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WO2025227032A1 - Methods for degradation of cyclin k and inhibition of cyclin dependent kinases - Google Patents

Methods for degradation of cyclin k and inhibition of cyclin dependent kinases

Info

Publication number
WO2025227032A1
WO2025227032A1 PCT/US2025/026371 US2025026371W WO2025227032A1 WO 2025227032 A1 WO2025227032 A1 WO 2025227032A1 US 2025026371 W US2025026371 W US 2025026371W WO 2025227032 A1 WO2025227032 A1 WO 2025227032A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
heteroaryl
ring
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/026371
Other languages
French (fr)
Inventor
Sudeep PRAJAPATI
David Jean Pierre KORNFILT
Gulseher Sarah SIRIN
Brandi M. HUDSON
Benoit Moreau
Jean-Marc Lapierre
Stepan Vyskocil
Brian Michael Andresen
Francois BRUCELLE
Derek LAPLACA
David Michael BOLDUC
Bryan DUNYAK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Remix Therapeutics Inc
Original Assignee
Remix Therapeutics Inc
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Filing date
Publication date
Application filed by Remix Therapeutics Inc filed Critical Remix Therapeutics Inc
Publication of WO2025227032A1 publication Critical patent/WO2025227032A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • 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
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • CDKs Cyclin dependent kinases
  • BACKGROUND Cyclin dependent kinases along with their cofactor cyclins regulate a number of fundamental cellular processes, including cell cycle progression and gene transcription.
  • Cell cycle progression and gene transcription are tightly regulated by CDKs to ensure that cells respond normally to a variety of internal and external stimuli.
  • Aberrant function of CDKs and cyclins, such as inhibition of activity or overexpression of these proteins, has shown to be related to many disease states.
  • Current therapeutic approaches to modulate CDK and cyclin activity are widespread; however, each of these modalities exhibit unique challenges as currently presented. As such, there is a need for new technologies to modulate CDK and cyclin activity.
  • CCNs cyclins
  • CDKs cyclin dependent kinases
  • the compounds described herein are compounds of Formula (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I- p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof.
  • the present disclosure additionally provides methods of using the compounds of the invention (e.g., compounds of (I), (I"), (I'), (I-02), (I-01), 1 Attorney Docket No.: R2103-7054WO (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I- m), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof), and compositions thereof, e.g., to target, and in embodiments bind or form a complex with
  • the compounds described herein may be used for the prevention and/or treatment of a disease, disorder, or condition, e.g., a disease, disorder or condition, e.g., associated with modulation of a cyclin or cyclin dependent kinase, e.g., a cancer.
  • a disease, disorder or condition e.g., associated with modulation of a cyclin or cyclin dependent kinase, e.g., a cancer.
  • the present disclosure provides compounds of Formula (I): compound of Formula (I): a pharmaceutically acceptable salt, solvate, hydrate , , , herein W 1 , W 2 , W 3 , and W 4 are each independently N or CR 4a ; X is N or CR 4b ; Ring A is a 6-membered aryl, 5-membered heteroaryl, or 6- 2 Attorney Docket No.: R2103-7054WO membered heteroaryl, each of which is optionally substituted with one or more R 5 ; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R 5 ; L is absent, a bond, -O-, -NR 8 -, -C(O)-, -P(O) y -, -S(O) x -, –NR B C(O)-, –C(O)NR B -, C 1 -
  • the present invention provides pharmaceutical compositions comprising a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I- m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.
  • a compound of Formula (I) e.g., a
  • the pharmaceutical compositions 4 Attorney Docket No.: R2103-7054WO described herein include an effective amount (e.g., a therapeutically effective amount) of a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisome
  • the present disclosure provides methods of down-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I- p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a
  • the present disclosure provides methods of up-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I- j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I- v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a
  • the present disclosure provides methods of altering the isoform of a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject.
  • a compound of Formula (I) e.g., a compound of Formulas (I), (
  • Another aspect of the disclosure relates to methods of inhibiting the activity of a target protein in a biological sample or subject.
  • administration of a compound of Formula (I) to a biological sample, a cell, or a subject comprises inhibition of cell growth or induction of cell death.
  • compositions for use in preventing and/or treating a disease, disorder, or condition in a subject by administering a compound of Formula (I) (e.g., a compound of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I- 5 Attorney Docket No.: R2103-7054WO i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or related compositions.
  • a compound of Formula (I)
  • the disease or disorder entails aberrant cyclin or cyclin dependent kinase splicing.
  • the disease or disorder is a proliferative disease, disorder, or condition.
  • Exemplary proliferative diseases include cancer, a benign neoplasm, or angiogenesis.
  • the present disclosure provides methods for treating and/or preventing a non-proliferative disease, disorder, or condition.
  • the present disclosure provides compositions for use in treating and/or preventing a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease.
  • compositions for use in down-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I- m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in
  • compositions for use in up-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in
  • compositions for use in altering the isoform of a target protein with a compound of Formula (I) e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically 6 Attorney Docket No.: R2103-7054WO acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in
  • compositions for use in inhibiting the activity of a target protein in a biological sample or subject comprises inhibition of cell growth or induction of cell death.
  • kits comprising a container with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof.
  • a compound of Formula (I) e.g., a compound of Formulas (I), (I
  • kits described herein further include instructions for administering the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or the pharmaceutical composition thereof.
  • the details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Examples, and the Claims.
  • D ETAILED D ESCRIPTION Selected Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein.
  • C 1 -C 6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4- C5, and C5-C6 alkyl.
  • the following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
  • alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms (“C 1 -C 24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1 -C 6 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -C 6 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”).
  • C 1 - C6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert– butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ).
  • alkyl groups include n–heptyl (C7), n–octyl (C8) and the like.
  • Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C1–C10 alkyl (e.g., –CH3).
  • the alkyl group is substituted C 1 –C 6 alkyl.
  • alkenyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon double bonds, and no triple 8 Attorney Docket No.: R2103-7054WO bonds (“C2-C24 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 -C 6 alkenyl”).
  • an alkenyl group has 2 carbon atoms (“C2 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 2 -C 4 alkenyl groups include 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 2 -C 6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like.
  • alkenyl examples include heptenyl (C7), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 1– C10 alkenyl.
  • the alkenyl group is substituted C2–C6 alkenyl.
  • alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon triple bonds (“C 2 -C 24 alkenyl”).
  • an alkynyl group has 2 to 10 carbon atoms (“C 2 -C 10 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”).
  • an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • Examples of C2-C4 alkynyl groups include ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1– butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2–10 alkynyl.
  • the alkynyl group is substituted C 2–6 alkynyl.
  • haloalkyl refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br, and I.
  • the halogen(s) F, Cl, Br, and I may be placed at any position of the haloalkyl group.
  • Each instance of a haloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted haloalkyl”) or substituted (a “substituted haloalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • heteroalkyl refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group.
  • heteroalkyl Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as –CH 2 O, –NR C R D , or the like, it will be understood that the terms heteroalkyl and –CH2O or –NR C R D are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH 2 O, –NR C R D , or the like.
  • Each instance of a heteroalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • An aryl group may be described as, e.g., a C6-C10-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C6-C14 aryl.
  • the aryl group is substituted C 6 -C 14 aryl.
  • heteroaryl refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ 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 (“5–10 membered heteroaryl”).
  • heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • 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 (aryl/heteroaryl) ring system.
  • Bicyclic 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, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
  • a heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the 11 Attorney Docket No.: R2103-7054WO moiety.
  • Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6– membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, thienopyridinyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyridazinyl, triazolopyridinyl, imidazopyridazinyl
  • Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, and pyridopyrazinyl.
  • Other exemplary heteroaryl groups include heme and heme derivatives.
  • cycloalkyl refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3 -C 10 cycloalkyl”) and zero heteroatoms in the non–aromatic ring system.
  • a cycloalkyl group has 3 to 8 ring carbon 12 Attorney Docket No.: R2103-7054WO atoms (“C3-C8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3 -C 6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 cycloalkyl”).
  • a cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Exemplary C 3 -C 6 cycloalkyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like.
  • Exemplary C 3 -C 10 cycloalkyl groups include, without limitation, the aforementioned C 3 -C 8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated.
  • “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system.
  • Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-C10 cycloalkyl.
  • the cycloalkyl group is a substituted C 3 -C 10 cycloalkyl.
  • Heterocyclyl refers to a radical of a 3– to 16–membered non–aromatic ring system having ring carbon atoms and 1 to 8 ring heteroatoms, wherein each heteroatom is 13 Attorney Docket No.: R2103-7054WO independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–16 membered heterocyclyl”).
  • R2103-7054WO independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic 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 cycloalkyl groups wherein the point of attachment is either on the cycloalkyl 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.
  • a heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non- hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety.
  • Each instance of heterocyclyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3–16 membered heterocyclyl.
  • the heterocyclyl group is substituted 3– 16 membered heterocyclyl.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione.
  • Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, dihydropyrazolyl, disulfuranyl, and oxazolidin–2–one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and 14 Attorney Docket No.: R2103-7054WO thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2- onyl), and thianyl.
  • piperidinyl e.g., 2,2,6,6-tetramethylpiperidinyl
  • tetrahydropyranyl dihydropyranyl
  • tetrahydropyridinyl dihydropyridinyl
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl.
  • Exemplary 6–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, azaspiro[2.4]heptanyl (e.g.5-azaspiro[2.4]heptanyl), oxepanyl, and thiepanyl.
  • Exemplary 7–membered heterocyclyl groups containing two heteroatoms include, without limitation, oxa-azaspiro[3.3]heptanyl (e.g., 6-oxa-1- azaspiro[3.3]heptanyl) and diazabicyclo[2.2.1]heptanyl.
  • Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azaspiro[2.5]octanyl (e.g.4- azaspiro[2.5]octanyl), quinuclidinyl, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 8–membered heterocyclyl groups containing two heteroatoms include, without limitation, oxa- azaspiro[3.4]octanyl (e.g., 6-oxa-1-azaspiro[3.4]octanyl).
  • Exemplary 9–membered heterocyclyl groups include, without limitation, azaspiro[4.4]nonanyl (e.g.1-azaspiro[4.4]nonanyl) and diazaspiro[3.5]nonanyl (e.g.2,7-diazaspiro[3.5]nonanyl).
  • Exemplary 5–membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 5–membered heterocyclyl groups fused to a heterocyclyl ring include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like.
  • Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring include, without limitation, diazaspirononanyl (e.g., 2,7- diazaspiro[3.5]nonanyl).
  • Exemplary 6–membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Exemplary 6–membered heterocyclyl 15 Attorney Docket No.: R2103-7054WO groups fused to a cycloalkyl ring include, without limitation, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl).
  • Exemplary 6–membered heterocyclyl groups fused to a cycloalkyl ring include, without limitation, azabicyclononanyl (e.g., 9- azabicyclo[3.3.1]nonanyl).
  • alkylene alkenylene, alkynylene, haloalkylene,” “heteroalkylene,” “cycloalkylene,” or “heterocyclylene,” alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl respectively.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene group may be described as, e.g., a C1-C6-membered alkylene, C 2 -C 6 -membered alkenylene, C 2 -C 6 -membered alkynylene, C 1 -C 6 -membered haloalkylene, C 1 - C6-membered heteroalkylene, C3-C8-membered cycloalkylene, or C3-C8-membered heterocyclylene, wherein the term “membered” refers to the non-hydrogen atoms within the moiety.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • the formula - C(O) 2 R’- may represent both -C(O) 2 R’- and –R’C(O) 2 -.
  • the terms “cyano” or “–CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C ⁇ N.
  • halogen or “halo” refer to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to –OH.
  • nitro refers to a substitutent having two oxygen atoms bound to a nitrogen atom, e.g., -NO 2 . 16 Attorney Docket No.: R2103-7054WO
  • nucleobase is a nitrogen-containing biological compounds found linked to a sugar within a nucleoside—the basic building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
  • the primary, or naturally occurring, nucleobases are cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA) and uracil (RNA), abbreviated as C, G, A, T, and U, respectively. Because A, G, C, and T appear in the DNA, these molecules are called DNA-bases; A, G, C, and U are called RNA-bases.
  • Adenine and guanine belong to the double-ringed class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines.
  • nucleobases that do not function as normal parts of the genetic code, are termed non-naturally occurring.
  • a nucleobase may be chemically modified, for example, with an alkyl (e.g., methyl), halo, -O-alkyl, or other modification.
  • nucleic acid refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form.
  • the term “nucleic acid” includes a gene, cDNA, pre-mRNA, or an mRNA.
  • the nucleic acid molecule is synthetic (e.g., chemically synthesized) or recombinant.
  • nucleic acids containing analogues or derivatives of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
  • a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementarity sequences as well as the sequence explicitly indicated.
  • oxo refers to a carbonyl, i.e., -C(O)-.
  • T he symbol “ ” as used herein in relation to a compound of Formula (I) refers to an attachment point to a nother moiety or functional group within the compound.
  • Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted.
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, 17 Attorney Docket No.: R2103-7054WO 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, such as any of the substituents described herein that result in the formation of a stable compound.
  • the present disclosure 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.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocyclyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring- forming substituents are attached to non-adjacent members of the base structure.
  • the compounds provided herein may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to: cis- and trans-forms; E- and Z-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric 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.
  • the stereochemistry depicted in a compound is relative rather than absolute.
  • 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. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising 19 Attorney Docket No.: R2103-7054WO an enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound.
  • the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound.
  • a pharmaceutical composition comprising an enantiomerically pure S– compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound.
  • the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R–compound, by total weight of the compound.
  • a diastereomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising a diastereometerically pure exo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure exo compound.
  • the diastereometerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most about 5% by weight endo compound, by total weight of the compound.
  • a pharmaceutical composition comprising a diastereometerically pure endo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure endo compound.
  • the diastereometerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo compound, by total weight of the compound.
  • an isomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising a isomerically pure exo compound can comprise, for example, about 90% excipient and about 10% isomerically pure exo compound.
  • the isomerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most about 5% by weight endo compound, by total weight of the compound.
  • a pharmaceutical composition comprising an isomerically pure endo compound can comprise, for 20 Attorney Docket No.: R2103-7054WO example, about 90% excipient and about 10% isomerically pure endo compound.
  • the isomerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • Compound described herein may also comprise one or more isotopic substitutions.
  • pharmaceutically acceptable salt is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • salts of amino acids such as arginate and the like
  • salts of organic acids like 21 Attorney Docket No.: R2103-7054WO glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art.
  • Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention.
  • the present disclosure provides compounds in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • the term “solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds of Formula (I) 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 isolable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • the term “hydrate” refers to a compound which is associated with water.
  • 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 wherein x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and 22 Attorney Docket No.: R2103-7054WO smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H2O) and hexahydrates (R ⁇ 6 H2O)).
  • tautomer refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • Other Definitions The following definitions are more general terms used throughout the present disclosure.
  • the articles “a” and “an” refer to one or more than one (e.g., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • the term “and/or” means either “and” or “or” unless indicated otherwise.
  • Directly acquiring means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity.
  • “Indirectly acquiring” refers to receiving the value or physical entity from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value).
  • Directly acquiring a value or physical entity includes performing a process that includes a physical 23 Attorney Docket No.: R2103-7054WO change in a physical substance or the use of a machine or device. Examples of directly acquiring a value include obtaining a sample from a human subject.
  • Directly acquiring a value includes performing a process that uses a machine or device, e.g., mass spectrometer to acquire mass spectrometry data.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.
  • condition refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition.
  • effective amount of a compound of Formula (I) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount of an inventive compound may reduce the tumor burden or stop the growth or spread of a tumor.
  • a “therapeutically effective amount” of a compound of Formula (I) 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 is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to 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.
  • terapéuticaally effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • 24 Attorney Docket No.: R2103-7054WO
  • the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds.
  • a protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprised therein.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds.
  • prevention refers to a treatment that comprises administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I)) prior to the onset of a disease, disorder, or condition in order to preclude the physical manifestation of said disease, disorder, or condition.
  • a therapy e.g., administering a compound described herein (e.g., a compound of Formula (I)) prior to the onset of a disease, disorder, or condition in order to preclude the physical manifestation of said disease, disorder, or condition.
  • prevention require that signs or symptoms of the disease, disorder, or condition have not yet developed or have not yet been observed.
  • treatment comprises prevention and in other embodiments it does not.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult, or senior adult)) and/or other non–human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).
  • mammals e.g., primates (e.g., cynomolgu
  • the animal is a mammal.
  • the animal may be a male or female and at any stage of development.
  • a non–human animal may be a transgenic animal.
  • the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of one or more of a symptom, manifestation, or underlying cause of a disease, disorder, or condition (e.g., as described herein), e.g., by administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I)).
  • treating comprises reducing, reversing, 25 Attorney Docket No.: R2103-7054WO alleviating, delaying the onset of, or inhibiting the progress of a symptom of a disease, disorder, or condition.
  • treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a manifestation of a disease, disorder, or condition.
  • treating comprises reducing, reversing, alleviating, reducing, or delaying the onset of, an underlying cause of a disease, disorder, or condition.
  • “treatment,” “treat,” and “treating” require that signs or symptoms of the disease, disorder, or condition have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition, e.g., in preventive treatment.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors).
  • Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • treatment comprises prevention and in other embodiments it does not.
  • a pharmaceutically acceptable salt, solvate, hydrate, tautom W 1 , W 2 , W 3 , and W 4 is each independently N or CR 4a ;
  • X is N or CR 4b ;
  • Ring A is a 6-membered aryl, 5-membered or 6-membered heteroaryl, or 5-membered or 6-membered heterocyclyl, each of which is optionally substituted with one or more R 5 ; in some embodiments, Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 ;
  • Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R 5 ;
  • L is absent, a bond, -O-, -NR 8 -, -C(O)-, -P(O) y -, -
  • Ring A is a 6-membered aryl, 5-membered or 6- membered heteroaryl, or 5-membered or 6-membered heterocyclyl, each of which is optionally substituted with one or more R 5 .
  • Ring A is a 6-membered 28 Attorney Docket No.: R2103-7054WO aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 .
  • Ring A is 6-membered aryl optionally substituted with one or more R 5 .
  • Ring A is 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 .
  • Ring A is 5- membered or 6-membered heterocycyl, each of which is optionally substituted with one or more R 5 .
  • Ring A is a 5-membered ring.
  • Ring A is a 6- membered ring.
  • Ring is a heteroaryl, e.g., a nitrogen-containing heteroaryl, optionally substituted with one or more R 5 .
  • Ring A is a nitrogen-containing 5-membered heteroaryl, optionally substituted with one or more R 5 .
  • Ring A is a nitrogen-containing 6-membered heteroaryl optionally substituted with one or more R 5 .
  • Attorney Docket No.: R2103-7054WO 5 is 5 is a s In some embodiments of Formula (I), Ring A is selected from , , Attorney Docket No.: R2103-7054WO , me In some embodiments of Formula (I), Ring A , wherein R 5 is as described herein.
  • R 5 is as 31 Attorney Docket No.: R2103-7054WO described herein.
  • Ring A s as described herein.
  • Ring A wherein R 5 is as described herein.
  • Ring A i wherein R 5 is as described herein.
  • Rin 5 is as described herein.
  • Ring A wherein R 5 is as described herein.
  • Ring A wherein R 5 is as described herein.
  • Ri wherein R 5 is as described herein.
  • Ri wherein R 5 is as described herein.
