WO2024097228A1 - Composés ciblant cdk11 et leurs méthodes d'utilisation - Google Patents

Composés ciblant cdk11 et leurs méthodes d'utilisation Download PDF

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WO2024097228A1
WO2024097228A1 PCT/US2023/036488 US2023036488W WO2024097228A1 WO 2024097228 A1 WO2024097228 A1 WO 2024097228A1 US 2023036488 W US2023036488 W US 2023036488W WO 2024097228 A1 WO2024097228 A1 WO 2024097228A1
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optionally substituted
compound
pharmaceutically acceptable
solvate
hydrate
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PCT/US2023/036488
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English (en)
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Jason M. SHELTZER
Peter C. SENNHENN
Claudio Edmundo Chuaqui
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Meliora Therapeutics, Inc.
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Publication of WO2024097228A1 publication Critical patent/WO2024097228A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • CDKs are also promising targets for cancer therapy (Asghar, U., Witkiewicz, A. K., Turner, N. C. & Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov.14, 130–146 (2015)).
  • the CDK4/CDK6 inhibitors Abemaciclib, Palbociclib, and Ribociclib have received FDA approval for use in hormone receptor-positive breast cancer, and drugs targeting CDK2, CDK7, and CDK9 are currently undergoing clinical trials in a variety of malignancies (Nur Husna, S. M., Tan, H.-T.
  • CDK11 is a relatively poorly characterized member of the CDK family. Early experiments identified various roles for CDK11 in transcription, splicing, and mitosis (Loyer, P. & Trembley, J. H.
  • Blocking CDK11 expression causes cell cycle arrest during mitosis, decreases phosphorylation of RNAP2, and blocks the expression of replication-dependent histones (Li, T., Inoue, A., Lahti, J. M. & Kidd, V. J. Failure To Proliferate and Mitotic Arrest of CDK11p110/p58-Null Mutant Mice at the Blastocyst Stage of Embryonic Cell Development. Mol. Cell. Biol.24, 3188–3197 (2004); Gajdu ⁇ ková, P. et al. CDK11 is required for transcription of replication-dependent histone genes. Nat. Struct. Mol. Biol.27, 500–510 (2020)).
  • CDK11 function was found to be controlled by an activating cyclin, which was subsequently named Cyclin L (Dickinson, L. A., Edgar, A. J., Ehley, J. & Gottesfeld, J. M. Cyclin L Is an RS Domain Protein Involved in Pre-mRNA Splicing. J. Biol. Chem.277, 25465–25473 (2002)).
  • Cyclin L Dickinson, L. A., Edgar, A. J., Ehley, J. & Gottesfeld, J. M. Cyclin L Is an RS Domain Protein Involved in Pre-mRNA Splicing. J. Biol. Chem.277, 25465–25473 (2002).
  • Assays conducted using RNAi revealed that CDK11 is essential for cell proliferation in multiple cancer lineages, and various reports suggest that CDK11 could be a promising target for therapeutic development in breast cancer, melanoma, and several other cancer types (Zhou, Y. et al.
  • Cyclin-dependent kinase 11 p110 (CDK11 p110 ) is crucial for human breast cancer cell proliferation and growth. Sci. Rep.5, 10433 (2015); Ahmed, R. L. et al. CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells. Pharmaceuticals 12, 50 (2019); Zhou, Y., Shen, J. K., Hornicek, F. J., Kan, Q. & Duan, Z. The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer. Oncotarget 7, 40846–40859 (2016)).
  • CDK11 function is required for the proliferation of multiple cancers, underscoring the clinical potential of CDK11 inhibition as an anti-cancer strategy (Lin, A. et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci. Transl. Med.11, eaaw8412 (2019)).
  • the present disclosure provides compounds of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: R 1 is -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , or -N(CH 2 CH 3 ) 2 ; R 2 and R 3 are each independently H or optionally substituted C 1 -C 6 alkyl, optionally wherein R 2 and R 3 are joined to form an optionally substituted carbocycle; R 4 is -OR a , wherein R a is H or optionally substituted C 1 -C 6 alkyl; R 5 is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted ary
  • the present disclosure provides compounds of Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: Ring A is aryl or heteroaryl; R 11 is -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NHCD 3 , -NHCD 2 CD 3 , - N(CD 3 ) 2 , or -N(CD 2 CD 3 ) 2 ; R 12 and R 13 are each independently H, halogen, or optionally substituted C 1 -C 6 alkyl, optionally wherein R 12 and R 13 are joined to form an optionally substituted carbocycle; R 14 is H, halogen, optionally substituted C 1 -C 6 alkyl, carbocyclyl, -OR a , -CN, or -N(R drug thereof, wherein: Ring A
  • the present disclosure provides compounds of Formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: R 21 is -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , or -N(CH 2 CH 3 ) 2 ; R 22 and R 23 are each independently H or optionally substituted C 1 -C 6 alkyl, optionally wherein R 22 and R 23 are joined to form an optionally substituted carbocycle; R 24 is -OR a , wherein R a is H or optionally substituted C 1 -C 6 alkyl; R 25 is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally
  • the present disclosure provides pharmaceutical compositions comprising any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides methods of inhibiting CDK11 in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein.
  • the present disclosure provides methods of inducing apoptosis in a cell in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein.
  • the present disclosure provides methods of treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject.
  • the present disclosure provides methods of treating a disease associated with aberrant activity of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in inhibiting CDK11 in a biological sample or a subject.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in inducing apoptosis in a cell in a biological sample or a subject.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in treating a disease associated with aberrant activity of CDK11 in a subject in need thereof.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in treating cancer in a subject in need thereof.
  • the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof.
  • the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with aberrant activity of CDK11 in a subject in need thereof.
  • the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating cancer in a subject in need thereof.
  • the present disclosure provides kits comprising any of the compounds provided herein or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or the pharmaceutical composition.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • the bond is a single bond
  • the dashed line is a single bond or absent
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • isotopes refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.
  • radiationoactivity or “radioactive decay” refers to the process by which a nucleus of an unstable isotope (e.g., 18 F) loses energy by emitting particles or rays (e.g., alpha particles, beta particles, and gamma rays) of ionizing radiation.
  • the term “specific activity” refers to the unit radioactivity of a material (e.g., a compound of Formula (I), Formula (II), Formula (III), or a salt, tautomer, stereoisomer, or isotopically labeled derivative (e.g., 18 F labeled derivative) thereof). In certain embodiments, the term “specific activity” refers to the radioactivity of a material per micromole ( ⁇ mol) of the material.
  • C 1-6 alkyl encompasses, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • alkyl refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”).
  • an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”).
  • an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert- butyl, sec-butyl, isobutyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), n-dodecyl (C 12 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1-12 alkyl (such as unsubstituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n- propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)).
  • unsubstituted C 1-6 alkyl e.g., ⁇ CH 3 (Me), unsubstituted ethy
  • the alkyl group is a substituted C 1–12 alkyl (such as substituted C 1-6 alkyl, e.g., –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 , – CH 2 CF 3 , or benzyl (Bn)).
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 20 carbon atoms (“C 1–20 haloalkyl”).
  • the haloalkyl moiety has 1 to 10 carbon atoms (“C 1–10 haloalkyl”).
  • the haloalkyl moiety has 1 to 9 carbon atoms (“C 1–9 haloalkyl”).
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C 1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C 1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C 1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group.
  • haloalkyl groups include –CHF 2 , ⁇ CH 2 F, ⁇ CF 3 , ⁇ CH 2 CF 3 , ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–11 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–7 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1–3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC 1-12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1–12 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C 1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C 1–12 alkenyl”).
  • an alkenyl group has 1 to 11 carbon atoms (“C 1-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C 1–10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C 1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C 1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C 1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C 1–6 alkenyl”).
  • an alkenyl group has 1 to 5 carbon atoms (“C 1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C 1-4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C 1–3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C 1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C 1 alkenyl”). 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 1-4 alkenyl groups include methylidenyl ( C 1 ), ethenyl (C 2 ), 1-propenyl (C 3 ), 2- propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 1–6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C 1-20 alkenyl.
  • the alkenyl group is a substituted C 1-20 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • heteroatom e.g., 1, 2, 3, or 4 heteroatoms
  • a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-11 alkenyl”).
  • a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–8 alkenyl”).
  • a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-7 alkenyl”). In some embodiments, a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkenyl”).
  • a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 1-2 alkenyl”).
  • a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1–6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 1-20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 1–20 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 1-20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C 1–10 alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C 1–9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C 1–8 alkynyl”).
  • an alkynyl group has 1 to 7 carbon atoms (“C 1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C 1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C 1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C 1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C 1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C 1-2 alkynyl”).
  • an alkynyl group has 1 carbon atom (“C 1 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 C 1-4 alkynyl groups include, without limitation, methylidynyl (C 1 ), ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 1-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 1-20 alkynyl.
  • the alkynyl group is a substituted C 1-20 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkynyl”).
  • a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–8 alkynyl”).
  • a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1-7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 1–6 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkynyl”).
  • a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC 1-4 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 1–2 alkynyl”).
  • a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 1 - 6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 1-20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 1-20 alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C 3-13 carbocyclyl”).
  • a carbocyclyl group has 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • a carbocyclyl group has 3 to 11 ring carbon atoms (“C 3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H- indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-10 carbocyclyl groups as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 - 14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3- 14 cycloalkyl.
  • the term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]di
  • 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 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 pi electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • the term “unsaturated bond” refers to a double or triple bond.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • the term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not limited in any manner by the exemplary substituents described herein.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, –SCN, or –NO 2 .
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C 1–10 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, –SCN, or –NO 2 , wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-
  • the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms.
  • halo or “halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • hydroxyl or “hydroxy” refers to the group ⁇ OH.
  • thiol refers to the group –SH.
  • amino refers to the group ⁇ NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb ) 3 and ⁇ N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
  • sulfonyl refers to a group selected from –SO 2 N(R bb ) 2 , –SO 2 R aa , and –SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each nitrogen protecting group is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-
  • each nitrogen protecting group is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carba
  • each nitrogen protecting group is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms),
  • Ts p-toluenesulfonamide
  • Mtr
  • each nitrogen protecting group is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3- diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenz
  • two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.
  • at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or an oxygen protecting group.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each oxygen protecting group is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclo
  • At least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a sulfur protecting group.
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors. [0082] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (e.g., including one formal negative charge).
  • An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 ⁇ , HSO 4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid
  • Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate,
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this invention include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, per
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
  • the term “stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent molecules are an integral part of the crystal lattice, in which they interact strongly with the compound and each other.
  • non-stoichiometric solvate refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent content may vary without major changes in the crystal structure.
  • the amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere. In the fully solvated state, non- stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound.
  • hydrate refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate.
  • a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
  • tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to- imine, and enamine-to-(a different enamine) tautomerizations.
  • isomers 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”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center 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 polarized 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 term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three-dimensional order.
  • a crystalline form of a solid is a solid form that is substantially not amorphous.
  • the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.
  • amorphous or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order.
  • an amorphous form of a solid is a solid form that is substantially not crystalline.
  • the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2 ⁇ of, e.g., between 20 and 70°, inclusive, using CuK ⁇ radiation.
  • the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures.
  • the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2 ⁇ of between 20 and 70°, inclusive is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band.
  • the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures.
  • co-crystal refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent.
  • At least one of the components is a solvent.
  • a co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid.
  • a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature.
  • a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature.
  • co-crystals in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein.
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • a human i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disease.
  • tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • administered refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition “disease,” and “disorder” are used interchangeably.
  • an “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severeity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for inhibiting CDK11. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer. In certain embodiments, cancer is melanoma or breast cancer. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting CDK11 to treat cancer. In certain embodiments, cancer is melanoma or breast cancer. [0109]
  • a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • prophylactically effective amount can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting CDK11. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating cancer. In certain embodiments, cancer is melanoma or breast cancer. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting CDK11 to treat cancer. In certain embodiments, cancer is melanoma or breast cancer.
  • the term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.
  • the term refers to a reduction of the level of enzyme activity, e.g., CDK11 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity.
  • the term refers to a reduction of the level of enzyme activity, e.g., CDK11 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • angiogenesis refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue.
  • angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer.
  • Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF).
  • VEGF growth factors
  • “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease.
  • the terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
  • a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
  • Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.”
  • An exemplary pre-malignant neoplasm is a teratoma.
  • a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • the term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
  • Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocar
  • Wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g.,bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • a “kinase” is a type of enzyme that transfers phosphate groups from high energy donor molecules, such as ATP, to specific substrates, referred to as phosphorylation.
  • Kinases are part of the larger family of phosphotransferases.
  • One of the largest groups of kinases are protein kinases, which act on and modify the activity of specific proteins.
  • Kinases are used extensively to transmit signals and control complex processes in cells.
  • Various other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides, either for signaling or to prime them for metabolic pathways.
  • Kinases are often named after their substrates. More than 500 different protein kinases have been identified in humans.
  • exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g,
  • kinases such as CDK11 are implicated in a wide variety of diseases (e.g., proliferative diseases, such as cancer).
  • diseases e.g., proliferative diseases, such as cancer.
  • the provided compounds may be kinase inhibitors.
  • the kinase is CDK11.
  • pharmaceutical compositions and kits including the provided compounds.
  • kits for inhibiting CDK11 in a biological sample or a subject inducing apoptosis in a cell in a biological sample or a subject, treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject, treating a disease associated with aberrant activity of CDK11 in a subject, and treating cancer in a subject.
  • R 1 is -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , or -N(CH 2 CH 3 ) 2 ;
  • R 2 and R 3 are each independently H or optionally substituted C 1 -C 6 alkyl, optionally wherein R 2 and R 3 are joined to form an optionally substituted carbocycle;
  • R 4 is -OR a , wherein R a is H or optionally substituted C 1 -C 6 alkyl;
  • R 5 is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl
  • one of X 1 , X 2 , X 3 , and X 4 is N, and the other three of X 1 , X 2 , X 3 , and X 4 are CR 7 .
  • each of X 1 , X 2 , and X 3 is CR 7 , and X 4 is N.
  • at least one instance of R 7 is optionally substituted C 1-6 alkyl.
  • the R 7 bound to X 1 is optionally substituted C 1-6 alkyl.
  • at least one instance of R 7 is methyl.
  • at least one instance of R 7 is OH.
  • At least one of X 1 , X 2 , X 3 , and X 4 is CH. In some embodiments, at least two of X 1 , X 2 , X 3 , and X 4 are CH. In certain embodiments, three of X 1 , X 2 , X 3 , and X 4 are CH.
  • the compounds are of Formula (I-a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • each of Y 1 , Y 2 , Y 3 , and Y 4 is CR 8 .
  • each of Y 1 , Y 2 , Y 3 , and Y 4 is CH.
  • the compounds are of Formula (I-b): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • the compounds are of Formula (I-c): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • R 1 is NH 2 .
