 2.99 (m, 1H), 2.81 – 2.66 (m, 3H), 2.39 (s), 2.37 – 2.33 (m, 1H), 1.06 (d, J = 6.0 Hz, 3H). Example 34. Synthesis of (S)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl- 7- (3-methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 117) -5-
Figure imgf000114_0001
methylpyridin-3-yl)-2-methylpiperazine-1-carboxylate [0499] To a mixture of diisopropylamine (0.9 mL, 6.6 mmol) in dry THF (25 mL) was added n-BuLi (4.5 mL, 7.2 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. tert-butyl (S)-4-(6-amino-5-methylpyridin-3-yl)-2-methylpiperazine- 1-carboxylate (1.38 g, 4.5 mmol) in dry THF (7 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carbonitrile (525 mg, 3.0 mmol) in dry THF (10 mL) was added to the mixture at -65 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (40 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18-flash to give title product (600 mg, yield: 41.5%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 8.83 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 11.7 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 4.35 (br.s, 1H), 3.95 (d, J = 13.3 Hz, 1H), 3.56 (d, J = 11.5 Hz, 1H), 3.49 – 3.42 (m, 1H), 3.25 (d, J = 3.5 Hz, 1H), 2.89 – 2.86 (m, 1H), 2.71 – 2.68 (m, 1H), 2.45 (s, 3H), 2.38 (s, 3H), 1.50 (s, 9H), 1.33 (d, J = 6.7 Hz, 3H). ESI-MS: [M+H]+ =482.1. Step 2: tert-butyl (S)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0500] To a solution of tert-butyl (S)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine- 6- carboximidamido)-5-methylpyridin-3-yl)-2-methylpiperazine-1-carboxylate (600 mg, 1.25 mmol) in THF (50 mL) and pyridine (10 mL) was added triphosgene (1.11 g, 3.74 mmol). The reaction mixture was stirred for 15 min at 0 oC. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was mixed with MeOH (40 mL), stirred for 1 hour at rt. The precipitate was filtered and dried in vacuo to give title product (310 mg, yield: 49%) as a yellow solid. ESI-MS: [M+H]+ = 508.2. Step 3: (S)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7- (3-methylpiperazin- 1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0501] To a solution of tert-butyl (S)-4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl) -9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.157 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (5 ml) at room temperature. The reaction mixture was stirred for 1 h. The precipitate was filtered and dried under vacuum to give title product (50 mg, yield: 64%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.68 (s, 1H), 8.68 (dd, J = 10.9, 0.9 Hz, 1H), 8.50 (d, J = 2.7 Hz, 1H), 8.31 – 8.24 (m, 2H), 4.03 – 3.98 (m, 2H), 3.59 – 3.56 (m, 2H), 3.38 – 3.36 (m, 1H), 3.26 – 3.20 (m, 1H), 3.02 – 3.00 (m, 1H), 2.76 (s, 3H), 2.62 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H). ESI-MS: [M+H] + 408.0. Example 35. Synthesis of 7-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-2-(8-fluoro-2- methylimidazo[1,2-a]pyridin- 6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 118)
Figure imgf000115_0001
mido)pyridin-3-yl)3,9-diazabicyclo[3.3.1]nonane-9-carboxylate [0502] To a mixture of diisopropylamine (184 mg, 1.06 mmol) in dry THF (10 mL) was added n-BuLi (0.81 mL, 1.30 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Tert-butyl 3-(6-aminopyridin-3-yl)-3,9- diazabicyclo[3.3.1]nonane-9-carboxylate (280 mg, 0.88 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2- methylimidazo[1,2-a]pyridine-6-carbonitrile (100 mg, 0.59 mmol) in dry THF (5 mL) was added to the mixture at -40 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2), the combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.05% HCl in water/CH3CN) to give title product (20 mg, yield: 7.1%) as a yellow solid. ESI-MS: [M+H] + :494.2. Step 2: tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-oxo-4H-pyrido [1,2- a][1,3,5]triazin-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate [0503] To a solution of tert-butyl 3-(6-(8-fluoro-2-methylimidazo[1,2-a] pyridine-6- carboximidamido)pyridin-3-yl) -3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (20 mg, 0.041 mmol) in THF (4 mL) and pyridine (0.4 mL) was added triphosgene (36 mg, 0.122 mmol). The reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.05% HCl in water / CH3CN) to give title product (18 mg, yield:85.7 %) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.22 (d, J = 1.2 Hz, 1H), 8.46 (d, J = 2.8 Hz, 1H), 7.96 – 7.92 (m, 2H), 7.67 (d, J = 9.4 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 4.49 – 4.48 (m, 1H), 4.38 – 4.33 (m, 1H), 3.72 – 3.69 (m, 1H), 3.63 (d, J = 11.6 Hz, 1H), 3.24 (d, J = 11.6 Hz, 2H), 2.50 (s, 3H), 2.29 – 2.19 (m, 2H), 1.97 – 1.88 (m, 2H), 1.83 – 1.78 (m, 2H), 1.51 (s, 9H). ESI-MS: [M+H] + : 520.0. Step 3: 7-(3,9-diazabicyclo[3.3.1]nonan-3-yl)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin- 6- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0504] To a solution of tert-butyl 3-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 4- oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (18 mg, 0.0347 mmol) in EtOAc (0.5 mL) was added 3M HCl/EtOAc (1 mL) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and dried under vacuum to give title product (8.08 mg, yield: 50.9%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.66 (s, 1H), 8.67 (d, J = 10.8 Hz, 1H), 8.55 (s, 1H), 8.47 (d, J = 10.8 Hz, 1H), 8.24 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 4.16 (d, J = 12.8 Hz, 2H), 3.92 – 3.86 (m, 2H), 3.54 (d, J = 12.4 Hz, 2H), 2.63 (s, 3H), 2.41 – 2.33 (m, 1H), 2.21 – 2.23 (m, 4H), 1.74 – 1.65 (m, 1H). ESI-MS: [M+H]+: 420.1. Example 36. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-8-methoxy-7- (piperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 119)
Figure imgf000117_0001
methoxypyridin-3-yl)piperazine-1-carboxylate [0505] To a mixture of diisopropylamine (121 mg,1.2 mmol) in dry THF (5 mL) was added n-BuLi (0.9 mL, 1.44 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Then tert-butyl 4-(6-amino-4-methoxypyridin-3-yl)piperazine-1- carboxylate (308 mg, 1 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carbonitrile (110 mg, 0.66 mmol) in dry THF (5 mL) was added to the mixture at -40 oC and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (70 mg, 21.2% yield) as a grey solid.1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.82 (s, 1H), 7.46 (s, 1H), 7.36 – 7.32 (m, 1H), 6.79 (s, 1H), 3.94 (s, 3H), 3.64 – 3.59 (m, 4H), 3.07 – 3.00 (m, 4H), 2.50 (s, 3H), 1.49 (s, 9H). Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)- 8-methoxy-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0506] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-4-methoxypyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.15 mmol) in THF (8 mL) and pyridine (1 mL) was added triphosgene (1.2 g, 2.22 mmol), the mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was suspended in MeOH, stirred for 1 h. The precipitate was filtered and the solid was dried to give title compound (30 mg, 41% yield) as a yellow solid. ESI-MS (M+H)+:510.2. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-8-methoxy-7- (piperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one. [0507] A solution of tert-butyl 4-(2-(8- fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-8- methoxy-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (30 mg, 0.05 mmol) in 3M HCl/EtOAc (4 mL) was stirred for 1 h at RT. The mixture was filtered and the solid was dried under vacuum to afford title compound (9 mg, 45% yield) as a yellow solid. ESI-MS (M+H) +:410.0.1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 2H), 9.56 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 11.8 Hz, 1H), 7.21 (s, 1H), 4.15 (s, 3H), 3.38 (br.s, 4H), 3.25 (br.s, 4H), 2.46 (s, 3H). Example 37. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methoxy-7- (piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one formic acid (Compound 120) Step
Figure imgf000118_0001
-2- methoxypyridin-3-yl)piperazine-1-carboxylate [0508] To a mixture of diisopropylamine (79 mg, 0.78 mmol) in dry THF (15 mL) was added n-BuLi (0.53 mL, 0.85 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. tert-butyl 4-(6-amino-2-methoxypyridin-3-yl)piperazine-1- carboxylate (200 mg, 0.65 mmol) in dry THF (2 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carbonitrile (80 mg, 0.45 mmol) in dry THF (5 mL) was added to the mixture at -65 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted wtih water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18 column to give title product as a white solid (20 mg, yield: 6.4%). ESI-MS: [M+H]+ 484.2. Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methoxy-4-oxo -4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0509] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-2-methoxypyridin-3-yl)piperazine-1-carboxylate (150 mg, 0.31 mmol) in THF (10 mL) and pyridine (2 mL) was added triphosgene (276 mg, 0.93 mmol). The reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was mixed with MeOH (40 mL), stirred for 1 hour at rt. The precipitate was filtered and dried in vacuo to give title product as a white solid (20 mg, 12.6%).1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.08 – 7.96 (m, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.26 – 7.17 (m, 1H), 6.85 (d, J = 9.3 Hz, 1H), 4.04 (s, 3H), 3.65 – 3.57 (m, 4H), 3.12 – 3.02 (m, 4H), 2.47 (s, 3H), 1.50 (s, 9H). ESI-MS: [M+H] + 510.2. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methoxy-7-(piperazin-1-yl)- 4H- pyrido[1,2-a][1,3,5]triazin-4-one formic acid. [0510] To a solution of tert-butyl 4-(2-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-6- methoxy-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (20 mg, 0.039 mmol) in EtOAc (1 mL) was added 3M HCl/EtOAc (2 mL) at room temperature. The reaction mixture was stirred for 2 h. After concentration, the residue was purified by pre- HPLC to give title product (10 mg, yield: 60%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 1H NMR (400 MHz, MeOD) δ 9.23 (s, 1H), 8.47 (s, 1H， HCO2H), 8.07 (s, 1H), 7.51 (dd, J = 20.0, 8.2 Hz, 2H), 7.28 – 7.25 (m, 1H), 4.06 (s, 3H), 3.40 (br s, 8H), 2.45 (s, 3H). ESI-MS: [M+H]+: 410.0. Example 38. Synthesis of (S)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9-fluoro-7-(3- methyl piperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 121)
Figure imgf000120_0001