  • Ring A wherein R 5 is as described herein.
  • Ring A 32 Attorney Docket No.: R2103-7054WO wherein R 5 is as described herein.
  • Ring A wherein R 5 is as described herein. In some embodiments of Formula (I), Ri wherein R 5 is as described herein. In some embodiments of Formula (I), Ring A wherein R 5 is as described herein. In some embodiments of Formula (I), Ring A wherein R 5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R 5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R 5 is as described herein. In some embodiments of Formula (I), Ring wherein R 5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R 5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R 5 is as described herein. In some embodiments of Formula (I), Ring wherein R 5 is as described herein. In some embodiments of Formula (I), Ring wherein R 5 is as described herein. In some embodiments of Formula (I), Ring wherein R 5 is as described herein.
  • Ring A is selected fro , , . , , Attorney Docket No.: R2103-7054WO , , , Attorney Docket No.: R2103-7054WO , , In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i ,. In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A i me embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring me Attorney Docket No.: R2103-7054WO embodiments of Formula (I), Ring A i .
  • Rin In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i ,. In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring A i .
  • Ring 39 Attorney Docket No.: R2103-7054WO n some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ri . In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), . In some embodiments of Formula (I), Ring A . In some ula (I), Ring A i . In some embodiments of Formula (I), Ring ome embodiments of Formula (I), Rin .
  • Ring A i .
  • Ring 40 Attorney Docket No.: R2103-7054WO
  • Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R 5 .
  • Ring B is aryl (e.g., 6-membered aryl), optionally substituted with one or more R 5 .
  • Ring B is heteroaryl (e.g., a 5-membered or 6-membered heteroaryl), optionally substituted with one or more R 5 .
  • Ring B is a monocyclic heteroaryl, optionally substituted with one or more R 5 . In some embodiments, Ring B is a bicyclic heteroaryl, optionally substituted with one or more R 5 . In some embodiments, Ring B is cycloalkyl (e.g., a 3-7 membered cycloalkyl), optionally substituted with one or more R 5 . In some embodiments, Ring B is heterocyclyl (e.g., a 3-10 membered cycloalkyl), optionally substituted with one or more R 5 . In some embodiments, Ring B is a monocyclic heterocyclyl, optionally substituted with one or more R 5 .
  • Ring B is a bicyclic heterocyclyl, optionally substituted with one or more R 5 .
  • Ring B is a nitrogen-containing heteroaryl or heterocyclyl.
  • Ring B selected from , , , Attorney Docket No.: R2103-7054WO , , , , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO Attorney Docket No.: R2103-7054WO , ach In some embodiments of Formula (I), Ring
  • Ring B is aryl optionally substituted with one or more R 5 . In some embodiments of Formula (I), Ring B is heteroaryl optionally substituted with one or more R 5 . In some embodiments of Formula (I), Ring B is cycloalkyl optionally substituted with one or more R 5 . In some embodiments of Formula (I), Ring B is heterocyclyl optionally substituted with one or more R 5 . In some embodiments of Formula (I), Ring B is a nitrogen-containing heteroaryl or heterocyclyl, each of which is optionally substituted with one or more R 5 . In some embodiments of Formula (I), Ring B is a nitrogen-containing heteroaryl optionally substituted with one or more R 5 .
  • Ring B is a nitrogen-containing heterocyclyl optionally substituted with one or more R 5 .
  • Ring B is selected fro , , Attorney Docket No.: R2103-7054WO O O S 5 N R5 5 , , Attorney Docket No.: R2103-7054WO nd
  • Ring B is selected from: , , d 0-4 N
  • Ring B selected fro , , , Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), Ring B .
  • Ring B is .
  • Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), O Ring B is . In some embodiments of Formula (I), Ring B 0-3 . In O some embodiments of Formula (I), Ring B i 0-2. In some embodiments of Attorney Docket No.: R2103-7054WO S Formula (I), Ring B is (R5)0-3 . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is .
  • Ring B i In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), 55 Attorney Docket No.: R2103-7054WO Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i .
  • Ring n some embodiments of Formula (I), Ring B .
  • Rin In some embodiments of Formula me embodiments of Formula (I), Ring B i .
  • Ring B is selected fro , , Attorney Docket No.: R2103-7054WO , , , Attorney Docket No.: R2103-7054WO , , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , , I n some embodiments of Formula (I), Ring .
  • Ring B is . In some embodiments of Formula (I), Ring B i . In s ome embodiments of Formula (I), Ring . In some embodiments of Formula (I), 60 Attorney Docket No.: R2103-7054WO R ing B is . In some embodiments of Formula (I), Ring B is . In some e mbodiments of Formula (I), Ring B is . In some embodiments of Formula (I), R ing B is . In some embodiments of Formula (I), Ring B is . In some e mbodiments of Formula (I), Ring . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i .
  • Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some e mbodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some e mbodiments of Formula (I), Rin In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring . In some 61 Attorney Docket No.: R2103-7054WO e mbodiments of Formula (I), Ring B is . In some embodiments of Formula (I), R ing B is .
  • Ring B i In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), R ing B is . In some embodiments of Formula (I), Ring B . In some e mbodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B is . In some e mbodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B i . In some e mbodiments of Formula (I), Ring In some embodiments of Formula (I), Ring B i s .
  • Rin In some embodiments 62 Attorney Docket No.: R2103-7054WO o f Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of F ormula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In s ome embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), R ing B is . In some embodiments of Formula (I), Ring . In some e mbodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Ring B .
  • Ring B is .
  • Ring B i In some embodiments of Formula (I), Ring B i .
  • Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula 65 Attorney Docket No.: R2103-7054WO a . In a n some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), 66 Attorney Docket No.: R2103-7054WO . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is .
  • Ring B In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B me embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B me mula (I), 67 Attorney Docket No.: R2103-7054WO Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is .
  • Rin In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B 68 Attorney Docket No.: R2103-7054WO is .
  • Ring B i In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring . ent, Ring A and Ring B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of one of the rings described above. In an embodiment, Ring A and Ring B are each independently a stereoisomer of one of the rings described above.
  • L is absent, a bond, -O-, -NR 8 -, -C(O)-, -S(O)x-, – NR B C(O)-,–C(O)NR B -, C 1 -C 6 -alkylene, or C 1 -C 6 -heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together.
  • L is absent, a bond, -O-, -NR 8 -, -C(O)-, or -S(O)x- wherein when L is absent, Ring A and Ring B are fused together.
  • L is absent, a bond, -O-, -NR 8 -, -C(O)-, -P(O)y-, - S(O)x-, –NR B C(O)-, –C(O)NR B -, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R 5 ;
  • L is absent, a bond, -O-, or -NR 8 -, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R 5 ;
  • L is absent, and Ring A and Ring B are fused together.
  • L is a bond.
  • L is -O-.
  • L is -NR 8 -.
  • L is -C(O)-.
  • L is -P(O) y -.
  • L is -S(O)x-.
  • L is –NR B C(O)- .
  • L is –C(O)NR B -.
  • L is C 1 -C 6 -alkylene. In some embodiments of Formula (I), L is C 1 -C 6 -heteroalkylene. In some embodiments, L is absent and Ring A and Ring B are fused together. In some embodiments, A-L-B is selected from , , , Attorney Docket No.: R2103-7054WO , . g B are fused together. In some embodiments of Formula (I), A-L-B is selected fro , , , Attorney Docket No.: R2103-7054WO , , . , nd Ring A and Ring B are fused together.
  • A-L-B is selected from 72 Attorney Docket No.: R2103-7054WO n d In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of For cted , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Form , ected from , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein.
  • Formul d from wherein each R 5 is as defined herein.
  • A-L-B is selected from , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formul , d from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R 5 is as defined herein. In some 74 Attorney Docket No.: R2103-7054WO embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula ( from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula (I from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein.
  • each R 5 is as defined herein.
  • A-L-B is selected from , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein.
  • A-L-B is selected from , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula (I), - - lected from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), 76 Attorney Docket No.: R2103-7054WO A-L-B is selected from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula ( from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R 5 is as defined herein.
  • A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula ( , from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula (I ), A-L-B is selected from 77 Attorney Docket No.: R2103-7054WO , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R 5 is as defined herein.
  • A-L-B is selected from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein. In some embodiments of Formula (I d , wherein each R 5 is as defined herein. In some embodiments of , d from , wherein each R 5 is as defined herein. In some embodiments of 78 Attorney Docket No.: R2103-7054WO Formula (I), A-L-B is selected from , wherein each R 5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R 5 is as defined herein.
  • each R 5 is as defined herein. , , , Attorney Docket No.: R2103-7054WO
  • A-L-B is selecte , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO Attorney Docket No.: R2103-7054WO ,
  • A-L-B is .
  • A-L-B is -L- A- me I), some embodiments of Formula (I), A-L-B i .
  • Formula 84 Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), . In some embodiments of Formul In some embodiments of Formula n some embodiments of Formul . In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula In some embodiments of Formula (I), A-L-B is 85 Attorney Docket No.: R2103-7054WO n some embodiments of Formul me embodiments of Formula In some embodiments of Formula (I), n some embodiments of Formu In some embodiments of Formula (I), A-L-B i .
  • A-L-B is . In some embodiments of Formula (I), A-L-B is n some embodiments of Formula (I), A-L-B me embodiments of Formula In some embodiments of Formula .
  • Attorney Docket No.: R2103-7054WO In some embodiments of Formul In some embodiments of is some embodiments of Formula In some embodiments of Formula (I), A- n some embodiments of Formul In some A- Attorney Docket No.: R2103-7054WO some embodiments of Formul In some embodiments of Formula n some embodiments of Formu .
  • A-L-B is . In some embodiments of Formula (I), A-L-B is .
  • A-L-B In some embodiments of Formula (I), A-L-B . In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A- L-B is . In some embodiments of Formula (I), A-L-B . In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A- L-B is . In some embodiments of Formula (I), A-L-B me 88 Attorney Docket No.: R2103-7054WO embodiments of Formula (I), A-L-B In some embodiments of Formula (I), A- L-B is . In some embodiments of Formul me embodiments of Formula (I), A-L-B i .
  • A- L-B is . In some embodiments of Formul In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A-L- n some embodiments of Formul In some embodiments of Formula In some embodiments of Formula (I), n some embodiments of Formu In some embodiments of Formul In some embodiments of 89 Attorney Docket No.: R2103-7054WO Formula n some embodiments of Formula (I), A-L-B is .
  • A-L-B is .
  • A-L-B is .
  • A-L-B is .
  • Formul me 91 Attorney Docket No.: R2103-7054WO embodiments of Formula In some embodiments of Formula (I), . In some embodiments of Formul of e I), In ula Attorney Docket No.: R2103-7054WO .
  • A-L-B In some embodiments of Formula (I), A-L-B . In s ome embodiments of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formul of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formul me embodiments of Formula In some embodiments of Formula (I), A-L- .
  • A-L-B is N N n some embodiments of Formul me N N embodiments of Formula In some embodiments of Formula (I), N N n some embodiments of Formul In some embodiments of Formul In some embodiments of Formula (I), In Formula .
  • A-L-B is .
  • A-L-B is In some embodiments of Formul In some embodiments of Formula me Attorney Docket No.: R2103-7054WO ula n some embodiments of Formul .
  • each R 5 is hydrogen. In some embodiments of Formula (I), R 5 is C 1 -C 6 -alkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 5 is C2-C6-alkenyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 5 is C2-C6-alkynyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 5 is C 1 -C 6 -heteroalkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 5 is C 1 -C 6 -haloalkyl optionally substituted with one or more R 6 .
  • R 5 is cycloalkyl optionally substituted 96 Attorney Docket No.: R2103-7054WO with one or more R 6 .
  • R 5 is heterocyclyl optionally substituted with one or more R 6 .
  • R 5 is aryl optionally substituted with one or more R 6 .
  • R 5 is C 1 -C 6 alkylene-aryl optionally substituted with one or more R 6 .
  • R 5 is C2-C6 alkenylene-aryl optionally substituted with one or more R 6 .
  • R 5 is halo.
  • R 5 is cyano. In some embodiments of Formula (I), R 5 is oxo. In some embodiments of Formula (I), R 5 is –OR A . In some embodiments of Formula (I), R 5 is –NR B R C . In some embodiments of Formula (I), R 5 is –NR B C(O)R D . In some embodiments of Formula (I), R 5 is –NO2. In some embodiments of Formula (I), R 5 is – C(O)NR B R C . In some embodiments of Formula (I), R 5 is –C(O)R D . In some embodiments of Formula (I), R 5 is –C(O)OR D .
  • R 5 is –S(O)xR D .
  • each of W 1 , W 2 , W 3 , and W 4 is independently N or CR 4a .
  • each of W 1 , W 2 , W 3 , and W 4 is CR 4a .
  • W 1 is N and each of W 2 , W 3 , and W 4 is CR 4a .
  • W 2 is N and each of W 1 , W 3 , and W 4 is CR 4a .
  • W 3 is N and each of W 1 , W 2 , and W 4 is CR 4a .
  • W 4 is N and each of W 1 , W 2 , and W 3 is CR 4a .
  • two of W 1 , W 2 , W 3 and W 4 is independently N.
  • each of W 1 and W 2 is N, and each of W 3 and W 4 is CR 4a .
  • each of W 2 and W 3 is N, and each of W 1 and W 4 is CR 4a .
  • each of W 3 and W 4 is N, and each of W 1 and W 2 is CR 4a .
  • W 1 is N or CR 4a .
  • W 2 is N or CR 4a .
  • W 3 is N or CR 4a .
  • W 4 is N or CR 4a .
  • one of W 1 , W 2 , W 3 and W 4 is independently N.
  • X is N or CR 4b .
  • X is N.
  • X is CR 4b .
  • the compound comprises 0, 1, 2, or 3 R 4a .
  • the compound comprises 0 R 4a .
  • the compound comprises 1 R 4a .
  • the compound comprises 2 R 4a . In some embodiments of Formula (I), the compound comprises 3 R 4a . In some embodiments of Formula (I), each R 4a is C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, halo, cyano, –OR A , or cycloalkyl. In some embodiments of Formula (I), each R 4a is C1-C6-alkyl, halo, or –OR A .
  • R 4a is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C 1 -C 6 -heteroalkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocyclyl, aryl, C 1 -C 6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –OR A , –NR B R C , –NR B C(O)R D , –NO2, –C(O)NR B R C , –C(O)R D , –C(O)OR D , or —S(O)xR D , wherein each alkyl, alkylene, alkenyl, alkynyl, hetero
  • R 4a is hydrogen. In some embodiments of Formula (I), R 4a is C1-C6-alkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4a is C2-C6-alkenyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4a is C 2 -C 6 - alkynyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4a is C1-C6-heteroalkyl optionally substituted with one or more R 6 .
  • R 4a is C 1 -C 6 -haloalkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4a is C1-C6-haloalkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4a is cycloalkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4a is heterocyclyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4a is aryl optionally substituted with one or more R 6 .
  • R 4a is C1-C6 alkylene-aryl optionally substituted with one 98 Attorney Docket No.: R2103-7054WO or more R 6 .
  • R 4a is C2-C6 alkenylene-aryl optionally substituted with one or more R 6 .
  • R 4a is heteroaryl optionally substituted with one or more R 6 .
  • R 4a is C 1 -C 6 alkylene-heteroaryl optionally substituted with one or more R 6 .
  • R 4a is C2-C6 alkenylene-heteroaryl optionally substituted with one or more R 6 .
  • R 4a is halo.
  • R 4a is cyano.
  • R 4a is –OR A .
  • R 4a is –NR B R C .
  • R 4a is –NR B C(O)R D .
  • R 4a is –NO2.
  • R 4a is – C(O)NR B R C .
  • R 4a is –C(O)R D . In some embodiments of Formula (I), R 4a is –C(O)OR D . In some embodiments of Formula (I), R 4a is –S(O)xR D .
  • R 4b is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2- C 6 -alkynyl, C 1 -C 6 -heteroalkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocyclyl, aryl, C 1 -C 6 alkylene- aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –OR A , –NR B R C , –NR B C(O)R D , –NO2, –C(O)NR B R C , –C(O)R D , –C(O)OR D , or — S(O) x R D , wherein each alkyl, alkylene, alkenyl, alkynyl, wherein each alkyl
  • R 4b is hydrogen. In some embodiments of Formula (I), R 4b is C1- C6-alkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4b is C 2 -C 6 -alkenyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4b is C2-C6-alkynyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4b is C1-C6-heteroalkyl optionally substituted with one or more R 6 .
  • R 4b is C 1 -C 6 -haloalkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4b is C1-C6-haloalkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4b is cycloalkyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4b is heterocyclyl optionally substituted with one or more R 6 . In some embodiments of Formula (I), R 4b is aryl optionally substituted with one or more R 6 .
  • R 4b is C1-C6 alkylene-aryl optionally 99 Attorney Docket No.: R2103-7054WO substituted with one or more R 6 .
  • R 4b is C2-C6 alkenylene- aryl optionally substituted with one or more R 6 .
  • R 4b is heteroaryl optionally substituted with one or more R 6 .
  • R 4b is C1-C6 alkylene-heteroaryl optionally substituted with one or more R 6 .
  • R 4b is C2-C6 alkenylene-heteroaryl optionally substituted with one or more R 6 .
  • R 4b is halo.
  • R 4b is cyano.
  • R 4b is –OR A .
  • R 4b is –NR B R C .
  • R 4b is –NR B C(O)R D .
  • R 4b is –NO2.
  • R 4b is – C(O)NR B R C .
  • R 4b is –C(O)R D . In some embodiments of Formula (I), R 4b is –C(O)OR D . In some embodiments of Formula (I), R 4b is –S(O)xR D .
  • each R 6 is independently C1-C6-alkyl, C2-C6- alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -heteroalkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –OR A , –NR B R C , –NR B C(O)R D , –NO2, –C(O)NR B R C , –C(O)R D , – C(O)OR D , or –S(O)xR D , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 7 .
  • R 6 is C 1 -C 6 -alkyl optionally substituted with one or more R 7 .
  • R 6 is C2-C6-alkenyl optionally substituted with one or more R 7 .
  • R 6 is C2-C6-alkynyl optionally substituted with one or more R 7 .
  • R 6 is C 1 -C 6 -heteroalkyl substituted with one or more R 7 .
  • R 6 is C1-C6-haloalkyl optionally substituted with one or more R 7 .
  • R 6 is cycloalkyl optionally substituted with one or more R 7 . In some embodiments of Formula (I), R 6 is heterocyclyl. In some embodiments of Formula (I), R 6 is aryl optionally substituted with one or more R 7 . In some embodiments of Formula (I), R 6 is heteroaryl optionally substituted with one or more R 7 . In some embodiments of Formula (I), R 6 is halo. In some embodiments of Formula (I), R 6 is cyano. In some embodiments of Formula (I), R 6 is oxo. In some embodiments of Formula (I), R 6 is – OR A . In some embodiments of Formula (I), R 6 is –NR B R C .
  • R 6 is –NR B C(O)R D .
  • R 6 is –NO2.
  • R 6 is –NO2.
  • R 6 is –C(O)NR B R C .
  • R 6 is –C(O)R D .
  • R 6 is – C(O)OR D .
  • R 6 is –S(O)xR D .
  • each R A is independently hydrogen, C1-C6-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -heteroalkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 6 alkylene-aryl, C 1 -C 6 alkylene-heteroaryl, –C(O)R D , or –S(O) x R D .