  • R 1 is N(CH 3 ) 2 .
  • R 1 is NHCH 3 .
  • R 2 is H. In some embodiments, R 3 is H. In certain embodiments, R 2 and R 3 are both H. In some embodiments, R 2 is C 1-6 alkyl. In some embodiments, R 3 is C 1-6 alkyl. In certain embodiments, one of R 2 or R 3 is C 1-6 alkyl, and the other of R 2 or R 3 is H. In some embodiments, R 2 is CH 3 . In some embodiments, R 3 is CH 3 . In certain embodiments, one of R 2 or R 3 is CH 3 , and the other of R 2 or R 3 is H. In certain embodiments, R 2 and R 3 are joined together to form a cyclopropyl ring.
  • R 4 is OH, OCH 3 , OCH 2 CH 3 , OCHF 2 , OCF 2 H, or OCF 3 . In certain embodiments, R 4 is OH. In certain embodiments, R 4 is OCH 3 . In certain embodiments, R 4 is CH 2 F, CHF 2 , or CF 3 .
  • R 5 is H, halogen, or haloalkyl. In certain embodiments, R 5 is H. In certain embodiments, R 5 is F. In certain embodiments, R 5 is CH 2 F, CHF 2 , or CF 3 .
  • R 6 is optionally substituted C 1-6 alkyl.
  • R 6 is haloalkyl. In certain embodiments, R 6 is CH 3 . In certain embodiments, R 6 is CH 2 F. [0129] In some embodiments, a compound of Formula (I) is selected from the group consisting of:
  • a compound of Formula (I) is selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof.
  • the present disclosure provides compounds of Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: Ring A is aryl or heteroaryl; R 11 is -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NHCD 3 , -NHCD 2 CD 3 , - N(CD 3 ) 2 , or -N(CD 2 CD 3 ) 2 ; R 12 and R 13 are each independently H, halogen, or optionally substituted C 1 -C 6 alkyl, optionally wherein R 12 and R 13 are joined to form an optionally substituted carbocycle; R 14 is H, halogen, optionally substituted C 1 -C 6 alkyl, carbocyclyl, -OR a , -CN, or -N(R drug thereof, wherein: Ring A
  • the compounds are of Formula (II-a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • each of Y 5 , Y 6 , Y 7 , and Y 8 is CR 17 .
  • each of Y 5 , Y 6 , Y 7 , and Y 8 is CH.
  • the compounds are of Formula (II-b): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • the compounds are of Formula (II-c): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • R 11 is NH 2 . In some embodiments, R 11 is N(CH 3 ) 2 . In some embodiments, R 11 is NHCH 3 . In some embodiments, R 11 is -NHCD 3 . In some embodiments, R 11 is -NHCD 2 CD 3 . In some embodiments, R 11 is -N(CD 3 ) 2 . In some embodiments, R 11 is - N(CD 2 CD 3 ) 2 .
  • R 12 is H.
  • R 13 is H. In certain embodiments, R 12 and R 13 are both H. In some embodiments, one of R 12 or R 13 is optionally substituted C 1-6 alkyl, and the other of R 12 or R 13 is H. In some embodiments, one of R 12 or R 13 is C 1-6 alkyl substituted with at least one instance of halogen, and the other of R 12 or R 13 is H. In some embodiments, one of R 12 or R 13 is CH 2 F, CHF 2 , or CF 3 , and the other of R 12 or R 13 is H. In some embodiments, R 12 is C 1-6 alkyl. In some embodiments, R 13 is C 1-6 alkyl.
  • R 12 or R 13 is C 1-6 alkyl, and the other of R 12 or R 13 is H.
  • R 12 is CH 3 .
  • R 13 is CH 3 .
  • one of R 12 or R 13 is CH 3 , and the other of R 12 or R 13 is H.
  • R 12 and R 13 are joined together to form a cyclopropyl or cyclobutyl ring.
  • R 14 is optionally substituted C 1 -C 6 alkyl.
  • R 14 is haloalkyl.
  • R 14 is CH 3 or CH 2 CH 3 .
  • R 14 is CH 2 F, CHF 2 or CF 3 . In certain embodiments, R 14 is -OR a . In certain embodiments, R 14 is OH, OCH 3 , OCH 2 CH 3 , OCHF 2 , OCF 2 H, or OCF 3 . In certain embodiments, R 14 is Cl. In certain embodiments, R 14 is cyclopropyl. [0140] In some embodiments, R 15 is H, halogen, optionally substituted C 1-6 alkyl, -NO 2 , or - N(R c ) 2 . In certain embodiments, R 15 is CH 3 . In certain embodiments, R 15 is CH 2 F, CHF 2 , or CF 3 .
  • R 15 is Cl. In certain embodiments, R 15 is NH 2 . In certain embodiments, R 15 is F. [0141] In some embodiments, R 16 is halogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -OR b . In certain embodiments, R 16 is CH 3 or CH 2 CH 3 . In certain embodiments, R 16 is C 1-6 haloalkyl. In certain embodiments, R 16 is CH 2 F, CHF 2 , or CF 3 . In certain embodiments, R 16 is F. In certain embodiments, R 16 is OH or OCH 3 . In certain embodiments, R 16 is C 1–10 heteroalkyl consisting of 1, 2, or 3 oxygens in the heteroalkyl chain.
  • R 16 is C 1-10 heteroalkyl consisting of 1 or 2 oxygens in the heteroalkyl chain. In certain embodiments, R 16 is selected from the group consisting of [0142] In some embodiments, n is 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. [0143] In some embodiments, a compound of Formula (II) is selected from the group consisting of:
  • a compound of Formula (II) is selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof.
  • the present disclosure provides compounds of Formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, wherein: R 21 is -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , or -N(CH 2 CH 3 ) 2 ; R 22 and R 23 are each independently H or optionally substituted C 1 -C 6 alkyl, optionally wherein R 22 and R 23 are joined to form an optionally substituted carbocycle; R 24 is -OR a , wherein R a is H or optionally substituted C 1 -C 6 alkyl; R 25 is H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally
  • one of X 5 , X 6 , X 7 , and X 8 are N, and the other three of X 5 , X 6 , X 7 , and X 8 are CR 26 .
  • each of X 5 , X 6 , and X 7 is CR 26 , and X 8 is N.
  • at least one instance of R 26 is optionally substituted C 1-6 alkyl.
  • the R 26 bound to X 5 is optionally substituted C 1-6 alkyl.
  • at least one instance of R 26 is methyl.
  • At least one of X 5 , X 6 , X 7 , and X 8 is CH. In some embodiments, at least two of X 5 , X 6 , X 7 , and X 8 are CH. In certain embodiments, three of X 5 , X 6 , X 7 , and X 8 are CH.
  • the compounds are of Formula (III-a): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • each of Y 9 , Y 10 , Y 11 , and Y 12 is CR 27 .
  • each of Y 9 , Y 10 , Y 11 , and Y 12 is CH.
  • the compounds are of Formula (III-b): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • the compounds are of Formula (III-c): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.
  • R 21 is NH 2 .
  • R 21 is N(CH 3 ) 2 .
  • R 22 is H.
  • R 23 is H.
  • R 22 and R 23 are both H.
  • R 22 is C 1-6 alkyl.
  • R 23 is C 1-6 alkyl.
  • one of R 22 or R 23 is C 1-6 alkyl, and the other of R 22 or R 23 is H.
  • R 22 is CH 3 .
  • R 23 is CH 3 .
  • one of R 22 or R 23 is CH 3 , and the other of R 22 or R 23 is H.
  • R 22 and R 23 are joined together to form a cyclopropyl ring.
  • R 24 is OH, OCH 3 , OCH 2 CH 3 , OCHF 2 , OCF 2 H, or OCF 3 . In certain embodiments, R 24 is OH. In certain embodiments, R 24 is OCH 3 . In certain embodiments, R 24 is CH 2 F, CHF 2 , or CF 3 .
  • R 25 is optionally substituted C 1-6 alkyl. In certain embodiments, R 25 is CH 2 F, CHF 2 , or CF 3 . In certain embodiments, R 25 is CH 3 , CH 2 F, or CH 2 OH.
  • R 26 is optionally substituted C 1-6 alkyl. In certain embodiments, R 26 is CH 3 .
  • a compound of Formula (III) is selected from the group consisting of:
  • a compound of Formula (III) is selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and prodrugs thereof.
  • the present disclosure provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides compounds of Formula (II), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides compounds of Formula (III), or a pharmaceutically acceptable salt thereof.
  • compositions comprising any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof.
  • the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof.
  • the proliferative disease is cancer.
  • the cancer is melanoma or breast cancer.
  • the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof.
  • a disease is a proliferative disease.
  • the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase in a subject or cell.
  • a protein kinase is CDK11.
  • the effective amount is an amount effective for inhibiting the activity of a protein kinase by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%.
  • a protein kinase is CDK11.
  • the subject is an animal. The animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human.
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
  • the subject is a fish or reptile.
  • the cell is present in vitro. In certain embodiments, the cell is present in vivo.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one- half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition comprises between 0.1% and 100% (w/w) active ingredient.
  • pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents are present in the composition.
  • diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, and/or powdered sugar, and mixtures thereof.
  • exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, and/or quaternary ammonium compounds, and mixtures thereof.
  • cross-linked poly(vinyl-pyrrolidone) crospovidone
  • sodium carboxymethyl starch sodium starch
  • exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), car
  • exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes
  • sugars e.g
  • exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and/or sodium sulfite.
  • exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and/or tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric
  • exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal.
  • exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid.
  • exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol.
  • exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and/or Euxyl ® .
  • exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, iso
  • exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, and/or sodium lauryl sulfate, and mixtures thereof.
  • exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana,
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, and/or silicone oil, and mixtures thereof.
  • liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs.
  • the liquid dosage forms comprise inert diluents commonly used in the art.
  • inert diluents include water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, and/or polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g.
  • the oral compositions include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • the compounds provided herein are provided in injectable preparations.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, are formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation is a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the vehicles and solvents employed are water, Ringer’s solution, U.S.P., and/or isotonic sodium chloride solution.
  • sterile, fixed oils are employed as a solvent or suspending medium.
  • any bland fixed oil is employed, including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, depends upon crystal size and crystalline form.
  • compositions comprising the compounds provided herein are formulated for rectal or vaginal administration.
  • compositions for rectal or vaginal administration are suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • solid dosage forms for oral administration are capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonit
  • the dosage form in the case of capsules, tablets, and pills, includes a buffering agent.
  • solid compositions of a similar type are employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology.
  • opacifying agents comprise opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions used include polymeric substances and/or waxes.
  • solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredient is in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules is prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient are admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • such dosage forms comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms comprise buffering agents.
  • the dosage forms optionally comprise opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating agents which can be used include polymeric substances and waxes.
  • dosage forms for topical and/or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers.
  • transdermal patches to deliver any of the compounds described herein, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • dosage forms are prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate is controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices.
  • intradermal compositions are administered by devices which limit the effective penetration length of a needle into the skin.
  • conventional syringes are used in the classical mantoux method of intradermal administration.
  • jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are used.
  • ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are used.
  • the present disclosure provides formulations comprising any of the compounds disclosed herein for topical administration.
  • formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • topically administrable formulations comprise from about 1% to about 10% (w/w) active ingredient.
  • the concentration of the active ingredient is as high as the solubility limit of the active ingredient in the solvent.
  • formulations for topical administration further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein is prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation comprises dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. In certain embodiments, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • dry powder compositions include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • the compositions provided herein include low boiling propellants. Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant constitutes 50 to 99.9% (w/w) of the composition, and the active ingredient constitutes 0.1 to 20% (w/w) of the composition.
  • the propellant further comprises additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent.
  • the solid diluent has a particle size of the same order as particles comprising the active ingredient.
  • such formulations are prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and are conveniently administered using any nebulization and/or atomization device.
  • such formulations further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • formulations for nasal administration comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and optionally comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein is prepared, packaged, and/or sold in a formulation for buccal administration.
  • such formulations are in the form of tablets and/or lozenges made using conventional methods, and contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • powdered, aerosolized, and/or aerosolized formulations when dispersed, have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and optionally further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein is prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • such formulations are in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • eye drops further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [0199] In some embodiments, compounds provided herein are formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein are administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal nasal, buc
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • an effective amount is included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses).
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein. [0202] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • a compound or composition, as described herein is administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents).
  • the compounds or compositions are administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the additional pharmaceutical agent achieves a desired effect for the same disorder.
  • the additional pharmaceutical agent achieves different effects.
  • the compound or composition is administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., a proliferative disease).
  • each additional pharmaceutical agent is administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents are administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain- relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins.
  • the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase.
  • the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation.
  • epigenetic or transcriptional modulators e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors
  • antimitotic drugs e.g., taxanes and vinca
  • the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • kits e.g., pharmaceutical packs.
  • kits provided comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
  • the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
  • kits are useful for treating a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase (e.g., CDK11) in a subject or a cell.
  • a protein kinase e.g., CDK11
  • kits described herein further includes instructions for using the kit.
  • a kit described herein also includes information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • the information included in the kits is prescribing information.
  • the kits and instructions provide for treating a disease (e.g., a proliferative disease) in a subject in need thereof.
  • the kits and instructions provide for preventing a disease (e.g., a proliferative disease) in a subject in need thereof.
  • kits and instructions provide for reducing the risk of developing a disease (e.g., a proliferative disease) in a subject in need thereof.
  • the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase (e.g., CDK11) in a subject or a cell.
  • a kit described herein includes one or more additional pharmaceutical agents described herein as a separate composition.
  • the present disclosure provides methods of inhibiting CDK11 in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein.
  • the subject is a human.
  • the present disclosure provides methods of inducing apoptosis in a cell in a biological sample or a subject, the method comprising contacting the biological sample with or administering to the subject an effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein.
  • the subject is a human.
  • the present disclosure provides methods of treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject.
  • the disease is a proliferative disease.
  • the disease is cancer.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • the present disclosure provides methods of treating a disease associated with aberrant activity of CDK11 in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject.
  • the disease is a proliferative disease.
  • the disease is cancer.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions disclosed herein, to the subject.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in inhibiting CDK11 in a biological sample or a subject.
  • the subject is a human.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in inducing apoptosis in a cell in a biological sample or a subject.
  • the subject is a human.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof.
  • the disease is a proliferative disease.
  • the disease is cancer.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in treating a disease associated with aberrant activity of CDK11 in a subject in need thereof.
  • the disease is a proliferative disease.
  • the disease is cancer.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein are for use in treating cancer in a subject in need thereof.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with overexpression and/or hyperactivation of CDK11 in a subject in need thereof.
  • the disease is a proliferative disease.
  • the disease is cancer.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating a disease associated with aberrant activity of CDK11 in a subject in need thereof.
  • the disease is a proliferative disease.