fluoropyridin-3-yl)-2-methylpiperazine-1-carboxylate [0511] To a mixture of diisopropylamine (0.9 mL, 5.4 mmol) in dry THF (20 mL) was added n-BuLi (4.2 mL, 6.6 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Tert-butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2- methylpiperazine- 1-carboxylate (1.40 g, 4.5 mmol) in dry THF (10 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.2,8-dimethylimidazo[1,2-a]pyridine-6- carbonitrile (513 mg, 3.0 mmol) in dry THF (10 mL) was added to the mixture at -40 oC and the mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1:1 to 0:1) to title product (133 mg, yield: 10%,) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.78 (d, J = 2.6 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.06 – 7.01 (m, 1H), 4.42 – 4.34 (m, 1H), 3.98 – 3.96 (m, 1H), 3.47 – 3.43 (m, 1H), 3.31 – 3.23 (m, 2H), 3.00 – 2.96 (m, 1H), 2.85 – 2.77 (m, 1H), 2.65 (s, 3H), 2.49 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). Step 2: tert-butyl (S)-4-(2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9- fluoro-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0512] To a solution of tert-butyl (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyridine -6- carboximidamido) -5-fluoropyridin-3-yl)-2-methylpiperazine-1-carboxylate (400 mg, 0.83 mmol) in THF (40 mL) and pyridine (4 mL) was added triphosgene (738 mg, 2.50 mmol) at 0 oC. The reaction mixture was stirred at 0 oC for 10 min. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.05% FA in water / CH3CN) to give title product (200 mg, 47.5%) as a yellow solid. ESI-MS: [M+H]+ 508.2. Step 3: (S)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9-fluoro-7-(3-methyl piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0513] To a solution of tert-butyl (S)-4-(2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9- fluoro-4-oxo-4H –pyrido [1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.39 mmol) in EtOAc (10 mL) was added 3M HCl/EtOAc (10 mL) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and dried under vacuum to give title product (130 mg, yield: 74.5%) as a yellow solid.1H NMR (400 MHz, MeOD- d4) δ 9.62 (s, 1H), 8.68 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.38 – 8.31 (m, 1H), 8.12 (d, J = 1.0 Hz, 1H), 4.09 – 3.96 (m, 2H), 3.64 – 3.54 (m, 2H), 3.44 – 3.32 (m, 2H), 3.09 – 3.05 (m, 1H), 2.73 (s, 3H), 2.61 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H). ESI-MS: [M+H] + 408.2. Example 39. Synthesis of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methyl-7- (piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 122)
Figure imgf000121_0001
methylpyridin-3-yl)piperazine-1-carboxylate [0514] To a mixture of diisopropylamine (300 mg, 3.0 mmol) in dry THF (15 mL) was added n-BuLi (2.0 mL, 3.2 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour, tert-butyl 4-(6-amino-2-methylpyridin-3-yl)piperazine-1-carboxylate (730 mg, 2.5 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (297 mg, 1.7 mmol) in dry THF (10 mL) was added to the mixture at -65 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18 column to give title product as a white solid (150 mg, yield: 12.6%). ESI-MS: [M+H]+:468.2. Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methyl-4-oxo- 4H- pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0515] To a solution of tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-2-methylpyridin-3-yl) piperazine-1-carboxylate (100 mg, 0.21 mmol) in THF (10 mL) and pyridine (2 mL) was added triphosgene (187 mg, 0.63 mmol). The reaction mixture was stirred for 1 h at rt, The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (40 mL) and stirred for 1 hour at rt. The precipitate was filtered and the solid was dried in vacuo to give title product as a yellow solid (60 mg, 57.9%).1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.40 – 7.33 (m, 2H), 7.09 (d, J = 8.5 Hz, 1H), 3.65 – 3.52 (m, 4H), 2.90 – 2.81 (m, 4H), 2.52 (s, 3H), 2.49 (s, 3H), 1.49 (s, 9H). ESI-MS: [M+H] + 494.2.2. Step 3: 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-methyl-7-(piperazin-1-yl)- 4H- pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0516] To a solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (20 mg, 0.041 mmol) in EtOAc (1 mL) was added 3M HCl/EtOAc (2 mL) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and the solid was dried under vacuum to give title product (5 mg, yield: 33%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.62 (s, 1H), 8.62 (d, J = 11.8 Hz, 1H), 8.27 – 8.20 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 3.48 – 3.46 (m, 4H), 3.37 – 3.35 (m, 4H), 3.03 (s, 3H), 2.62 (s, 3H). ESI-MS: [M+H] + 394.0.
Example 40. Synthesis of (S)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7-(3- methylpi perazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 123) S
Figure imgf000123_0001
methylpyridin-3-yl)-2-methylpiperazine-1-carboxylate [0517] To a mixture of diisopropylamine (303 mg, 3.0 mmol) in dry THF (10 mL) was added n-BuLi (2.6 mL, 4.2 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. Tert-butyl (S)-4-(6-amino-5-methylpyridin-3-yl)-2-methylpiperazine- 1-carboxylate (612 mg, 2.0 mmol) in dry THF (5 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.2,8-dimethylimidazo[1,2-a]pyridine-6- carbonitrile (171 mg, 1.0 mmol) in dry THF (5 mL) was added to the mixture at -40 oC and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1:1 to 0:1) to give title product (90 mg, yield: 18%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.83 (d, J = 2.9 Hz, 1H), 7.42 – 7.40 m, 2H), 7.15 (d, J = 2.5 Hz, 1H), 4.40 – 4.33 (m, 1H), 3.97 (d, J = 13.4 Hz, 1H), 3.45 (d, J = 10.1 Hz, 1H), 3.34 – 3.22 (m, 2H), 2.93 (dd, J = 11.8, 3.8 Hz, 1H), 2.78 – 2.72 (m, 1H), 2.65 (s, 3H), 2.50 (s, 3H), 2.49 (s, 3H), 1.49 (s, 9H), 1.33 (d, J = 6.8 Hz, 3H). ESI-MS: [M+H] + 478.1. Step 2: tert-butyl (S)-4-(2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0518] To a solution of tert-butyl (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyridine- 6- carboximidamido) -5-methylpyridin-3-yl)-2-methylpiperazine-1-carboxylate (90 mg, 0.18 mmol) in THF (10 mL) and pyridine (1 mL) was added triphosgene (162 mg, 0.55 mmol) at 0 oC. The reaction mixture was stirred at 0 oC for 30 min. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (10 mL), stirred for 1 hour at rt, the precipitate was filtered and dried in vacuo to give title product (70 mg, yield: 73.7%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 0.9 Hz, 1H), 8.39 (d, J = 2.7 Hz, 1H), 8.05 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.42 (s, 1H), 4.45 – 4.40 (m, 1H), 4.05 – 4.00 (m, 1H), 3.60 – 3.56 (m, 1H), 3.44 – 3.41 (m, 1H), 3.31 – 3.27 (m, 1H), 3.08 (dd, J = 12.0, 4.0 Hz, 1H), 2.92 – 2.86 (m, 1H), 2.71 (s, 3H), 2.67 (s, 3H), 2.50 (s, 3H), 1.50 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). ESI-MS: [M+H] + 504.2. Step 3: (S)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7-(3-methylpi perazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0519] To a solution of tert-butyl (S)-4-(2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H- pyrido [1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (70 mg, 0.139 mmol) in EtOAc (4 mL) was added 3M HCl/EtOAc (2 ml) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and dried under vacuum to give title product (43 mg, yield: 70.5%) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.64 (s, 1H), 8.71 (s, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 4.03 (dd, J = 10.6, 7.4 Hz, 2H), 3.61 – 3.57 (m, 2H), 3.42 – 3.36 (m, 1H), 3.25 – 3.18 (m, 1H), 3.02 – 2.96 (m, 1H), 2.76 (s, 3H), 2.73 (s, 3H), 2.61 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H).ESI-MS: [M+H] + 404.1. Example 41. Synthesis of (S)-7-(3,4-dimethylpiperazin-1-yl)-2-(8-fluoro-2- methylimidazo[1,2-a] pyridin-6-yl)-9-methyl-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 124) [05
Figure imgf000124_0001
7-(3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (40 mg, 0.09 mmol) in MeOH (5 mL) was added Polyoxymethylene (15 mg, 0.45 mmol), AcOH (cat.) at RT. The mixture was stirred at this temperature for 0.5 hour, NaBH(OAc)3 (19 mg, 0.27 mmol) was added. The mixture was stirred for 16 h. The mixture was diluted with water (10 mL), extracted with DCM (10 mL x 2). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.05%NH3.H2O in water/CH3CN) to give title product (30 mg, yield: 78.9 %,) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.43 (d, J = 1.1 Hz, 1H), 8.27 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 12.3 Hz, 1H), 3.67 (t, J = 10.5 Hz, 2H), 2.89 (t, J = 9.6 Hz, 2H), 2.61 (s, 3H), 2.53 (d, J = 8.9 Hz, 1H), 2.38 (s, 3H), 2.29 (dd, J = 17.8, 7.2 Hz, 1H), 2.24 (s, 3H), 2.18 (d, J = 6.3 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3H). ESI-MS: [M+H]+ =422.0. Example 42. Synthesis of 7-(3,3-dimethylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-9-methyl-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 125)
Figure imgf000125_0001
methylpyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate [0521] To a mixture of diisopropylamine (666 mg, 6.6 mmo) in dry THF (15 mL) was added n-BuLi (4.5 mL, 7.2 mmol, 1.6M) dropwise at – 65 oC. The mixture was stirred at this temperature for 1 hour. tert-butyl 4-(6-amino-5-methylpyridin-3-yl)-2,2-dimethylpiperazine - 1-carboxylate (1.5 g, 4.5 mmol) in THF (20 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carbonitrile(525 mg, 3 mmol) in dry THF (5 mL) was added to the mixture at -40 oC and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound (400 mg, 30% yield) as a grey solid. ESI-MS (M+H)+:496.3.1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 1.1 Hz, 1H), 7.72 (d, J = 3.0 Hz, 1H), 7.48 – 7.45 (m, 2H), 6.98 (d, J = 2.9 Hz, 1H), 3.82 – 3.77 (m, 2H), 3.41 – 3.36 (m, 2H), 3.27 (s, 2H), 2.49 (s, 3H), 2.48 (s, 3H), 1.50 (s, 9H), 1.44 (s, 6H). Step 2: tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate [0522] The tert-butyl 4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboximidamido)-5- methylpyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate (400 mg, 0.808 mmol) was dissolved in THF (20 mL) and pyridine (2 mL) and triphosgene (1.2 g, 2.22 mmol) was added at 0 oC. The mixture was stirred at r.t for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was suspended in MeOH, stirred for 1 h. The precipitate was filtered to give title compound (300 mg, 71% yield) as a yellow solid. ESI-MS (M+H)+:522.3.1H NMR (400 MHz, CDCl3) δ 9.22 – 9.17 (m, 1H), 8.31 – 8.25 (m, 1H), 7.96 – 7.89 (m, 1H), 7.60 – 7.57 (m, 1H), 7.49 – 7.46 (m, 1H), 3.91 – 3.87 (m, 2H), 3.51 – 3.49 (m, 2H), 3.41 (s, 2H), 2.71 (s, 3H), 2.50 (s, 3H), 1.51 (s, 9H), 1.46 (s, 6H). Step 3: 7-(3,3-dimethylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo [1,2-a]pyridin-6-yl)-9- methyl-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0523] A solution of tert-butyl 4-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate (300 mg, 0.57 mmol) in 3M HCl/EtOAc (10 mL) was stirred for 2 h at RT. The mixture was filtered and the solid washed with EtOAc (3 mL) and dried under vacuum to afford title compound (250 mg, 95.1%) as a yellow solid, ESI-MS (M+H)+:422.0.1H NMR (400 MHz, MeOD-d4) δ 9.69 – 9.66 (m, 1H), 8.68 – 8.64 (m, 1H), 8.53 – 8.49 (m, 1H), 8.32 – 8.27 (m, 2H), 3.67 – 3.62 (m, 2H), 3.53 – 3.49 (m, 4H), 2.77 (s, 3H), 2.63 (s, 3H), 1.55 (s, 6H).