  • R A is hydrogen.
  • R A is C1-C6- alkyl.
  • R A is C2-C6-alkenyl. In some embodiments of Formula (I), R A is C 2 -C 6 -alkynyl. In some embodiments of Formula (I), R A is C 1 -C 6 -heteroalkyl. In some embodiments of Formula (I), R A is C1-C6-haloalkyl. In some embodiments of Formula (I), R A is cycloalkyl. In some embodiments of Formula (I), R A is heterocyclyl. In some embodiments of Formula (I), R A is heterocyclyl. In some embodiments of Formula (I), R A is heterocyclyl. In some embodiments of Formula (I), R A is heterocyclyl. In some embodiments of Formula (I), R A is aryl.
  • R A is aryl. In some embodiments of Formula (I), R A is heteroaryl. In some embodiments of Formula (I), R A is C 1 -C 6 alkylene-aryl. In some embodiments of Formula (I), R A is C 1 -C 6 alkylene-heteroaryl. In some embodiments of Formula (I), R A is –C(O)R D . In some embodiments of Formula (I), R A is –S(O)xR D .
  • each of R B and R C is independently hydrogen, C1- C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -heteroalkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocyclyl, or –OR A ; or R B and R C together with the atom to which they are attached form a 3- 7-membered heterocyclyl ring optionally substituted with one or more R 7 .
  • R B is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 - alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, or –OR A .
  • R B is hydrogen.
  • R B is C1-C6- alkyl.
  • R B is C 2 -C 6 -alkenyl.
  • R B is C 2 -C 6 -alkynyl.
  • R B is C 1 -C 6 -heteroalkyl. In some embodiments of Formula (I), R B is C1-C6-haloalkyl. In some embodiments of Formula 101 Attorney Docket No.: R2103-7054WO (I), R B is cycloalkyl. In some embodiments of Formula (I), R B is heterocyclyl. In some embodiments of Formula (I), R B is –OR A .
  • R C is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 - alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, or –OR A .
  • R C is hydrogen.
  • R C is C1-C6- alkyl.
  • R C is C 2 -C 6 -alkenyl.
  • R C is C 2 -C 6 -alkynyl.
  • R C is C 1 -C 6 -heteroalkyl. In some embodiments of Formula (I), R C is C1-C6-haloalkyl. In some embodiments of Formula (I), R C is cycloalkyl. In some embodiments of Formula (I), R C is heterocyclyl. In some embodiments of Formula (I), R C is –OR A .
  • each R D is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 6 alkylene-aryl, C 1 -C 6 alkylene-heteroaryl, or -N(R B1 )(R C1 ) , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 .
  • each R D is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 6 alkylene-aryl, or C 1 -C 6 alkylene- heteroaryl.
  • R D is hydrogen.
  • R D is C1-C6 alkyl.
  • R D is C2-C6 alkenyl.
  • R D is C 2 -C 6 alkynyl. In some embodiments of Formula (I), R D is C1-C6 heteroalkyl. In some embodiments of Formula (I), R D is C1-C6 heteroalkyl. In some embodiments of Formula (I), R D is C1-C6 heteroalkyl. In some embodiments of Formula (I), R D is C 1 -C 6 haloalkyl. In some embodiments of Formula (I), R D is cycloalkyl. In some embodiments of Formula (I), R D is heterocyclyl. In some embodiments of Formula (I), R D is aryl. In some embodiments of Formula (I), R D is heteroaryl.
  • R D is C1-C6 alkylene-aryl. In some embodiments of Formula (I), R D is C 1 -C 6 alkylene-heteroaryl. In some embodiments of Formula (I), R D is -N(R B1 )(R C1 ).
  • each R E is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 6 alkylene-aryl, C 1 -C 6 alkylene-heteroaryl, or -N(R B1 )(R C1 ).
  • each R E is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C 1 -C 6 alkylene-heteroaryl.
  • R E is hydrogen.
  • R E is C 1 -C 6 alkyl.
  • R E is C2-C6 alkenyl.
  • R E is C2-C6 alkynyl. In some embodiments of Formula (I), R E is C1-C6 heteroalkyl. In some embodiments of Formula (I), R E is C 1 -C 6 heteroalkyl. In some embodiments of Formula (I), R E is C 1 -C 6 heteroalkyl. In some embodiments of Formula (I), R E is C1-C6 haloalkyl. In some embodiments of Formula (I), R E is cycloalkyl. In some embodiments of Formula (I), R E is heterocyclyl. In some embodiments of Formula (I), R E is aryl. In some embodiments of Formula (I), R E is heteroaryl.
  • R E is C1-C6 alkylene-aryl. In some embodiments of Formula (I), R E is C1-C6 alkylene-heteroaryl. In some embodiments of Formula (I), R E is -N(R B1 )(R C1 ).
  • each R 7 is independently C 1 -C 6 -alkyl, C 1 -C 6 - heteroalkyl, C 1 -C 6 -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NR B R C , oxo, –OR A , -C(O)NR B R C , or -C(O)R D , wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 .
  • each R 7 is independently C 1 -C 6 -alkyl, C 1 -C 6 -heteroalkyl, C 1 -C 6 - haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or –OR A .
  • R 7 is C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or –OR A .
  • R 8 is hydrogen or C1-C6-alkyl. In some embodiments of Formula (I), R 8 is hydrogen. In some embodiments of Formula (I), R 8 is C1-C6- alkyl. In some embodiments of Formula (I), each R 9 is independently C 1 -C 6 -alkyl, cycloalkyl, heterocyclyl, oxo, -OR A1 , or -N(R B1 )(R C1 ). In some embodiments of Formula (I), R 9 is C1-C6- 103 Attorney Docket No.: R2103-7054WO alkyl. In some embodiments of Formula (I), R 9 is cycloalkyl.
  • R 9 is heterocyclyl. In some embodiments of Formula (I), R 9 is oxo. In some embodiments of Formula (I), R 9 is -OR A1 . In some embodiments of Formula (I), R 9 is -N(R B1 )(R C1 ). In some embodiments of Formula (I), each R A1 is independently hydrogen or C1-C6-alkyl. In some embodiments of Formula (I), R A1 is hydrogen. In some embodiments of Formula (I), R A1 is C 1 -C 6 -alkyl. In some embodiments of Formula (I), each R B1 is independently hydrogen or C 1 -C 6 -alkyl. In some embodiments of Formula (I), R B1 is hydrogen.
  • R B1 is independently C1-C6-alkyl. In some embodiments of Formula (I), each R C1 is independently hydrogen or C 1 -C 6 -alkyl. In some embodiments of Formula (I), R C1 is hydrogen. In some embodiments of Formula (I), R C1 is independently C1-C6-alkyl. In some embodiments of Formula (I), n is 0, 1, 2, or 3. In some embodiments of Formula (I), n is 0. In some embodiments of Formula (I), n is 1. In some embodiments of Formula (I), n is 2. In some embodiments of Formula (I), n is 3. In some embodiments of Formula (I), n is not 0, 2, or 3.
  • the compound of Formula (I) is a compound of Formula (I”): a pharmaceutically acceptable salt, solvate, hydrate , , , erein: W 1 , W 2 , W 3 , and W 4 is each independently N or CR 4a ; X is N or CR 4b ; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 ; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R 5 ; 104 Attorney Docket No.: R2103-7054WO L is absent, a bond, -O-, -NR 8 -,
  • the present disclosure provides compounds of Formula (I-02): a pharmaceutically acceptable salt, solvate, hydrate ein W 1 , W 2 , W 3 , 4 and W is each independently N or CR 4a ;
  • X is N or CR 4b ;
  • Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 ;
  • Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is each of which is optionally substituted with one or more R 5 ;
  • L is absent, a bond, -O-, -NR 8 -, -C(O)-, -P(O)y-, -S(O)x-, –NR B C(O)-,– C(O)NR B -, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent,
  • the compound of Formula (I) is a compound of Formula (I-01): a pharmaceutically acceptable salt, solvate, hydrate ein: W 1 , W 2 , W 3 , and W 4 is each independently N or CR 4a ; X is N or CR 4b ; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 ; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R 5 ; L is absent, a bond, -O-, -NR 8 -, -C(O)-, -S(O) x -, –NR B C(O)-,–C(O)NR B -, C 1 -C 6 -alkylene, or C 1 - C 6 -heteroalkylene, wherein when L is absent, Ring A and Ring B
  • the compound of Formula (I) is a compound of Formula (I-a): a pharmaceutically acceptable salt, solvate, hydrate erein: W 1 , W 2 , W 3 , and W 4 is each independently N or CR 4a ; X is N or CR 4b ; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 ; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R 5 ; L is absent, a bond, -O-, -NR 8 -, -C(O)-, -S(O) x -, –NR B C(O)-, –C(O)NR B -, C 1 -C 6 -alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and
  • the compound of Formula (I) is a compound of Formula (I-b): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, A, B, L, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-c): 113 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, rein each of W 1 , A, B, L, and R 4a are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-d): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , A, B, L, R 4a , and R 4b , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-e): a pharmaceutically acceptable salt, solvate, hydrate, each of X, A, B, L, R 4a , 4b and R , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-f): a pharmaceutically acceptable salt, solvate, hydrate, n each of X, A, B, L, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-g): 114 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, B, and R 4a , are as defined herein, and each of Z 1 , Z 2 , Z 3 , and Z 4 is independently N or CR 4b .
  • the compound of Formula (I) is a compound of Formula (I-h): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, B, R 4a , and R 5 , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-h’): ate, in.
  • the compound of Formula (I) is a compound of Formula (I-i): a pharmaceutically acceptable salt, solvate, , , , erein each of W 1 , X, A, B, L, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-i’): 115 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, rein each of W 1 , X, B, L, and R 4a , are as defined herein, and A’ is a 5-membered heteroaryl optionally substituted with one or more R 6 .
  • the compound of Formula (I) is a compound of Formula (I-j): O 1 B O W L a pharmaceutically acceptable salt, solvate, herein each of W 1 , X, A, B, L, R 4a , and R A , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-j’): a pharmaceutically acceptable salt, solvate, hydrate, V 1 is halogen, and each 1 4a of W , X, A, B, L, and R are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-j”): a pharmaceutically acceptable salt, solvate, hydrate, V 2 is C 1 -C 6 -haloalkyl, and each of W 1 , X, A, B, L, and R 4a are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-k): a pharmaceutically acceptable salt, solvate, hydrate, rein each of W 1 , X, A, B, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-k’): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, A, B, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-l): a pharmaceutically acceptable salt, solvate, hydrate, rein each of W 1 , X, A, B, and 4a R , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-l’): O R 4a W 1 a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, A, B, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-m): 117 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, ein each of W 1 , X, A, B, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-m’): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, A, B, and R 4a , are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-n): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, B, and R 4a , are as defined herein, and wherein each of Z 5 and Z 6 is independently N, NR 5 , O, or CR 5 .
  • the compound of Formula (I) is a compound of Formula (I-n’): a pharmaceutically acceptable salt, solvate, hydrate, ach of W 1 , X, B, and R 4a , are as defined herein, and wherein each of Z 5 and Z 6 is independently N, O, or CR 4b .
  • the compound of Formula (I) is a compound of Formula (I-o): 118 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, B, R 4a , and R 5 are as defined herein, and wherein Z 2 is independently N or CR 5 .
  • the compound of Formula (I) is a compound of Formula (I-p): O R 4a W 1 Z 2 NH a pharmaceutically acceptable salt, solvate, hydrate, ein each of W 1 , X, B, R 4a , and R 5 are as defined herein, and wherein Z 2 is independently N or CR 5 .
  • the compound of Formula (I) is a compound of Formula (I-q): a pharmaceutically acceptable salt, solvate, hydrate, 1 4a 5 ach of W , X, B, R , and R are as defined herein, and wherein Z 7 , Z 8 , and Z 9 form part of an aromatic ring and are each independently C, N, CR 5 , NR 5 , O, or S.
  • the compound of Formula (I) is a compound of Formula (I-r): a pharmaceutically acceptable salt, solvate, hydrate, , , ein each of W 1 , X, B, R 4a , and R 5 are as defined herein, 119 Attorney Docket No.: R2103-7054WO and wherein Z 7’ , Z 8 , and Z 9 form part of an aromatic ring and are each independently C, N, CR 5 , NR 5 , O, or S.
  • the compound of Formula (I) is a compound of Formula (I-s): a pharmaceutically acceptable salt, solvate, rein each of W 1 , X, A, R 4a , R 5 , and R A are as defined herein.
  • the compound of Formula (I) is a compound of Formula (I-t): a pharmaceutically acceptable salt, solvate, erein each of W 1 , X 4a 5 , A, R , and R are as defined herein, and wherein V 3 is halogen or C 1 -C 6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-u): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , X, A, R 4a , and R 5 are as defined herein, and wherein Z D is N or CR 5 .
  • the compound of Formula (I) is a compound of Formula (I-v): 120 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, rein each of W 1 , X, A, R 4a , and R 5 are as defined herein, and wherein Z A , Z B , and Z C form part of an aromatic ring and are each independently C, N, CR 5 , NR 5 , O or S.
  • the compound of Formula (I) is a compound of Formula (I-w): O R 4a W 1 Z C NH Z B a pharmaceutically acceptable salt, solvate, ein each of 1 4a 5 W , X, A, R , and R are as defined herein, and wherein Z A , Z B , and Z C form part of an aromatic ring and are each independently C, N, CR 5 , NR 5 , O, or S.
  • the compound of Formula (I) is selected from a compound in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
  • Table 1 Exemplary compounds of Formula (I) # Structure # Structure # Structure 121 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 127 Attorney Docket No.: R2103-7054WO # Structure # Structure 12 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure O O F Attorney Docket No.: R2103-7054WO # Structure # Structure 131 Attorney Docket No.: R2103-7054WO # Structure # Structure # Structure 132 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R
  • the pharmaceutical composition described herein comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof 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.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • Such preparatory methods include the steps of bringing the compound of Formula (I) (the “active ingredient”) into association with a carrier 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.
  • Pharmaceutical 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, for example, 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 of the invention 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 may comprise between 0.1% and 100% (w/w) active ingredient.
  • pharmaceutically acceptable excipient refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention are any of those that are well known in the art of pharmaceutical formulation and 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.
  • compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate,
  • compositions of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • provided compounds or compositions are administrable intravenously and/or orally.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or 171 Attorney Docket No.: R2103-7054WO solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • a provided oral formulation is formulated for immediate release or sustained/delayed release.
  • the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles.
  • a provided compound can also be in micro-encapsulated form.
  • pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration.
  • Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • provided pharmaceutically acceptable compositions may be formulated as micronized suspensions or in an ointment such as petrolatum.
  • compositions In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. 172 Attorney Docket No.: R2103-7054WO Although the descriptions of pharmaceutical 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.
  • 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.
  • Compounds provided herein are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending 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 exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be 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 can be 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 may comprise about 0.0001 mg to about 3000 mg, 173 Attorney Docket No.: R2103-7054WO 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 Formula (I) may be 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. It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound or composition can be 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.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered 174 Attorney Docket No.: R2103-7054WO together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • additional pharmaceutical agents utilized 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.
  • additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S.
  • kits e.g., pharmaceutical packs.
  • kits may be useful for preventing and/or treating a proliferative disease or a non-proliferative disease, e.g., as described herein.
  • the kits provided may comprise an inventive pharmaceutical composition or compound 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 may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one-unit dosage form.
  • kits including a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof.
  • the kit 175 Attorney Docket No.: R2103-7054WO of the disclosure includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the kits are useful in preventing and/or treating a disease, disorder, or condition described herein in a subject (e.g., a proliferative disease or a non-proliferative disease).
  • kits further include instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof, to a subject to prevent and/or treat a proliferative disease or a non-proliferative disease.
  • CDK cyclin dependent kinase
  • cyclin protein expression e.g., Cyclin K
  • a compound of Formula (I) modulates the activity of a CDK and/or cyclin.
  • Cyclin K Degradation Cyclins are a family of genes that regulate the enzymatic activity of cyclin dependent kinases (CDKs). Every CDK must be complexed with a partner cyclin to be catalytically active. Cyclin K plays a role as an important regulator of gene transcription by activating the cyclin dependent kinases CDK12 and CDK13. In the absence of Cyclin K, both CDK12 and CDK13 are functionally inactive.
  • Cyclin K therefore plays a pivotal role in regulating cellular processes downstream of CDK12 and CDK13 activity, including gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression, and cell proliferation. It has been demonstrated that Cyclin K protein levels can be modulated by small molecule compounds, such as molecular glue degraders (molecular glues). Molecular glues result in proteasome mediated degradation of Cyclin K by inducing ternary complex formation between CDK12 (or CDK13) and the ubiquitin ligase scaffolding protein DDB1.
  • molecular glues molecular glues
  • DDB1 positions the CDK12/Cyclin K (or CDK13/Cyclin K) complex in the proximity of an E2 176 Attorney Docket No.: R2103-7054WO ubiquitin ligase for efficient ubiquitination of Cyclin K, which results in the degradation of Cyclin K by the proteasome.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is capable of modulating an activity of Cyclin K.
  • the compound of Formula (I) may inhibit the activity of Cyclin K.
  • the compound of Formula (I) inhibits the activity of Cyclin K, e.g., by about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%.8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%....90%, 95%, 99%, or more, e.g., relative to a reference standard.
  • the compound of Formula (I) inhibits the activity of Cyclin K between about 1% and 50%.
  • the compound of Formula (I) slows the activity of Cyclin K.
  • the compound of Formula (I) slows the activity of Cyclin K by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 15%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 20%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 25%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 50%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 75%.
  • the compound of Formula (I) slows the activity of Cyclin K by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at
  • the compound of Formula (I) slows the activity of Cyclin K by at least 90%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 95%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 99%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by more than 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K, e.g., in a cell or sample.
  • the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more).
  • the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 5%.
  • the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 10%.
  • the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 20%.
  • the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 30%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 40%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 50%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 75%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 90%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 95%.
  • the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by more than 99%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 5%.
  • the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 10%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 20%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 30%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 40%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 50%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 75%.
  • the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 90%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 95%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 178 Attorney Docket No.: R2103-7054WO 99%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by more than 99%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 0.5%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 1%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 2%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 10%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 15%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 20%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 25%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 50%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 75%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 90%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound 179 Attorney Docket No.: R2103-7054WO of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 0.5%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 1%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 2%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 50%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by more than about 95%.
  • CDK12/13 Inhibition The cell cycle is a highly regulated process governing cell division and is controlled by several cyclins and cyclin-dependent kinases (CDKs), a group of serine/threonine protein kinases.
  • CDKs cyclins and cyclin-dependent kinases
  • Cyclins phosphorylate CDKs, forming complexes that play crucial roles in cell cycle regulation and gene transcription (see, e.g., Ding, L. et al. International Journal of Molecular Sciences. (2020) 21:65-78). While cyclins activate CDKs, there are other regulatory molecules that can inhibit their function. Under normal conditions, the activation and inhibition of CDK complexes controls the behavior of the cell at many important cell cycle checkpoints to regulate healthy division. However, this process can become dysregulated and promote uncontrolled division of cells, leading to cancer. In fact, in many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional.
  • CDKs can promote cell cycle arrest and 180 Attorney Docket No.: R2103-7054WO attenuate cell proliferation (Malumbres, M., et al. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer (2009) 9:153–166).