  • the disease is cancer.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • the present disclosure provides uses of any of the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, in the manufacture of a medicament for treating cancer in a subject in need thereof.
  • the cancer is breast cancer.
  • the cancer is melanoma.
  • the subject is a human.
  • kits comprising any of the compounds provided herein or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or any of the pharmaceutical compositions provided herein, and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or prodrug thereof, or the pharmaceutical composition.
  • EXAMPLES Example 1. Synthesis of Compounds General Methods and Materials [0223] The urea formation was performed using a Discovery Microwave Synthesizer. All reactions were monitored by TLC with 0.25 mm E.
  • reaction products were carried out by column chromatography using commercially available silica or flash chromatography using Combiflash Rf with Teledyne IscoRediSepRfHigh Performance Gold or SilicycleSiliaSep High Performance columns (40, 80, or 120 g). The purity of all final compounds was over 95% and was analysed with Waters LCMS system.
  • 1 H NMR spectra were recorded on Varion400 MHz spectrometers and are reported in ppm with the solvent resonance employed as the internal standard [CDCl 3 at 7.26 ppm, DMSO- d6 at 2.50 ppm].
  • Scheme 1 Synthesis of I-1000, I-1001, and I-1002
  • Scheme 1a Synthesis of key intermediate 7: Step-1: [0228] To a stirred solution of compound 1 (20 g, 0.099 mol) in DCM (200 mL) was added oxalyl chloride (37.42 g, 0.297 mol) then reaction mixture was stirred at RT for 4h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and crude was used for next step without purification.
  • Step-2 [0231] To a stirred solution of compound 3 (25 g, 0.077 mol) in DCM was added NaH (3.14 g, 0.13 mol) at 0 o C followed by PMB-Cl (10.20 g, 0.06 mol) then reaction mixture was stirred at RT for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 4 (28 g, Yield: 81.6%) as an off white solid.
  • Step-3 [0234] To a stirred solution of compound 4 (1.5 g, 0.004 mmol) in DMA (15 mL) was added potassium acetate (1.2 g, 0.012 mol) followed by Pd(P t Bu3) 2 catalyst (127 mg, 0.002 mmol) then reaction mixture was stirred at 150 o C for 4h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x200 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was used for next step without purification.
  • Step-4 [0237] Trifluoro acetic acid (20 mL) was added to compound 5 (1.4 g, 0.003 mol) at 0 o C. The resulting reaction mixture allowed to room temperature and stirred at 100 °C for 16h. Completion of the reaction was monitored by TLC, after completion, the reaction mixture quenched with aq. NaHCO 3 solution and extracted with EtOAc (2x200 mL). The organic washed with brine solution (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-5 [0240] To a stirred solution of compound 6 (1 g, 0.004 mol) in 2 mL (1:1) DCM-AcOH was added 1,3 dibromo,5,5 dimethyl hydantoin (356 mg, 0.001 mol) at 0 o C then reaction mixture was stirred at room temperature for 3h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x100 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-2 [0244] To a solution mixture of compound 2 (20 g, 95.2 mmol) in THF (100 mL) was added BH 3 .DMS (10 M in DMS) (10.5 mL, 104.7 mmol) at reflux temperature. Reaction mixture was kept for 30 min at reflux, cooled to room temperature and pH adjusted to 2.0 with 6N HCl and neutralized with aq.6N NaOH, this solution was extracted with DCM (2x200 mL). Combined organic layer was dried over Na 2 SO 4 and concentrated under vacuo to afford compound 3 (20 g, crude).
  • Step-3 [0247] To a solution mixture of compound 3 (20 g, 93.4 mmol) in DCM (200 mL) was added TEA (19.6 mL, 140.1 mmol) and followed by (Boc) 2 O (25.7 mL, 112.0 mmol) at 0 o C. Reaction mixture was kept at room temperature for 2h and evaporated under vacuo. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 5% EtOAc in Hexane to afford compound 4 (13 g, Yield: 44.3%) as an off white solid.
  • Step-4 To a solution mixture of compound 4 (6.0 g, 19.10 mmol) in Dioxane (60 mL) was added Bis(pinacolato)diboron (5.82 g, 22.9 mmol), Pd(dppf)Cl2 (567.1 mg, 0.76 mmol) followed by KOAc (3.74 g, 38.2 mmol) at rt and degassed with N 2 for 5 min at room temperature. Reaction mixture was kept for 15h at 90 o C. After completion, reaction mixture was cooled to rt and quenched with water (100 mL) and extracted with EtOAc (2x100 mL). Combined organic layers were washed with water and brine, concentrated under vacuo.
  • Step-7 Synthesis of I-1000 [0257] To a stirred solution of compound 9 (500 mg, 1.054 mol) in 1,4-dioxane (5 mL) was added 4M HCl in dioxane (5 mL) at 0 o C then reaction mixture was stirred at rt for 4h. Reaction was monitored by TLC; after completion, reaction mixture was diluted with water (5 mL) and washed with ethyl acetate (2x50 mL). Aqueous layer was quenched with aq. NaHCO 3 and extracted with 10% MeOH in DCM (2x50 mL). Organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-9 Synthesis of I-1002 [0265] To a stirred solution of compound I-1001 (100 mg, 0.278 mol) in methanol (10 mL) was added formaldehyde (16 mg, 0.533 mol) followed by sodium cyanoborohydride (36 mg, 0.573 mol) and catalytic amount of acetic acid (0.2 mL). Reaction was monitored by TLC; after completion of reaction, solvent was evaporated then reaction mixture was quenched in water and (10 mL) extracted with DCM (2x10 mL). Organic layer was concentrated and washed with pentane. Crude was purified by preparative HPLC to afford compound I-1002 as white solid (20 mg, Yield: 11.8%).
  • Step-1 [0269] To a stirred solution of compound 1 (20 g, 0.099 mol) in DCM (200 mL) was added oxalyl chloride (25.4 mL, 0.297 mol) followed by DMF (2 mL) at 0 °C. Then the reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC; after completion of reaction, solvent was evaporated by reduced pressure under N 2 atmosphere. The resulting crude dissolved in DCM (50 mL) and added to a solution of compound 2 (10.8 g, 0.079 mol) in DCM (150 mL) and TEA (41 mL, 0.297 mol) at 0 °C.
  • Step-7 Synthesis of I-1005 [0289] To a stirred solution of compound 7 (200 mg, 0.422 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (2 mL) at 0 o C then reaction mixture was stirred at rt for 4h. Reaction was monitored by TLC; after completion of reaction, reaction mixture poured into ice cold water and basified using sat NaHCO 3 and extracted with 10% MeOH in DCM. The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Crude compound was triturated with acetonitrile and filtered to afford I-1005 (80 mg, Yield: 50.9%) as a pale brown solid.
  • Step-9 Synthesis of I-1007 [0297] To a stirred solution of I-1006 (25 mg, 0.069 mmol) in MeOH (3 mL) was added formaldehyde (12 mg, 0.139 mmol), sodium cyanoborohydride (9 mg, 0.139 mmol) and 2 drops of acetic acid. The reaction mixture stirred at room temperature for 15h. Completion of the reaction was monitored by LCMS; after completion, solvent was evaporated under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with water (5 mL), brine solution (5 mL). The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-2 [0304] To a stirred solution of compound 3 (28.6 g, 0.089 mol) in DMF (280 mL) was added NaH (60%, 13 g, 0.267 mol) at 0 o C and stirred for 20 min. PMB-Cl (18.1 mL, 0.133 mol) added at same temperature. The resulting reaction mixture allowed to stir at rt for 5h. Completion of the reaction was monitored by TLC and after completion of the reaction, the reaction mixture quenched with saturated aq. NH4Cl solution and extracted with EtOAc (2x1L).
  • Step-5 [0313] To a stirred solution of compound 6 (1 g, 0.004 mol) in H 2 SO 4 (10 mL) was added 1,3- dibromo-5,5-dimethylhydantoin (DBDMH) (1.1 g, 0.004 mol) at 0 °C. The resulting mixture was stirred at room temperature for 3h. Completion of the reaction was monitored by TLC and LCMS. After completion, reaction mass poured into crushed ice and extracted with EtOAc. The organic layer was washed with sat. NaHCO 3 , water and brine solution and dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 7 as brown solid.
  • DBDMH 1,3- dibromo-5,5-dimethylhydantoin
  • Step-6 [0316] To a stirred solution of compound 7 (400 mg, 1.257 mmol) and compound 8 (683 mg, 1.886 mmol) in Dioxane (16 mL) and water (1 mL) was added K2CO 3 (520 mg, 3.773 mmol), Pd-118 (40 mg, 0.062 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture heated to 150 °C and stirred for 30 min. Completion of the reaction was monitored by TLC and LCMS. Crude was washed with n- pentane and ether to afford compound 9 (280 mg, Yield: 50%) as a pale brown solid.
  • Step-7 Synthesis of I-1008 [0319] To a stirred solution of compound 9 (900 mg, 1.898 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in dioxane (10 mL) at 0 o C then reaction mixture was stirred at rt for 2h. Reaction was monitored by TLC; after completion of reaction mixture was diluted with water and washed with ethyl acetate (2x300 L). Aqueous layer was quenched with aq. NaHCO 3 and extracted with 10% MeOH in DCM (2x200 mL). Organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-9 Synthesis of I-1010 [0327] To a stirred solution of compound I-1009 (30 mg, 0.083 mmol) in methanol (1 mL) was added formaldehyde (0.1 mL) followed by sodium cyanoborohydride (10 mg, 0.167 mmol) and catalytic amount of acetic acid (0.1 mL). Reaction was monitored by TLC; after completion of reaction solvent was evaporated, then reaction mixture was quenched in water and extracted with DCM (2x5 mL). Organic layer was concentrated and washed with pentane. Crude was purified by preparative HPLC to afford I-1010 (10 mg, Yield: 35%) as white solid.
  • Reaction mixture was degassed for 15 minutes, then Pd(dppf)Cl2 catalyst (112 mg, 0.053 mmol) was added and again degassed for 10 minutes. The reaction mixture was stirred at 85 o C for 15h. Reaction was monitored by LCMS. Reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x100 mL). Organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh). Compound was eluted using 20% EtOAc in Hexane to afford pure compound 8 (60 mg, Yield: 8%) as a white solid.
  • Step-6 Synthesis of II-1001 [0346] To a stirred solution of compound 8 (500 mg, 1.04 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in dioxane (2.5 mL) at 0 o C then reaction mixture was stirred at rt for 15h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was diluted with water and washed with ethyl acetate (2x100 mL). Aqueous Layer was quenched with aq. NaHCO 3 and extracted with 10% MeOH in DCM (2x100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-7 Synthesis of II-1002: [0350] To a stirred solution of compound II-1001 (300 mg, 0.791 mmol) was added Hydrogen bromide (3 mL) at 0 o C then reaction mixture was stirred at 100 0 C for 16h. Reaction was monitored by TLC. reaction mixture was poured into ice water. Water layer directly concentrated and purified by reverse-phase C-18 using acetonitrile/water (with 0.01% HCOOH) to afford II- 1002 (11 mg, Yield: 2.6 %) as a white solid. [0351] LCMS: m/z: 365.12[M+H] + , 98.52% (1.20 min).
  • Step-8 Synthesis of II-1003 [0354] To a stirred solution of compound II-1002 (100 mg, 0.27 mmol) in methanol (5 mL) was formaldehyde (16.4 mg, 0.54 mmol) followed by sodium cyanoborohydride (34.2 mg, 0.547 mmol) and catalytic amount of acetic acid (one drop). Reaction was monitored by TLC; after completion of reaction, solvent was evaporated then reaction mixture was quenched in water and extracted with DCM (2x10 mL). Organic layer was concentrated and washed with pentane. Crude was purified using reverse phase C-18 using acetonitrile/water (0.01% FA) to afford II- 1003 (8 mg, Yield: 7.4%) as an off white solid.
  • Step-1 [0358] To a stirred solution of compound 1 (20 g, 0.099 mol) in DCM (200 mL) was added Oxalyl chloride (25 mL, 0.297 mol) then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and crude was used for next step without purification. Acid chloride was dissolved in DCM (200 mL) was added compound 2 (10.9 g, 0.079 mmol) followed by TEA (27 mL, 0.099 mol) then reaction mixture was stirred at RT for 18h.
  • Step-5 To a stirred solution of compound 6 (1 g, 0.004 mol) in DCM-AcOH (50 mL, 1:1) was added NBS (2.2 g, 0.124 mol) at 0 o C then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC. Reaction mixture was poured into ice cold water and extracted with DCM (2x200 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude was washed with n-pentane and ether to afford compound 7 (500 mg, Yield: 38%) as a pale brown solid.
  • Step 4 [0393] To a stirred solution of compound 4 (2 g, 0.009 mol) and compound 5 (3.5 g, 0.009 mol) in Dioxane (20 mL) and water (2 mL) was added K2CO 3 (3.3 g, 0.024 mol), Pd-118 (264 mg, 0.024 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture heated to 90 °C and stirred for 6h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x100 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound 6.
  • Step 5 [0396] To a stirred solution of compound 6 (4 g, 0.010 mol) in THF (20 mL) and water (6.8 ml) was added Iron Powder (5 g,0.050 mol) and NH 4 Cl (6.7 g,0.107 mol) at room temperature. The resulting mixture stirred at 80 o C for 10 h. Completion of the reaction was monitored by TLC. After completion, reaction mass reaction mixture was filter and pass the celite and evaporated under vacuum than extracted with EtOAc and water. Organic layer washed with brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude compound was used for next step. (2 g, Yield: 50 %) as a white solid.
  • Step 8 To a stirred solution of compound 11 (2.2 g, 0.003 mol) in DMA (22 mL) was added KOAc (1.2 g, 0.012 mol), Pd(P t Bu 3 ) 2 (950 mg, 0.0001 mol) at room temperature. The reaction mixture degassed with nitrogen for 20 min, then heated at 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mixture poured crushed into ice and filtered the solid. The solid was dissolved in 10% MeOH in DCM (100 mL), washed with brine solution (100 mL), dried over Na 2 SO 4, filtered and concentrated in vacuo.
  • KOAc 1.2 g, 0.012 mol
  • Pd(P t Bu 3 ) 2 950 mg, 0.0001 mol
  • Step 9 [0408] Trifluoroacetic acid (3 mL) was added to the compound 12 (280 mg, 0.449 mmol) in a sealed tube at room temperature. The resulting mixture heated to 100 °C and stirred for 16h. Completion of the reaction was monitored by TLC, after completion, reaction mixture quenched in crushed ice and extracted with EtOAc. The organic layer washed with sat. NaHCO 3 , water and brine solution. The organic layer dried over Na 2 SO 4, filtered and concentrated in vacuo.