Example 43. Synthesis of 2-2,8-dimethylimidazo[1,2-a]pyridin-6-yl-7-(piperazin-1-yl)- 4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 126) Step 1
Figure imgf000127_0001
[0524] 5-Chloro-2-nitropyridine (150.0 g, 946.12 mmol), tert-butyl piperazine-1-carboxylate (185.03 g, 993.43 mmol) and potassium carbonate (326.9 g, 2.37 mol) were mixed in DMF (1000 mL) The reaction mixture was stirred for 12 h at 75 oC. The reaction mixture was diluted with water (4000 mL) and extracted with EtOAc (3x800 mL). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by silica gel column chromatography to give title compound (110 g; 38% yield).1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 3.0 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 9.3, 3.0 Hz, 1H), 3.49 (q, J = 6.0 Hz, 8H), 1.44 – 1.38 (s, 9H). Step 2: tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate [0525] To a mixture of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (9.5 g, 30.81 mmol) in MeOH (200mL) was added 10% Pd/C (2 g). The reaction mixture was stirred for 16h at rt under hydrogen atmosphere (balloon pressure). The solvent was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give title product (8 g; 93% yield).1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 3.0 Hz, 1H), 7.17 (dd, J = 8.8, 3.0 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 5.48 (br s, 2H), 3.42 (t, J = 4.9 Hz, 4H), 2.84 (t, J = 5.0 Hz, 4H), 1.40 (s, 9H). ESI-MS: 279.2 [M+H]. Step 3: methyl 2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylate [0526] 2,8-Dimethylimidazo[1,2-a]pyridine-6-carboxylic acid hydrochloride (10.0 g, 44.11 mmol) was dissolved in MeOH (100 mL) and thionyl chloride (15.74 g, 132.34 mmol, 9.6 ml, 3.0 equiv) was added dropwise and the resulting mixture was stirred 18h at room temperature. The mixture was then concentrated and DCM (250 mL) was added. Saturated NaHCO3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated NaHCO3 (150 mL), water (200 mL), and saturated aqueous NaCl (200 mL), then dried over Na2SO4, filtered and concentrated to give methyl 2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylate ( 8 g, 89% yield).1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.41 – 7.35 (m, 1H), 3.85 (s, 3H), 2.46 (s, 3H), 2.34 (s, 3H). ESI-MS: 205.2 [M+H]. Step 4: 2,8-dimethylimidazo[1,2-a]pyridine-6-carboxamide [0527] To a solution of methyl 2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylate (5.8 g, 28.4 mmol) in MeOH (60 mL) 25% methanolic ammonia solution (80 mL) was added and the mixture in autoclave and heated at 80 °C for 12 hours. The mixture was concentrated in vacuo to give the product (5 g, 93% yield).1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.41 (d, J = 12.4 Hz, 2H), 2.33 (s, 3H). Step 5: 2,8-dimethylimidazo[1,2-a]pyridine-6-carbonitrile [0528] 2,8-Dimethylimidazo[1,2-a]pyridine-6-carboxamide (5.0 g, 26.44 mmol) was dissolved in DCM(100 ml). Then triethylamine (10.7 g, 105.75 mmol, 14.74 ml, 4.0 equiv) was added. TFAA (8.33 g, 39.66 mmol, 5.56 ml, 1.5 equiv) was added dropwise at 0C.The mixture was stirred at this temperature for 20 min and allowed to warm to room temperature and stirred for 16h. The mixture was diluted with water (150 mL), extracted with DCM (2x50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo The residue was purified by column chromatography (CHCl3/ACN) to give title product (2.5 g, 55% yield). ESI-MS: 172.1 [M+H]. Step 6: tert-butyl 4-(6-2,8-dimethylimidazo[1,2-a]pyridine-6-imidamidopyridin-3-yl) piperazine-1-carboxylate [0529] To a mixture of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (1.5 g, 5.39 mmol) in dry THF (25 mL) was added lithium bis(trimethylsilyl)amide (1.08 g, 6.47 mmol, 5.39 ml, 1.2 equiv) dropwise at –780 C. The mixture was allowed to warm to -40oC and stirred for 1h.2,8-Dimethylimidazo[1,2-a]pyridine-6-carbonitrile (922.35 mg, 5.39 mmol) in dry THF (10 mL) was added at - 78 C. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (50 mL), extracted with EtOAc (2x40 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ACN/MeOH) to give title product (1.5 g, 62% yield). ESI-MS: 450.2 [M+H]. Step 7: tert-butyl 4-(2-2,8-dimethylimidazo[1,2-a]pyridin-6-yl-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0530] To a mixture of tert-butyl 4-(6-2,8-dimethylimidazo[1,2-a]pyridine-6- imidamidopyridin-3-yl) piperazine-1-carboxylate (502.92 mg, 1.12 mmol) and triethylamine (566.28 mg, 5.6 mmol, 780.0 µl, 5.0 equiv) in THF (15 mL) was added ditrichloromethyl carbonate (331.98 mg, 1.12 mmol). The reaction mixture was stirred for 15h at rt. The mixture was filtered, washed with THF(15 ml) and water (2x15 ml) and dried in vacuo to give title product (0.2 g, 38% yield).1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.27 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 3.51 (s, 4H), 3.27 (s, 4H), 2.99 (d, J = 3.1 Hz, 3H), 2.34 (s, 3H), 1.41 (d, J = 5.0 Hz, 9H). Step 8: 2-2,8-dimethylimidazo[1,2-a]pyridin-6-yl-7-(piperazin-1-yl)-4H-pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0531] Tert-butyl 4-(2-2,8-dimethylimidazo[1,2-a]pyridin-6-yl-4-oxo-4H -pyrido[1,2- a][1,3,5]triazin-7-yl) piperazine-1-carboxylate (99.98 mg, 210.25 µmol) in MeOH (10 mL) was added HCl in dioxane( 1mL) at 0 C. The mixture was stirred for 12h at rt. After concentration, the residue was stirred with EtOAc. The precipitate was filtered and the solid was dried to give title product (26 mg, 30% yield).1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.52 (s, 2H), 8.49 (s, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 3.59 (s, 4H), 3.24 (s, 4H), 2.67 (s, 3H). ESI-MS: 376.2 [M+H].
Example 44. Synthesis of 7-2,6-diazaspiro[3.3]heptan-2-yl-2-8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl-4H-pyrido[1,2-a][1,3,5]triazin-4-one trifluoroacetic acid (Compound 127)
Figure imgf000130_0001
[0532] To a solution of methyl 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylate (8.0 g, 38.43 mmol) in MeOH (60 mL) 25% methanolic ammonia solution (100 mL) was added and the mixture was sealed in autoclave and heated at 80 °C for 12 hours. The mixture was concentrated in vacuo to give the product (5.9 g, 79% yield). ESI-MS: 194.0 [M+H]. Step 2: 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile [0533] 8-Fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxamide (5.9 g, 30.53 mmol) was dissolved in DCM (100 ml). Then triethylamine (9.27 g, 91.58 mmol, 12.76 ml, 3.0 equiv) was added. TFAA (9.62 g, 45.79 mmol, 6.42 ml, 1.5 equiv) was added dropwise at 0°C.The mixture was stirred at this temperature for 20 min and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (150 mL), extracted with DCM (2x50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (CHCl3/ACN) to give title product (3g, 56% yield).1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.91 (s, 1H), 7.54 (d, J = 11.1 Hz, 1H), 2.38 (s, 3H). ESI-MS: 176.2 [M+H]. Step 3: N-(5-bromopyridin-2-yl)-8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamide [0534] To a solution of 5-bromopyridin-2-amine (2.96 g, 17.13 mmol) in THF (30 ml) sodium bis(trimethylsilyl)amide (3.74 g, 20.38 mmol, 8.77 ml, 1.19 equiv) was added dropwise while the reaction mixture was magnetically stirred under Ar at ice-bath temperature. After completed addition, the mixture was stirred for 30 min, and 8-fluoro-2- methylimidazo[1,2-a]pyridine-6-carbonitrile (3.0 g, 17.13 mmol) was added in one portion. The resulting mixture was stirred overnight at r.t. The precipitate that had formed was collected by filtration, washing of the precipitate with H2O and MTBE and drying in vacuo to give title product (4.5 g 75% yield).1H NMR (500 MHz, DMSO-d6) δ 9.77 – 9.71 (m, 1H), 8.72 (s, 1H), 8.22 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 8.6, 2.8 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 13.2 Hz, 1H), 2.18 (s, 3H). Step 4: 7-bromo-2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4H-pyrido[1,2- a][1,3,5]triazin-4-one [0535] To a solution of N-(5-bromopyridin-2-yl)-8-fluoro-2-methylimidazo[1,2-a]pyridine- 6-carboximidamide (4.5 g, 12.92 mmol) in THF (60 mL) and triethylamine (6.54 g, 64.62 mmol, 9.01 ml, 5.0 equiv) was added ditrichloromethyl carbonate (3.84 g, 12.92 mmol). The reaction mixture was stirred for 12h at rt. The mixture was filtered, washed with THF (2x50 ml) and water (2x45 ml) and dried in vacuo to give title product (3 g, 62% yield).1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.33 (dd, J = 8.6, 2.5 Hz, 1H), 8.07 – 7.99 (m, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 10.6 Hz, 1H), 2.34 (s, 3H). ESI- MS: [M+H] + 376.0. Step 5: tert-butyl 6-(2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [0536] A mixture of 7-bromo-2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4H- pyrido[1,2-a][1,3,5]triazin-4-one (997.2 mg, 2.66 mmol) , tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate hydrochloride (1.251 g, 5.33 mmol), SPhos (109.4 mg, 266.5 µmol), Pd2(dba)3 (244.1 mg, 266.5 µmol), cesium carbonate (2.605 g, 8 mmol) in toluene (25 mL)was stirred at 110 °C under Ar for 45 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 2). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography to give title compound ( 20 mg, 1.5% yield). ESI- MS: 492.2 [M+H]. Step 6: 7-2,6-diazaspiro[3.3]heptan-2-yl-2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4H- pyrido[1,2-a][1,3,5]triazin-4-one trifluoroacetic acid [0537] To a solution of tert-butyl 6-(2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (20.0 mg, 40.69 µmol) in DCM (1 mL) was added TFA (232.37 mg, 2.04 mmol, 160.0 µl, 50.0 equiv) at 0 oC. The reaction mixture was warmed to rt and stirred for 15 h. After concentration, the residue was purified by prep-HPLC (MeCN/0.05 % formic acid in water) to give title product 7-2,6-diazaspiro[3.3]heptan-2-yl-2-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-4H- pyrido[1,2-a][1,3,5]triazin-4-one; trifluoroacetic acid (6 mg; 29% yield). ESI-MS: 392.2 [M+H]. Example 45. Synthesis of 7-[(3S)-3-ethylpiperazin-1-yl]-9-fluoro-2-{8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl}-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 128)
Figure imgf000132_0001
Step 1: Preparation of tert-butyl (S)-2-ethyl-4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2- a]pyridine-6-carboximidamido)pyridin-3-yl)piperazine-1-carboxylate [0538] Fresh prepared LDA (2.16 mmol, THF) was added dropwise to a solution of tert- butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2-ethylpiperazine-1-carboxylate (486 mg, 1.5 mmol) in THF (5 mL) at -60 °C, the mixture was stirred for 1.5 h at rt. The mixture was cooled down to -60 °C again. Then 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carbonitrile (175 mg, 1 mmol) in THF (5 mL) was added slowly, the mixture was stirred overnight at rt. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography eluted with MeCN: H2O=80% to 95% to give title compound (120 mg, Y: 42.1%) as a yellow solid. ESI- MS (M+H)+: 500.1. Step 2: Preparation of tert-butyl (S)-2-ethyl-4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate [0539] To a solution of tert-butyl (S)-2-ethyl-4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2- a]pyridine-6-carboximidamido)pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) in THF (50 mL) and pyridine (1.0 mL) was added triphosgene (178 mg, 0.60 mmol) at r.t, the mixture was stirred for 15 min at rt. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was treated wtih MeOH (10 mL), stirred at room temperature for 1h. The precipitate was filtered to give title compound (70 mg, Y: 66.7%) as a yellow solid. ESI-MS (M+H)+:526.1. Step 3: Preparation of (S)-7-(3-ethylpiperazin-1-yl)-9-fluoro-2-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one [0540] To a solution of tert-butyl (S)-2-ethyl-4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)piperazine-1-carboxylate (50 mg, 0.095 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (2 mL) at room temperature. The reaction mixture was stirred for 2 h. The mixture was concentrated in vacuo and sat.Na2CO3 (10 mL) was added. The resulting mixture was stirred at rt for 30 min, the precipitate was filtered and dried to give title compound (35 mg, 87.5%) as a yellow solid. ESI-MS (M+H)+:426.1. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.32 (s, 1H), 7.96 (d, J = 11.5 Hz, 1H), 7.68 (d, J = 10.5 Hz, 1H), 7.49 (s, 1H), 3.58 – 3.57 (m, 2H), 3.22 – 3.21 (m, 1H), 3.02 – 2.93 (m, 2H), 2.88 – 2.72 (m, 1H), 2.57 – 2.56 (m, 1H), 2.50 (s, 3H), 1.57 – 1.49 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H).