  • CDKs are divided into two subfamilies, including cell cycle-associated CDKs and transcription-associated CDKs.
  • Cell cycle-associated CDKs mainly contain CDK1, CDK2, CDK4 and CDK6, which directly regulate the cell cycle progression.
  • the transcription- associated CDKs consisting of CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13, control gene transcription.
  • Cyclin-dependent kinase 12 is known to regulate gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression, and cell proliferation.
  • CDK12 complexes with cyclin K to regulate gene transcription elongation via phosphorylating RNA polymerase II (RNAP II) and additionally regulates translation.
  • CDK12 is mainly composed of three domains: a central Cdc2-related protein kinase domain (KD), an N-terminal “arm”, about 700 amino acids, and a C-terminal “arm”, about 500 amino acids.
  • the central KD is composed of 300 amino acids, and its main function is to mediate phosphorylation of the C-terminal domain of RNAP II.
  • the RS domain which is enriched arginine and serine, is a prominent feature of CDK12.
  • CDK12 There are 21 RS motifs in the first 400 amino acids of CDK12, and one RS motif in the rest of the approximately 1000 amino acids.
  • the RS domain mainly functions to target CDK12 to the nuclear speckles.
  • the central KD and the RS domain give CDK12 the capacity to directly link transcription with splicing machinery.
  • Proline-rich motifs PRM are located between the RS domain and the central KD and are also found in the C-terminal region.
  • the PRM contains the consensus binding sites for Src homology 3 (SH3) and tryptophan (WW) regions, which mediate protein–protein interactions by binding proline-rich modules in ligands.
  • SH3 consensus binding sites for Src homology 3
  • WW tryptophan
  • the presence of the RS domain and PRM domain indicates that CDK12 can take part in numerous protein–protein interactions.
  • CDK12 is bound to cyclin K, the complex functions as an RNA polymerase II (RNAP II) C-terminal domain kinase. Inhibition of CDK12 reduces RNAP II processivity and is correlated with defective transcription elongation (Chirackal Manavalan A.P., et al. EMBO Rep. (2019) 20:e47592).
  • CDK12 phosphorylates 4E-BP1 (the mRNA 5’ cap-binding repressor) 181 Attorney Docket No.: R2103-7054WO at Ser65 and Thr70 and is known to suppress intronic polyadenylation (Krajewska M., et al. Nat. Commun. (2019) 10:1757).
  • the closest human homologue of CDK12 is CDK13. While their KD sequences are highly homologous (sharing 43% sequence identity), their C- and N-terminal regions differ.
  • CDK12/13 phosphorylate Ser5 and Ser2 of the RNAP II C-terminal domain when complexed with cyclin K. CDK13 has been shown to be involved in alternative splicing (R.
  • CDK12 comprises the amino acid sequence of SEQ ID NO 1: MPNSERHGGKKDGSGGASGTLQPSSGGGSSNSRERHRLVSKHKRHKSKHSKDMGLVTP EAASLGTVIKPLVEYDDISSDSDTFSDDMAFKLDRRENDERRGSDRSDRLHKHRHHQHR RSRDLLKAKQTEKEKSQEVSSKSGSMKDRISGSSKRSNEETDDYGKAQVAKSSSKESRS SKLHKEKTRKERELKSGHKDRSKSHRKRETPKSYKTVDSPKRRSRSPHRKWSDSSKQD DSPSGASYGQDYDLSPSRSHTSSNYDSYKKSPGSTSRRQSVSPPYKEPSAYQSSTRSPSPY SRRQRSVSPYSRRRSSSYERSGSYSGRSPSPYGRRRSSSPFLSKRSLSRSPLPSRKSMKSRS RSPAYSRHSSSHSKKKRSSSRSRHSSISPVRLPLNSSLGAELSRKKKERAAAAAAAKM
  • CDK12 comprises an amino acid sequence having at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or greater) sequence identity to SEQ ID NO: 1.
  • CDK13 comprises the amino acid sequence of SEQ ID NO 2: MPSSSDTALGGGGGLSWAEKKLEERRKRRRFLSPQQPPLLLPLLQPQLLQPPPPPLLFL AAPGTAAAAAAAAAASSSCFSPGPPLEVKRLARGKRRAGGRQKRRRGPRAGQEAEKRR VFSLPQPQQDGGGGASSGGGVTPLVEYEDVSSQSEQGLLLGGASAATAATAAGGTGGS GGSPASSSGTQRRGEGSERRPRRDRRSSSGRSKERHREHRRRDGQRGGSEASKSRSRHS HSGEERAEVAKSGSSSGGRRKSASATSSSSSSRKDRDSKAHRSRTKSSKEPPSAYKEPP KAYREDKTEPKAYRRRRSLSPLGGRDDSPVSHRASQSLRSRKSPSPAGGGSSPYSRRLPR SPSPYSRRRSPSYSRHSSYERGGDVSPSPYSSSSWRRSRSPYSPVLRRSGKSRSRSPYSSRH
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is capable of modulating an activity of a CDK, e.g., CDK12 and/or CDK13.
  • the compound of Formula (I) may inhibit the activity of a CDK, e.g., CDK12 and/or CDK13.
  • the compound of Formula (I) inhibits the activity of a CDK, e.g., CDK12 and/or CDK13 by about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%.8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%....90%, 95%, 99%, or more, e.g., relative to a reference standard.
  • the compound of Formula (I) inhibits the activity of a CDK, e.g., CDK12 and/or CDK13 between about 1% and 50%. In an embodiment, the compound of Formula (I) does not substantially inhibit the activity of CDK13. In some embodiments, the compound of Formula (I) slows the activity of a CDK, e.g., CDK12 and/or CDK13. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 15%.
  • the compound of Formula (I) slows the activity of CDK12 by at least 20%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 25%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 50%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 75%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 90%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 95%.
  • the compound of 184 Attorney Docket No.: R2103-7054WO Formula (I) slows the activity of CDK12 by at least 99%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by more than 99%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 15%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 20%.
  • the compound of Formula (I) slows the activity of CDK13 by at least 25%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 50%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 75%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 90%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 95%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 99%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by more than 99%.
  • the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 5%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 10%.
  • the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 20%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 30%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 40%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 50%.
  • the compound of Formula (I) is capable of reducing the level of phosphorylation 185 Attorney Docket No.: R2103-7054WO of RNAP II by CDK12 by at least 75%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 90%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 95%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 99%.
  • the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by more than 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 5%.
  • the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 10%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 20%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 30%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 40%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 50%.
  • the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 75%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 90%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 95%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 99%.
  • the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by more than 99%.
  • 186 Attorney Docket No.: R2103-7054WO the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12.
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more).
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 5%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 10%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 20%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 30%.
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 40%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 50%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 75%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 90%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 95%.
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by more than 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more).
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 5%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 10%. In some 187 Attorney Docket No.: R2103-7054WO embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 20%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 30%.
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 40%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 50%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 75%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 90%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 95%.
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by more than 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 10% (e.g., about 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 25%.
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 50%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 75%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 90%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 95%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 99%.
  • the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by more than 99%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 0.5%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 1%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 2%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 10%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 15%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 20%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 25%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 50%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 75%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 90%.
  • the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding 189 Attorney Docket No.: R2103-7054WO of CDK13 to RNAP II by about 1%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 2%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 10%.
  • the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 15%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 20%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 25%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 50%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 75%.
  • the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 90%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 0.5%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 1%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 2%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity 190 Attorney Docket No.: R2103-7054WO of CDK12 for RNAP II by about 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 25%.
  • the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 50%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II.
  • the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 0.5%.
  • the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 1%.
  • the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 2%.
  • the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 50%.
  • the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 95%. In some embodiments, the 191 Attorney Docket No.: R2103-7054WO compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 0.1% (e.g., 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 0.5%.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 1%.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 2%.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 50%.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by more than 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 0.1% (e.g., 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more).
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 0.5%.
  • 192 Attorney Docket No.: R2103-7054WO the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 1%.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 2%.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 50%.
  • the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by more than 95%.
  • Methods of Treatment The present disclosure also provides methods for the treatment or prevention of a disease, disorder, or condition.
  • the disease, disorder or condition is related to (e.g., caused by) modulation of a phosphorylation event, such as an unwanted, aberrant, or alternative phosphorylation event.
  • the disease, disorder or condition comprises a proliferative disease (e.g., cancer, benign neoplasm, or inflammatory disease) or non- proliferative disease.
  • a proliferative disease e.g., cancer, benign neoplasm, or inflammatory disease
  • Such methods comprise the step of administering to the subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof.
  • the methods described herein include administering to a subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or 193 Attorney Docket No.: R2103-7054WO a pharmaceutical composition thereof.
  • the disease or disorder to be treated or prevented using the compounds of Formula (I) is cancer.
  • cancer refers to a malignant neoplasm (Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • 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 neuroendocrine 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 adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • the cancer is breast cancer, gastroesophageal cancer, salivary cancer, bladder cancer, colorectal cancer, uterine cancer, ovarian cancer, or lung cancer.
  • the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.
  • the cancer is a carcinoma.
  • the cancer is a sarcoma.
  • the cancer is a lymphoma.
  • the cancer is a leukemia.
  • the cancer is a melanoma.
  • the cancer is a mesothelioma. In some embodiments, the cancer is a multiple myeloma. In some embodiments, the cancer is a seminoma. In some embodiments, the disease or disorder is associated with a benign neoplasm.
  • a benign neoplasm may include adenoma, fibroma, hemangioma, tuberous sclerosis, and lipoma. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • the disease or disorder is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • a compound of Formula (I) may slow progression of tumor growth, reduce tumor size, slow and/or prevent cell division, accelerate cell death, prevent metastasis, enhance immune recognition of the tumor, and/or reduce inflammation.
  • a compound of Formula (I) slows progression of tumor growth.
  • a compound of Formula (I) reduces tumor size.
  • a compound of Formula (I) slows and/or prevents cell division.
  • a compound of Formula (I) accelerates cell death.
  • a compound of Formula (I) slows and/or prevents metastasis.
  • a compound of Formula (I) enhances immune recognition of the tumor. In some embodiments, a compound of Formula (I) reduces inflammation. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%.
  • the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type- matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%.
  • the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type- matched cancer cell, by at least 95%.
  • the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer 197 Attorney Docket No.: R2103-7054WO cell, by at least 99%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%.
  • the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more).
  • the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%.
  • the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 30%.
  • the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%.
  • the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 95%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 99%.
  • the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%.
  • the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more).
  • the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%.
  • the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., 198 Attorney Docket No.: R2103-7054WO relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%.
  • the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 95%.
  • the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type- matched cancer cell, by at least 99%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%. In some embodiments, the compound of Formula (I) results in the death of a cancer cell.
  • a compound of Formula (I) may be used to treat a subject having or diagnosed having a cancer.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat a a neurological disease, autoimmune disorder, immunodeficiency disorder, lysosomal storage disease, cardiovascular condition, metabolic disorder, respiratory condition, inflammatory disease, renal disease, or infectious disease.
  • the disease is a neurological disease.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat a neurological disease, disorder, or condition.
  • a neurological disease, disorder, or condition may include a neurodegenerative disease, a psychiatric condition, or a musculoskeletal disease.
  • Exemplary neurological diseases, disorders, and conditions include Alzheimer’s disease, Huntington’s chorea, a prion disease (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), a mental retardation disorder (e.g., a disorder caused by a 199 Attorney Docket No.: R2103-7054WO SETD5 gene mutation, e.g., intellectual disability-facial dysmorphism syndrome, autism spectrum disorder), Lewy Body disease, diffuse Lewy body disease (DLBD), dementia, progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick’s disease, primary progressive aphasia, corticobasal dementia, Parkinson’s disease, Down’s syndrome, multiple system atrophy, spinal muscular atrophy (SMA), progressive spinobulbar muscular atrophy (e
  • the neurological disease comprises Friedrich’s ataxia or Sturge Weber syndrome. In some embodiments, the neurological disease comprises Huntington’s disease. In some embodiments, the neurological disease comprises spinal muscular atrophy. All types of neurological diseases disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • the disease is an autoimmune disorder or an immunodeficiency disorder.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat an autoimmune disease, disorder, or condition, or an immunodeficiency disease, disorder, or condition.
  • Exemplary autoimmune and 200 Attorney Docket No.: R2103-7054WO immunodeficiency diseases, disorders, and conditions include arthritis (e.g., rheumatoid arthritis, osteoarthritis, gout), Chagas disease, chronic obstructive pulmonary disease (COPD), dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture’s syndrome, Graves’ disease, Guillain-Barr ⁇ syndrome (GBS), Hashiomoto’s disease, Hidradenitis suppurativa, Kawasaki disease, ankylosing spondylitis, IgA nephropathy, idiopathic thrombocytopenic purpura, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, infective colitis, indeterminate colitisinterstitial cystitis, lupus (
  • the autoimmune or immunodeficiency disorder comprises chronic mucocutaneous candidiasis. All types of autoimmune disorders and immunodeficiency disorders disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • the disease is a cardiovascular condition.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat a cardiovascular disease, disorder, or condition.
  • a cardiovascular disease, disorder, or condition may include a condition relating to the heart or vascular system, such as the arteries, veins, or blood.
  • Exemplary cardiovascular diseases, disorders, or conditions include angina, arrhythmias (atrial or ventricular or both), heart failure, arteriosclerosis, atheroma, atherosclerosis, cardiac hypertrophy, cardiac or vascular aneurysm, cardiac myocyte dysfunction, 201 Attorney Docket No.: R2103-7054WO carotid obstructive disease, endothelial damage after PTCA (percutaneous transluminal coronary angioplasty), hypertension including essential hypertension, pulmonary hypertension and secondary hypertension (renovascular hypertension, chronic glomerulonephritis), myocardial infarction, myocardial ischemia, peripheral obstructive arteriopathy of a limb, an organ, or a tissue; peripheral artery occlusive disease (PAOD), reperfusion injury following ischemia of the brain, heart or other organ or tissue, restenosis, stroke, thrombosis, transient ischemic attack (TIA), vascular occlusion, vasculitis, and va
  • the disease is a metabolic disorder.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat a metabolic disease, disorder, or condition.
  • a metabolic disease, disorder, or condition may include a disorder or condition that is characterized by abnormal metabolism, such as those disorders relating to the consumption of food and water, digestion, nutrient processing, and waste removal.
  • a metabolic disease, disorder, or condition may include an acid-base imbalance, a mitochondrial disease, a wasting syndrome, a malabsorption disorder, an iron metabolism disorder, a calcium metabolism disorder, a DNA repair deficiency disorder, a glucose metabolism disorder, hyperlactatemia, a disorder of the gut microbiota.
  • Exemplary metabolic conditions include obesity, diabetes (Type I or Type II), insulin resistance, glucose intolerance, lactose intolerance, eczema, hypertension, Hunter syndrome, Krabbe disease, sickle cell anemia, maple syrup urine disease, Pompe disease, and metachromatic leukodystrophy. All types of metabolic diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • the disease is a respiratory condition.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat a respiratory disease, disorder, or condition.
  • a respiratory disease, disorder, or condition 202 Attorney Docket No.: R2103-7054WO can include a disorder or condition relating to any part of the respiratory system, such as the lungs, alveoli, trachea, bronchi, nasal passages, or nose.
  • Exemplary respiratory diseases, disorders, or conditions include asthma, allergies, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), lung cancer, oxygen toxicity, emphysema, chronic bronchitis, and acute respiratory distress syndrome. All types of respiratory diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • the disease is a renal disease.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat a renal disease, disorder, or condition.
  • a renal disease, disorder, or condition can include a disease, disorder, or condition relating to any part of the waste production, storage, and removal system, including the kidneys, ureter, bladder, urethra, adrenal gland, and pelvis.
  • Exemplary renal diseases include acute kidney failure, amyloidosis, Alport syndrome, adenovirus nephritis, acute lobar nephronia, tubular necrosis, glomerulonephritis, kidney stones, urinary tract infections, chronic kidney disease, polycystic kidney disease, and focal segmental glomerulosclerosis (FSGS).
  • the renal disease, disorder, or condition comprises HIV-associated nephropathy or hypertensive nephropathy.
  • the disease is an infectious disease.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof is used to prevent or treat an infectious disease, disorder, or condition.
  • An infectious disease may be caused by a pathogen such as a virus or bacteria.
  • infectious diseases include human immunodeficiency syndrome (HIV), acquired immunodeficiency syndrome (AIDS), meningitis, African sleeping sickness, actinomycosis, pneumonia, botulism, chlamydia, Chagas disease, Colorado tick fever, cholera, typhus, giardiasis, food poisoning, ebola hemorrhagic fever, diphtheria, Dengue fever, gonorrhea, streptococcal infection (e.g., Group A or Group B), 203 Attorney Docket No.: R2103-7054WO hepatitis A, hepatitis B, hepatitis C, herpes simplex, hookworm infection, influenza, Epstein-Barr infection, Kawasaki disease, kuru, leprosy, leishmaniasis, measles, mumps, norovirus, meningococcal disease, malaria, Lyme disease, listeriosis, rabies, rhinovirus, rubella, tetan
  • the infectious disease comprises cytomegalovirus. All types of infectious diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure.
  • the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal.
  • the subject is a research animal such as a rodent, dog, or non-human primate.
  • the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.
  • the methods described herein comprise the additional step of administering one or more additional pharmaceutical agents in combination with the compound of Formula (I), a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof.
  • additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent.
  • the additional pharmaceutical agent(s) may synergistically augment the modulation of CDK activity induced by the inventive compounds or compositions of this disclosure in the biological sample or subject.
  • the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating, for example, a cancer or other disease, disorder, or condition resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.
  • ENUMERATED EMBODIMENTS 204 Attorney Docket No.: R2103-7054WO 1.
  • Ring A is 6-membered aryl (e.g., phenyl) optionally substituted with one or more R 5 .
  • Ring A is 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 .
  • Ring A is a nitrogen- containing 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R 5 .
  • Ring B is selected from (R 5 ) 0-4 N nd 17.
  • Ring B is selected from (R 5 ) 0-4 , wherein R 5 is as described in embodiment 18.
  • Ring B is selected , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO 20.
  • each R 4a is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -heteroalkyl, C 1 -C 6 -haloalkyl, halo, cyano, –OR A , or cycloalkyl.
  • each R 4a is hydrogen, C 1 -C 6 -alkyl, halo, or –OR A .
  • R 4a is hydrogen.
  • X is N. 43.
  • the compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-d): a pharmaceutically acceptable salt, solvate, hydrate, each of W 1 , A, B, L, R 4a , and R 4b , are as defined in embodiment 1. 53.
  • the compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-e): a pharmaceutically acceptable salt, solvate, hydrate, each of X, A, B, L, R 4a , and R 4b , are as defined in embodiment 1.
  • the compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-f): a pharmaceutically acceptable salt, solvate, hydrate, n each of X, A, B, L, and R 4a are as defined in embodiment 1. 55.
  • the compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-i): a pharmaceutically acceptable salt, solvate, erein each of W 1 , X, A, B, L, and R 4a , are as defined in embodiment 1.
  • the compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-j): 234 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, erein each of W 1 , X, A, B, L, R 4a , and R A are as defined in embodiment 1. 59.
  • a pharmaceutical composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable excipient.
  • a method of modulating the rate of degradation of a cyclin (e.g., cyclin K) in a sample or subject comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) as described in any one of embodiments 1-67. 237 Attorney Docket No.: R2103-7054WO 70.