  • Step 10 To a stirred solution of compound II-1004 (300 mg, 1.074 mmol) in DCM (15 mL) was added Boron tribromide (30 ml, 10.746 mmol) at 0 o C then reaction mixture was heated to 100 °C and stirred for 3h. Reaction was monitored by TLC; after completion of reaction, solvent was evaporated then reaction mixture was quenched in water and extracted with DCM. Aqueous layer was purified by C-18 reverse phase column chromatography to afford II-1005 (5 mg, Yield: 1.8 %) as a white solid. [0413] LCMS: m/z: 376.41 [M+1] + , 94.58% (1.47 min).
  • Step 1 To a stirred solution of compound 1 (20 g, 96.618 mmol) in DMF (200 mL) was added compound 2 (13.3 g, 96.61 mmol) followed by HATU (55.07 g, 144.92 mmol) and DIPEA (31.15 g, 241.54 mmol) then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated by reduced pressure and crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 3 (18.5 g, Yield: 58.6%) as an off white solid.
  • Step 3 [0422] To a stirred solution of compound 4 (5 g, 13.51 mmol) in DMA (50 mL) was added KOAc (5.29 g, 54.05 mmol), Pd(t-Bu 3 P) 2 (414 mg, 0.81 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 15 min. Then the reaction mixture heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC. After completion, reaction mass cooled to rt, quenched with cold water and extracted with EtOAc (2x500 mL). Organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 4 [0425] To a stirred solution of compound 5 (800 mg, 2.758 mmol) in THF (8 mL) was added LDA (5.5 mg, 5.517 mmol) at -78 o C and stirred for 30 min. Methyl iodide (583 mg, 4.137 mmol) added at -78 o C. The resulting reaction mixture allowed to stir at -78 o C for 2h. Completion of the reaction was monitored by TLC, after completion of reaction, reaction mixture quenched with water and extracted with EtOAc (2x300 mL). The organic washed brine solution, dried over Na 2 SO 4, filtered and concentrated in vacuo.
  • Step 5 [0428] To a stirred solution of compound 6 (200 mg, 0.657 mmol) in H 2 SO 4 (2 mL) was added 1,3- dibromo5,5-dimethyl hydatoin (112 mg, 0.394 mmol) then reaction mixture was stirred at room temperature for 2h. Reaction was monitored by TLC; after completion of reaction, mixture was quenched in ice water and extracted with DCM. Organic layer was concentrated under reduced pressure; Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 7 (106 mg, Yield: 23.8%) as an off white solid.
  • reaction mixture was degassed for 15 minutes then Pd(dppf)Cl 2 catalyst (10 mg, 0.014 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 o C for 15h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100: 200 mesh) and compound was eluted using 10% EtOAc in Hexane to afford compound 9 (26 mg, Yield: 14.9%) as an off white solid.
  • Step 7 To a stirred solution of compound 9 (60 mg, 0.121 mmol) in 1,4-dioxane (1 mL) was added 4M HCl in dioxane (0.300 mL) at 0 o C then reaction mixture was stirred at rt for 2h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was quenched with aq. NaHCO 3 and extracted with ethyl acetate. Crude was purified by C-18 reverse phase column chromatography to afford II-1006 (3.7 mg, Yield: 7.7%) as a white solid. [0435] LCMS: m/z: 394.30 [M+1] + , 99.16 % (1.57 min).
  • Step 2 [0439] To a stirred solution of compound 2 (25 g, 0.108 mol) in DCM (500 mL) was added Methane sulphonic acid (25 mL) followed by DBDMH (3.08 g, 0.108 mol) at 0 o C then reaction mixture was stirred at room temperature for 18h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x1L), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound. The crude compound was purified by silica gel column chromatography (10% EtOAc in hexane as eluent) to afford 4 (30 g, Yield: 90%) as brown solid.
  • Step-2 [0455] To a stirred solution of compound 3 (28.6 g, 0.089 mol) in DMF (280 mL) was added 60% NaH (13 g, 0.267 mol) at 0 o C and stirred for 20 min. PMB-Cl (18.1 mL, 0.133 mol) was added at same temperature. The resulting reaction mixture allowed to stir at room temperature for 5h. Completion of the reaction was monitored by TLC, after completion of the reaction, reaction mixture quenched with sat. NH 4 Cl solution and extracted with EtOAc (2x1L). The organic layer washed with water (1L), brine solution (1L), dried over Na 2 SO 4, filtered and concentrated in vacuo to afford crude compound as brown gum.
  • Step-3 [0458] To a stirred solution of compound 4 (16.1 g, 0.036 mol) in DMA (160 mL) was added KOAc (14.3 g, 0.146 mol) followed by Pd(P t Bu 3 ) 2 (1.1 g, 0.002 mol) at room temperature. The reaction mixture degassed with nitrogen for 20 min, then heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mixture poured crushed into ice and filtered the solid. The solid was dissolved in 10% MeOH in DCM (1L), washed with brine solution (1L), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 3 [0483] To a stirred solution of compound 3 (28 g, 0.111 mol) in MeOH (280 mL) was added Sodium methoxide (7.5 g,0.140 mol) at 0 °C. The resulting mixture stirred at 80 o C for 3 h. Completion of the reaction was monitored by TLC. After completion, reaction mass reaction mixture was evaporated under vacuum than extracted with EtOAc and water. Organic layer washed with brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 4 (20 g, Yield: 74.0%) as brown solid.
  • Step 4 [0486] To a stirred solution of compound 4 (2 g, 0.009 mol) and compound 5 (3.5 g, 0.009 mol) in Dioxane (20 mL) and water (2 ml) was added K 2 CO 3 (3.3 g, 0.024 mol), Pd-118 (264 mg, 0.024 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture heated to 80 °C and stirred for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound 6.
  • reaction mass reaction mixture was filter and pass the celite room temperature and evaporated under vacume than extracted with EtOAc (2x500 mL) and water (500 mL). Organic layer washed with brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo. Crude compound was purified by column chromatography using silica gel (100: 200 mesh). Compound was eluted using 10% EtOAc in Hexane to afford compound 7 (2 g, Yield: 50 %) as a white solid. [0490] LCMS: m/z: 372.24 [M+1H] + , 79.48 % (1.53 min).
  • Step 7 [0493] To a stirred solution of compound 9 (1.6 g, 0.008 mol) in DCM (40 mL) was added TEA (3.4 mL, 0.024 mmol) at room temperature. Compound 10 (4 g, 0.004 mmol) added at 0 o C. The resulting reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC, after completion, reaction mass diluted with DCM and washed with aq. NaHCO 3 solution and brine solution. Organic layer dried over Na 2 SO 4 , filtered and concentrate in vacuo.
  • Step 8 [0496] To a stirred solution of compound 11 (1.6 g, 0.002 mol) in DMA (16 mL) was added KOAc (1.29 g, 0.009 mol), Pd(P t Bu 3 ) 2 (61 mg, 0.0001 mol) at room temperature. The reaction mixture degassed with nitrogen for 20 min, then heated to 150 °C and stirred for 4h. Completion of the reaction was monitored by TLC, after completion, reaction mixture poured crushed into ice and filtered the solid. The solid was dissolved in 10% MeOH in DCM, washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 10 [0502] To a stirred solution of compound 13 (100 mg,0.273 mmol) was added POCl 3 (2 ml) at 0 o C then reaction mixture was stirred at100 o C room temperature for 16h. Reaction was monitored by TLC; after completion of reaction solvent was evaporated then reaction mixture was quenched in water and extracted with DCM. Aqueous layer was purified by C-18 reverse phase column chromatography to afford crude compound II-1007 (4 mg, Yield: 4 %) as a yellow solid. [0503] LCMS: m/z: 384.17 [M+1H] + , 99.43% (1.81 min).
  • Step 2 [0508] To a stirred solution of compound 2 (12.8 g, 51.200 mmol) in Dioxane (128 ml) solution was added compound 2 (3.98 g, 66.560 mmol) followed by Cs2CO 3 (50.06 g, 153.600 mmol). Reaction mixture was degassed for 15 minutes then Palladium catalyst (2.2 g, 3.072 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 o C for 16 h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step 8 [0525] To a stirred solution of compound 9 (1 g, 4.219 mmol) in Dioxane (10 mL) solution was added compound 10 (2.2 g, 6.329 mmol) followed by K2CO 3 (1.7 g, 12.657 mmol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 catalyst (164 mg, 0.253 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 o C for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x300 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step 9 [0528] To a stirred solution of compound 11 (486 mg, 0.989 mmol) in 1,4-dioxane (4.8 mL) was added dioxane/HCl (2.969 mL) at 0 o C then reaction mixture was stirred at room temperature for 2h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was quenched with aq. NaHCO 3 and extracted with ethyl acetate. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 40% EtOAc in Hexane to afford compound 12 (200 mg, Yield: 51.7%) as a white solid.
  • Step-2 [0535] To a stirred solution of compound 3 (10 g, 0.030 mol) in DMF (100 mL) was added NaH (2.2 g, 0.09 mol) at 0 o C followed by PMB-Cl (7 mL, 0.06 mol) then reaction mixture was stirred at for 3h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with EtoAc (2x500 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-3 [0538] To a stirred solution of compound 4 (15 g, 0.033 mmol) in DMA (150 mL) was added potassium acetate (13.1 g, 0.134 mol) followed by Pd (P t Bu 3 ) 2 catalyst (1.01 g, 0.002 mmol) then reaction mixture was stirred at 150 o C for 4h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x200 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was used for next step without purification.
  • Step-4 [0539] Trifluoro acetic acid (50 mL) was added to compound 5 (11 g, 0.030 mol) at 0 o C. The resulting reaction mixture allowed to room temperature and stirred at 100 °C for 16h. Completion of the reaction was monitored by TLC, after completion, the reaction mixture quenched with aq. NaHCO 3 solution and extracted with EtOAc (2x200 mL).
  • Step-5 [0542] To a stirred solution of compound 6 (1 g, 0.004 mol) in 2 mL (1:1) DCM was added NBS (863 mg, 0.004 mol) at 0 o C then reaction mixture was stirred at room temperature for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with DCM (2x100 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was purified by column chromatography using silica gel (100:200 mesh) and compound was eluted using 20% EtOAc in Hexane to afford compound 7 (500 mg, Yield: 38%) as an off white solid.
  • Step-3 [0553] To a stirred solution of compound 4 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 mL) was added Iron Powder (1.9 g, 35.06 mmol) and NH4Cl (3.7 g, 70.12 mmol) The resulting mixture stirred at 80 °C for overnight. Progress of the reaction was monitored by TLC. After completion of the reaction, filtered the reaction mass through celite and washed with EtOAc, separated the two layers. Organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-4 [0556] To a stirred solution of compound 5 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 6 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature and stirred for 1h. The reaction mixture cooled to 0 °C and added NaBH 4 (385 mg, 10.14 mmol) portion wise and continued the stirring at rt for 2h. The reaction progress was monitored by TLC, after completion of the reaction, reaction mass quenched with water and extracted with EtOAc. The organic layer washed with cold water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-5 To a stirred solution of compound 8 (915 g, 4.42 mmol) in DCM (20 mL) was added oxalyl chloride (1.1 mL, 13.26 mmol as per acid) followed by cat DMF (0.2 mL) at 0 °C. Then the reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC; after completion of reaction solvent was evaporated under reduced pressure at N2 atmosphere. The resulting crude dissolved in DCM (20 mL) and added to a solution of compound 7 (700 mg, 1.47 mmol) in DCM (30 mL) and TEA (3 mL, 22.10 mmol as per acid) at 0 °C.
  • Step-1 [0565] To a stirred solution of compound 1 (22 g, 194.6 mmol) in acetone (29 ml, 389.3 mmol) was added piperidine (1 ml) and acetic acid (22 ml) stirred at 90 o C for 24h. The progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was cooled to rt and then concentrated under vacuum. The residue was diluted with 50 ml of water and extracted with ethyl acetate. The organic layer washed with brine solution, dried over Na 2 SO 4, filtered, and concentrated in vacuo to afford crude compound.
  • Step-2 [0568] N, N-Dimethylformamide dimethyl acetal (19 ml, 143.79 mmol) was added dropwise to a stirred solution of compound 2 (20 g 130.71 mmol) in ethanol (200 ml). The resulting solution was stirred for 15 h at 80 o C. After completion of the reaction, the reaction mixture was cooled to rt and concentrated under vacuum. The residue was diluted with 50 ml of water and extracted with ethyl acetate (200 ml). The organic layer washed with brine solution, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford crude compound.
  • Step-3 [0571] HBr (40% in acetic acid, 125 ml) was added dropwise to a 40 o C stirred solution of compound 3 (25 g, 120.19 mmol) in acetic acid (125 ml), and the resulting solution was stirred for 15h at 55 o C.
  • the reaction mixture was cooled to rt and then poured into 10 ml of cold water.
  • the pH value of the solution was adjusted to 9 with 2M aqueous sodium carbonate solution. Concentrated under vacuum.
  • the resulting mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with brine solution, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford crude compound.
  • Step-5 [0577] Compound 5 (4 g, 18.604 mmol) in SOCl 2 (40 ml) was stirred at 70 o C for 2 h. Completion of the reaction was monitored by TLC. After completion of reaction, solvent was evaporated under reduced pressure at N2 atmosphere. The resulting crude dissolved in DCM (20 ml) and added to a solution of compound 6 (2.3 g, 14.833 mmol) in DCM (20 ml) and TEA (10 ml, 74.418 mmol) at 0 °C. The resulting mixture stirred at rt for 4 h. Completion of the reaction was monitored by TLC.
  • Step-9 [0589] To a stirred solution of compound 10 (500 mg, 1.428 mmol) in 5 ml of dioxane, compound 11 (773 mg, 2.142 mmol) was added, followed by potassium carbonate (591 mg, 4.285 mmol). The reaction mixture was degassed for 15 minutes, and then Pd(dppf)Cl2 (63 mg, 0.085 mmol) was added. It was degassed again for 10 minutes, and the reaction mixture was stirred at 85°C for 1 hour under microwave irradiation. The reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate.
  • Step-10 [0592] To a stirred solution of crude compound 12 (300 mg, 0.594 mmol) in 1,4-dioxane (3 ml), dioxane/HCl (4 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the excess TFA was evaporated in vacuo. The residue was purified by preparative HPLC and lyophilized to yield I-1016 (5 mg, 2.08%) as a white solid. [0593] LCMS: m/z: 406.35 [M+1] + , 96.96% (1.82 min).
  • Step 1 To a stirred solution of compound 1 (30 g, 0.194 mol) in DMF (300 mL) was added NBS (41.5 g,0.233 mol) at 0 °C. The resulting mixture stirred at 60 o C for 16 h. Completion of the reaction was monitored by TLC. After completion, the reaction was extracted with EtOAc. The organic layer was washed with sat. NaHCO 3, water, and brine solution. The organic layer was then dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude compound was triturated with ether, filtered, and dried to afford to afford compound 2 as a brown solid (34.9 g, Yield: 77.6%) as an off white solid.