Example 46. Synthesis of 2-{2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl}-9-methyl-7-[(3S)- 3-methylpiperazin-1-yl]-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 129)
Figure imgf000134_0001
carboximidamido)-5-methylpyridin-3-yl)-2-methylpiperazine-1-carboxylate [0541] To a clean and dry flask was added DIPA (0.6 mL , 4.8 mmol) and THF(15 mL), the mixture was cooled down to -60 °C, then 1.6 M n-Buli (3.3 mL, 5.28 mmol) was added dropwised at -60 °C under N2 and stirred for 1h. Tert-butyl (S)-4-(6-amino-5-methylpyridin- 3-yl)-2-methylpiperazine-1-carboxylate (1.24 g, 4 mmol) in THF (10 mL) was added dropwise at -60 °C, the mixture was stirred for 1.5 h at rt. The mixture was cooled down to - 60 °C again, 2,7-dimethylpyrazolo[1,5-a]pyridine-5-carbonitrile (340 mg, 2 mmol) in THF (10 mL) was added slowly, the mixture was stirred overnight at rt. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography eluted with MeCN: H2O=80% to 95% to give title compound (150 mg, Y: 15.8%) as a yellow solid. ESI-MS (M+H)+: 478.3. Step 2: Preparation of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0542] To a solution of tert-butyl (S)-4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5- carboximidamido)-5-methylpyridin-3-yl)-2-methylpiperazine-1-carboxylate (130 mg, 0.273 mmol) in THF (60 mL) and pyridine (1.5 mL) was added triphosgene (242 mg, 0.819 mmol) at r.t, the mixture was stirred for 15 min at rt. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was added MeOH (10 mL), stirred at room temperature for 1h, the precipitate was filtered to give title compound (100 mg, Y: 65.7%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.39 (d, J = 2.7 Hz, 1H), 7.73 – 7.67 (m, 2H), 6.98 (s, 1H), 6.54 (s, 1H), 4.45 – 4.44 (m, 1H), 4.05 – 4.00 (m, 1H), 3.61 – 3.56 (m, 1H), 3.45 – 3.41 (m, 1H), 3.34 – 3.27 (m, 1H), 3.10 – 3.06 (m, 1H), 2.93 – 2.86 (m, 1H), 2.80 (s, 3H), 2.72 (s, 3H), 2.56 (s, 3H), 1.50 (s, 9H), 1.32 (d, J = 6.7 Hz, 3H). Step 3: Preparation of (S)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-methyl-7-(3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one [0543] To a solution of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (75 mg, 0.15 mmol) in EtOAc (2 mL) was added 3M HCl/EtOAc (3 ml) at room temperature. The reaction mixture was stirred for 2 h. The mixture was concentrated in vacuo, the residue was added sat.Na2CO3 (10 mL), stirred at rt for 30 min, the precipitate was filtered to give title compound (50 mg, 83.3%) as a yellow solid. ESI-MS (M+H)+:404.2. 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.40 (d, J = 2.7 Hz, 1H), 7.77 – 7.71 (m, 2H)
Figure imgf000135_0001
6.53 (s, 1H), 3.61 – 3.54 (m, 2H), 3.19 – 3.17 (m, 1H), 3.08 – 2.97 (m, 2H), 2.86 – 2.85 (m, 1H), 2.81 (s, 3H), 2.71 (s, 3H), 2.56 (s, 3H), 2.51 – 2.47 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H). Example 47. Synthesis of 7-(3,3-dimethylpiperazin-1-yl)-9-fluoro-2-{8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl}-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 130)
Figure imgf000135_0002
Step 1: Preparation of tert-butyl 4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate [0544] To a mixture of diisopropylamine (0.34 mL, 2.4 mmol) in dry.THF (10 mL) was added n-BuLi (1.15 mL, 2.88 mmol, 2.5 M) dropwise at – 65 °C. The mixture was stirred at this temperature for 1 hour, tert-butyl 4-(6-amino-5-fluoropyridin-3-yl)-2,2- dimethylpiperazine-1-carboxylate (620 mg, 2.0 mmol) in dry.THF (4 mL) was added. The mixture was allowed to warm to room temperature and stirred for 1 h.8-fluoro-2-methyl- 3,8a-dihydroimidazo[1,2-a]pyridine-6-carbonitrile (175 mg, 1.0 mmol) in dry.THF (4 mL) was added to the mixture at -65 °C and allowed to warm to room temperature and stirred for 16 h. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL), extracted with EtOAc (80 mLx2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18-flash (0.1% NH3.H2O in water / CH3CN) to give title product (170 mg, Y: 33.9 %) as a yellow solid. ESI-MS: [M+H]+:500.2. Step 2: Preparation of tert-butyl 4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate [0545] To a solution of tert-butyl 4-(5-fluoro-6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)pyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate (170 mg, 0.339 mmol) in THF (18 mL) and pyridine (1.8 mL) was added triphosgene ( 322 mg, 1.08 mmol). The reaction mixture was stirred for 10 min at rt. LCMS showed the reaction was completed. The mixture was diluted with water (50 mL), extracted with EtOAc (100 mL*2). The combined organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (30 mL), stirred for 1 hour , the precipitate was filtered and dried in vacuo to give title product (80 mg, 44.6 %) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.21 (d, J = 1.3 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 11.6, 1.3 Hz, 1H), 7.56 – 7.46 (m, 2H), 3.91 (t, J = 5.6 Hz, 2H), 3.51 (t, J = 5.7 Hz, 2H), 3.44 (s, 2H), 2.50 (s, 3H), 1.51 (s, 9H), 1.47 (s, 6H). ESI-MS: [M+H] +:526.3. Step 3: 7-(3,3-dimethylpiperazin-1-yl)-9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride [0546] To a solution of tert-butyl 4-(9-fluoro-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (3 mL) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and lyophilizied to give title product (18 mg, yield: 28.1 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J = 1.0 Hz, 1H), 9.51 (s, 2H), 8.49 (dd, J = 12.0, 2.4 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.22 (s, 1H), 8.12 (d, J = 11.9 Hz, 1H), 3.58 (d, J = 5.2 Hz, 4H), 3.31 (s, 2H), 2.47 (s, 3H), 1.41 (s, 6H). ESI-MS: [M+H] +:426.1. Example 48. Synthesis of 2-{2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl}-9-fluoro-7-[(3S)-3- methylpiperazin-1-yl]-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 131)
Figure imgf000137_0001
Step 1: Preparation of tert-butyl (S)-4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5- carboximidamido)-5-fluoropyridin-3-yl)-2-methylpiperazine-1-carboxylate [0547] Fresh prepared LDA was added to tert-butyl (S)-4-(6-amino-5-fluoropyridin-3-yl)-2- methylpiperazine-1-carboxylate (1.82 g, 5.84 mmol) in THF (50 mL) dropwised at -60 °C, the mixture was stirred for 1.5 h at rt. The mixture was cool down to -60 °C again. Then 2,7- dimethylpyrazolo[1,5-a]pyridine-5-carbonitrile (500 mg, 2.92 mmol) in THF (10 mL) was added slowly, the mixture was stirred overnight at rt. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (460 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography eluted with MeCN: H2O=80% to 95% to give title compound (200 mg, Y: 28%) as a yellow solid. ESI-MS (M+H)+: 482.2.1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.3 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.24 (s, 1H), 7.04 (dd, J = 12.4, 2.7 Hz, 1H), 6.45 (s, 1H), 4.43 – 4.33 (m, 1H), 3.98 (d, J = 13.3 Hz, 1H), 3.48 (d, J = 11.8 Hz, 1H), 3.35 – 3.24 (m, 2H), 3.01 (dd, J = 12.0, 3.8 Hz, 1H), 2.83 (dd, J = 11.7, 3.6 Hz, 1H), 2.78 (s, 3H), 2.54 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). Step 2: Preparation of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl) -9- fluoro-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0548] To a solution of tert-butyl (S)-4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5- carboximidamido)-5- fluoropyridin-3-yl)-2-methylpiperazine-1-carboxylate (150 mg, 0.312 mmol) in THF (60 mL) and pyridine(1.5 mL) was added triphosgene (277 mg, 0.936 mmol) at rt, the mixture was stirred for 15 min at rt. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was diluted with MeOH ( 10 mL) and stirred at room temperature for 1h, the precipitate was filtered and dried to give title compound (180 mg, Y: 85.7%) as a yellow solid. ESI-MS (M+H)+:508.2.1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 1.4 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.62 (dd, J = 10.6, 2.6 Hz, 1H), 6.55 (s, 1H), 4.49 – 4.37 (m, 1H), 4.09 – 3.96 (m, 1H), 3.58 (d, J = 12.1 Hz, 1H), 3.41 (d, J = 12.3 Hz, 1H), 3.35 – 3.27 (m, 1H), 3.16 (dd, J = 12.2, 3.9 Hz, 1H), 3.01 – 2.94 (m, 1H), 2.80 (s, 3H), 2.56 (s, 3H), 1.50 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H). Step 3: Preparation of (S)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro-7- (3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one [0549] To a solution of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9- fluoro-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (180 mg, 0.35 mmol) in EtOAc (10 mL) was added 3M HCl/EtOAc (15 ml) at room temperature. The reaction mixture was stirred for 2 h. The mixture was concentrated in vacuo, and sat.Na2CO3 (10 mL) was added, stirred at rt for 30 min, the precipitate was filtered to give title compound (100 mg, 69%) as a yellow solid. ESI-MS (M+H)+:408.1. 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.32 (d, J = 1.9 Hz, 1H), 7.71 (s, 1H), 7.66 (dd, J = 10.9, 2.6 Hz, 1H), 6.54 (s, 1H), 3.55 (t, J = 11.4 Hz, 2H), 3.20 (d, J = 12.0 Hz, 1H), 3.08 – 2.95 (m, 2H), 2.92 (dd, J = 11.4, 3.1 Hz, 1H), 2.80 (s, 3H), 2.56 (s, 3H), 2.54 – 2.51 (m, 1H), 1.19 (d, J = 6.3 Hz, 3H).