  • a cyclin e.g., cyclin K
  • a method of modulating the level of a cyclin (e.g., cyclin K) in a sample or subject comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) as described in any one of embodiments 1-67. 72.
  • a cyclin e.g., cyclin K
  • a cyclin dependent kinase CDK
  • CDK cyclin dependent kinase
  • the disease or disorder comprises a proliferative disease (e.g., cancer, a benign neoplasm, or angiogenesis).
  • a proliferative disease e.g., cancer, a benign neoplasm, or angiogenesis.
  • the disease or disorder comprises cancer.
  • the cancer is selected from breast cancer, prostate cancer, lung cancer, skin cancer, blood cancer, or ovarian cancer.
  • the disease or disorder comprises a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease.
  • a composition for use in treating a disease or disorder in a subject comprising a compound of Formula (I) according to any one of embodiments 1-67 or the pharmaceutical composition of embodiment 68.
  • EXAMPLES 239 Attorney Docket No.: R2103-7054WO
  • the examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
  • the compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art.
  • reactions can be purified or analyzed according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrome (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • NMR nuclear magnetic resonance
  • IR infrared
  • MS mass spectrome
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • Mobile phase A Water/5mM NH4HCO3,
  • Mobile phase B CH3CN).
  • Step 2 was ran at room temperature for 16 h - J ).
  • g, J .6 d, J m - 3 5- Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran in DMF for 16 h.
  • Step 2 was ran at room temperature for 16 h g, J 3 7 g, J 9 5 m Attorney Docket No.: R2103-7054WO Gradient 9) to afford 6-methoxy-2-[(4- pyrrol-1-ylphenyl)methyl]-3H-pyrido-[3,4- d i idi 4 1 2 g, , 6 4 d 5 , l- J C d % Attorney Docket No.: R2103-7054WO [M+H] + .
  • Step 1 was ran at room temperature for 1 h.
  • Step 1 was ran for 8 h. The residue was purified by reversed-phase fl h h h dii 2 dint 3- % 07 ⁇ 41 (s, ).
  • Step 2 was ran at room f 2 h se nt 5- d S z, .2 z, 76 05 m se nt 4- 4, d.
  • Th id ifid b P HPLC 7- - g, S, z, 46 ), z, ), 2 C 7- g, S, z, 98 ), .4 (s, m se nt y- % 78 ⁇ d, z, ), 86 m C Attorney Docket No.: R2103-7054WO The mixture was acidified to pH 8 with 1 M HCl, and poured into water (20 mL).
  • Step 1 was ran at room temperature for 30 min.
  • Step 2 was ran at f 1 h N re (5 sh to H- de % 69 ⁇ z, ), z, m at se nt H- de % 85 ⁇ 99 z, m se nt 6- 4- g, S, z, 87 (s, ).
  • Step 1 was ran at room temperature for 16 h.
  • Step 1 used 1.5 equiv. TCFH as amide coupling reagent and 3 equiv. N- h li id l b i M oC. n to n- - ol, 72 ⁇ 53 ), z, H N- m v. by to 6- 2- % 06 ⁇ J 07 ).
  • Step 2 used LiOH ⁇ H2O in THF at 2 h er 30 es nd 8- 6, S oC 70 n to l- )- .6 S, re he gh re N re 10 o- - nd 9) % 18 308
  • Step 1 and Step 2 were each ran for 2 h. Th i idifid H 5 ih 2 N as er 7- 3- ne S m nd as 7- ]- - 80 d.
  • Th id ifid b hse 2, l- 2- % 20 ⁇ 87 ), d, 86 ), F n to 2- % 87 ⁇ (s, ), F n to 2- g, S z, 98 ), 00 313
  • Step 2 used LiOH ⁇ H 2 O in THF at 70 oC over 3 h.
  • Th i i d der nd he by L) 1- 73 S, m se nt 6- - - .7 S, z, 96 ), (t, ), 71 (s, (s, m n to 4- - 00 d.
  • Step 2 was run at room temperature for 2 h. Th i i idifid H 5 ng n, to ol, 51 F er re er 3- ol, 00 at C 4- % .1 ⁇ 43 ), (s, Scheme B: 317 Attorney Docket No.: R2103-7054WO 3b, and B-3c.
  • the residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to ff d h 2 4 hl l1- d) H 59 .0 (s, b. m ep C 3- 6, d.
  • the general protocol in Scheme B can be prepared using exemplary conditions for Step 3 as described in Condition B-3c. plary conditions for Step 3 as described in Condition B-3d (see intermediate C91) or Condition B-3e (see Compound 517 and Compound 546).
  • 333 Attorney Docket No.: R2103-7054WO Ex Exa p e : y es s o o pou , one (A70, 150 mg, 354.4 ⁇ mol) and 3-fluoropyrrolidine hydrochloride (67.2 mg, 531.7 ⁇ mol) in dioxane (3 mL) were added Cs 2 CO 3 (346.4 mg, 1.1 mmol) and Pd-PEPPSI-IPentCl (28.1 mg, 35.4 ⁇ mol) at room temperature under nitrogen atmosphere.
  • Step 3 was ran at 110 °C for 16 h. d- on o- - a H s, s, 80 ), .0 C 6- .9 d. R ), .5 ), s, z, J C 4- 24 d. R ), .4 87 35
  • Step 3 was ran at 110 °C for 2 h.
  • Step 2 was ran with LiOH and without H 2 O 2 at room temperature v. C 2- g, S 00 (s, 6- (s, H re v. C he o- .9 S, z, m, z, s, th 16 v. e- on 3- 02 S 35 Attorney Docket No.: R2103-7054WO (ES, m/z): 427 [M+H] + .
  • Example 7 Synthesis of Compound 180 356 Attorney Docket No.: R2103-7054WO mg, 475.9 ⁇ mol) and tributyl(2-furyl)stannane (203.9 mg, 571.1 ⁇ mol, 179.9 ⁇ L) in dioxane (3 mL) were added Pd(PPh3)4 (55.0 mg, 47.6 ⁇ mol), and the reaction was stirred for 2 h at 100°C under nitrogen atmosphere.
  • Pd(PPh3)4 55.0 mg, 47.6 ⁇ mol
  • Step 1 was ran at room m C 00 n ) 1, 4- d a R d, .2 ), 46 88 Scheme K: e pay ooco:
  • Example 10 Synthesis of Compound 136, 221-222 Synthesis of A29 368 Attorney Docket No.: R2103-7054WO To a and 2-(4-bromo- phenyl)acetyl chloride (1.04 g, 4.4 mmol) in NMP (4 mL), and the reaction was irradiated with microwave radiation for 4 h at 200 °C.
  • Example 12 Synthesis of Compound 106 Synthesis of Compound 106 374 Attorney Docket No.: R2103-7054WO py y p y y q 4-one (Compound 190, 260 mg, 683.8 ⁇ mol) and Zn(CN)2 (241 mg, 2.1 mmol) in DMF (3 mL) was added Pd(PPh 3 ) 4 (39 mg, 34.2 ⁇ mol) in portions, and the reaction was stirred for 16 h at 90 °C. The reaction was quenched with Water/Ice and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered.
  • Example 15 Synthesis of Compound 215 Synthesis of A38 T o a souton o -(-pyrro--ypeny)acetc ac ( g, mmo) an -amino-5-iodo- benzonitrile (1.2 g, 5 mmol) in pyridine (10 mL) was added T 3 P (10 mL), and the reaction was stirred for 3 h at room temperature. The resulting mixture was diluted with water (50 mL).
  • Example 16 Synthesis of Compound 220, 209 O O O N HO N NH NH n-4-one (Compound 127, 100 mg, 301.8 ⁇ mol) in DCE (2.3 mL) was added BBr3 (0.5 mL) dropwise, and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and basified to pH 8 with 7 M NH3(g) in MeOH.
  • Example 19 Synthesis of Compound 349 Synthesis of A103 To a stirred solution of 2-[[6-(4-fluoropyrazol-1-yl)-3-pyridyl]methyl]-7-methoxy-3H- quinazolin-4-one (Compound 347, 0.1 g, 284.6 ⁇ mol) in DMF (5 mL) was added MeSNa (398.4 mg, 5.7 mmol), and the reaction was stirred for 4 h at 120 °C.
  • 6- bromo-8-morpholino-2-[(6-pyrrol-1-yl-3-pyridyl)methyl]-3,1-benzoxazin-4-one (A113, 80 mg, 171.2 ⁇ mol) in portion, and the reaction was stirred at 110°C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was quenched by addition of water (10 mL) at 0°C and extracted with EtOAc (3 x 5 mL). The combined organic phase was washed with brine (5 mL), and dried over anhydrous Na2SO4, and filtered.
  • the filtrate 428 Attorney Docket No.: R2103-7054WO was concentrated under reduced pressure and purified by Prep-HPLC (Condition 15, Gradient 1) to afford 6-bromo-8-morpholino-2-[(6-pyrrol-1-yl-3-pyridyl)methyl]-3H-quinazolin-4-one (Compound 303, 15 mg, 32.2 ⁇ mol, 19% yield) as a solid.
  • Example 21 Synthesis of Compound 353 Synthesis of A115 100 mg, 254.3 ⁇ mol) and tert-butyl piperazine-1-carboxylate (95 mg, 510.1 ⁇ mol) in dioxane (2 mL) was added Cs 2 CO 3 (249 mg, 764.2 ⁇ mol) and Pd-PEPPSI-IPentCl (22 mg, 26.2 ⁇ mol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100°C for 16 h under nitrogen atmosphere.
  • Example 23 Synthesis of Compound 632 436 Attorney Docket No.: R2103-7054WO , 4.5 mmol) in DMAC (8 mL) were added NiCl2 (195 mg, 1.5 mmol) and picolinimidamide hydrochloride (71 mg, 450.9 ⁇ mol) under nitrogen atmosphere, and the reaction was stirred for 4 h at 60°C under nitrogen atmosphere. To the above mixture were added 3-bromo-6-isopropoxy- quinoline (400 mg, 1.50 mmol) and Zinc (295 mg, 4.51 mmol) at room temperature under nitrogen atmosphere, and the resulting mixture was stirred for an additional 16 h at 60°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature.
  • Example 24 Synthesis of Compound 379 Synthesis of A127 , 7, 500 mg, 1.83 mmol) and 2-amino-4,5-dimethoxy-benzonitrile (326 mg, 1.83 mmol) in THF (10 mL) was added LiHMDS (1 M in THF, 4.6 mL), and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered.
  • Example 25 Synthesis of Compound 478 Synthesis of A130 N O HN Br O Br To a stirred mixture of 2-(chloromethyl)-6,7-dimethoxy-3H-quinazolin-4-one (A129, 1 g, 3.93 mmol) and 4-bromo-2H-triazole (581.0 mg, 3.93 mmol) in DMF (10 mL) was added Cs 2 CO 3 (3.8 g, 11.78 mmol), and the reaction was ran at room temperature for 16 h. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL).
  • Example 27 Synthesis of Compound 393 so ut on o 6-bromo-7-met oxy- -[[6-(3-met y pyrro - -y )-3-pyrdy ]met y ]-3H- quinazolin-4-one (Compound 365, 0.2 g, 470.3 ⁇ mol), 1M diisopropylzinc in toluene (0.94 mL, 940.6 ⁇ mol), Pd-PEPPSI-IPentCl (75 mg, 94.1 ⁇ mol) and Cs 2 CO 3 (307 mg, 940.6 ⁇ mol) in dioxane (5 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere.
  • Example 28 Synthesis of Compound 547 A mixture of 7-bromo-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6-methoxy-3H- quinazolin-4-one (Compound 551, 130 mg, 283.7 ⁇ mol) and methylsulfinyloxysodium (57.9 mg, 567.4 ⁇ mol) and N,N’-dimethylethane-1,2-diamine (5 mg, 56.7 ⁇ mol) in DMF (2 mL) were added 446 Attorney Docket No.: R2103-7054WO CuI (11 mg, 56.7 ⁇ mol) and stirred for 16 h at 90 °C under nitrogen atmosphere.
  • Example 29 Synthesis of Compound 451 To a solution of 6-bromo-2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-7-methoxy- quinazolin-4(3H)-one (Compound 433, 0.15 g, 0.43 mmol) in 2 M MeNH2 in THF (3 mL) were added BrettPhos Pd G3 (0.03 g, 0.03 mmol), NaOt-Am (0.11 g, 0.98 mmol), and the reaction was stirred for 16 h at 80 °C under a nitrogen atmosphere.
  • Example 31 Synthesis of Compound 465 3H- quinazolin-4-one (Compound 466, 100 mg, 259.5 ⁇ mol) in tetrahydropyran-4-ol (2 mL) was added t-BuOK (116.4 mg, 1.04 mmol), and the reaction was stirred for 12 h at 100°C.
  • Example 33 Synthesis of Compound 562 450 Attorney Docket No.: R2103-7054WO so ut on o 6-bromo-7-met oxy- -[[6-(3-met y pyrro - -y )-3-pyrdy ]met y ]-3H- quinazolin-4-one (Compound 365, 0.2 g, 470.3 ⁇ mol), 1-vinyloxybutane (141 mg, 1.41 mmol), TEA (143 mg, 1.41 mmol), Pd(AcO)2 (21 mg, 94.1 ⁇ mol) and dppp (39 mg, 94.1 ⁇ mol) in Ethylene glycol, 99% (4 mL) was stirred at 120 °C for 16 h under nitrogen atmosphere.
  • the mixture was allowed to cool down to room temperature.
  • the mixture was acidified to pH 3 with 1 M HCl (1.5 mL).
  • the mixture was stirred at room temperature for 1 h.
  • the mixture was poured into ice water.
  • the resulting mixture was extracted with DCM (20 mL x 3).
  • the combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na 2 SO 4 , and filtered.
  • reaction solution was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na 2 SO 4 , and filtered.
  • the resulting mixture was diluted 457 Attorney Docket No.: R2103-7054WO with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered.
  • Step 4 was ran without Et 3 SiH, for 2 h.
  • Example 40 Synthesis of Compound 610 Synthesis of A191 470 Attorney Docket No.: R2103-7054WO ethoxy- quinazolin-4-yl]-N,N-diphenylcarbamate (A189, 100 mg, 169.3 ⁇ mol), tert-butyl 4- iodopiperidine-1-carboxylate (105 mg, 337.5 ⁇ mol) and K2CO3 (50 mg, 361.8 ⁇ mol) in CH3CN (1 mL) was stirred for 1 h at 60°C under nitrogen atmosphere.
  • Example 41 Synthesis of Compound 620 Synthesis of A192 oxy- 3H-quinazolin-4-one (Compound 551, 200 mg, 436.4 ⁇ mol) and tert-butyl 3-aminopyrrolidine- 1-carboxylate (162 mg, 872.9 ⁇ mol) in DMF (4 mL) were added Ruphos (102 mg, 218.2 ⁇ mol), RuPhos Pd G3 (73 mg, 87.3 ⁇ mol) and Cs2CO3 (426 mg, 1.3 mmol) in portions, and the reaction was stirred at 100°C for 16 h under nitrogen atmosphere. The reaction was allowed to cool down to room temperature.
  • Step 1 used Pd-PEPPSI- IPentCl as catalyst.
  • Step 1 used Pd-PEPPSI- IPentCl as catalyst at 90 oC over 2 h.
  • Step 1 used Pd-PEPPSI- IPentCl as catalyst at 80 oC.
  • Step 2 used TFA/D M 1 l i i 2 h se 2, 5- )- ol, 10 ⁇ z, 1- 01 (s, 3- , J ), I- ed he 7- - a ep S, 480 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used Pd-PEPPSI- IPentCl as catalyst.
  • Example 42 Synthesis of Compound 604 Synthesis of A193 486 Attorney Docket No.: R2103-7054WO lin-4- one (150 mg, 351.9 ⁇ mol) and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrazole (146.8 mg, 527.8 ⁇ mol) in dioxane (3 mL) and H 2 O (0.6 mL) were added K 3 PO 4 (224.0 mg, 1.06 mmol) and Pd(dppf)Cl2 (25.7 mg, 35.2 ⁇ mol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere.
  • Example 44 Synthesis of Compound 615 Synthesis of A197 , y y y y y y y y 3H- quinazolin-4-one (Compound 551, 520 mg, 1.13 mmol) and MeNaS (119.3 mg, 1.7 mmol) and DIEA (733.3 mg, 5.7 mmol) and XantPhos (196.9 mg, 340.4 ⁇ mol) and Pd 2 (dba) 3 (311.7 mg, 340.4 ⁇ mol) in dioxane (5 mL) were stirred for 16 h at 110 °C under nitrogen atmosphere. The 489 Attorney Docket No.: R2103-7054WO reaction was allowed to cool down to room temperature.
  • Example 45 Synthesis of Compound 528 Synthesis of A201 Attorney Docket No.: R2103-7054WO
  • NIS 1.09 g, 4.87 mmol
  • the resulting mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered.
  • the resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by sat. NH 4 Cl (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with DCM/MeOH (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered.
  • Example 47 Synthesis of Compound 579 , y y y q y ethyl]-3H- quinazolin-4-one (Compound 556, 100 mg, 255.5 ⁇ mol) in H2O (3 mL) was added HCl (1 M, 0.5 mL), and the reaction was stirred for 2 h at room temperature. The resulting mixture was 494 Attorney Docket No.: R2103-7054WO lyophilized to afford 2-((4-hydroxy-8-methylquinolin-3-yl)methyl)-6,7-dimethoxyquinazolin- 4(3H)-one hydrochloride (Compound 579, 16.6 mg, 40.1 ⁇ mol, 16% yield) as a solid.
  • Example 48 Synthesis of Compound 535 Synthesis of A227 To a stirred mixture of (3-bromo-5-fluorophenyl)methanamine hydrochloride (1.5 g, 6.24 mmol) and Boc2O (2.72 g, 12.48 mmol, 2.86 mL) in DCM (15 mL) was added Et3N (630 mg, 6.22 mmol), and the reaction was stirred for 16 h at room temperature.
  • Example 52 Synthesis of Compound 412 Synthesis of A263 o a s rre m x ure o -[( - o o- -pyr y )me y ]- , - me oxy- -qu joso n-4-one (4 g, 9.5 mmol) and 2-[3-fluoro-2-(methoxymethoxy)-5-methyl-phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (A262, 4.20 g, 14.2 mmol) in dioxane (40 mL) and H 2 O (8 mL) were 502 Attorney Docket No.: R2103-7054WO added K3PO4 (6.02 g, 28.4 mmol) and Pd(dppf)Cl2 (691.5 mg, 945.2 ⁇ mol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere.
  • the resulting mixture was stirred at 0°C for 0.5 h. The mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was quenched with sat. NH 4 Cl (50 mL), and then the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, and filtered.
  • Example 56 Synthesis of Compound 496 Attorney Docket No.: R2103-7054WO
  • 4-(3,5-difluorophenyl)-2-[(6,7-dimethoxy-4-oxo-3H-quinazolin-2- yl)methyl]-N,N-dimethyl-imidazole-1-sulfonamide (A305, 60 mg, 118.7 ⁇ mol) in DCM (1 mL) was added 4M HCl (gas) in dioxane (1 mL), and the reaction was stirred for 4 h at room temperature under nitrogen atmosphere.