  • Step 4 [0615] To a stirre d solution of compound 4 (2 g, 0.009 mol) and compound 5 (3.5 g, 0.009 mol) in Dioxane (20 mL) and water (2 ml) was added K2CO 3 (3.3 g, 0.024 mol) and Pd-118 (264 mg, 0.024 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 10 min. Then the reaction mixture heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC. The reaction mixture was then poured into ice cold water and extracted with ethyl acetate, and the organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound 6.
  • Step 5 To a stirred solution of compound 6 (4 g, 0.010 mol) in THF (20 mL) and water (6.8 mL) was added Iron Powder (5 g, 0.050 mol) and NH4Cl (6.7 g, 0.107 mol). The resulting mixture stirred at 80 0 C for 10h. Completion of the reaction was monitored by TLC. After completion, the reaction mixture was filter, passed through celite at room temperature, and evaporated under vacuum, then extracted with EtOAc (2x500 mL) and water (500 mL). The organic layer was washed with brine solution. Then the organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step 6 To a stirred solution of compound 7 (2.6 g, 0.010 mol) in MeOH (30 mL) was added AcOH (2 mL) followed by compound 8 (1.4 mL, 0.011 mol) at room temperature. The resulting reaction mixture was allowed to stir at room temperature for 1 h, then NaBH4 (785 mg, 0.021 mmol) was added slowly at 0 o C. The resulting reaction mixture was allowed to stir at room temperature for 2 h. Completion of the reaction was monitored by TLC, and after completion, the reaction was directly evaporated under vacuum than extracted with DCM (300 mL) and water (300 mL) and washed with brine solution (300 mL).
  • Step 7 [0622] To a stirred solution of compound 9 (1.6 g, 0.008 mol) in DCM (40 mL) was added TEA (3.4 mL, 0.024 mmol) at room temperature. Compound 10 (4 g, 0.004 mmol) was added at 0 o C. The resulting reaction mixture was allowed to stir at room temperature for 3 h.
  • Step 10 [0631] To a stirred solution of compound 13 (100 mg,0.273 mmol) was added POCl 3 (2 ml) at 0 o C, and then the reaction mixture was stirred at100 o C for 16h. The reaction was monitored by TLC; after completion of the reaction, solvent was evaporated, and then the reaction mixture was quenched in water and extracted with DCM. The aqueous layer was purified by C-18 reverse phase column chromatography to afford crude compound II-1007 (4 mg, Yield: 4 %) as a yellow solid. [0632] LCMS: m/z: 384.17 [M+1H] + , 99.43% (1.81 min).
  • Step 2 [0637] To a stirred solution of compound 2 (12.8 g, 51.200 mmol) in Dioxane (128 ml) solution was added compound 2 (3.98 g, 66.560 mmol) followed by Cs 2 CO 3 (50.06 g, 153.600 mmol). Reaction mixture was degassed for 15 minutes then Palladium catalyst (2.2 g, 3.072 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 o C for 16 h. The reaction was monitored by TLC. The reaction mixture was thenpoured into ice cold water and extracted with ethyl acetate, and the organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step 9 [0657] To a stirred solution of compound 11 (486 mg, 0.989 mmol) in 1,4-dioxane (4.8 mL) was added dioxane/HCl (2.969 mL) at 0 o C then reaction mixture was stirred at room temperature for 2h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with aq. NaHCO 3 and extracted with ethyl acetate. Crude compound was purified by column chromatography using silica gel (100:200 mesh), and compound was eluted using 40% EtOAc in Hexane to afford compound 12 (200 mg, Yield: 51.7%) as a white solid.
  • Step 10 To a stirred solution of compound 12 (150 mg, 0.383 mmol) in DCM (1.5 ml) was added boron tribromide (1.1 mL, 1.150 mmol) at 0 0 C, and then the reaction mixture was stirred at RT for 15h. The reaction was monitored by TLC; after completion of the reaction, solvent was evaporated, and then the reaction mixture was quenched in water and extracted with DCM. The aqueous layer was purified by C-18 reverse phase column chromatography to afford I-1011.
  • Step-2 [0664] To a stirred solution of compound 3 (10 g, 0.030 mol) in DMF (100 mL) was added NaH (2.2 g, 0.09 mol) at 0 o C followed by PMB-Cl (7 mL, 0.06 mol), and then the reaction mixture was stirred at rt for 3h. The reaction was monitored by TLC. The reaction mixture was then poured into ice cold water and extracted with EtOAc (2x500 mL), and the organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-3 [0667] To a stirred solution of compound 4 (15 g, 0.033 mmol) in DMA (150 mL) was added potassium acetate (13.1 g, 0.134 mol) followed by Pd (P t Bu 3 ) 2 catalyst (1.01 g, 0.002 mmol), and then the reaction mixture was stirred at 150 o C for 4h. The reaction was monitored by TLC; the reaction mixture was then poured into ice cold water and extracted with ethyl acetate (2x 200 mL), and the organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was used for the next step without purification.
  • Step-4 [0668] Trifluoro acetic acid (50 mL) was added to compound 5 (11 g, 0.030 mol) at 0 o C. The resulting reaction mixture was allowed to warm to room temperature and stirred at 100 °C for 16h. Completion of the reaction was monitored by TLC, and after completion, the reaction mixture was quenched with aq. NaHCO 3 solution and extracted with EtOAc (2x200 mL).
  • Step-2 [0678] To a stirred solution of compound 2 (2 g, 8.63 mmol) and compound 3 (4.7 g, 12.95 mmol) in Dioxane (20 ml) and water (2 ml) was added NaHCO 3 (2.17 g, 25.89 mmol) and Pd(dppf)Cl 2 (315 mg, 0.43 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 10 min. Then the reaction mixture was stirred at 90 °C for 6h. The progress of the reaction was monitored by TLC, and after completion of the reaction, the solvent was evaporated. The residue was dissolved in EtOAc and washed with water and brine solution.
  • Step-3 To a stirred solution of compound 4 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 mL) was added Iron Powder (1.9 g, 35.06 mmol) and NH 4 Cl (3.7 g, 70.12 mmol). The resulting mixture was stirred at 80 °C overnight. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was filtered through celite and washed with EtOAc, and the two layers were separated. The organic layer was washed with brine solution, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step-4 [0685] To a stirred solution of compound 5 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 6 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature, and the reaction was stirred for 1h. The reaction mixture was cooled to 0 °C, and NaBH4 (385 mg, 10.14 mmol) was added portion wise. Stirring was continued at rt for 2h. The reaction progress was monitored by TLC, and after completion of the reaction, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with cold water and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step-5 To a stirred solution of compound 8 (915 g, 4.42 mmol) in DCM (20 mL) was added oxalyl chloride (1.1 mL, 13.26 mmol as per acid) followed by cat DMF (0.2 mL) at 0 °C. Then the reaction mixture allowed to stir at room temperature for 3h. Completion of the reaction was monitored by TLC; after completion of the reaction, solvent was evaporated under reduced pressure at N 2 atmosphere. The resulting crude was dissolved in DCM (20 mL) and added to a solution of compound 7 (700 mg, 1.47 mmol) in DCM (30 mL) and TEA (3 mL, 22.10 mmol as per acid) at 0 °C.
  • Step-2 [0695] To a stirred solution of compound 3 (14 g, 40 mmol) in DMF (140 ml), NaH (3.14 g, 130 mmol) was added at 0°C, followed by PMB-Cl (10.20 g, 60 mmol). The reaction mixture was stirred at room temperature for 18 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with DCM. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield the crude compound.
  • Step-3 [0701] To a stirred solution of compound 4 (1.5 g, 3.40 mmol) in DMA (15 mL), potassium acetate (1.2 g, 12.3 mmol) was added, followed by a palladium catalyst (127 mg, 0.014 mmol). The reaction mixture was stirred at 150°C for 4h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield crude compound 5 (600 mg, 49.1% yield) as a yellowish gummy. The crude compound was used for the next step without further purification.
  • Step-5 [0713] A solution of compound 6 (200 mg, 0.83 mmol) in 2 mL of a 1:1 mixture of dichloromethane (DCM) and acetic acid (AcOH) was stirred at 0°C, and N-bromosuccinimide (NBS) (177 mg, 1.00 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours with TLC used for reaction monitoring. Upon completion, the reaction mixture was quenched by pouring it into ice-cold water and subsequently extracted with DCM. The organic layer was desiccated over anhydrous sodium sulfate (Na 2 SO 4 ) and evaporated to yield crude compound 7 (240 mg, 90% yield).
  • DCM dichloromethane
  • AcOH acetic acid
  • NBS N-bromosuccinimide
  • Step-6 [0719] To a stirred solution of compound 7 (200 mg, 0.62 mmol) in Dioxane (4 ml) solution was added compound 8 (272mg, 0.75 mmol) followed by CS 2 CO 3 (613 mg, 1.886 mmol). Reaction mixture was degassed for 15 minutes then Pd (dppf)Cl2, (23 mg, 0.003 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 150 o C for 1 h under microwave conditions. Reaction was monitored by LCMS. LCMS showed 20 % of product reaction mixture was poured into water and extracted with DCM, organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound 9 (100 mg, 33.6%).
  • Step-7 [0725] To a stirred solution of compound 9 (500 mg, 1.05 mmol) in 1,4-dioxane (5 ml) was added 4M HCl in dioxane (5 ml) at 0 o C then reaction mixture was stirred at rt for 2 h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was concentrated under reduced pressure and diluted with cold water. Aqueous Layer was quenched with aq. NaHCO 3 and extracted with 10% MeOH in DCM. Organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound 10 (250 mg, 63.4% yield). The crude compound was used as such for the next step without any purification.
  • Step-9 [0739] To a stirred solution of I-1001 (700 mg, 1.94 mmol) in methanol (10 mL), formaldehyde (116 mg, 3.88 mmol), followed by sodium cyanoborohydride (244 mg, 0.388 mmol) and a catalytic amount of acetic acid (0.1 mL), were added. The reaction was monitored by TLC. After the completion of the reaction, the solvent was evaporated, and the reaction mixture was quenched in water and then extracted with DCM. The organic layer was concentrated and washed with pentane. The crude product was purified by preparative HPLC to yield I-1002 (90 mg, 11.9%) as a white solid.
  • Step-1 [0746] To a cold solution of compound 1 (3 g, 11.90 mmol) in THF (30 mL) was added 60% NaH (525 mg, 13.147 mmol) followed by diethylmalonate (2.2 mL, 13.147 mmol). After completion of addition stirred the reaction mixture for 15 min and evaporated the solvent under reduced pressure. The resulting residue was stirred at 110 °C for 1.5 h. Then again reaction mixture to 0 °C and added 6M aqueous H 2 SO 4 (17 mL). The resulting suspension was stirred at 110 °C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass poured into cold water and basified with NaHCO 3.
  • Step-2 [0752] To a stirred solution of compound 2 (2 g, 8.63 mmol) and compound 3 (4.7 g, 12.95 mmol) in Dioxane (20 ml) and water (2 ml) was added NaHCO 3 (2.17 g, 25.89 mmol), Pd(dppf)Cl2 (315 mg, 0.43 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. Then the reaction mixture stirred at 90 °C for 6 h. The progress of the reaction was monitored by TLC, after completion of the reaction evaporated the solvent. The residue was dissolved in EtOAc and washed with water, brine solution.
  • Step-3 [0759] To a stirred solution of compound 4 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 ml) were added Iron Powder (1.9 g, 35.06 mmol), NH 4 Cl (3.7 g, 70.12 mmol) at room temperature. The resulting mixture stirred at 70 °C for overnight. Progress of the reaction was monitored by TLC. After completion of the reaction, filtered the reaction mass through celite and washed with EtOAc, separated the two layers. Organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-4 [0764] To a stirred solution of compound 5 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 6 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature and continued te stirring for 1h. The reaction mixture cooled to 0 °C and added NaBH4 (385 mg, 10.14 mmol) portion wise. The resulting reaction mixture stirred at room temperature for 2 h. The reaction progress was monitored by TLC, after completion of the reaction, reaction mass quenched with water and extracted with EtOAc. The organic layer washed with cold water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-5 [0769] To a solution of compound 7 (700 mg, 1.47 mmol), triethylamine (3 mL, 22.10 mmol) in DCM (30 mL) was added freshly prepared compound 8 (915 g, 4.42 mmol) in DCM (10 ml) drop wise at 0 °C. The resulting mixture stirred at room temperature for 3 h. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM (100 ml) and washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-6 [0774] To a solution of compound 9 (40 mg, 0.06 mmol) in DMA (10 mL) was added KOAc (30 mg, 0.30 mmol) and Pd(tBu 3 P) 2 (3 mg, 0.006 mmol) at rt. The reaction mixture degassed with nitrogen for 10 min. The reaction mixture stirred at 150 °C in microwave for 4 h. Progress of the reaction was monitored by TLC, after completion of the reaction, reaction mass poured into ice- cold water and extracted with EtOAc. The organic layer washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-7 [0779] Trifluoroacetic acid (2 mL) was added to the compound 10 (200 mg, 0.343 mmol) in a seal tube at room temperature. The resulting mixture stir at 100 °C for 4 h. Completion of the reaction was monitored by TLC and LCMS, after completion, reaction mixture was directly evaporated under reduced pressure. The residue was diluted with water and washed with DCM. The aqueous layer concentrated in vacuo and resulting residue was purified by RP C-18 column (30% ACN in 0.1% FA as an eluent and lyophilized) to afford II-1008 (17 mg, 13.7%) as white solid.
  • Step-8 [0785] To a stirred solution of II-1008 (50 mg, 0.137 mmol) 35% HCHO (0.1 mL) in methanol (3 mL) was added two drops of acetic acid followed by sodium cyanoborohydride (25 mg, 0.413 mmol) at room temperature. The reaction mixture stirred for 5 h at room temperature. The progress of the reaction was monitored by LCMS; after completion of reaction solvent was evaporated in vacuo. The residue was diluted with water and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-2 [0808] Compound 2 (10 g, 40 mmol) was added portion wise to pyridine HF (40 mL) at 0 °C and stirred for 10 min. Then added NaNO 2 (3 g, 44 mmol) portion wise to the reaction mixture at same temperature. The resulting reaction mixture stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC, after completion, the reaction mass poured into ice cold water and extracted with EtOAc (2 x 250 ml). The organic layer washed with sat NaHCO 3 (300 mL), brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford compound 3 (9 g, yield: 90%) as pale-yellow solid.
  • Step-3 [0814] To a stirred solution of compound 3 (1 g, 3.984 mmol) in conc. HCl (15 ml) was added Iron Powder (2.2 g, 39.84 mmol) at room temperature. The resulting mixture heat to reflux for overnight. Progress of the reaction was monitored by TLC, after completion, the reaction mass cooled to room temperature and filtered through celite pad. The filtrate was basified with 20% NaOH solution and extracted with DCM. The organic layer washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford compound 4 (750 mg, yield: 85%) as brown solid. The crude compound was used for next step without further purification.