Example 49. Synthesis of 7-{4,7-diazaspiro[2.5]octan-7-yl}-2-{8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl}-9-methyl-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 132)
Figure imgf000139_0001
diazaspiro[2.5]octane-4-carboxylate [0550] To a mixture of 5-bromo-2-chloro-3-methylpyridine (1 g, 4.854 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (926 mg, 4.36 mmol) in toluene (20 mL) was added t-BuONa (932 mg, 9.708 mmol), Xantphos (561 mg, 0.9708 mmol) and Pd2(dba)3 (445 mg, 0.485 mmol), the mixture was charged with N2 for three times and stirred at 80 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mLx3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified silica gel column chromatography eluted with (EtOAc: PE=1:5) to give title compound (0.9 g, 55 % yield) as a grey solid. ESI-MS (M+H) +:338.2 Step 2: Preparation of tert-butyl 7-(6-((diphenylmethylene)amino)-5-methylpyridin-3-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate [0551] To a mixture of tert-butyl 7-(6-chloro-5-methylpyridin-3-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (0.9 g, 2.670 mmol), diphenylmethanimine (507 mg, 2.804 mmol) in 1,4-dioxane (40 mL) was added Cs2CO3 (1.74 g, 5.34 mol), BINAP (332 mg, 0.534 mmol) and Pd(OAc)2 (60 mg, 0.267 mmol), the mixture was charged with N2 for three times and stirred at 100 °C for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mLx3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude title compound. The crude was purified by silica gel column chromatography eluted with (EtOAc/PE=4:1) to give title compound (1.2 g, 93% yield) as a brown solid. ESI-MS (M+H) +:483.3. Step 3: Preparation of tert-butyl 7-(6-amino-5-methylpyridin-3-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate [0552] To a solution of tert-butyl 7-(6-((diphenylmethylene)amino)-5-methylpyridin-3-yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate. (1.2 g, 2.489 mmol) in MeOH (20 mL) was added NaOAc (612 mg, 7.469 mmol) and hydroxylamine hydrochloride (858 mg, 12.445 mmol) at RT, the mixture was stirred for 1h at RT. The mixture was diluted with water (20 mL), acidized to pH=2 by 1N HCl, extracted with EtOAc (100mL x2). Aqueous phase was based with NaHCO3(aq) to pH=9, extracted with EtOAc (60mL x3), the combined organic layers were washed with brine, dried over Na2SO4, and filtered filtrate were concentrated to afford title compound (600 mg, 75.8% yield) as a grey solid.1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 2.7 Hz, 1H), 7.03 – 6.94 (m, 1H), 4.17 – 4.11 (m, 2H), 3.72 – 3.67 (m, 2H), 3.03 – 2.99 (m, 2H), 2.81 (s, 2H), 2.11 (s, 3H), 1.47 (s, 9H), 1.09 – 1.00 (m, 2H), 0.88 – 0.82 (m, 2H).ESI-MS (M+H) +: 319.2. Step 4: Preparation of tert-butyl 7-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-5-methylpyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate [0553] Fresh prepared LDA was added to a solution of 6-amino-5-methylpyridin-3-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (1 g, 3 mmol) in THF(5 mL) dropwised at -60 °C, the mixture was stirred for 1.5 at RT. The mixture was cool down to -60 °C. Then 8-fluoro-2- methylimidazo[1,2-a]pyridine-6-carbonitrile (350 mg, 2 mmol) in THF (5 mL) was added slowly. The mixture was stirred overnight at RT. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by C18 column chromatography eluted with MeCN: H2O=0% to 100% to give title compound (130 mg, 13.1% yield) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.55 – 8.53 (m, 1H), 7.81 – 7.77 (m, 1H), 7.48 – 7.43 (m, 2H), 7.14 – 7.11 (m, 1H), 3.76 – 3.71 (m, 2H), 3.19 – 3.15 (m, 2H), 2.98 – 2.95 (m, 2H), 2.50 (s, 3H), 2.46 (s, 3H), 1.48 (s, 9H), 1.11 – 1.07 (m, 2H), 0.89 – 0.86 (m, 2H).ESI-MS (M+H)+:494.2. Step 5: Preparation of tert-butyl 7-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate [0554] To a solution of t-butyl 7-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6- carboximidamido)-5-methylpyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (130 mg, 0.15 mmol) in THF (30 mL) and pyridine(3 mL) was added triphosgene (234 mg, 0.791 mmol), the mixture was stirred at rt for 15 min. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine, dried with Na2SO4 and evaporated to give crude title compound. The residue was purified by pre-HPLC (0.1% NH3.H2O in water / CH3CN) to afford title compound (60 mg, 44.1% yield) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J = 2.7 Hz, 1H), 3.78 – 3.73 (m, 2H), 3.31 – 3.26 (m, 2H), 3.06 (s, 2H), 2.69 (s, 3H), 2.50 (s, 3H), 1.49 (s, 9H), 1.14 – 1.10 (m, 2H), 0.90 – 0.87 (m, 2H).ESI-MS (M+H)+:520.1. Step 6: Preparation of 2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9-methyl-7-(4,7- diazaspiro[2.5]octan-7-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one HCl salt [0555] A solution of tert-butyl 7-(2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-9- methyl-4-oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (60 mg, 0.116 mmol) in 3M HCl/EtOAc (4 mL) was stirred for 2 h at RT. The mixture was filtered and the filter cake was washed with EtOAc (2 mL) and dried to afford title compound (30 mg, 60% yield) as a yellow solid. ESI-MS (M+H)+:420.1.1H NMR (400 MHz, MeOD- d4) δ 9.69 – 9.66 (m, 1H), 8.67 – 8.63 (m, 1H), 8.49 – 8.46 (m, 1H), 8.33 – 8.27 (m, 2H), 3.77 – 3.71 (m, 2H), 3.61 – 3.57 (m, 4H), 2.76 (s, 3H), 2.63 (s, 3H), 1.25 – 1.20 (m, 2H), 1.18 – 1.14 (m, 2H). Example 49. Synthesis of (S)-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (Compound 133) )-
Figure imgf000142_0001
2-methylpiperazine-1-carboxylate [0556] To a solution of fresh prepared LDA (2.625 mmol) in dry THF (10 mL) was added dropwise at – 65 °C a solution of tert-butyl (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine- 1-carboxylate (523 mg, 1.79 mmol) in dry THF (4 mL). The mixture was allowed to warm to room temperature and stirred for 1 h.7-fluoro-2-methyl-2H-indazole-5-carbonitrile (210 mg, 1.193 mmol) in dry.THF (4 mL) was added to the mixture at -65 °C and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted wth water (80 mL) and extracted with EtOAc (80 mL*2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18-flash (0.1% NH3.H2O in water / CH3CN) to give tert-butyl (S)-4-(6-(7-fluoro-2- methyl-2H-indazole-5-carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (40 mg, Y: 7.1%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 2.5 Hz, 1H), 7.98 – 7.95 (m, 2H), 7.62 (d, J = 12.4 Hz, 1H), 7.30 (dd, J = 8.9, 3.0 Hz, 1H), 7.25 (s, 1H), 4.37 (br.s, 1H), 4.27 (s, 3H), 3.98 (d, J = 13.4 Hz, 1H), 3.46 (d, J = 11.9 Hz, 1H), 3.35 – 3.23 (m, 2H), 2.95 (dd, J = 11.9, 3.8 Hz, 1H), 2.81 – 2.73 (m, 1H), 1.49 (s, 9H), 1.33 (d, J = 6.7 Hz, 3H). ESI-MS: [M+H]+: 468.3. Step 2: tert-butyl (S)-4-(2-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0557] To a solution of tert-butyl (S)-4-(6-(7-fluoro-2-methyl-2H-indazole-5- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.085 mmol) in THF (35 mL) and pyridine (3 mL) was added triphosgene (76 mg, 0.257 mmol). The reaction mixture was stirred for 15 min at rt. The mixture was diluted with water (25 mL) and extracted with EtOAc (50 mL*2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (40 mL) and stirred for 1 hour at rt. The precipitate was filtered and dried in vacuo to give tert-butyl (S)-4-(2-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (30 mg, 71.1 %) as a brown solid. ESI-MS: [M+H] +:494.6.1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 0.9 Hz, 1H), 8.45 (d, J = 2.7 Hz, 1H), 8.12 (dd, J = 16.0, 1.8 Hz, 2H), 7.85 (dd, J = 9.6, 2.8 Hz, 1H), 7.65 (d, J = 9.6 Hz, 1H), 4.44 (br.s, 1H), 4.28 (s, 3H), 4.03 (d, J = 13.2 Hz, 1H), 3.59 (d, J = 11.4 Hz, 1H), 3.43 (d, J = 12.0 Hz, 1H), 3.37 – 3.27 (m, 1H), 3.11 (dd, J = 12.1, 3.8 Hz, 1H), 2.98 – 2.88 (m, 1H), 1.50 (s, 9H), 1.32 (d, J = 6.7 Hz, 3H). Step 3: (S)-2-(7-fluoro-2-methyl-2H-indazol-5-yl)-7-(3-methylpiperazin-1-yl)-4H-pyrido[1,2- a][1,3,5]triazin-4-one hydrochloride [0558] To a solution of tert-butyl (S)-4-(2-(7-fluoro-2-methyl-2H-indazol-5-yl)-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (30 mg, 0.061 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (5 ml) at room temperature. The reaction mixture was stirred for 2 h. The precipitate was filtered and dried to give (S)-2-(7-fluoro-2-methyl- 2H-indazol-5-yl)-7-(3-methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one hydrochloride (20 mg, yield: 83.7 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.42 (s, 1H), 8.79 – 8.67 (m, 2H), 8.35 (d, J = 7.4 Hz, 2H), 7.96 (d, J = 13.4 Hz, 1H), 7.80 (d, J = 10.3 Hz, 1H), 4.25 (s, 3H), 4.00 – 3.88 (m, 2H), 3.43 (d, J = 9.4 Hz, 2H), 3.25 – 3.12 (m, 2H), 3.02 – 2.93 (m, 1H), 1.35 (d, J = 6.5 Hz, 3H). ESI-MS: [M+H] +: 394.0.