  • Example 58 Synthesis of Compound 405 Synthesis of A318 ol) and 2- amino-5-bromo-3-iodo-benzamide (427.0 mg, 1.25 mmol) in DMF (4 mL) were added T 3 P (996.2 mg, 1.57 mmol, 50 wt. % in EtOAc) and Pyridine (165.1 mg, 2.09 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (10 mL).
  • Example 60 Synthesis of Compound 491 Synthesis of A326 515 Attorney Docket No.: R2103-7054WO
  • a solution of 6-bromo-7-methoxy-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H- quinazolin-4-one (Compound 365, 3 g, 7.05 mmol), DIEA (9.12 g, 70.5 mmol) and bromo- (methoxy)methane (3.53 g, 28.2 mmol, 2.3 mL) in DMF (30 mL) was stirred at room temperature for 2 days.
  • Example 61 Synthesis of Compound 510 Synthesis of A333 To a stirre mol) and (COCl)2 (3 mL) in DCM (38 mL) were added DMF (236.0 mg, 3.23 mmol, 0.25 mL) for 1 min at 0°C, and the reaction was stirred for 1 h at 0 °C. The resulting mixture was concentrated under reduced pressure to afford 2-(6-iodo-3-pyridyl)acetyl chloride (A333, 1.7 g, 6.04 mmol, 42% yield) as a solid.
  • Example 62 Synthesis of Compound 477 519 Attorney Docket No.: R2103-7054WO -1-one (A335, 110 mg, 260.5 ⁇ mol) in dioxane (2.2 mL) was added 3,4-dimethyl-1H-pyrazole (50 mg, 520.1 ⁇ mol), Pd-PEPPSI-IHEPTCl (25 mg, 25.7 ⁇ mol), potassium tert-butoxide (59 mg, 525.8 ⁇ mol), and the reaction was stirred for 6 h at 120 °C under nitrogen.
  • Example 63 Synthesis of Compound 456 To a solution of 3-[(6-chloro-3-pyridyl)methyl]-6,7-dimethoxy-2H-isoquinolin-1-one (A336, 100 mg, 302.3 ⁇ mol) in dioxane (1.5 mL) and H2O (0.15 mL) were added (3,5- difluorophenyl)boronic acid (200 mg, 1265.8 ⁇ mol), Pd(dppf)Cl 2 (11 mg, 15.1 ⁇ mol), K 2 CO 3 (125 mg, 907.0 ⁇ mol), and the reaction was stirred for 2 h at 90 °C under nitrogen atmosphere.
  • Example 65 Synthesis of Compound 520 To a stirred solution of 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7-hydroxy- 3H-quinazolin-4-one (Compound 521, 100 mg, 250.1 ⁇ mol) and 4-iodotetrahydropyran (106 mg, 500.3 ⁇ mol) in DMF (2 mL) was added K 2 CO 3 (69 mg, 500.3 ⁇ mol), and the reaction was stirred for 16 h at 60 °C.
  • Example 66 Synthesis of Compound 548 Synthesis of A344 522 Attorney Docket No.: R2103-7054WO l)methyl]- piperidine-1-carboxylate (A343, 450 mg, 1.09 mmol) and 2-[6-(3,5-difluorophenyl)-3-pyridyl]- acetic acid (271.9 mg, 1.09 mmol) in DMF (4.5 mL) were added T3P (1.04 g, 3.27 mmol, 50% in EtOAc) and pyridine (129.4 mg, 1.64 mmol) dropwise, and the reaction was stirred for 72 h at 50°C.
  • reaction solution was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered.
  • Example 67 Synthesis of Compound 460 Synthesis of A356 Attorney Docket No.: R2103-7054WO To a stirred solution of [4-bromo-3-(methoxymethoxy)phenyl]acetic acid (A355, 300 mg, 1.09 mmol) and pyridine (259 mg, 3.27 mmol) in DMF (6 mL) were added T3P (1388 mg, 2.18 mmol, 50% wt. in EtOAc) and 2-amino-4,5-dimethoxybenzamide (236 mg, 1.2 mmol), and the reaction was stirred at room temperature for 16 h.
  • Example 69 Synthesis of Compound 518 Synthesis of A372 - - - - - - - y y y y p py amino]- 4,5-dimethoxy-benzamide (A371, 1.44 g, 3.63 mmol) and 2-[6-(3-fluorophenyl)-3-pyridyl]acetic acid (700 mg, 3.03 mmol) in DMF (10 mL) were added T3P (2.89 g, 4.54 mmol, 50% purity) and pyridine (718 mg, 9.08 mmol), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL).
  • Example 72 Synthesis of Compound 641 quinazolin-4-one (Compound 519, 18 mg, 44.3 ⁇ mol) was purified by Chiral-HPLC (Condition 21, Gradient 1) to afford 2-[(1R)-1-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-methylpropyl]-6,7- dimethoxy-3H-quinazolin-4-one (B35, 5.5 mg, 13.5 ⁇ mol, 31% yield) as a solid and 2-[(1S)-1- (5,6-dimethyl-1H-benzimidazol-2-yl)-2-methylpropyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 641, 3.8 mg, 9.4 ⁇ mol, 21% yield) as a solid.
  • Example 73 Synthesis of Compound 652 Synthesis of B52 0 mg, 2.07 mmol) and 2-amino-4,5-dimethoxybenzamide (610 mg, 3.1 mmol) in DMF (10 mL) were added T3P (50 wt. % in EtOAc) (2 g, 3.1 mmol) and pyridine (0.5 g, 6.2 mmol), and the reaction was stirred for 2 h at room temperature. The resulting mixture was diluted with water (20 mL). The precipitated solids were collected by filtration and washed with water (5 mL).
  • Example 76 Synthesis of Compound 668 Synthesis of B41 -3H- quinazolin-4-one (Compound 637, 0.2 g, 473.5 ⁇ mol) and 2-bromoethoxy-tert-butyl-dimethyl- silane (339 mg, 1.42 mmol) in DMF (4 mL) was added Cs 2 CO 3 (462 mg, 1.42 mmol), and the reaction was stirred for 16 h at room temperature. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , and filtered.
  • Example 77 Synthesis of Compound 671 , -3H- quinazolin-4-one (A42, 100 mg, 196.2 ⁇ mol) and trans-4-amino-1-methyl-pyrrolidin-3-ol (27 mg, 235.4 ⁇ mol) in dioxane (2 mL) were added t-BuONa (57 mg, 588.6 ⁇ mol) and GPhos Pd G6 (18 mg, 19.6 ⁇ mol), and the reaction was stirred for 16 h at 80 °C under nitrogen atmosphere.
  • Example 79 Synthesis of Compound 665 Synthesis of B61 o a s rre so u on o [ -( , - me y m azo[ , -a]pyr n- -y )ace y ]oxylithium (B60, 2 g, 9.52 mmol) and 2-amino-3-bromo-4,5-dimethoxybenzamide (3.9 g, 14.2 mmol) in DMF (20 mL) was added T3P (9 g, 14.1 mmol, 50 wt.
  • Example 80 Synthesis of Compound 670 To a stirred solution of 7-bromo-6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]- 3H-quinazolin-4-one (Compound 454, 150 mg, 324.2 ⁇ mol) and potassium trifluoro(morpholinomethyl)borate (81 mg, 389.0 ⁇ mol) in dioxane (4.8 mL) and H2O (0.8 mL) were added Cs 2 CO 3 (317 mg, 972.6 ⁇ mol), CataCXium A (butyldi(1-adamantyl)phosphine, 23.3 mg, 64.8 ⁇ mol) and diacetoxypalladium (8 mg, 32.4 ⁇ mol) at room temperature under nitrogen atmosphere.
  • Compound 454 150 mg, 324.2 ⁇ mol
  • potassium trifluoro(morpholinomethyl)borate 81 mg, 389.0 ⁇ mol
  • dioxane
  • the resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered.
  • Example 82 Synthesis of Compound 699 Synthesis of B73 , g, 722.3 ⁇ mol) and 2-amino-4-bromo-5-(difluoromethoxy)benzamide (B72, 223.3 mg, 794.5 ⁇ mol) in DMF (3.6 mL) were added pyridine (114.3 mg, 1.44 mmol) and T3P (50 wt. % in EtOAc) (689.4 mg, 1.08 mmol), and the reaction was stirred for 16 h at room temperature.
  • Example 83 Synthesis of Compound 679 Synthesis of B77 A 312 mg, 1.23 mmol), NiCl2 (16 mg, 122.8 ⁇ mol) and 2-(2-pyridyl)pyridine (19 mg, 122.8 ⁇ mol) in DMAc (5 mL) was stirred for 4 h at 60 °C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature.6-bromo-2,3-dimethyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2- b]pyridine (B76, 250 mg, 613.8 ⁇ mol) and Zn (117 mg, 1.84 mmol) were added into the mixture, and the resulting mixture was stirred for 16 h at 60 °C.
  • Example 84 Synthesis of Compound 680 T e (639.0 mg, 2.5 mmol) in DMAc (1.98 mL) were added NiCl2 (54 mg, 418.2 ⁇ mol) and 4,4’-di-tert-butyl-2,2’- bipyridine (112 mg, 418.2 ⁇ mol) under nitrogen atmosphere, and the reaction was stirred at 60°C for additional 4 h.
  • 5-bromo-1,2,3-trimethyl-pyrrolo[2,3-b]pyridine (B80, 200 mg, 836.4 ⁇ mol) and Zn (547 mg, 8.36 mmol) were then added, and the resulting mixture was stirred at 60°C for additional 16 h.
  • the operation was repeated 2 times.
  • the reaction solution was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered.
  • Example 87 Synthesis of Compound 693 Synthesis of B83 .28 g, 3.92 mmol) and 2,2’-bipyridine (613 mg, 3.92 mmol) in DMAc (40 mL) were added NiCl2 (508 mg, 3.92 mmol) under nitrogen atmosphere, and the reaction was stirred for 4 h at 60 °C under nitrogen atmosphere.
  • Example 88 Synthesis of Compound 686 Synthesis of B93 568 Attorney Docket No.: R2103-7054WO yrrolo[3,2- b]pyridin-2-yl]acetic acid (B92, 350 mg, 905.7 ⁇ mol) and 2-amino-4,5-dimethoxy-benzamide (213 mg, 1.09 mmol) in CH3CN (7 mL) were added NMI (297 mg, 3.62 mmol, 287.0 ⁇ L) and TCFH (381 mg, 1.36 mmol), and the reaction was stirred for 16 h at 50 °C.
  • Example 89 Synthesis of Compound 704 To a stirred mixture of 3-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-4-iodo-6,7- dimethoxy-2H-isoquinolin-1-one (C1, 100 mg, 187.2 ⁇ mol) in DMF (2.0 mL) was added CuI (7.0 mg, 36.8 ⁇ mol), DMCyDA (11 mg, 77.3 ⁇ mol), morpholine (100 mg, 1.15 mmol) and Cs 2 CO 3 (183 mg, 561.7 ⁇ mol) at r.t. under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 80 °C under nitrogen atmosphere and then allowed to cool down to r.t.
  • Example 91 Synthesis of Compound 722 To a stirred solution of 2-((8-bromoquinolin-3-yl)methyl)-6,7-dimethoxyquinazolin- 4(3H)-one (C12, 100 mg, 0.23 mmol) and 1H-imidazole (133 mg, 1.95 mmol) in DMF (3.5 mL) was added CuI (166 mg, 0.87 mmol) and Pd(OAc)2 (33 mg, 0.14 mmol) at room temperature.
  • Example 92 Synthesis of Compound 725 573 Attorney Docket No.: R2103-7054WO
  • MeOH MeOH
  • Pd/C 10% on carbon, wetted with ⁇ 55% water
  • Example 93 Synthesis of Compound 750 Synthesis of C36 , 6,7- dimethoxy-3H-quinazolin-4-one (C32, 320 mg, 745.5 ⁇ mol) in MeOH (7 mL) was added TEA (377 mg, 3.73 mmol) and Pd(dppf)Cl2 (61 mg, 74.6 ⁇ mol) in a pressure tank. The mixture was purged with nitrogen for 2 min and then was pressurized to 20 atm with carbon monoxide at 80 °C for 16 h.
  • Example 97 Synthesis of Compound 820 , [[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino]-3H-quinazolin-4-one (D25, 50 mg, 107.3 ⁇ mol) and iodoethane (16 mg, 107.3 ⁇ mol, 8.63 ⁇ L) in DMF (2 mL) were added DIEA (13 mg, 107.3 ⁇ mol, 18.69 ⁇ L). The resulting mixture was stirred for 16 h at 50 °C under nitrogen atmosphere.
  • R2103-7054WO Modification The reaction was run at room temperature over 6 h. Th id ifid b d- hy 7- nd as ] + .
  • Example 100 Synthesis of Compound 912 ,7- dimethoxyquinazolin-4(3H)-one (E22, 150 mg, 0.38 mmol) in DCM (5 mL) was added DAST (305 mg, 1.89 mmol) at 0 °C.
  • the hot solution was treated with activated 601 Attorney Docket No.: R2103-7054WO charcoal (0.5 g) and stirred for 1 h, while cooling slowly to room temperature. Afterwards the charcoal was filtered off by means of a small column with neutral aluminum oxide using methanol (80 mL) for rinsing. The filtrate was concentrated partially under reduced pressure. The resulting suspension was heated till the precipitate was re-dissolved. The flask was sealed under N2 with a rubber septum after cooling to room temperature and allowed to stand in the freezer (-20°C) overnight.
  • Step 2 was ran using TMSOK in THF at room d o- S h. .). n, 5- id d. h. .). n, 5- id d. h. or L) as er th as 6- 0 S, 1 .). d H- 4 Attorney Docket No.: R2103-7054WO mmol, 68% yield) as a solid.
  • Example 107 Synthesis of A35 Synthesis of A34 604 Attorney Docket No.: R2103-7054WO A and tributyl(2- pyridyl)stannane (1.51 g, 4.11 mmol, 1.33 mL) in THF (10 mL) were added Pd(PPh3)4 (475.4 mg, 411.4 ⁇ mol) at 80°C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at reflux under nitrogen atmosphere. The mixture was allowed to cool down to room temperature.

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Abstract

The present disclosure features compounds and related compositions that, inter alia, modulate cyclin K (CCNK) and/or cyclin dependent kinase (CDK) activity, e.g., CDK12 or CDK13 activity, and methods of use thereof.