  • Step-4 [0819] To a stirred solution of compound 4 (5 g, 0.021 mol) and compound 5 (9.3 g, 0.026 mol) in Dioxane (50 ml) and water (5 ml) was added K2CO 3 (5.45 g, 0.065 mol), Pd-118 (791 mg, 0.001 mol) at room temperature. The resulting reaction mixture degassed with nitrogen for 20 min. Then the reaction mixture stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass cooled to room temperature and filtered through celite pad, washed with EtOAc (250 ml). The filtrate was washed with water, brine solution.
  • Step-6 [0829] To a stirred solution of compound 8 (1.9 g, 3.838 mmol), triethylamine (2.67 ml, 19.190 mmol) in DCM (15 ml) was added a solution of freshly prepared compound 9 (1.2 g, 5.757 mmol) in DCM (5 ml) drop wise at 0 °C. The resulting mixture allowed to stir at room temperature for 3 h. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-7 [0835] To a solution of compound 10 (1.2 g, 1.756 mmol) in DMA (15 mL) was added KOAc (688 mg, 7.024 mmol) and Pd(tBu 3 P) 2 (54 mg, 0.105 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 150 °C in a microwave for 2 h. Progress of the reaction was monitored by LCMS, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc (100 ml). The organic layer washed with water, brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-8 [0840] Trifluoroacetic acid (1 mL) was added to compound 11 (60 mg, 0.099 mmol) in a sealed tube at room temperature. The resulting mixture stirred at 100 °C for 4 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass was directly evaporated in vacuo. The resulting residue was purified by reverse phase C-18 column (20% ACN in 0.1% FA as eluent and lyophilized) to afford II-1017 (3 mg, yield: 7.8%) as an off-white solid.
  • reaction mixture was quenched with cold water and extracted with DCM.
  • the aqueous layer was evaporated under reduced pressure.
  • the resulting residue was purified by reverse phase C-18 column (25% ACN in 0.1% FA as eluent and lyophilized) to afford II-1021 (8 mg, 6.5%) as an off-white solid.
  • Step-10 [0852] To a stirred solution of II-1021 (80 mg, 0.216 mmol) 35% HCHO (0.3 mL) in methanol (3 mL) was added acetic acid (0.05 mL) followed by sodium cyanoborohydride (68 mg, 1.084 mmol) at room temperature. The resulting reaction mixture stirred at room temperature for 5 h. The progress of the reaction was monitored by LCMS; after completion, reaction mass quenched with water and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-11 To a stirred solution of II-1017 (70 mg, 0.182 mmol) 35% HCHO (0.1 mL) in methanol (2 mL) was added acetic acid (0.1 mL) followed by sodium cyanoborohydride (57 mg, 0.911 mmol) at room temperature. The resulting reaction mixture stirred at room temperature for 5 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass quenched with water and extracted with 10% MeOH in DCM (50 ml). The organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-2 [0869] To a stirred solution of compound 3 (1.5 g, 4.001 mmol) in MeOH (20 mL) was added compound 4 (0.82 mL, 6.002 mmol), cat AcOH (0.5 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cool to 0 °C and added NaBH4 (456 mg, 12.001 mmol) portion wise. The resulting mixture stirred at room temperature for 3 h. The reaction progress was monitored by TLC, after completion, the reaction mixture quenched with cold water and extracted with EtOAc (2 x 100 ml). The organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-3 [0875] To a solution of compound 5 (1.6 g, 3.232 mmol), triethylamine (2.3 ml, 16.160 mmol) in DCM (20 ml) was added a solution of freshly prepared compound 6 (1.1 g, 5.757 mmol) in DCM (10 ml) drop wise at 0 °C. The resulting mixture allowed to stir at room temperature for 1 h. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-4 [0880] To a solution of compound 7 (500 mg, 0.796 mmol) in DMA (10 mL) was added KOAc (312 mg, 3.184 mmol) and Pd(tBu3P) 2 (25 mg, 0.047 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 150 °C in a microwave for 2 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc (2 x 100 ml). The organic layers washed with water, brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-5 To a stirred solution of compound 8 (250 mg, 0.414 mmol) in DCE (5 mL) was added BBr3 in DCM (5 mL) at 0 °C. The resulting mixture allow to stir at room temperature for overnight. The progress of the reaction was monitored by LCMS, after completion, the reaction mixture was quenched with cold water and DCM (50 ml), separated the two layers. The aqueous layer was evaporated under reduced pressure. The resulting residue was purified by reverse phase C-18 column (15% ACN in 0.1% FA as eluent and lyophilized) to afford II-1021(R) (20 mg, 13%) as a white solid.
  • Step-2 [0897] To a stirred solution of compound 3 (2.7 g, 7.01 mmol) in THF (30 mL) and water (4.5 ml) were added Iron Powder (1.9 g, 35.06 mmol), NH 4 Cl (3.7 g, 70.12 mmol) at room temperature. The resulting mixture stirred at 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, filtered the reaction mass through celite and washed with EtOAc, separated the two layers. Organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-3 [0902] To a stirred solution of compound 4 (1.2 g, 3.38 mmol) in MeOH (10 mL) was added compound 5 (0.6 mL, 4.05 mmol) followed by cat AcOH (0.1 mL) at room temperature and continued the stirring for 1h. The reaction mixture cooled to 0 °C and added NaBH4 (385 mg, 10.14 mmol) portion wise and stirred for 2 h at room temperature. The reaction progress was monitored by TLC, after completion of the reaction, the reaction mass quenched with water and extracted with EtOAc (2 x 50 ml). The organic layer washed with cold water, brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-4 [0907] To a solution of compound 6 (700 mg, 1.47 mmol), triethylamine (3 mL, 22.10 mmol) in DCM (20 mL) was added freshly prepared compound 7 (915 g, 4.42 mmol) in DCM (10 ml) drop wise at 0 °C. The resulting mixture stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-5 [0912] To a solution of compound 8 (40 mg, 0.06 mmol) in DMA (10 mL) was added KOAc (30 mg, 0.30 mmol) and Pd(tBu 3 P) 2 (3 mg, 0.006 mmol) at rt. The reaction mixture degassed with nitrogen for 10 min. The reaction mixture stirred at 150 °C in microwave for 1.5h. Progress of the reaction was monitored by TLC, after completion of the reaction, reaction mass poured into ice-cold water and extracted with EtOAc. The organic layer washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-6 [0917] Trifluoroacetic acid (2 mL) was added to the compound 9 (60 mg, 0.151 mmol) in a sealed tube at room temperature. The resulting reaction mixture stirred at 100 °C for 4 h. The progress of the reaction was monitored by LCMS, after completion, the reaction mass was directly evaporated under reduced pressure. The residue was purified by Prep HPLC and lyophilized to afford II-1028 (6 mg, 15.8%) as white solid.
  • Step-2 [0924] To a stirred solution of compound 2 (1 g, 4.424 mmol) in DCM (10 mL) was added TEA (1.8 mL, 13.274 mmol) followed by (Boc) 2 O (1.5 mL, 6.636 mmol) at 0 °C. The resulting mixture stirred at room temperature for overnight. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-3 [0930] To a stirred solution of compound 3 (900 mg, 2.846 mmol), B2Pin2 (1 g, 4.269 mmol) in Dioxane (10 mL) was added KOAc (557 mg, 0.5.693 mmol), Pd(dppf)Cl2 (83 mg, 0.113 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 90°C for overnight. The progress of the reaction was monitored by TLC, after completion, the reaction mass filtered through celite and washed with EtOAc (100 ml). the organic layer washed with water, brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-4 [0937] To a stirred solution of compound 4 (161 mg, 0.432 mmol) and compound 5 (100 mg, 0.432 mmol) in Dioxane (2 ml) and water (0.5 ml) was added NaHCO 3 (109 mg, 1.298 mmol), Pd(dppf)Cl2 (19 mg, 0.025 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min and stirred at 90 °C for 16h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with EtOAc (50 ml), filtered through celite pad. The filtrate was washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-5 [0942] To a stirred suspension of compound 6 (200 mg, 0.503 mmol) in THF (6 mL) and water (2 ml) was added NH 4 Cl (269 mg, 5.037 mmol) followed by Iron Powder (140 mg, 2.518 mmol) at room temperature. The resulting mixture heated to 80 °C and stirred for overnight. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with EtOAc (50 ml), filtered through celite pad. The filtrate was washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo to get compound 7 (150 mg, yield: 85%) as yellow syrup.
  • Step-6 [0947] To a stirred solution of compound 7 (1.4 g, 3.814 mmol) in MeOH (15 mL) was added compound 8 (0.7 mL, 5.722 mmol) followed by AcOH (0.5 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cooled to 0 °C and added NaBH4 (434 mg, 11.444 mmol) portion wise. The reaction mixture allowed to stir at room temperature for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass quenched with cold water and extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-7 [0952] To a stirred solution of compound-9 (150 mg, 0.308 mmol) and TEA (0.1 mL, 0.924 mmol) in DCM (5 mL) was added a solution of freshly prepared compound 10 (103 mg, 0.462 mmol) in DCM (2 mL) at 0 °C. The resulting mixture allowed to stir at room temperature for 1 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM (50 ml) and washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-8 [0957] To a stirred solution of compound 11 (500 mg, 0.739 mmol) in DMA (5 mL) was added KOAc (289 mg, 2.958 mmol) and Pd(tBu 3 P) 2 (23 mg, 0.044 mmol) at room temperature. The reaction mixture degassed with nitrogen for 10 min and stirred at 150 °C in a microwave for 1 h. the progress of the reaction was monitored by TLC, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with cold water, brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-9 [0962] Trifluoroacetic acid (2 mL) was added to the compound 12 (100 mg, 0.167 mmol) room temperature. The resulting mixture stirred at 100 °C for 4 h. The progress of the reaction was monitored by LCMS, after completion, evaporated the solvent under reduced pressure. The resulting residue was purified by reverse phase C-18 column (10% ACN in 0.1% FA as eluent and lyophilized) to afford II-1029 (15 mg, 23.8%) as a white solid.
  • Trifluoroacetic acid (1.5 mL) was added to the compound-13 (110 mg, 0.164 mmol) at room temperature. The resulting mixture stirred at 100 °C for 4 h. Completion of the reaction was monitored by LCMS; after completion, evaporated the solvent under reduced pressure. The resulting residue was purified by reverse phase C-18 column (5% ACN in 0.1% FA as eluent and lyophilized) to afford compound as off-white solid. Resulting solid was treated with basic resin in methanol at rt for 1 h and filtered. The filtrated was evaporated and lyophilized to afford II- 1032 (5 mg, 15.6%) as an off-white solid.
  • Step-3 [0983] To a stirred solution of compound 3 (12 g, 0.047 mol) in MeOH (120 mL) was added Sodium methoxide (3.2 g, 0.060 mol) portion wise at 0 °C. The resulting mixture allow to stir at 80 °C for 3 h. Progress of the reaction was monitored by TLC, after completion, evaporated the solvent under reduced pressure. The resulting residue diluted with water and extracted with EtOAc. The organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude compound was triturated with ether, filtered and dried to afford compound 4 (5.5 g, yield: 46.6%) as brown solid.
  • Step-4 [0988] To a stirred solution of 4 (5 g, 0.020 mol) and compound 5 (8.7 g, 0.024 mol) in Dioxane (50 mL) and water (5 mL) was added NaHCO 3 (5.1 g, 0.060 mol), Pd(dppf)Cl 2 (740 mg, 0.001 mol) at room temperature. The resulting reaction mixture degassed with nitrogen for 20 min and stirred at 90°C for 16h. Progress of the reaction was monitored by TLC, after completion, the reaction mass filtered through celite pad and washed with EtOAc. The filtrate was washed with water, brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-5 [0993] To a stirred suspension of compound 6 (2 g, 4.987 mmol) in THF (30 mL) and water (10 ml) was added NH4Cl (1.33 g, 24.937 mmol) followed by Iron Powder (6.97 g, 24.937 mmol) at room temperature. The resulting mixture allow to stir at 80 °C for 16h. The progress of the reaction was monitored by TLC, after completion, the reaction mass filtered through celite pad and washed with EtOAc (150 ml). The filtrate was washed with water, brine solution. The organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo to get compound 7 (1.8 g, 97.2%).
  • Step-6 To a stirred suspension of 7 (1.8 g, 4.851 mmol) in MeOH (20 mL) was added compound 8 (0.99 g, 7.277 mmol), cat AcOH (0.1 mL) at room temperature and continued the stirring for 1 h. Then reaction mixture cool to 0 °C and added NaBH4 (210 mg, 5.513 mmol) portion wise. The resulting mixture allowed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mixture quenched with cold water and extracted with DCM (2 x 100 ml).
  • Step-7 [0995] To a stirred solution of 9 (2.5 g, 5.091 mmol) and compound 10 (1.23 g, 6.109 mmol) in DCM (25 mL) was added EDCI (1.46 g, 7.637 mmol) at room temperature and continued the stirring for overnight. The reaction progress was monitored by TLC, after completion, the reaction mass diluted with DCM and washed with water, brine solution.
  • Step-8 [1000] To a solution of 11 (500 mg, 0.742 mmol) in DMA (5 mL) was added KOAc (291 mg, 2.967 mmol) and Pd(tBu 3 P) 2 (38 mg, 0.074 mmol) at room temperature. The reaction mixture degassed with nitrogen for 15 min and stirred at 150 °C in a microwave for 2 h. Progress of the reaction was monitored by TLC, after completion, the reaction mass poured into ice-cold water and extracted with EtOAc. The organic layer washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-9 [1006] Trifluoroacetic acid (1mL) was added to the compound 12 (100 mg, 0.168 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. Progress of the reaction was monitored by LCMS, after completion, the reaction mixture was evaporated in vacuo. The resulting residue was purified by reverse phase C-18 column (25% ACN in 0.1% FA as eluent and lyophilized) to afford compound III-1003 (15 mg, yield: 24.7%) as a white solid.
  • Step-10 [1012] To a stirred solution of III-1003 (30 mg, 0.080 mmol) 35% HCHO (0.2 mL) in methanol (1 mL) was added acetic acid (0.05 mL) followed by sodium cyanoborohydride (16 mg, 0.240 mmol) at room temperature. The resulting reaction mixture stirred at room temperature for overnight. The progress of the reaction was monitored by LCMS, after completion, the reaction mass quenched with water and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-1 [1018] To a stirred solution of compound 1 (20 g, 97 mmol) in DMF (250 mL), compound 2 (13.3 g, 97 mmol) was added, followed by DIPEA (53 mL, 289 mmol) and HATU (54 g, 144 mmol). The reaction mixture was then stirred at room temperature for 5 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2x 500 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford the crude compound.
  • Step-2 [1021] To a stirred solution of compound 3 (10 g, 30.5 mmol) in DMF (100 mL), NaH (2.2 g, 91.7 mmol) was added at 0°C, followed by PMB-Cl (7 mL, 61 mmol). The reaction mixture was stirred for 3 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (2x 500 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield the crude compound.