Example 50. Synthesis of (S)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-7-(3- methylpiperazin-1-yl)-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 134)
Figure imgf000144_0001
2-methylpiperazine-1-carboxylate [0559] To a solution of fresh prepared LDA (2.2 mmol) in dry THF (10 mL) was added dropwise at – 65 °C a solution of tert-butyl (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine- 1-carboxylate (438 mg, 1.5 mmol) in dry THF (4 mL). The mixture was allowed to warm to room temperature and stirred for 1 h.2,7-dimethylpyrazolo[1,5-a]pyridine-5-carbonitrile (171 mg, 1.0 mmol) in dry THF (4 mL) was added to the mixture at -65 °C and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL*2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18-flash (0.1% NH3.H2O in water / CH3CN) to give tert-butyl (S)-4-(6-(7-fluoro-2- methyl-2H-indazole-5-carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (120 mg, Y: 17.3 %) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 3.1 Hz, 1H), 7.46 – 7.38 (m, 2H), 7.10 (d, J = 8.9 Hz, 1H), 6.58 (s, 1H), 4.22 – 4.21 (m, 1H), 3.82 – 3.81 (m, 1H), 3.58 – 3.57 (m, 1H), 3.49 – 3.48 (m, 1H), 3.23 – 3.12 (m, 1H), 2.86 – 2.80 (m, 1H), 2.68 (d, J = 5.3 Hz, 3H), 2.67 – 2.60 (m, 1H), 2.44 (s, 3H), 1.43 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H). ESI-MS: [M+H]+:464.1. Step 2: tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-oxo-4H-pyrido[1,2- a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate [0560] To a solution of tert-butyl (S)-4-(6-(7-fluoro-2-methyl-2H-indazole-5- carboximidamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.259 mmol) in THF (10 mL) and pyridine (1.5 mL) was added triphosgene ( 231 mg, 0.778 mmol). The reaction mixture was stirred for 10 min at rt. The mixture was diluted with water (25 mL), extracted with EtOAc (15 mL*2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (30 mL), stirred for 1 hour at rt. The precipitate was filtered and dried in vacuo to give title product (65 mg, 51.3 %) as a yellow solid. ESI-MS: [M+H]+:490.2.1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 1.2 Hz, 1H), 8.33 – 8.25 (m, 2H), 7.75 (d, J = 9.5 Hz, 1H), 7.64 – 7.61 (m, 1H), 6.69 (s, 1H), 4.27 – 4.26 (m, 1H), 3.86 – 3.85 (m, 1H), 3.72 – 3.71 (m, 1H), 3.65 – 3.64 (, 1H), 3.26 – 3.20 (m, 1H), 3.11 – 3.04 (m, 1H), 2.91 – 2.82 (m, 1H), 2.72 (s, 3H), 2.46 (s, 3H), 1.44 (s, 9H), 1.21 (d, J = 6.7 Hz, 3H). Step 3: (S)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-7-(3-methylpiperazin-1-yl)-4H- pyrido[1,2-a][1,3,5]triazin-4-one [0561] To a solution of tert-butyl (S)-4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-4-oxo- 4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2-methylpiperazine-1-carboxylate (65 mg, 0.133 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (3 ml) at room temperature. The reaction mixture was stirred for 2 h. The mixture was concentrated in vacuo, to the residue was added sat. NaHCO3 (5 mL), stirred for 30 min. The precipitate was filtered and lyophilizied to give title compound (21 mg, yield: 40.6 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.34 (d, J = 9.5 Hz, 1H), 8.25 (s, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.64 (s, 1H), 6.70 (s, 1H), 3.66 – 3.65 (m, 2H), 3.02 – 3.01 (m, 1H), 2.87 – 2.77 (m, 2H), 2.73 (s, 3H), 2.46 (s, 3H), 2.41 – 2.25 (m, 2H), 1.07 (d, J = 6.3 Hz, 3H). ESI-MS: [M+H]+:390.1
Example 51. Synthesis of 7-(3,3-dimethylpiperazin-1-yl)-2-(2,7-dimethylpyrazolo[1,5- a]pyridin-5-yl)-9-fluoro-4H-pyrido[1,2-a][1,3,5]triazin-4-one (Compound 135)
Figure imgf000146_0001
Step 1: tert-butyl 4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5-carboximidamido)-5- fluoropyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate [0562] To a solution of fresh prepared LDA (2.2 mmol) in dry THF (10 mL) was added tert- butyl 4-(6-amino-5-fluoropyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate (486 mg, 1.5 mmol) in dry THF (4 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 1 h.2,7-dimethylpyrazolo[1,5-a]pyridine-5-carbonitrile (171 mg, 1.0 mmol) in dry.THF (4 mL) was added to the mixture at -65 °C and allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL*2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18-flash (0.1% NH3.H2O in water / CH3CN) to give tert-butyl 4-(6-(2,7-dimethylpyrazolo[1,5- a]pyridine-5-carboximidamido)-5-fluoropyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate (50 mg, Y: 10.1 %) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.4 Hz, 1H), 7.66 (d, J = 2.7 Hz, 1H), 7.25 (d, J = 0.8 Hz, 1H), 6.90 – 6.85 (m, 1H), 6.44 (s, 1H), 3.86 – 3.80 (m, 2H), 3.44 – 3.39 (m, 2H), 3.32 (s, 2H), 2.78 (s, 3H), 2.54 (s, 3H), 1.50 (s, 9H), 1.44 (s, 6H). ESI-MS: [M+H]+:496.1. Step 2: tert-butyl 4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro-4-oxo-4H- pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate [0563] To a solution of tert-butyl 4-(6-(2,7-dimethylpyrazolo[1,5-a]pyridine-5- carboximidamido)-5-fluoropyridin-3-yl)-2,2-dimethylpiperazine-1-carboxylate (90 mg, 0.182 mmol) in THF (10 mL) and pyridine (1.5 mL) was added triphosgene ( 162 mg, 0.545 mmol). The reaction mixture was stirred for 10 min at rt. The mixture was diluted with water (25 mL), extracted with EtOAc (15 mL*2). The combined organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with MeOH (30 mL), stirred for 1 hour. The precipitate was filtered and dried in vacuo to give title product (60 mg, 63.4 %) as a yellow solid. ESI-MS: [M+H] +:522.1.1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.71 (s, 1H), 7.52 (dd, J = 10.8, 2.7 Hz, 1H), 6.54 (s, 1H), 3.93 – 3.88 (m, 2H), 3.53 – 3.48 (m, 2H), 3.42 (s, 2H), 2.80 (s, 3H), 2.56 (s, 3H), 1.51 (s, 9H), 1.47 (s, 6H). Step 3: 7-(3,3-dimethylpiperazin-1-yl)-2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro- 4H-pyrido[1,2-a][1,3,5]triazin-4-one [0564] To a solution of tert-butyl 4-(2-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-9-fluoro-4- oxo-4H-pyrido[1,2-a][1,3,5]triazin-7-yl)-2,2-dimethylpiperazine-1-carboxylate (60 mg, 0.115 mmol) in EtOAC (2 mL) was added 3M HCl/EtOAc (3 ml) at room temperature. The reaction mixture was stirred for 2 h. The mixture was concentrated in vacuo, to the residue was added sat. NaHCO3 (5 mL), stirred for 30 min. The precipitate was filtered and lyophilized to give title product (19 mg, yield: 39.2 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.43 – 8.37 (m, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 6.71 (s, 1H), 3.19 – 3.14 (m, 2H), 3.03 (s, 2H), 2.93 – 2.87 (m, 2H), 2.73 (s, 3H), 2.46 (s, 3H), 1.12 (s, 6H). ESI- MS: [M+H] +: 422.1. Table 1 Compound No. Structure 99
Figure imgf000147_0001
Compound No. Structure 100
Figure imgf000148_0001
Compound No. Structure 106
Figure imgf000149_0001
Compound No. Structure 112
Figure imgf000150_0001
Compound No. Structure 118
Figure imgf000151_0001
Compound No. Structure 124
Figure imgf000152_0001
Figure imgf000153_0001
Biological Activity of the Compounds of the Present Disclosure [0565] The biological activity of the compounds of the present disclosure was determined utilizing the assay described herein. Example 52. Measurement of compound effect on cell viability measured by CellTiter- Glo (CTG) assay Materials ● RPMI 1640 medium: Gibco # 11875119 ● IMDM medium: DearyTech #DT-12200 ● FBS Fetal Bovine Serum: Gibco #10091-148 ● CellTiter-Glo Luminescent Cell Viability Assay: Promega #G7573 ● HPE compound: Staurosporine ● White, 384-well assay plate: Corning #3570 ● Microclime environmental plate lid: Labcyte #LLS-0310 Table 2: Cell lines and cell culture conditions No. Cell Line Source Culture Medium Culture Condition °
Figure imgf000154_0001
[0566] Cancer cell lines listed above were treated with the compounds of the present disclosure to assess their effect on inhibiting cell proliferation. [0567] For compound preparation, test compounds were diluted in duplicates from 10 mM stocks in 11-points 1:3 serial dilutions in DMSO. Then 100 nL test compounds at the serial dilutions were dispensed into 384-well assay plate using Echo dispenser. Staurosporine (5 μM final concentration) and DMSO (0.5% final concentration) were used as the positive (HPE) and negative (ZPE) controls respectively. [0568] To prepare cell lines, each frozen cell line stock was resuspended and grown in proper growth medium to a density of <100,000 cells/mL. [0569] Then 20 μL of cell suspension were dispensed into the assay plate to give seed cell density at 1,000 cells/well, compounds at 50 μM top concentration with 11-point serial dilutions, and 0.5% DMSO final concentration. Assay plates were then centrifuged at 300 rpm for 1 minute. Microclime plate lids were filled with ~ 8 mL sterile water and used to cover the cell plates. The plates were incubated at 37 °C, 95% humidity, 5% CO2 for 72 hours. After the 72 hour incubation, the assay plate and its contents were equilibrated at room temperature for approximately 30 minutes.20 μL of CellTiterGlo reagent was added to the assay plate and the plates were centrifuged at 500 rpm for 1 minute and equilibrated for 5 min. The luminescence (RLU) signals in each well were recorded using Envision plate reader, then converted to percentage inhibition values using the signals in HPE and ZPE treated wells as the references. IC50 values were determined by curve fitting in Levenberg– Marquardt algorithm. [0570] The percent activity was calculated as: % Inhibition = (Value – ZPE)/(HPE – ZPE) x 100% [0571] In Table 3 below, A indicates a IC50 (µM) < 1 µM, B indicates a IC50 (µM) 1 µM to < 10 µM, and C indicates a IC50 (µM) ≥ 10 µM. Table 3. – CTG Assay Data – COLO205, HL60, MOLM13, and MV4-11 Compound IC50 (µM) IC50 (µM) IC50 (µM) IC50 (µM) No. COLO205 HL60 MOLM13 MV4-11
Figure imgf000155_0001
Compound IC50 (µM) IC50 (µM) IC50 (µM) IC50 (µM) No. COLO205 HL60 MOLM13 MV4-11 Examp
Figure imgf000156_0001
. MYB Mini-gene reporter assay [0572] Mini-gene reporter constructs for each target site can be constructed by first PCR amplifying the region-of-interest including the sequence of the alternatively skipped sequences of the immediate upstream and downstream introns, and sequences of the immediate upstream and downstream exons. Then the 3’end of the amplified sequence can be ligated to a firefly luciferase reporter gene and cloned into the pcDNA3.1 vector backbone. The final reporter construct can be transiently transfected into HEK293 cells using Lipofectamine 3000 transfection reagents. Compounds that can induce the inclusion of the skipped exon in the reporter construct would increase the reporter firefly luciferase activity. Materials ● DMEM medium: Gibco #12100-046 ● FBS Fetal Bovine Serum: Gibco #10091-148 ● Culture medium: DMEM + 10% FBS + 1% P/S ● ONE-Glo Luciferase Assay System: Promega # E6130 ● HPE compound: Branaplam (CAS# 1562338-42-4) ● White, 384-well assay plate: Corning #3570 [0573] For compound preparation, test compounds were diluted in duplicates from 10mM stocks in 11-points 1:3 serial dilutions in DMSO. Then 100 nL test compounds at the serial dilutions were dispensed into 384-well assay plate using Echo dispenser. Branaplam (HPE; 16.7 μM final concentration) and DMSO (ZPE; 0.5% final concentration) were used as the positive and negative controls, respectively. [0574] To prepare cell lines, ready-to-use transfected cells were thawed, transferred to a 15 ml tube containing DMEM medium. The tubes were centrifuged at 1000 rpm for 5 min to pellet the cells. The cells were resuspended to 500,000 cells/mL in the culture medium. Then 20 μL of cell suspension were dispensed into the assay plate containing compounds to give seed cell density at 10,000 cells/well. Assay plates were then centrifuged at 300 rpm for 1 minute and then incubated at 37 °C, 95% humidity, 5% CO2 for 16 hours. After incubation, the assay plate and its contents were equilibrated at room temperature for approximately 20 minutes.20 μL of One-Glo reagent was added to the assay plate and the plates were centrifuged at 500 rpm for 1 minute and equilibrated for 5 min. The luminescence (RLU) signals in each well were recorded using Envision plate reader, then converted to percentage inhibition values using the signals in HPE and ZPE treated wells as the references. EC50 values were determined by curve fitting in Levenberg–Marquardt algorithm. [0575] The percent activity was calculated as: % Inhibition = (Value – ZPE)/(HPE – ZPE) x 100%  [0576] In Table 4 below, A indicates a EC50 (µM) < 1 µM, B indicates a EC50 (µM) 1 µM to < 10 µM, and C indicates a EC50 (µM) ≥ 10 µM.