Description

Attorney Docket No.: R2103-7054WO COMPOUNDS AND RELATED METHODS USEFUL FOR DEGRADATION OF CYCLIN K AND INHIBITION OF CYCLIN DEPENDENT KINASES CLAIM OF PRIORITY The instant application claims priority to U.S. Application No.63/639,208, filed on April 26, 2024; U.S. Application No.63/681,769, filed on August 9, 2024; and U.S. Application No. 63/728,380, filed on December 5, 2024. The contents of the foregoing applications are incorporated herein by reference in their entirety. BACKGROUND Cyclin dependent kinases (CDKs) along with their cofactor cyclins regulate a number of fundamental cellular processes, including cell cycle progression and gene transcription. Cell cycle progression and gene transcription are tightly regulated by CDKs to ensure that cells respond normally to a variety of internal and external stimuli. Aberrant function of CDKs and cyclins, such as inhibition of activity or overexpression of these proteins, has shown to be related to many disease states. Current therapeutic approaches to modulate CDK and cyclin activity are widespread; however, each of these modalities exhibit unique challenges as currently presented. As such, there is a need for new technologies to modulate CDK and cyclin activity. SUMMARY The present disclosure features compounds and related compositions that, inter alia, modulate the activity of cyclins (CCNs), e.g., cyclin K, and cyclin dependent kinases (CDKs), e.g., CDK12 or CDK13, as well as methods of use thereof. In an embodiment, the compounds described herein are compounds of Formula (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I- p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. The present disclosure additionally provides methods of using the compounds of the invention (e.g., compounds of (I), (I"), (I'), (I-02), (I-01), 1 Attorney Docket No.: R2103-7054WO (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I- m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof), and compositions thereof, e.g., to target, and in embodiments bind or form a complex with, a nucleic acid or a protein (e.g., a cyclin, e.g., CCNK; a cyclin dependent kinase, e.g., CDK12 or CDK13). In another aspect, the compounds described herein may be used for the prevention and/or treatment of a disease, disorder, or condition, e.g., a disease, disorder or condition, e.g., associated with modulation of a cyclin or cyclin dependent kinase, e.g., a cancer. In some embodiments, the compounds described herein (e.g., compounds of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I- l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used for the prevention and/or treatment of a proliferative disease, disorder, or condition (e.g., a disease, disorder, or condition characterized by unwanted cell proliferation, e.g., a cancer or a benign neoplasm) in a subject. In some embodiments, the compounds described herein (e.g., compounds of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I- m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used for the prevention and/or treatment of a non-proliferative disease, disorder, or condition. In one aspect, the present disclosure provides compounds of Formula (I): compound of Formula (I): a pharmaceutically acceptable salt, solvate, hydrate , , , herein W1, W2, W3, and W4 are each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl, 5-membered heteroaryl, or 6- 2 Attorney Docket No.: R2103-7054WO membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, -P(O)y-, -S(O)x-, –NRBC(O)-, –C(O)NRB-, C1- C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2- C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, –NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD; each of R4a and R4b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene- heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, -S(O)(=NH)RD, or –S(O)xRD, rocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1- C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene- heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3- 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, 3 Attorney Docket No.: R2103-7054WO alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, –C(O)RD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, -P(O)yRD, -S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD and RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, or -N(RB1)(RC1), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each R7 is independently C1-C6-alkyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NRB1RC1, oxo, –ORA1, –C(O)NRB1RC1, or –C(O)RD1, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; each R9 is independently C1-C6-alkyl, cycloalkyl, heterocyclyl, oxo, - ORA1, or -N(RB1)(RC1); each RA1 is independently hydrogen or C1-C6-alkyl; each of RB1, RC1, and RD1 is independently hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I- m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical compositions 4 Attorney Docket No.: R2103-7054WO described herein include an effective amount (e.g., a therapeutically effective amount) of a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the present disclosure provides methods of down-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I- p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides methods of up-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I- j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I- v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides methods of altering the isoform of a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. Another aspect of the disclosure relates to methods of inhibiting the activity of a target protein in a biological sample or subject. In some embodiments, administration of a compound of Formula (I) to a biological sample, a cell, or a subject comprises inhibition of cell growth or induction of cell death. In another aspect, the present disclosure provides compositions for use in preventing and/or treating a disease, disorder, or condition in a subject by administering a compound of Formula (I) (e.g., a compound of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I- 5 Attorney Docket No.: R2103-7054WO i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or related compositions. In some embodiments, the disease or disorder entails aberrant cyclin or cyclin dependent kinase splicing. In some embodiments, the disease or disorder is a proliferative disease, disorder, or condition. Exemplary proliferative diseases include cancer, a benign neoplasm, or angiogenesis. In other embodiments, the present disclosure provides methods for treating and/or preventing a non-proliferative disease, disorder, or condition. In still other embodiments, the present disclosure provides compositions for use in treating and/or preventing a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease. In another aspect, the present disclosure provides compositions for use in down-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I- m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides compositions for use in up-regulating the expression of (e.g., the level of or the rate of production of) a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. In another aspect, the present disclosure provides compositions for use in altering the isoform of a target protein with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I- m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)) or a pharmaceutically 6 Attorney Docket No.: R2103-7054WO acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof in a biological sample or subject. Another aspect of the disclosure relates to compositions for use in inhibiting the activity of a target protein in a biological sample or subject. In some embodiments, administration of a compound of Formula (I) to a biological sample, a cell, or a subject comprises inhibition of cell growth or induction of cell death. In another aspect, the present disclosure features kits comprising a container with a compound of Formula (I) (e.g., a compound of Formulas (I), (I"), (I'), (I-02), (I-01), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-j’), (I-j”), (I-k), (I-k’), (I-l), (I-l’), (I-m), (I-m’), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), or (I-w)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits described herein further include instructions for administering the compound of Formula (I) or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or the pharmaceutical composition thereof. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Examples, and the Claims. DETAILED DESCRIPTION Selected Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and 7 Attorney Docket No.: R2103-7054WO Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C1-C6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4- C5, and C5-C6 alkyl. The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. As used herein, “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms (“C1-C24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1- C6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert– butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n–octyl (C8) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1–C10 alkyl (e.g., –CH3). In certain embodiments, the alkyl group is substituted C1–C6 alkyl. As used herein, “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon double bonds, and no triple 8 Attorney Docket No.: R2103-7054WO bonds (“C2-C24 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 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 C2-C4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C1– C10 alkenyl. In certain embodiments, the alkenyl group is substituted C2–C6 alkenyl. As used herein, the term “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon triple bonds (“C2-C24 alkenyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1– butynyl (C4), 2–butynyl (C4), and the like. Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2–10 alkynyl. In certain embodiments, the alkynyl group is substituted C2–6 alkynyl. 9 Attorney Docket No.: R2103-7054WO As used herein, the term "haloalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br, and I. The halogen(s) F, Cl, Br, and I may be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CCl3, -CH2-CF3, -CH2-CCl3, -CH2-CBr3, -CH2-CI3, -CH2-CH2-CH(CF3)-CH3, - CH2-CH2-CH(Br)-CH3, and -CH2-CH=CH-CH2-CF3. Each instance of a haloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted haloalkyl”) or substituted (a “substituted haloalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. As used herein, the term "heteroalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH- CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, - CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2- CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like, it will be understood that the terms heteroalkyl and –CH2O or –NRCRD are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like. Each instance of a heteroalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 10 Attorney Docket No.: R2103-7054WO As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). An aryl group may be described as, e.g., a C6-C10-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-C14 aryl. In certain embodiments, the aryl group is substituted C6-C14 aryl. As used herein, “heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π 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 (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “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 (aryl/heteroaryl) ring system. Bicyclic 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, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). A heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the 11 Attorney Docket No.: R2103-7054WO moiety. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6– membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, thienopyridinyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyridazinyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, and purinyl. Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, and pyridopyrazinyl. Other exemplary heteroaryl groups include heme and heme derivatives. As used herein, “cycloalkyl” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-C10 cycloalkyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon 12 Attorney Docket No.: R2103-7054WO atoms (“C3-C8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl. “Heterocyclyl” as used herein refers to a radical of a 3– to 16–membered non–aromatic ring system having ring carbon atoms and 1 to 8 ring heteroatoms, wherein each heteroatom is 13 Attorney Docket No.: R2103-7054WO independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–16 membered heterocyclyl”). In 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 a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic 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 cycloalkyl groups wherein the point of attachment is either on the cycloalkyl 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. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non- hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3–16 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3– 16 membered heterocyclyl. Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, dihydropyrazolyl, disulfuranyl, and oxazolidin–2–one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and 14 Attorney Docket No.: R2103-7054WO thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2- onyl), and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, azaspiro[2.4]heptanyl (e.g.5-azaspiro[2.4]heptanyl), oxepanyl, and thiepanyl. Exemplary 7–membered heterocyclyl groups containing two heteroatoms include, without limitation, oxa-azaspiro[3.3]heptanyl (e.g., 6-oxa-1- azaspiro[3.3]heptanyl) and diazabicyclo[2.2.1]heptanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azaspiro[2.5]octanyl (e.g.4- azaspiro[2.5]octanyl), quinuclidinyl, azocanyl, oxecanyl and thiocanyl. Exemplary 8–membered heterocyclyl groups containing two heteroatoms include, without limitation, oxa- azaspiro[3.4]octanyl (e.g., 6-oxa-1-azaspiro[3.4]octanyl). Exemplary 9–membered heterocyclyl groups include, without limitation, azaspiro[4.4]nonanyl (e.g.1-azaspiro[4.4]nonanyl) and diazaspiro[3.5]nonanyl (e.g.2,7-diazaspiro[3.5]nonanyl). Exemplary 5–membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6–bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5–membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5–bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7- diazaspiro[3.5]nonanyl). Exemplary 6–membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6–bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6–membered heterocyclyl 15 Attorney Docket No.: R2103-7054WO groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6–membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9- azabicyclo[3.3.1]nonanyl). The terms "alkylene," “alkenylene,” “alkynylene,” “haloalkylene,” “heteroalkylene,” “cycloalkylene,” or “heterocyclylene,” alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl respectively. For example, the term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene group may be described as, e.g., a C1-C6-membered alkylene, C2-C6-membered alkenylene, C2-C6-membered alkynylene, C1-C6-membered haloalkylene, C1- C6-membered heteroalkylene, C3-C8-membered cycloalkylene, or C3-C8-membered heterocyclylene, wherein the term “membered” refers to the non-hydrogen atoms within the moiety. In the case of heteroalkylene and heterocyclylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)2R’- may represent both -C(O)2R’- and –R’C(O)2-. As used herein, the terms “cyano” or “–CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N. As used herein, the terms “halogen” or “halo” refer to fluorine, chlorine, bromine or iodine. As used herein, the term “hydroxy” refers to –OH. As used herein, the term “nitro” refers to a substitutent having two oxygen atoms bound to a nitrogen atom, e.g., -NO2. 16 Attorney Docket No.: R2103-7054WO As used herein, the term “nucleobase” as used herein, is a nitrogen-containing biological compounds found linked to a sugar within a nucleoside—the basic building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The primary, or naturally occurring, nucleobases are cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA) and uracil (RNA), abbreviated as C, G, A, T, and U, respectively. Because A, G, C, and T appear in the DNA, these molecules are called DNA-bases; A, G, C, and U are called RNA-bases. Adenine and guanine belong to the double-ringed class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines. Other nucleobases that do not function as normal parts of the genetic code, are termed non-naturally occurring. In an embodiment, a nucleobase may be chemically modified, for example, with an alkyl (e.g., methyl), halo, -O-alkyl, or other modification. As used herein, the term “nucleic acid” refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. The term “nucleic acid” includes a gene, cDNA, pre-mRNA, or an mRNA. In one embodiment, the nucleic acid molecule is synthetic (e.g., chemically synthesized) or recombinant. Unless specifically limited, the term encompasses nucleic acids containing analogues or derivatives of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementarity sequences as well as the sequence explicitly indicated. As used herein, “oxo” refers to a carbonyl, i.e., -C(O)-. The symbol “ ” as used herein in relation to a compound of Formula (I) refers to an attachment point to a nother moiety or functional group within the compound. Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, 17 Attorney Docket No.: R2103-7054WO 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. Unless otherwise indicated, 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. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, such as any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, 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. Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocyclyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure. The compounds provided herein may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to: cis- and trans-forms; E- and Z-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms"). 18 Attorney Docket No.: R2103-7054WO Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, 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. In an embodiment, the stereochemistry depicted in a compound is relative rather than absolute. 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. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising 19 Attorney Docket No.: R2103-7054WO an enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In certain embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S– compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In certain embodiments, the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R–compound, by total weight of the compound. In some embodiments, a diastereomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising a diastereometerically pure exo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure exo compound. In certain embodiments, the diastereometerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most about 5% by weight endo compound, by total weight of the compound. For example, a pharmaceutical composition comprising a diastereometerically pure endo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure endo compound. In certain embodiments, the diastereometerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo compound, by total weight of the compound. In some embodiments, an isomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising a isomerically pure exo compound can comprise, for example, about 90% excipient and about 10% isomerically pure exo compound. In certain embodiments, the isomerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most about 5% by weight endo compound, by total weight of the compound. For example, a pharmaceutical composition comprising an isomerically pure endo compound can comprise, for 20 Attorney Docket No.: R2103-7054WO example, about 90% excipient and about 10% isomerically pure endo compound. In certain embodiments, the isomerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; N may be in any isotopic form, including 14N and 15N; F may be in any isotopic form, including 18F, 19F, and the like. The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like 21 Attorney Docket No.: R2103-7054WO glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. In addition to salt forms, the present disclosure provides compounds in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. The term “solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds of Formula (I) 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. In certain instances, 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 isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates. The term “hydrate” refers to a compound which 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. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H2O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and 22 Attorney Docket No.: R2103-7054WO smaller than 1, e.g., hemihydrates (R⋅0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H2O) and hexahydrates (R⋅6 H2O)). The term “tautomer” refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. Other Definitions The following definitions are more general terms used throughout the present disclosure. The articles “a” and “an” refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The term “and/or” means either “and” or “or” unless indicated otherwise. The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. “Acquire” or “acquiring” as used herein, refer to obtaining possession of a value, e.g., a numerical value, or image, or a physical entity (e.g., a sample), by “directly acquiring” or “indirectly acquiring” the value or physical entity. “Directly acquiring” means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity. “Indirectly acquiring” refers to receiving the value or physical entity from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Directly acquiring a value or physical entity includes performing a process that includes a physical 23 Attorney Docket No.: R2103-7054WO change in a physical substance or the use of a machine or device. Examples of directly acquiring a value include obtaining a sample from a human subject. Directly acquiring a value includes performing a process that uses a machine or device, e.g., mass spectrometer to acquire mass spectrometry data. The terms “administer,” “administering,” or “administration,” as used herein refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof. As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound of Formula (I) refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of Formula (I) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of an inventive compound may reduce the tumor burden or stop the growth or spread of a tumor. A “therapeutically effective amount” of a compound of Formula (I) 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. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to 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 or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. 24 Attorney Docket No.: R2103-7054WO The terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprised therein. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Prevention,” “prevent,” and “preventing” as used herein refers to a treatment that comprises administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I)) prior to the onset of a disease, disorder, or condition in order to preclude the physical manifestation of said disease, disorder, or condition. In some embodiments, “prevention,” “prevent,” and “preventing” require that signs or symptoms of the disease, disorder, or condition have not yet developed or have not yet been observed. In some embodiments, treatment comprises prevention and in other embodiments it does not. A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult, or senior adult)) and/or other non–human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non–human animal may be a transgenic animal. As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of one or more of a symptom, manifestation, or underlying cause of a disease, disorder, or condition (e.g., as described herein), e.g., by administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I)). In an embodiment, treating comprises reducing, reversing, 25 Attorney Docket No.: R2103-7054WO alleviating, delaying the onset of, or inhibiting the progress of a symptom of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a manifestation of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, reducing, or delaying the onset of, an underlying cause of a disease, disorder, or condition. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease, disorder, or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition, e.g., in preventive treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In some embodiments, treatment comprises prevention and in other embodiments it does not. Compounds The present disclosure features a compound of Formula (I): a pharmaceutically acceptable salt, solvate, hydrate, tautom W1, W2, W3, and W4 is each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl, 5-membered or 6-membered heteroaryl, or 5-membered or 6-membered heterocyclyl, each of which is optionally substituted with one or more R5; in some embodiments, Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, -P(O)y-, -S(O)x-, –NRBC(O)-, –C(O)NRB-, C1-C6- 26 Attorney Docket No.: R2103-7054WO alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2- C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, –NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD; each of R4a and R4b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene- heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, -S(O)(=NH)RD, or –S(O)xRD, h r in h lk l lk l n lk n l lk n l h t r lk l h l lk l l lk l h t rocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1- C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene- heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3- 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C1- C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, 27 Attorney Docket No.: R2103-7054WO C1-C6 alkylene-heteroaryl, –C(O)RD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, -P(O)yRD, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD and RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, or - N(RB1)(RC1), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; in some embodiments, each RD and RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each R7 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NRB1RC1, oxo, –ORA1, -C(O)NRB1RC1, or -C(O)RD1, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; in some embodiments each R7 is independently C1- C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or –ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; each R9 is independently C1-C6-alkyl, cycloalkyl, heterocyclyl, oxo, -ORA1, or -N(RB1)(RC1); each RA1 is independently hydrogen or C1-C6-alkyl; each of RB1, RC1, and RD1 is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2. In some embodiments of Formula (I), Ring A is a 6-membered aryl, 5-membered or 6- membered heteroaryl, or 5-membered or 6-membered heterocyclyl, each of which is optionally substituted with one or more R5. In some embodiments of Formula (I), Ring A is a 6-membered 28 Attorney Docket No.: R2103-7054WO aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, Ring A is 6-membered aryl optionally substituted with one or more R5. In some embodiments, Ring A is 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, Ring A is 5- membered or 6-membered heterocycyl, each of which is optionally substituted with one or more R5. In some embodiments, Ring A is a 5-membered ring. In some embodiments, Ring A is a 6- membered ring. In some embodiments, Ring is a heteroaryl, e.g., a nitrogen-containing heteroaryl, optionally substituted with one or more R5. In some embodiments, Ring A is a nitrogen-containing 5-membered heteroaryl, optionally substituted with one or more R5. In some embodiments, Ring A is a nitrogen-containing 6-membered heteroaryl optionally substituted with one or more R5. , Attorney Docket No.: R2103-7054WO 5 is 5 is as In some embodiments of Formula (I), Ring A is selected from , , Attorney Docket No.: R2103-7054WO , me In some embodiments of Formula (I), Ring A , wherein R5 is as described herein. In some embodiments of Formula (I), Rin , wherein R5 is as 31 Attorney Docket No.: R2103-7054WO described herein. In some embodiments of Formula (I), Ring A s as described herein. In some embodiments of Formula (I), Ring A wherein R5 is as described herein. In some embodiments of Formula (I), Ring A i wherein R5 is as described herein. In some embodiments of Formula (I), Rin 5 is as described herein. In some embodiments of Formula (I), Ring A wherein R5 is as described herein. In some embodiments of Formula (I), Ring A wherein R5 is as described herein. In some embodiments of Formula (I), Ri wherein R5 is as described herein. In some embodiments of Formula (I), Ri wherein R5 is as described herein. In some embodiments of Formula (I), Ring A wherein R5 is as described herein. In some embodiments of Formula (I), Ring A 32 Attorney Docket No.: R2103-7054WO wherein R5 is as described herein. In some embodiments of Formula (I), Ring A wherein R5 is as described herein. In some embodiments of Formula (I), Ri wherein R5 is as described herein. In some embodiments of Formula (I), Ring A wherein R5 is as described herein. In some embodiments of Formula (I), Ring A wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring wherein R5 is as described herein. In some embodiments of Formula (I), 33 Attorney Docket No.: R2103-7054WO Ring wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring A is wherein R5 is as described herein. In some embodiments of Formula (I), Ring wherein R5 is as described herein. 