  • Step-3 [1024] To a stirred solution of compound 4 (15 g, 33 mmol) in DMA (150 mL), potassium acetate (13.1 g, 134 mmol) was added, followed by Pd (PtBu3) 2 catalyst (1.01 g, 2.0 mmol). The reaction mixture was stirred at 150°C for 4 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2x 200 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield the crude compound. The crude compound was used for the next step without purification.
  • the reaction mixture was degassed for 15 minutes, and then Pd(dppf)Cl2 catalyst (112 mg, 0.053 mmol) was added, followed by another 10-minute degassing.
  • the reaction mixture was stirred at 85°C for 15 hours. The reaction progress was monitored by LCMS. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2x100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield the crude compound.
  • the crude compound was purified by column chromatography using silica gel (100:200 mesh). The compound was eluted using 20% EtOAc in hexane to afford pure compound 9 (60 mg, Yield: 8%) as a white solid.
  • reaction mixture was then stirred at room temperature for 15 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and washed with ethyl acetate (2x100 mL). The aqueous layer was quenched with aqueous NaHCO 3 and extracted with 10% MeOH in DCM (2x100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield the crude compound. The crude compound was purified by column chromatography using silica gel (100:200 mesh).
  • Step-8 [1040] To a stirred solution of compound 10 (100 mg, 0.263 mmol) in methanol (2 mL), 35% HCHO (0.1 mL) was added, followed by two drops of acetic acid, and then sodium cyanoborohydride (35 mg, 0.527 mmol) at room temperature. The reaction mixture was stirred for 5 hours at room temperature. The progress of the reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step-2 [1052] To a stirred solution of compound 3 (6 g, 17.92 mol) in DMF (60 mL) was added NaH (1.2 g, 53.25 mol) at 0 o C followed by MOM-Cl (3 mL,26.20 mol) then reaction mixture was stirred at for 3h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with EtoAc (2x500 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-3 [1054] To a stirred solution of compound 4 (7 g, 0.018 mmol) in DMA (70 mL) was added potassium acetate (5.2 g, 0.56 mol) followed by Pd (P t Bu3) 2 catalyst (943 mg, 5.4 mmol) then reaction mixture was stirred at 150 o C for 4h.
  • Step-6 [1072] To a stirred solution of compound 8 (30 mg, 0.608 mmol) in 1,4-dioxane (3 mL) was added 4M HCl in dioxane (1.5 mL) at 0 o C then reaction mixture was stirred at rt for 2h. Reaction was monitored by TLC; after completion of reaction, reaction mixture was quenched with aq. NaHCO 3 and extracted with ethyl acetate. Crude was purified by C-18 reverse phase column chromatography to afford II-1018 (1 mg, Yield: 4 %) as a white solid.
  • Step 2 [1088] To a stirred solution of compound 2 (12.8 g, 51.2 mmol) in Dioxane (128 ml) solution was added methyl boronic acid (3.98 g, 66.5 mmol) followed by Cs 2 CO 3 (50.0 g, 153 mmol). Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 (2.2 g, 3.072 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 o C for 16 h. The reaction progress was monitored by TLC, reaction mixture was poured into ice cold water and extracted with ethyl acetate, organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • methyl boronic acid 3.98 g, 66.5 mmol
  • Cs 2 CO 3 50.0 g, 153 mmol
  • reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 catalyst (164 mg, 0.253 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 85 o C for 16h. Reaction was monitored by TLC; reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x300 mL), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound. Crude compound was purified by column chromatography using a silica gel (100: 200 mesh) compound was eluted using 20% EtOAc in Hexane to afford compound 11 (243 mg, Yield: 16 %) as a white solid.
  • Step-10 [1112] To a stirred solution of compound-9 (150 mg, 0.445 mmol) and compound-10A (200 mg, 0.534 mmol) in Dioxane:H 2 O (2.2 ml, 2:0.2) was added K 2 CO 3 (123 mg, 0.890 mmol), Pd(OAc)2 (40 mg, 0.044 mmol) and xanthphos (51.4 mg, 0.089 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min. The reaction mixture heated to 90°C in a microwave and stirred for 2 h. progress of the reaction was monitored by LCMS; after completion, reaction mass diluted with EtOAc and filtered through celite.
  • Step-2 [1122] N, N-Dimethylformamide dimethyl acetal (19 ml, 143.79 mmol) was added dropwise to a stirred solution of compound 2 (20 g 130.71 mmol) in ethanol (200 ml). The resulting solution was stirred for 15h at 80 o C. After completion of the reaction the reaction mixture was cooled to rt and concentrated under vacuum. The residue was diluted with 50 ml of water and extracted with ethyl acetate (200 ml). The organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford crude compound.
  • Step-3 [1125] HBr (40% in acetic acid, 125 ml) was added dropwise to a 40 o C stirred solution of compound 3 (25 g, 120.19 mmol) in acetic acid (125 ml), and the resulting solution was stirred for 15h at 55 o C.
  • the reaction mixture was cooled to rt and then poured into 10 ml of cold water.
  • the pH value of the solution was adjusted to 9 with 2M aqueous sodium carbonate solution. Concentrated under vacuum.
  • the resulting mixture was extracted with ethyl acetate (500 ml). The organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford crude compound.
  • Step-6 [1134] To a stirred solution of compound 7 (4 g, 11.363 mmol) in DMF (40 mL) was added NaH (818 mg, 34.083 mmol) at 0 o C followed by MOM-Cl (1.36 g, 17.045 mmol) then reaction mixture was stirred at rt for 6 h. Reaction was monitored by TLC, the reaction mixture was poured into ice cold water and extracted with DCM (200 ml), organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford crude compound.
  • Step-7 [1137] To a stirred solution of compound 8 (2.0 g, 5.05 mmol) in DMA (20 ml), potassium acetate (2.47 g, 25.252 mmol) was added, followed by Pd(PtBu3)2 (258 mg, 0.252 mmol). The reaction mixture was then stirred at 150°C for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (200 ml X 3). The organic layers were dried over anhydrous Na 2 SO 4 and evaporated to afford the crude compound.
  • Step-8 [1140] To a stirred mixture of compound 9 (1.1 g, 3.481 mmol) in H 2 SO 4 (11 ml), 1,3- Dibromo-5,5-dimethyl hydantoin (992 mg, 3.481 mmol) was added at 0°C, and the reaction was continued at 0°C for 1 hour. The reaction progress was monitored by TLC. After the completion of the reaction, the mixture was quenched in ice water and extracted with DCM. The organic layer was concentrated under reduced pressure to yield crude compound 10 as a brown solid (800 mg, 66.1%). The crude product was used for the next step without purification.
  • reaction mixture was degassed for 15 minutes, and then Pd(dppf)Cl2 (63 mg, 0.085 mmol) was added. It was degassed again for 10 minutes, and the reaction mixture was stirred at 85°C for 1 hour under microwave irradiation. The reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to obtain the crude compound.
  • Step-10 [1146] To a stirred solution of crude compound 12 (300 mg, 0.594 mmol) in 1,4-dioxane (3 ml), dioxane/HCl (4 ml) was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the excess TFA was evaporated in vacuo. The residue was purified by preparative HPLC and lyophilized to yield I-1016 (5 mg, 2.08%) as a white solid.
  • Step-2 [1161] To a stirred solution of compound 3 (10 g, 30.5 mmol) in DMF (100 mL), NaH (2.2 g, 91.7 mmol) was added at 0°C, followed by PMB-Cl (7 mL, 61 mmol). The reaction mixture was stirred for 3 hours and monitored by TLC. After the reaction was complete, the mixture was poured into ice-cold water and extracted with EtOAc (2x500 mL). The organic layer was dried over anhydrous Na 2 SO 4 and then evaporated to yield the crude compound.
  • Step-3 [1164] To a stirred solution of compound 4 (15 g, 33.55 mmol) in DMA (150 mL), potassium acetate (13.1 g, 134 mmol) was added, followed by Pd (PtBu3) 2 catalyst (1.01 g, 2.0 mmol). The reaction mixture was stirred at 150°C for 4 hours and monitored by TLC. After the reaction was complete, the mixture was poured into ice-cold water and extracted with ethyl acetate (2x200 mL). The organic layer was dried over anhydrous Na 2 SO 4 and then evaporated to yield the crude compound. The crude compound was used for the next step without purification.
  • reaction mixture was degassed with nitrogen for 10 minutes, and then Pd-118 (100 mg, 4.6 mmol) was added. The mixture was degassed again for 10 minutes. The resulting reaction mixture was stirred at 85°C for 15 hours. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2x100 mL). The organic layer was washed with a brine solution (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step-7 [1178] To a stirred solution of compound 8 (300 mg, 0.682 mmol) in 1,4-dioxane (5 mL), dioxane/HCl (2.5 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours and monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water (10 mL) and washed with ethyl acetate (50 mL x 2). The aqueous layer was quenched with aqueous NaHCO 3 and extracted with a 10% MeOH in DCM solution (50 mL x 2). The organic layer was dried over anhydrous Na 2 SO 4 and then evaporated to yield the crude compound.
  • reaction mixture Upon completion of the reaction, the reaction mixture was cooled and quenched with cold water. The reaction mixture was then extracted with 50 mL of DCM to remove organic impurities. The aqueous layer was concentrated and purified using reverse-phase C-18 column chromatography with acetonitrile/water (containing 0.01% HCOOH) as the eluent. This resulted in the isolation of compound II-1016 (6 mg) with a yield of 5.20% as a white solid.
  • Step-2 [1196] To a stirred solution of compound 2 (12.6 g, 0.054 mol) in DCM (126 ml), TEA (12.6 mL) was added, followed by Boc anhydride (31 ml, 0.135 mol) and DMAP (2.65 g, 0.022 mol). The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After the completion of the reaction, the mixture was poured into ice-cold water and extracted with DCM (300 ml ⁇ 3). The separated organic layers were dried over anhydrous Na 2 SO 4 and then evaporated to yield crude compound 3 as a pale brown oil (13.0 g, 55.3% yield). The crude compound was used for the next step without any purification.
  • Step-3 [1199] To a stirred solution of compound 3 (13 g, 30.16 mmol) in THF:Water (3:1) (130 ml), Fe (16.9 g, 301.62 mmol) was added, followed by NH4Cl (16.3 g, 301.62 mmol). The reaction mixture was stirred at 60°C for 6 hours. Reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with DCM (200 ml ⁇ 2). The separated organic layers were dried over anhydrous Na 2 SO 4 and then evaporated to yield the crude compound.
  • Step-4 [1202] To a stirred solution of compound 4 (5 g, 12.4 mmol) in DCM:AcOH (25:1, 52 ml), NBS (2.66 g, 14.9 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water (100 ml) and extracted with DCM (100 ml ⁇ 3). The organic layer was dried over anhydrous Na 2 SO 4 and then evaporated to yield the crude compound.
  • Step-5 [1205] To a stirred solution of compound 5 (1.0 g, 2.08 mmol) in Dioxane:H 2 O (9:1, 10 mL), compound 6 (970 mg, 0.52 mmol) was added, followed by K2CO 3 (864 mg, 6.26 mmol) at room temperature. The reaction mixture was degassed for 15 minutes, and then Pd-118 (136 mg, 0.208 mmol) was added. It was degassed again for 10 minutes, and the reaction mixture was stirred at 70°C for 5 hours. The reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered through celite. The celite bed was washed with ethyl acetate (100 ml ⁇ 2).
  • the filtrate was diluted with water (50 ml) and extracted with ethyl acetate (50 ml ⁇ 4).
  • the separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude compound 7.
  • the crude product was purified by silica gel (100-200 mesh) column chromatography using a 30% ethyl acetate:hexane eluent, resulting in compound 7 as a yellow liquid (600 mg, 53.5% yield).
  • reaction progress was monitored by TLC. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was diluted with 10% methanol in DCM, followed by decanting. The decanted organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to yield compound 8 as a pale brown solid (1.4 g, 84.3% yield). The crude compound was used as-is for the next step without any further purification.
  • Step-2 [1212] To a solution mixture of compound 2 (20 g, 95.2 mmol) in THF (100 mL), BH 3 .DMS (10 M in DMS) (10.5 mL, 104.7 mmol) was added at reflux temperature. The reaction mixture was kept at reflux for 30 minutes, then cooled to room temperature. The pH was adjusted to 2.0 with 6N HCl and neutralized with aqueous 6N NaOH. This solution was extracted with DCM (2 ⁇ 200 mL). The combined organic layer was dried over Na 2 SO 4 and concentrated under vacuum to yield compound 3 (20 g, crude).
  • Step-3 [1215] To a solution mixture of compound 3 (20 g, 93.4 mmol) in DCM (200 mL), TEA (19.6 mL, 140.1 mmol) was added, followed by (Boc) 2 O (25.7 mL, 112.0 mmol) at 0°C. The reaction mixture was kept at room temperature for 2 hours and then evaporated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), eluting the compound with 5% EtOAc in hexane to yield compound 4 (13 g, yield: 44.3%) as an off-white solid.
  • Step-4 [1218] To a solution mixture of compound 4 (6.0 g, 19.1 mmol) in Dioxane (60 mL), Bis(pinacolato)diboron (5.82 g, 22.9 mmol), Pd(dppf)Cl2 (567.1 mg, 0.76 mmol), and KOAc (3.74 g, 38.2 mmol) were added at room temperature. The reaction mixture was degassed with N2 for 5 minutes, then kept at 90°C for 15 hours. After completion, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with EtOAc (2 ⁇ 100 mL). The combined organic layers were washed with water and brine, and then concentrated under vacuum.
  • the resulting reaction mixture was allowed to stir at room temperature for 1 hour.
  • the reaction mixture was then cooled to 0°C, and methane sulfonic acid (30 mL, 1.2 vol) was added, followed by DBDMH (30 g, 108 mol) added portion- wise over 10 minutes.
  • the resulting mixture was stirred at room temperature overnight.
  • the progress of the reaction was monitored by TLC.
  • the reaction mass was slowly quenched with cold water and extracted with DCM (500 ml). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the resulting crude product was used as-is for the next step without any further purification.
  • Step-3 [1223] To a stirred solution of compound 4 (45 g, 0.145 mol) in MeOH (225 mL, 5 vol) was added 2N aq NaOH (225 mL, 5 vol) at 0 °C. The resulting reaction mixture allow to stir at rt for 4 h. Progress of the reaction was monitored by TLC; after completion, Evaporated the solvent under reduced pressure. The resulting residue was diluted with water and extracted with DCM. The organic layer washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude compound used as such for next without any purification.