Table 4. MYB Mini-gene reporter assay activtiy Compound No. EC 50 (µM) 100 A
Figure imgf000158_0001
Example 54. Measurement of compound effect on pre-mRNA splicing using a MYB HiBit assay [0577] CRISPR-Cas9 gene editing allows for cell line generation where an endogenous protein can be tagged with a small 11-amino acid HiBiT tag. When exposed to its larger LgBiT subunit, the HiBiT tag binds with high affinity to produce a complex with luciferase activity that will release luminescent signal when treated with furimazine substrate. This system allows for quantitative measurement of a desired protein upon treatment with compound. Materials ^ IMDM medium: DearyTech #DT-12200 ^ FBS Fetal Bovine Serum: Gibco #10091-148 ^ Nano-Glo HiBiT Lytic Detection System: Promega #N3050 ^ White, 384-well assay plate: Corning #3570 ^ Plate reader: PerkinElmer Envision [0578] For compound preparation, test compounds were diluted in duplicates from 10 mM stocks in 11-points 1:3 serial dilutions in DMSO. Then 100 nL test compounds at the serial dilutions were dispensed into 384-well assay plate using Echo dispenser. Positive control (HPE; final concentration 2 μM) and negative control (ZPE; final 0.5% DMSO) were dispensed to respective columns. [0579] To prepare cell lines, K562/MYB-HiBiT cells were transferred to a 15 ml tube and centrifuged at 1000 rpm for 5 min to pellet the cells. The cells were resuspended to 20,0000 cells/mL in the IMDM medium. Then 20 μL of cell suspension were dispensed into the assay plate containing compounds to give seed cell density at 4,000 cells/well. Assay plates were then centrifuged at 300 rpm for 1 minute and then incubated at 37 °C, 5% CO2 for 24 hours. After incubation, the assay plate and its contents were equilibrated at room temperature for approximately 20 minutes.20 μL of Nano-Glo HiBiT lytic reagent was added to the assay plate and the plates were centrifuged at 500 rpm for 1 minute and equilibrated for 15 min. The luminescence (RLU) signals in each well were recorded using Envision plate reader, then converted to percentage inhibition values using the signals in HPE and ZPE treated wells as the references. IC50 values were determined by curve fitting in Levenberg–Marquardt algorithm. [0580] The percent activity was calculated as: % Inhibition = (Value – ZPE)/(HPE – ZPE) x 100%  [0581] In Table 5 below, A indicates a IC50 (µM) < 1 µM, B indicates a IC50 (µM) 1 µM to < 10 µM, and C indicates a IC50 (µM) ≥ 10 µM. Table 5. MYB HiBiT assay activity Compound No. IC 50 (µM) 100 A Example 55. In vivo t
Figure imgf000160_0001
umor growth inhibition of Compound 116 in human adenoid cystic carcinoma xenograft model [0582] This example describes a study to investigate the in vivo efficacy of Compound 116 in a patient-derived adenoid cystic carcinoma xenograft model in immune-deficient mice. Abbreviations Description Abbreviation Definition al
Figure imgf000160_0002
Drug administration schedule: daily (QD), twice Schedule -- daily (BID), weekly (Q7D), twice weekly (2xwkl )
Figure imgf000161_0001
Study details/protocols: Animal Strain: Athymic Nude, Outbred Homozygous (Crl:NU(NCr)-Foxn1nu), Strain Animal Age / Sex: 6-12 weeks / Female
Figure imgf000161_0002
u y ea e s: Group -N- T X Dose Route of administration / (mg/kg) Schedule
Figure imgf000161_0003
Materials Test Agent Vehicle
Figure imgf000161_0004
10 mL/kg—weighed daily to determine dosing volume), or by flat dose using a fixed concentration and administration volume. Methods [0584] Female athymic nude (Crl:NU(NCr)-Foxn1nu) mice, between 6-12 weeks of age, weighing an approximate minimum of 20 grams on Day 0, were acclimated for a minimum of 24 hours and housed on irradiated corncob bedding (Teklad) in individual HEPA ventilated cages (Sealsafe® Plus, Techniplast USA) on a 12-hour light-dark cycle at 70-74°F (21-23°C) and 40-60% humidity. Animals were fed water ad libitum (reverse osmosis, 2 ppm Cl2) and an irradiated standard rodent diet (Teklad 2919) consisting of 19% protein, 9% fat, and 4% fiber. [0585] Tumor models - Patient-Derived Xenograft (XPDX) models were established from viable human tumor tissue or fluid that had been serially passaged in animals a limited number of times to maintain tumor heterogeneity. In subcutaneous models, athymic nude (Crl:NU(NCr)-Foxn1nu) mice were implanted unilaterally on the flank with tumor fragments harvested from host animals each implanted from a specific passage lot. Pre-study tumor volumes were recorded for each experiment beginning approximately one week prior to its estimated start date. When tumors reached the appropriate Tumor Volume Initiation (TVI) range (150-300 mm3), animals were assigned to treatment and control groups so that groups had equal mean starting volume and dosing initiated (Day 0); animals in all studies were followed individually, via ear notch, throughout each experiment. [0586] Protocol methodology - Animals were ear notched and sorted by mean tumor volume into treatment and control groups, all with similar mean tumor volumes of approximately 150-300 mm3 and treatment initiated on Day 0. Animals were observed once daily and weight and tumor dimension data collected twice weekly, unless otherwise specified; data including individual and gram weights (Mean We ± SD), mean percent weight change versus Day 0 (%vD0), and individual and estimated tumor volumes (Mean TV ± SEM) were recorded for each group. Animal deaths and/or clinical signs were recorded daily and designated as drug-related (D), technical (T), tumor related (B), or unknown (U) based on weight loss and gross observation. [0587] Animals reporting >20% weight loss over a period of 24 hours were removed from the study. Maximum %vD0 (weight nadir) for each treatment group was reported at study completion. Each study was ended once appropriate criteria were met; individual mice reaching a TV of ≥2.5 cm3 were removed from the study and the final measurement included in the group mean until reached volume endpoint or time endpoint. Samples from each efficacy study were collected at the designated endpoint; blood was collected using either mandibular puncture (in vivo) or axillary vessel cutdown (terminal), plasma or serum extracted using appropriate collections vials and then flash frozen using liquid nitrogen in a screw-top vial. Tumor tissue was harvested, sectioned to yield a ~5x5 mm3 fragment, and flash frozen using liquid nitrogen in a screw-top vial. Flash frozen samples were stored on- site at a temperature of -80 °C until shipment. [0588] Efficacy calculations - A percent tumor growth inhibition (%TGI) value was calculated and reported for each treatment group (T) versus control (C) using initial (i) and final (f) tumor measurements using the following formula: %TGI = 1 - Tf-Ti / Cf-Ci. Individual mice reporting a tumor volume ≤50% of the Day 0 measurement for two consecutive measurements over a seven day period were considered partial responders (PR). If the PR persisted until study completion, percent tumor regression (%TR) was determined using the following formula: %TR = 1 - Tf / Ti x 100; a mean value was calculated if multiple PRs occur in one group. Individual animals lacking palpable tumors (<4x4 mm2) for two consecutive measurements over a seven day period were considered complete responders (CR). A CR that persisted until study completion was considered a tumor-free survivor (TFS); TFS were excluded from efficacy calculations. [0589] Statistical analysis - Statistical differences in tumor volume were determined using a two-tailed One-Way Analysis of Variance (ANOVA) followed by the Dunnett’s multiple comparisons test comparing treated groups with control and further, combinations with single agent, where relevant. In cases where the animal was missing due to a TV ≥2.5 cm3 resulting in a sacrifice prior to study termination, the last measurement of the TV was recorded to its next measurements, but for no more than two time points. Results [0590] The mean tumor volume in the Vehicle and Compound 116 treatment groups from Day 0 to Day 24 are provided in Table 6 and Table 7, respectively. The mean changes in tumor volume from Day 0 to Day 24 for the Vehicle and Compound 116 treatment groups are depicted in FIG.1. Table 6. Tumor volume of vehicle treatment group Day 0-24, n = 7 Day: -8 0 3 6 11 13 17 20 24 T mor ol me (mm3) 1 1
Figure imgf000163_0001
Table 7. Tumor volume of Compound 116 treatment group Day 0-24, n = 7 Day: -8 0 3 6 11 13 17 20 24 Tumor volume (mm3) 8
Figure imgf000164_0001
4 corresponded to a percent tumor growth inhibition (%TGI) of 73%, which was statistically significant (p = 0.0041). EQUIVALENTS [0592] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [0593] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

CLAIMS 1. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I): I), or a pharmaceutically acceptable thereof, wherein:
Figure imgf000165_0001
A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6alkyl, -C(O)O-C1-C6alkyl, C1-C7alkyl, C1-C8heteroalkyl, C1- 7alkoxy-heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -(CH2)0-2-C3- C8cycloalkyl, 4-7-membered monocyclic heterocycloalkyl, NH2, NH(C1-C6alkyl), N(C1- C6alkyl)2, -NHC(O)-C1-C6alkyl, -N(C1-C6alkyl)-C(O)-C1-C6alkyl, -C(O)-NH2, -C(O)-NH(C1- C6alkyl), and -C(O)-N(C1-C6alkyl)2, wherein the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl or NH2, and wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, or NH2; or two R6 on the same carbon can be taken together as keto (=O); or two R6 together form C1-7alkylene; each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH; R16 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; and. R17 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl. 2. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount a compound of Formula (I): I), or a pharmaceutically acceptable thereof, wherein:
Figure imgf000166_0001
A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH; R16 is H, halo, C1-7alkyl, or OR5; and. R17 is H, halo, C1-7alkyl, or OR5.
3. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount a compound of Formula (I): I), or a pharmaceutically acceptable thereof, wherein: A is a nitrogen-containing
Figure imgf000167_0001
heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 can be optionally substituted with 1, 2, or 3 R7; each R5 is independently H, C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; each R7 is independently halo, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, or C1-7haloalkoxy; R16 is H, halo, C1-7alkyl, or OR5; and. R17 is H, halo, C1-7alkyl, or OR5. 4. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount a compound of Formula (II): I), or a pharmaceutically acceptable s
Figure imgf000167_0002
g thereof, wherein: A is saturated or partially unsaturated mono- or bi-cyclic 4- to 9-membered heterocycloalkyl or NR1R2, wherein the heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R1 is heterocycloalkyl comprising 1 nitrogen ring atom, optionally substituted with 1, 2, 3, or 4 R6; R2 is hydrogen, C1-7alkyl, or C3-8cycloalkyl; R3 is H, halo, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is aryl or bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein R4 is optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; and each R7 is independently halo, cyano, C1-7alkyl, C1-7haloalkyl, C1-7alkoxy, C1-7 haloalkoxy, or C3-8cycloalkyl, wherein the C1-7alkyl is optionally substituted with OH. 5. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount a compound of Formula (II): I), or a pharmaceutically acceptable
Figure imgf000168_0001
thereof, wherein: A is nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6; R3 is H, C1-7alkyl, OR5, N(R5)2, C3-8cycloalkyl, or heterocycloalkyl; R4 is a bicyclic 9-membered heteroaryl comprising 2, 3, or 4 heteroatoms independently selected from N and O, wherein R4 can be optionally substituted with 1, 2, or 3 R7; each R5 is independently C1-7alkyl, C3-8cycloalkyl, or heterocycloalkyl; each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, and C1-7alkoxy-heterocycloalkyl, or two R6 together form C1-7alkylene; and each R7 is independently halo or C1-7alkyl. 6. The method according to any of claims 1-5, wherein: A is nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3, or 4 R6, and is bonded to formula (I) or (II) by one of its nitrogen atoms; and each R6 is independently C1-7alkyl, amino, amino-C1-7alkyl, C3-8cycloalkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl or two R6 together form C1- 7alkylene. 7. The method according to any one of claims 1-6, wherein each R6 is independently C1-7 alkyl, heterocycloalkyl, or C1-7alkoxy-heterocycloalkyl or two R6 together form C1- 7alkylene. 8. The method according to any one of claims 1-7, wherein each R6 is independently methyl, ethyl, isopropyl, methoxy-azetidinyl, or pyrrolidinyl, or two R6 together form ethylene or propylene. 9. The method according to any one of claims 1-8, wherein
Figure imgf000169_0001
CH; R9 is hydrogen, C1-7alkyl, or (CH2)m-NR14R15; R10 is hydrogen or C1-7alkyl; R11 is hydrogen or C1-7alkyl; R12 is hydrogen or C1-7alkyl; R13 is hydrogen or C1-7alkyl; each R14 and R15 are independently hydrogen, C1-7alkyl and C3-8cycloalkyl; n is 0, 1 or 2; m is 0, 1 or 2; or R9 and R10 together form C1-7alkylene; or R9 and R12 together form C1-7alkylene; or R10 and R11 together form C2-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl; or R10 and R12 together form C1-7alkylene or 4- to 6-membered heterocycloalkyl optionally substituted with C1-7alkyl; or R10 and R14 together form C1-7alkylene; or R12 and R13 together form C2-7alkylene; or R12 and R14 together form C1-7alkylene; or R14 and R15 together form C2-7alkylene which is optionally substituted with C1- 7alkoxy. 10. The method according to claim 9, wherein Y is N. 11. The method according to claim 9, wherein Y is CH and R9 is (CH2)m-NR14R15. 12. The method according to any one of claims 9-11, wherein n is 1. 13. The method according to any one of claims 9-10 and 12, wherein R9 is hydrogen, pyrrolidinyl, or methoxy-azetidinyl . 14. The method according to any one of claims 9-13, wherein R10 is hydrogen, methyl, ethyl or isopropyl. 15. The method according to any one of claims 9-14, wherein R11 is hydrogen or methyl. 16. The method according to any one of claims 9-15, wherein R12 is hydrogen or methyl. 17. The method according to any one of claims 9-16, wherein R13 is hydrogen. 18. The method according to any one of claims 9-17, wherein R9 and R10 together form propylene. 19. The method according to any one of claims 9-17, wherein R10 and R11 together form ethylene. 20. The method according to any one of claims 9-19, wherein R14 and R15 together form propylene or butylene. 21. The method according to any one of claims 1-20, wherein A is ,
Figure imgf000171_0001
hydrogen or C1-7alkyl. 22. The method according to any one of claims 1-21, wherein A is piperazinyl, diazepanyl, octahydropyrrolopyrazinyl, diazaspirooctanyl, pyrrolidinyl, octahydropyrrolopyrroyl, diazaspirononanyl, diazaspiroheptanyl, or diazabicyclooctanyl, wherein piperazinyl, diazepanyl, octahydropyrrolopyrazinyl, diazaspirooctanyl, pyrrolidinyl, octahydropyrrolopyrroyl, diazaspirononanyl, diazaspiroheptanyl, or diazabicyclooctanyl are each optionally substituted with 1, 2, 3, or 4 R6. 23. The method according to any one of claims 1-22, wherein A is NR1R2. 24. The method according to any one of claims 1-22, wherein A is , ,
Figure imgf000171_0002
,
Figure imgf000172_0001
25. The method according to any one of claims 1-24, wherein R4 is a bicyclic 9-membered heteroaryl comprising 2 heteroatoms independently selected from N and O, optionally substituted with 1, 2, or 3 R7. 26. The method according to any one of claims 1-25, wherein R4 is a bicyclic 9-membered heteroaryl comprising two heteroatoms independently selected from N and O, substituted with 1 or 2 R7. 27. The method according to any one of claims 1-26, wherein R4 is ,
Figure imgf000172_0002
Figure imgf000172_0003
29. The method according to any one of claims 1-26, wherein R4 is imidazo[1,2-a]pyrazine, benzo[d]oxazole, triazolo-pyridazinyl, or imidazo[1,2-a]pyrazine, wherein imidazo[1,2- a]pyrazine, benzo[d]oxazole, triazolo-pyridazinyl, or imidazo[1,2-a]pyrazine each are optionally substituted with 1, 2, 3, or 4 R7. 30. The method according to any one of claims 1-26, wherein R4 is ,
Figure imgf000173_0001
31. The method according to any one of claims 1-26, wherein R4 is .
Figure imgf000173_0002
. e met o accor ng to any one o c a ms - , w ere n t e compound of Formula (I) or Formula (II) or pharmaceutically acceptable salt, solvate, or prodrug thereof is a compound of Table 1 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a compound of the disclosure. 33. The method according to any one of claims 1-32, wherein the compound of Formula (I) or Formula (II) or pharmaceutically acceptable salt, solvate, or prodrug thereof is a therapeutically active substance. 34. The method according to any one of claims 1-32, wherein the compound of Formula (I) or Formula (II) or pharmaceutically acceptable salt, solvate, or prodrug thereof is a small molecule splicing modulator.
35. The method according to any one of claims 1-32, wherein the compound of Formula (I) or Formula (II) or pharmaceutically acceptable salt, solvate, or prodrug thereof is a small molecule splicing modulator of MYB. 36. The method according to any one of claims 1-32, wherein the compound of Formula (I) or Formula (II) or pharmaceutically acceptable salt, solvate, or prodrug thereof is a MYB inhibitor. 37. The method of any of claims 1-36, wherein the disease or disorder is a MYB-related disease or disorder. 38. The method of any of claims 1-37, wherein the disease or disorder is cancer. 39. The method claim 38, wherein the cancer is selected from the group consisting of adenoid cystic carcinoma (ACC), hepatocellular carcinoma (HCC), breast cancer, prostate cancer, pancreatic cancer, lung cancer, adenocarcinoma, osteosarcoma, colorectal cancer, and blood cancer. 40. The method of claim 39, wherein the cancer is lung cancer. 41. The method of claim 40, wherein the lung cancer is small cell lung cancer. 42. The method of claim 39, wherein the cancer is blood cancer. 43. The method of claim 42, wherein the blood cancer is leukemia 44. The methof of claim 43, wherein the leukemia is acute myeloid leukemia. 45. The method of claim 43, wherein the leukemia is acute promyelocytic leukemia. 46. The method of claim 42, wherein the blood cancer is lymphoma. 47. The method of claim 46, wherein the lymphoma is selected from the group consisting of non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt lymphoma, B-cell lymphoma, and T-cell lymphoma. 48. The method of claim 42, wherein the blood cancer is adult T-cell leukemia/lymphoma. 49. The method of claim 39, wherein the cancer is adenoid cystic carcinoma.
50. The method of claim 39, wherein the cancer is hepatocellular carcinoma. 51. The method of claim 39, wherein the cancer is breast cancer. 52. The method of claim 39, wherein the cancer is prostate cancer. 53. The method of claim 39, wherein the cancer is pancreatic cancer. 54. The method of claim 39, wherein the cancer is adenocarcinoma. 55. The method of claim 39, wherein the cancer is osteosarcoma. 56. The method of claim 39, wherein the cancer is colorectal cancer.
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