  • Step-4 [1224] To a stirred solution of compound 5 (29 g, 0.135 mol) in DCM (290 mL, 10 vol), TEA (54 mL, 0.405 mol, 3 eq) was added, followed by (Boc) 2 O (46 mL, 0.203 mol, 1.5 eq) at 0 °C. The resulting reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS. After the reaction was completed, it was diluted with DCM and washed with water and a brine solution. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step-5 [1227] To a stirred suspension of compound 6 (30 g, 0.095 mol) and B2Pin2 (36 g, 0.143 mol) in Dioxane (300 ml, 10 vol), KOAc (27 g, 0.285 mol) was added at room temperature. The resulting mixture was degassed with nitrogen for 15 minutes, and Pd(dppf)Cl2 (3.4 g, 0.0047 mol) was added. The reaction mixture was degassed again for 10 minutes and stirred at 90°C overnight. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mass was cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted with EtOAc.
  • Step-2 [1233] To a stirred suspension of compound 8 (30 g, 0.0914 mol) and B2Pin2 (34 g, 0.137 mol) in dioxane (300 mL, 10 vol), KOAc (26 g, 0.247 mol) was added at room temperature. The resulting mixture was degassed with nitrogen for 15 minutes, and then Pd(dppf)Cl2 (3.3 g, 0.0046 mol, 0.05 eq) was added. The reaction mixture was degassed again for 10 minutes and stirred at 90°C for 15 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mass was cooled to room temperature and filtered through celite.
  • Step-2 [1239] To a stirred solution of Compound 9 (10 mg, 0.021 mmol) in DCM (0.2 ml), TFA (0.2 ml) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 6 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the excess TFA was evaporated in vacuo. The residue was purified by preparative HPLC and then lyophilized, yielding II-1033 as a white solid (1.5 mg, 19.2% yield).
  • Step-2 [1246] To a stirred solution of compound 9 (80 mg, 0.172 mmol) in DCM (0.8 mL), TFA (0.4 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield the crude compound. The crude product was then purified by preparative HPLC and subsequently lyophilized, resulting in the isolation of II-1033(R) as a white solid (22 mg, 35% yield).
  • Step-1 [1254] To a stirred solution of compound 9 (40 mg, 0.086 mmol) in 47% HBr in water (1.2 mL), NaNO 2 (13.1 mg, 0.189 mmol) was added, followed by CuBr (27 mg, 0.189 mmol) at 0°C. The resulting mixture was stirred at 80°C for 2 hours. The reaction was monitored by LCMS, which indicated a 61.5% yield of the desired product. After the completion of the reaction, HBr was evaporated under reduced pressure to yield the crude compound. The crude product was then purified by preparative HPLC, resulting in the isolation of II-1038(R) as a white solid (4 mg, 10.8% yield).
  • Step-2 [1261] To a stirred solution of compound 10 (90 mg, 0.188 mmol) in DCM (1.8 mL), TFA (0.9 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield the crude compound.
  • Step-4 [1293] To a stirred solution of compound 4 (10 g, 0.043 mol) in DMSO (100 mL) was added CuI (1.63 g, 0.0.0086 mol), L-Proline (1.98 g, 0.017 mol) followed by K2CO 3 (8.9 g, 0.064 mol) in a seal tube at rt. The resulting reaction mixture degassed with N 2 for 15 min and added aq ammonia (10 mL, 1 vol). The seal tube was fitted with cap and stirred at 100 °C for 7 h. After completion, reaction mass quenched with cold water and filtered through celite. The filtrate was extracted with EtOAc and washed with cold water, brine solution.
  • Step-5 [1299] To a stirred solution of compound 5 (7 g, 42 mmol) and compound 6 (8.67 g, 42 mmol) in MeCN (140 mL) was added TCFH (23.5 g, 84 mmol) followed by NMI (17 mL, 209 mmol) at 0 °C. The resulting mixture stirred at 80 °C for 5 h. Progress of the reaction was monitored by TLC; after completion, reaction mass quenched with cold water and extracted with EtAOc. Organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-7 [1312] To a stirred solution of compound 8 (3 g, 6.289 mmol) in DMA (30 mL) was added KOAc (2.46 g, 25.157 mmol) at room temperature. The resulting mixture degassed with nitrogen for 15 min. Then added Pd(tBu 3 P) 2 (194 mg, 0.377 mmol) and again degassed for another 10 min. The resulting mixture stirred at 150 °C for overnight. Completion of the reaction was monitored by LCMS; after completion, reaction mass poured into ice cold water and extracted with ethyl acetate.
  • Step-8 [1318] To a stirred suspension of compound 9 (9 g, 0.022 mol) in THF (135 mL) and water (25 mL) was added NH 4 Cl (12.1 g, 0.226 mol) followed by Iron powder (12.6 g, 0.226 mol) at room temperature. The resulting mixture stirred at 80 °C for overnight. Progress of the reaction was monitored by TLC; after completion, reaction mass diluted with ethyl acetate and filtered through celite. The filtrate was washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo to get compound 10 (7 g, yield: 84.6%) as brown gum. The crude material used as such for next step without any purification.
  • Step-9 [1324] To a stirred suspension of CuBr (2.74 g, 19.178 mmol) in MeCN (30 mL) was added tert- butylnitrite (2.3 mL, 19.178 mmol) at 0 °C. The resulting mixture stirred at same temperature for 20 min. Then added a solution of compound 10 (3.5 g, 9.589 mmol) dissolved in MeCN (20 mL) at 0 °C. The reaction mixture allowed to stir at room temperature for 2 h. After completion, reaction mass quenched with water and filtered through celite, washed with ethyl acetate. The filtrate was extracted with ethyl acetate and washed with brine solution.
  • Step-2 [1336] Trifluoroacetic acid (30 mL) was added to compound 3 (3 g, 5.025 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. After completion, evaporated the excess TFA reduced pressure. The resulting residue was diluted with water and dichloromethane, separated the two layers. The aqueous layer basified with saturated NaHCO 3 upto pH ⁇ 9 and extracted with 10% MeOH in DCM. The organic layer washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting solid was sonication in MeCN, filtered and washed with cold MeCN.
  • Step-2 [1349] To a stirred solution of compound 13 (120 mg, 0.205 mmol) in DMF (3 mL) was added NaH (24 mg, 0.617 mmol) at 0 °C and continued the stirring for 20 min before being addition of CD 3 I (90 mg, 0.617 mmol). The resulting mixture stirred at room temperature for overnight. Reaction was monitored by LCMS; after completion of reaction, reaction mass quenched with cold water and extracted with ethyl acetate. Organic layer washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-3 [1355] Trifluoroacetic acid (1.5 mL) was added to the compound 14 (60 mg, 0.10 mmol) at room temperature. The resulting mixture stirred at 100 °C for 3 h. After completion of reaction, evaporated the excess TFA reduced pressure. The resulting residue was purified by prep HPLC and lyophilized to afford compound II-1046(R) (16 mg, yield: 21.5%) as a white solid.
  • reaction mixture degassed with nitrogen for 10 min.
  • the reaction mixture stirred at 90 °C for 6 h.
  • reaction mass filtered through celite, washed with ethyl acetate.
  • the filtrate was washed with water, brine solution.
  • the organic layer dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the crude compound was purified by reverse phase C-18 column chromatography (65% MeCN in 0.1% FA as an eluent and extracted) to afford compound 3 (40 mg, yield: 60.6%) as pale brown gum.
  • Step-2 [1382] To a solution mixture of compound 2 (5 g, 23.8 mmol) in THF (50 mL) was added BH 3 .DMS (10 M in DMS) (5 mL) at reflux temperature. Reaction mixture was continuous for 30 min at reflux, cooled to rt and pH adjusted to 2 with 6N HCl and neutralize with 6N NaOH, this solution was extracted with DCM (2x50 ml). Combined organic layer was dried over Na 2 SO 4 and concentrated under vacuo to afford compound 3 (5 g, 97.8%).
  • Step-3 [1383] To a solution mixture of compound 3 (5 g, 20 mmol) in DCM (50 ml) was added TEA (4 mL, 60 mmol) and followed by (Boc) 2 O (5.6 mL, 20 mmol) at 0oC. Reaction mixture was continuous for 2h at rt and evaporated under vacuo. Crude compound was purified by column chromatography silica gel (100: 200 mesh) using 5% EtOAc in Hexane as an eluent to afford compound 4 (2.1 g, Yield-29%) as an off white solid.
  • Step-4 [1384] To a stirred solution of compound 4 (300 mg, 0.955 mmol) in Dioxane (3 ml) was added Bis(pinacolato)diboron (291 mg, 1.14 mmol) and potassium Acetate (280 mg, 2.857 mmol) Reaction mixture was degassed for 15 minutes then Pd(dppf)Cl2 (70 mg, 0.095 mmol) was added and again degassed for 10 minutes then reaction mixture was stirred at 90oC for 15 h. The reaction was monitored by TLC and LCMS, After completion of reaction, The filtrate was diluted with water and extracted with 10% methanol in DCM (100 ml).
  • Step-1 [1398] To a stirred solution of compound 11 (200 mg, 0.465 mmol) CHCl3 (2 ml) was added mCPBA (88 mg, 0.511 mmol) at 0 ° C under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 4 h. After completion of reaction, the reaction mixture was diluted with DCM (50 ml) and washed with water. The organic layer washed with NaHCO 3 (50 ml), brine solution. The organic layer dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was triturated with ether and dried to afford compound 12 (200 mg, yield: 96%) as an off-white solid.
  • Step-2 [1399] To a stirred solution of compound 12 (200 mg, 0.448 mmol) in Ac 2 O (2 ml) at room temperature. The resulting mixture stirred at 100 °C for 3 h. The progress of the reaction was monitored by TLC, after completion, the reaction mass diluted with DCM and purified by silica gel (100-200) column chromatography (50% ethyl acetate in hexane as an eluent) to afford compound 13 (150 mg, yield: 68.8%) as an off-white solid.
  • Step-3 [1404] To a stirred solution of compound 13 (150 mg, 0.308 mmol) and compound 14 (111 mg, 0.308 mmol) in dioxane (2 ml) and water (0.2 ml) was added K2CO 3 (127 mg, 0.924 mmol) and Pd-118 (10 mg, 0.015 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 10 minutes and stirred at 90°C overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mass was diluted with EtOAc (100 ml) and filtered through a celite pad. The filtrate was washed with a brine solution, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step-4 [1409] To a stirred solution of compound 15 (100 mg, 0.156 mmol) in MeOH (1 ml), K2CO 3 (22 mg, 0.156 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was filtered and washed with DCM The crude The filtrate was concentrated under reduced pressure to get compound 16 (80 mg, yield: 86%) as pale yellow solid. The solid compound used as such for next step without any purification.
  • Step-6 [1420] To a stirred solution of compound 13 (200 mg, 0.416 mmol) and compound 17 (146 mg, 0.410 mmol) in Dioxane (2 ml) and water (0.2 ml) was added K2CO 3 (170 mg, 1.232 mmol), Pd- 118 (16 mg, 0.024 mmol) at room temperature. The resulting reaction mixture degassed with nitrogen for 10 min and stirred at 90 °C for overnight. Progress of the reaction was monitored by TLC; after completion, the reaction mass diluted with EtOAc (100 ml) and filtered through celite pad. The filtrate was washed with brine solution, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step-7 [1426] To a stirred solution of compound 18 (120 mg, 0.183 mmol) in MeOH (2 ml), K2CO 3 (25 mg, 0.183 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was diluted with DCM and filtered through celite. The celite was washed with DCM (10 ml). The filtrate was concentrated under reduced pressure to get compound 19 (30 mg, yield: 26%) as an off-white solid. The crude compound used as such for next step. [1427] LCMS: m/z: 613, 77.
  • reaction mixture was quenched with 1N HCl. Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield compound 2 (8 g, 96.15%) as a pale brown liquid. The crude compound was used for the next step without purification.
  • reaction mixture was then stirred for 30 minutes at 0°C. The progress of the reaction was monitored by TLC analysis. After the completion of the reaction, the reaction mixture was filtered through a celite bed, washed with DCM, and ice-cold water (100 mL) was added. The mixture was then extracted with DCM (3 x 100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield compound 5 (3 g, 95.20%) as a pale yellow liquid. The crude compound was used for the next step without purification.
  • reaction mixture was then stirred for 2 hours at 70°C. The progress of the reaction was monitored by TLC and LCMS analysis. After the completion of the reaction, the reaction mixture was quenched with ice-cold water, resulting in the formation of a precipitate. This was filtered through a celite bed, washed with ethyl acetate (100 ml X 3). Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to afford the crude compound (3 g).
  • Step-6 [1448] To a stirred solution of compound 6 (0.650 g, 1.951 mmol) in MeOH (20 mL), NaBH4 (37 mg, 0.975 mmol) was added at 0°C. The reaction mixture was then stirred for 4 hours at room temperature. The progress of the reaction was monitored by TLC and LCMS analysis. After the completion of the reaction, the reaction mass was evaporated under reduced vacuum. Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and evaporated to yield compound 7 & 7A (500 mg, 76.56%) as a pale yellow liquid.
  • Step-7 [1451] To a stirred solution of compound 7 & 7A (300 mg, 0.892 mmol) in 1,4-Dioxane (6 mL) under an argon atmosphere, potassium acetate (263 mg, 2.676 mmol), and B2Pin2 (451 mg, 1.785 mmol) were added. The reaction mixture was degassed for 5 minutes. Pd-118 (60 mg, 0.089 mmol) was then added, and the reaction mixture was degassed again for 5 minutes. The reaction mixture was stirred for 16 hours at 100°C. The progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, the reaction mixture was filtered through a celite bed.
  • Step-8 [1452] To a stirred solution of compound 11 (200 mg, 0.46 mmol) in 1,4-Dioxane (4 mL) and H 2 O (1 mL) under an argon atmosphere, potassium carbonate (192 mg, 1.3953 mmol), and compound 8 & 8A (890 mg, 2.32 mmol) were added. The reaction mixture was degassed for 5 minutes.

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Abstract

La présente invention concerne des composés de formule (I), de formule (II) et de formule (III), et leurs sels, solvates, hydrates, tautomères, stéréoisomères ou promédicaments pharmaceutiquement acceptables. Les composés selon l'invention peuvent être des inhibiteurs de kinase (par exemple, CDK11). L'invention concerne également des compositions pharmaceutiques et des kits comprenant les composés selon l'invention. L'invention concerne en outre des méthodes d'utilisation des composés selon l'invention, des compositions pharmaceutiques et des kits (par exemple, pour traiter des maladies, telles que des maladies prolifératives, chez un sujet qui le nécessite).
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WO2011123419A1 (fr) * 2010-03-29 2011-10-06 Oncotherapy Science, Inc. Composés tricycliques et inhibiteurs de pbk les contenant
CN109761902A (zh) * 2017-11-09 2019-05-17 四川大学 6-菲啶酮衍生物及其制备方法和用途
WO2021108927A1 (fr) * 2019-12-06 2021-06-10 The Governing Council Of The University Of Toronto Procédés et compositions pour traiter des cancers ayant des altérations dans la protéine f-box et à répétition wd (fbxw7) et/ou un gain ou une amplification de la cycline l1 (ccnl1)

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