34 Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), Ring A is selected fro , , . , , Attorney Docket No.: R2103-7054WO , , , Attorney Docket No.: R2103-7054WO , , In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i ,. In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A i me embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring me Attorney Docket No.: R2103-7054WO embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring some embodiments of Formula (I), Rin In some mula (I), Ring A i . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring Attorney Docket No.: R2103-7054WO . In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i ,. In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring 39 Attorney Docket No.: R2103-7054WO n some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ri . In some embodiments of Formula (I), Ring A . In some embodiments of Formula (I), Ring A is . In some embodiments of Formula (I), Ring A In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), . In some embodiments of Formula (I), Ring A . In some ula (I), Ring A i . In some embodiments of Formula (I), Ring ome embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring A i . In some embodiments of Formula (I), Ring 40 Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5. In some embodiments, Ring B is aryl (e.g., 6-membered aryl), optionally substituted with one or more R5. In some embodiments, Ring B is heteroaryl (e.g., a 5-membered or 6-membered heteroaryl), optionally substituted with one or more R5. In some embodiments, Ring B is a monocyclic heteroaryl, optionally substituted with one or more R5. In some embodiments, Ring B is a bicyclic heteroaryl, optionally substituted with one or more R5. In some embodiments, Ring B is cycloalkyl (e.g., a 3-7 membered cycloalkyl), optionally substituted with one or more R5. In some embodiments, Ring B is heterocyclyl (e.g., a 3-10 membered cycloalkyl), optionally substituted with one or more R5. In some embodiments, Ring B is a monocyclic heterocyclyl, optionally substituted with one or more R5. In some embodiments, Ring B is a bicyclic heterocyclyl, optionally substituted with one or more R5. In some embodiments, Ring B is a nitrogen-containing heteroaryl or heterocyclyl. In some embodiments, Ring B selected from , , , Attorney Docket No.: R2103-7054WO , , , , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , , Attorney Docket No.: R2103-7054WO Attorney Docket No.: R2103-7054WO Attorney Docket No.: R2103-7054WO , ach In some embodiments of Formula (I), Ring B is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is aryl optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is heteroaryl optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is cycloalkyl optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is heterocyclyl optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is a nitrogen-containing heteroaryl or heterocyclyl, each of which is optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is a nitrogen-containing heteroaryl optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is a nitrogen-containing heterocyclyl optionally substituted with one or more R5. In some embodiments of Formula (I), Ring B is selected fro , , Attorney Docket No.: R2103-7054WO O O S 5 N R5 5 , , Attorney Docket No.: R2103-7054WO nd In some embodiments of Formula (I), Ring B is selected from: , , d 0-4 N In some embodiments of Formula (I), Ring B selected fro , , , Attorney Docket No.: R2103-7054WO , In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), O Ring B is . In some embodiments of Formula (I), Ring B 0-3 . In O some embodiments of Formula (I), Ring B i 0-2. In some embodiments of Attorney Docket No.: R2103-7054WO S Formula (I), Ring B is (R5)0-3. In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), 55 Attorney Docket No.: R2103-7054WO Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (R5)0-8 (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Rin In some embodiments of Formula me embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is selected fro , , Attorney Docket No.: R2103-7054WO , , , Attorney Docket No.: R2103-7054WO , , , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , , , , In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), 60 Attorney Docket No.: R2103-7054WO Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring . In some 61 Attorney Docket No.: R2103-7054WO embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Rin In some embodiments 62 Attorney Docket No.: R2103-7054WO of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring 63 Attorney Docket No.: R2103-7054WO B . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is , . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Rin me embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring me Attorney Docket No.: R2103-7054WO embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Rin me embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula 65 Attorney Docket No.: R2103-7054WO a . In a n some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Rin . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), 66 Attorney Docket No.: R2103-7054WO . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B me embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B me mula (I), 67 Attorney Docket No.: R2103-7054WO Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Rin In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B is n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B 68 Attorney Docket No.: R2103-7054WO is . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring B is . In some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring n some embodiments of Formula (I), Ring B . In some embodiments of Formula (I), Ring B i . In some embodiments of Formula (I), Ring . ent, Ring A and Ring B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of one of the rings described above. In an embodiment, Ring A and Ring B are each independently a stereoisomer of one of the rings described above. In some embodiments of Formula (I), L is absent, a bond, -O-, -NR8-, -C(O)-, -S(O)x-, – NRBC(O)-,–C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together. In some embodiments of Formula (I), L is absent, a bond, -O-, -NR8-, -C(O)-, or -S(O)x- wherein when L is absent, Ring A and Ring B are fused together. 69 Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), L is absent, a bond, -O-, -NR8-, -C(O)-, -P(O)y-, - S(O)x-, –NRBC(O)-, –C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; In some embodiments of Formula (I), L is absent, a bond, -O-, or -NR8-, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; In some embodiments of Formula (I), L is absent, and Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5. In some embodiments of Formula (I), L is absent, and Ring A and Ring B are fused together. In some embodiments of Formula (I), L is a bond. In some embodiments of Formula (I), L is -O-. In some embodiments of Formula (I), L is -NR8-. In some embodiments of Formula (I), L is -C(O)-. In some embodiments of Formula (I), L is -P(O)y-. In some embodiments of Formula (I), L is -S(O)x-. In some embodiments of Formula (I), L is –NRBC(O)- . In some embodiments of Formula (I), L is –C(O)NRB-. In some embodiments of Formula (I), L is C1-C6-alkylene. In some embodiments of Formula (I), L is C1-C6-heteroalkylene. In some embodiments, L is absent and Ring A and Ring B are fused together. In some embodiments, A-L-B is selected from , , , Attorney Docket No.: R2103-7054WO , . g B are fused together. In some embodiments of Formula (I), A-L-B is selected fro , , , Attorney Docket No.: R2103-7054WO , , . , nd Ring A and Ring B are fused together. In some embodiments of Formula (I), A-L-B is selected from 72 Attorney Docket No.: R2103-7054WO nd In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of For cted , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Form , ected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. 73 Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I from A- embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formul d from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formul , d from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some 74 Attorney Docket No.: R2103-7054WO embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula ( from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I ), - - s se ected from 75 Attorney Docket No.: R2103-7054WO , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula ( from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I), - - lected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), 76 Attorney Docket No.: R2103-7054WO A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula ( from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula ( , from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I ), A-L-B is selected from 77 Attorney Docket No.: R2103-7054WO , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I d , wherein each R5 is as defined herein. In some embodiments of , d from , wherein each R5 is as defined herein. In some embodiments of 78 Attorney Docket No.: R2103-7054WO Formula (I), A-L-B is selected from , wherein each R5 is as defined herein. In some embodiments of Formula (I), A-L-B is selected fro , wherein each R5 is as defined herein. In some embodiments of Formula (I), d from , wherein each R5 is as defined herein. , , , Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), A-L-B is selecte , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO Attorney Docket No.: R2103-7054WO , In some embodiments, A-L-B is . In some embodiments, A-L-B is -L- A- me I), some embodiments of Formula (I), A-L-B i . In some embodiments of Formula 84 Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), . In some embodiments of Formul In some embodiments of Formula n some embodiments of Formul . In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula In some embodiments of Formula (I), A-L-B is 85 Attorney Docket No.: R2103-7054WO n some embodiments of Formul me embodiments of Formula In some embodiments of Formula (I), n some embodiments of Formu In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is n some embodiments of Formula (I), A-L-B me embodiments of Formula In some embodiments of Formula . Attorney Docket No.: R2103-7054WO In some embodiments of Formul In some embodiments of is some embodiments of Formula In some embodiments of Formula (I), A- n some embodiments of Formul In some A- Attorney Docket No.: R2103-7054WO some embodiments of Formul In some embodiments of Formula n some embodiments of Formu . In some embodiments of Formul of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B . In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A- L-B is . In some embodiments of Formula (I), A-L-B . In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A- L-B is . In some embodiments of Formula (I), A-L-B me 88 Attorney Docket No.: R2103-7054WO embodiments of Formula (I), A-L-B In some embodiments of Formula (I), A- L-B is . In some embodiments of Formul me embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A- L-B is . In some embodiments of Formul In some embodiments of Formula (I), A-L-B i . In some embodiments of Formula (I), A-L- n some embodiments of Formul In some embodiments of Formula In some embodiments of Formula (I), n some embodiments of Formu In some embodiments of Formul In some embodiments of 89 Attorney Docket No.: R2103-7054WO Formula n some embodiments of Formula (I), A-L-B is . In some embodiments of Formul me embodiments of Formula In some embodiments of Formula (I), n some embodiments of Formu In some embodiments of Formul In some embodiments of Formula n some embodiments of Formula (I), A-L-B is . In some embodiments of Formul me 90 Attorney Docket No.: R2103-7054WO embodiments of Formula In some embodiments of Formula me embodiments of Formula In some embodiments of Formula (I), n some embodiments of Formul In some embodiments of Formul . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formul me 91 Attorney Docket No.: R2103-7054WO embodiments of Formula In some embodiments of Formula (I), . In some embodiments of Formul of e I), In ula Attorney Docket No.: R2103-7054WO . In some embodiments of Formula (I), A-L-B . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formul of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is . In some embodiments of Formul me embodiments of Formula In some embodiments of Formula (I), A-L- . In some embodiments of Formul In some embodiments of 93 Attorney Docket No.: R2103-7054WO Formula n some embodiments of Formula (I), A-L-B is N N n some embodiments of Formul me N N embodiments of Formula In some embodiments of Formula (I), N N n some embodiments of Formul In some embodiments of Formul In some embodiments of Formula (I), In Formula . In Attorney Docket No.: R2103-7054WO some embodiments of Formul In some embodiments of Formula . In some embodiments of Formul of Formula (I), A-L-B is . In some embodiments of Formula (I), A-L-B is In some embodiments of Formul In some embodiments of Formula me Attorney Docket No.: R2103-7054WO ula n some embodiments of Formul . iments of Formula (I), 5 each R i n, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, – C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3-7- membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6. In some embodiments of Formula (I), each R5 is hydrogen. In some embodiments of Formula (I), R5 is C1-C6-alkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is C2-C6-alkenyl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is C2-C6-alkynyl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is C1-C6-heteroalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is C1-C6-haloalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is cycloalkyl optionally substituted 96 Attorney Docket No.: R2103-7054WO with one or more R6. In some embodiments of Formula (I), R5 is heterocyclyl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is aryl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is C1-C6 alkylene-aryl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is C2-C6 alkenylene-aryl optionally substituted with one or more R6. In some embodiments of Formula (I), R5 is halo. In some embodiments of Formula (I), R5 is cyano. In some embodiments of Formula (I), R5 is oxo. In some embodiments of Formula (I), R5 is –ORA. In some embodiments of Formula (I), R5 is –NRBRC. In some embodiments of Formula (I), R5 is –NRBC(O)RD. In some embodiments of Formula (I), R5 is –NO2. In some embodiments of Formula (I), R5 is – C(O)NRBRC. In some embodiments of Formula (I), R5 is –C(O)RD. In some embodiments of Formula (I), R5 is –C(O)ORD. In some embodiments of Formula (I), R5 is –S(O)xRD. In some embodiments of Formula (I), two R5 groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6. In some embodiments of Formula (I), each of W1, W2, W3, and W4 is independently N or CR4a. In some embodiments of Formula (I), each of W1, W2, W3, and W4 is CR4a. In some embodiments of Formula (I), W1 is N and each of W2, W3, and W4 is CR4a. In some embodiments of Formula (I), W2 is N and each of W1, W3, and W4 is CR4a. In some embodiments of Formula (I), W3 is N and each of W1, W2, and W4 is CR4a. In some embodiments of Formula (I), W4 is N and each of W1, W2, and W3 is CR4a. In some embodiments of Formula (I), two of W1, W2, W3 and W4 is independently N. In some embodiments of Formula (I), each of W1 and W2 is N, and each of W3 and W4 is CR4a. In some embodiments of Formula (I), each of W2 and W3 is N, and each of W1 and W4 is CR4a. In some embodiments of Formula (I), each of W3 and W4 is N, and each of W1 and W2 is CR4a. In some embodiments of Formula (I), W1 is N or CR4a. In some embodiments of Formula (I), W2 is N or CR4a. In some embodiments of Formula (I), W3 is N or CR4a. In some 97 Attorney Docket No.: R2103-7054WO embodiments of Formula (I), W4 is N or CR4a. In some embodiments of Formula (I), one of W1, W2, W3 and W4 is independently N. In some embodiments of Formula (I), X is N or CR4b. In some embodiments of Formula (I), X is N. In some embodiments of Formula (I), X is CR4b. In some embodiments of Formula (I), the compound comprises 0, 1, 2, or 3 R4a. In some embodiments of Formula (I), the compound comprises 0 R4a. In some embodiments of Formula (I), the compound comprises 1 R4a. In some embodiments of Formula (I), the compound comprises 2 R4a. In some embodiments of Formula (I), the compound comprises 3 R4a. In some embodiments of Formula (I), each R4a is C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, halo, cyano, –ORA, or cycloalkyl. In some embodiments of Formula (I), each R4a is C1-C6-alkyl, halo, or –ORA. In some embodiments of Formula (I), R4a is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is hydrogen. In some embodiments of Formula (I), R4a is C1-C6-alkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C2-C6-alkenyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C2-C6- alkynyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C1-C6-heteroalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C1-C6-haloalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C1-C6-haloalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is cycloalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is heterocyclyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is aryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C1-C6 alkylene-aryl optionally substituted with one 98 Attorney Docket No.: R2103-7054WO or more R6. In some embodiments of Formula (I), R4a is C2-C6 alkenylene-aryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is heteroaryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C1-C6 alkylene-heteroaryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is C2-C6 alkenylene-heteroaryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4a is halo. In some embodiments of Formula (I), R4a is cyano. In some embodiments of Formula (I), R4a is –ORA. In some embodiments of Formula (I), R4a is –NRBRC. In some embodiments of Formula (I), R4a is –NRBC(O)RD. In some embodiments of Formula (I), R4a is –NO2. In some embodiments of Formula (I), R4a is – C(O)NRBRC. In some embodiments of Formula (I), R4a is –C(O)RD. In some embodiments of Formula (I), R4a is –C(O)ORD. In some embodiments of Formula (I), R4a is –S(O)xRD. In some embodiments of Formula (I), R4b is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2- C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene- aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or – S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is hydrogen. In some embodiments of Formula (I), R4b is C1- C6-alkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C2-C6-alkenyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C2-C6-alkynyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C1-C6-heteroalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C1-C6-haloalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C1-C6-haloalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is cycloalkyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is heterocyclyl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is aryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C1-C6 alkylene-aryl optionally 99 Attorney Docket No.: R2103-7054WO substituted with one or more R6. In some embodiments of Formula (I), R4b is C2-C6 alkenylene- aryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is heteroaryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C1-C6 alkylene-heteroaryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is C2-C6 alkenylene-heteroaryl optionally substituted with one or more R6. In some embodiments of Formula (I), R4b is halo. In some embodiments of Formula (I), R4b is cyano. In some embodiments of Formula (I), R4b is –ORA. In some embodiments of Formula (I), R4b is –NRBRC. In some embodiments of Formula (I), R4b is –NRBC(O)RD. In some embodiments of Formula (I), R4b is –NO2. In some embodiments of Formula (I), R4b is – C(O)NRBRC. In some embodiments of Formula (I), R4b is –C(O)RD. In some embodiments of Formula (I), R4b is –C(O)ORD. In some embodiments of Formula (I), R4b is –S(O)xRD. In some embodiments of Formula (I), each R6 is independently C1-C6-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, – C(O)ORD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is C1-C6-alkyl optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is C2-C6-alkenyl optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is C2-C6-alkynyl optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is C1-C6-heteroalkyl substituted with one or more R7. In some embodiments of Formula (I), R6 is C1-C6-haloalkyl optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is cycloalkyl optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is heterocyclyl. In some embodiments of Formula (I), R6 is aryl optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is heteroaryl optionally substituted with one or more R7. In some embodiments of Formula (I), R6 is halo. In some embodiments of Formula (I), R6 is cyano. In some embodiments of Formula (I), R6 is oxo. In some embodiments of Formula (I), R6 is – ORA. In some embodiments of Formula (I), R6 is –NRBRC. In some embodiments of Formula (I), 100 Attorney Docket No.: R2103-7054WO R6 is –NRBC(O)RD. In some embodiments of Formula (I), R6 is –NO2. In some embodiments of Formula (I), R6 is –NO2. In some embodiments of Formula (I), R6 is –C(O)NRBRC. In some embodiments of Formula (I), R6 is –C(O)RD. In some embodiments of Formula (I), R6 is – C(O)ORD. In some embodiments of Formula (I), R6 is –S(O)xRD. In some embodiments of Formula (I), each RA is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, –C(O)RD, or –S(O)xRD. In some embodiments of Formula (I), RA is hydrogen. In some embodiments of Formula (I), RA is C1-C6- alkyl. In some embodiments of Formula (I), RA is C2-C6-alkenyl. In some embodiments of Formula (I), RA is C2-C6-alkynyl. In some embodiments of Formula (I), RA is C1-C6-heteroalkyl. In some embodiments of Formula (I), RA is C1-C6-haloalkyl. In some embodiments of Formula (I), RA is cycloalkyl. In some embodiments of Formula (I), RA is heterocyclyl. In some embodiments of Formula (I), RA is heterocyclyl. In some embodiments of Formula (I), RA is heterocyclyl. In some embodiments of Formula (I), RA is aryl. In some embodiments of Formula (I), RA is aryl. In some embodiments of Formula (I), RA is heteroaryl. In some embodiments of Formula (I), RA is C1-C6 alkylene-aryl. In some embodiments of Formula (I), RA is C1-C6 alkylene-heteroaryl. In some embodiments of Formula (I), RA is –C(O)RD. In some embodiments of Formula (I), RA is –S(O)xRD. In some embodiments of Formula (I), each of RB and RC is independently hydrogen, C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, or –ORA; or RB and RC together with the atom to which they are attached form a 3- 7-membered heterocyclyl ring optionally substituted with one or more R7. In some embodiments of Formula (I), RB is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, or –ORA. In some embodiments of Formula (I), RB is hydrogen. In some embodiments of Formula (I), RB is C1-C6- alkyl. In some embodiments of Formula (I), RB is C2-C6-alkenyl. In some embodiments of Formula (I), RB is C2-C6-alkynyl. In some embodiments of Formula (I), RB is C1-C6-heteroalkyl. In some embodiments of Formula (I), RB is C1-C6-haloalkyl. In some embodiments of Formula 101 Attorney Docket No.: R2103-7054WO (I), RB is cycloalkyl. In some embodiments of Formula (I), RB is heterocyclyl. In some embodiments of Formula (I), RB is –ORA. In some embodiments of Formula (I), RC is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, or –ORA. In some embodiments of Formula (I), RC is hydrogen. In some embodiments of Formula (I), RC is C1-C6- alkyl. In some embodiments of Formula (I), RC is C2-C6-alkenyl. In some embodiments of Formula (I), RC is C2-C6-alkynyl. In some embodiments of Formula (I), RC is C1-C6-heteroalkyl. In some embodiments of Formula (I), RC is C1-C6-haloalkyl. In some embodiments of Formula (I), RC is cycloalkyl. In some embodiments of Formula (I), RC is heterocyclyl. In some embodiments of Formula (I), RC is –ORA. In some embodiments of Formula (I), each RD is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, or -N(RB1)(RC1) , wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9. In some embodiments of Formula (I), each RD is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene- heteroaryl. In some embodiments of Formula (I), RD is hydrogen. In some embodiments of Formula (I), RD is C1-C6 alkyl. In some embodiments of Formula (I), RD is C2-C6 alkenyl. In some embodiments of Formula (I), RD is C2-C6 alkynyl. In some embodiments of Formula (I), RD is C1-C6 heteroalkyl. In some embodiments of Formula (I), RD is C1-C6 heteroalkyl. In some embodiments of Formula (I), RD is C1-C6 heteroalkyl. In some embodiments of Formula (I), RD is C1-C6 haloalkyl. In some embodiments of Formula (I), RD is cycloalkyl. In some embodiments of Formula (I), RD is heterocyclyl. In some embodiments of Formula (I), RD is aryl. In some embodiments of Formula (I), RD is heteroaryl. In some embodiments of Formula (I), RD is C1-C6 alkylene-aryl. In some embodiments of Formula (I), RD is C1-C6 alkylene-heteroaryl. In some embodiments of Formula (I), RD is -N(RB1)(RC1). 102 Attorney Docket No.: R2103-7054WO In some embodiments of Formula (I), each RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, or -N(RB1)(RC1). In some embodiments of Formula (I), each RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl. In some embodiments of Formula (I), RE is hydrogen. In some embodiments of Formula (I), RE is C1-C6 alkyl. In some embodiments of Formula (I), RE is C2-C6 alkenyl. In some embodiments of Formula (I), RE is C2-C6 alkynyl. In some embodiments of Formula (I), RE is C1-C6 heteroalkyl. In some embodiments of Formula (I), RE is C1-C6 heteroalkyl. In some embodiments of Formula (I), RE is C1-C6 heteroalkyl. In some embodiments of Formula (I), RE is C1-C6 haloalkyl. In some embodiments of Formula (I), RE is cycloalkyl. In some embodiments of Formula (I), RE is heterocyclyl. In some embodiments of Formula (I), RE is aryl. In some embodiments of Formula (I), RE is heteroaryl. In some embodiments of Formula (I), RE is C1-C6 alkylene-aryl. In some embodiments of Formula (I), RE is C1-C6 alkylene-heteroaryl. In some embodiments of Formula (I), RE is -N(RB1)(RC1). In some embodiments of Formula (I), each R7 is independently C1-C6-alkyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NRBRC, oxo, –ORA, -C(O)NRBRC, or -C(O)RD, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9. In some embodiments of Formula (I), each R7 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or –ORA. In some embodiments of Formula (I), R7 is C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or –ORA. In some embodiments of Formula (I), R8 is hydrogen or C1-C6-alkyl. In some embodiments of Formula (I), R8 is hydrogen. In some embodiments of Formula (I), R8 is C1-C6- alkyl. In some embodiments of Formula (I), each R9 is independently C1-C6-alkyl, cycloalkyl, heterocyclyl, oxo, -ORA1, or -N(RB1)(RC1). In some embodiments of Formula (I), R9 is C1-C6- 103 Attorney Docket No.: R2103-7054WO alkyl. In some embodiments of Formula (I), R9 is cycloalkyl. In some embodiments of Formula (I), R9 is heterocyclyl. In some embodiments of Formula (I), R9 is oxo. In some embodiments of Formula (I), R9 is -ORA1. In some embodiments of Formula (I), R9 is -N(RB1)(RC1). In some embodiments of Formula (I), each RA1 is independently hydrogen or C1-C6-alkyl. In some embodiments of Formula (I), RA1 is hydrogen. In some embodiments of Formula (I), RA1 is C1-C6-alkyl. In some embodiments of Formula (I), each RB1 is independently hydrogen or C1-C6-alkyl. In some embodiments of Formula (I), RB1 is hydrogen. In some embodiments of Formula (I), RB1 is independently C1-C6-alkyl. In some embodiments of Formula (I), each RC1 is independently hydrogen or C1-C6-alkyl. In some embodiments of Formula (I), RC1 is hydrogen. In some embodiments of Formula (I), RC1 is independently C1-C6-alkyl. In some embodiments of Formula (I), n is 0, 1, 2, or 3. In some embodiments of Formula (I), n is 0. In some embodiments of Formula (I), n is 1. In some embodiments of Formula (I), n is 2. In some embodiments of Formula (I), n is 3. In some embodiments of Formula (I), n is not 0, 2, or 3. In some embodiments of Formula (I), x is 0, 1, or 2. In some embodiments of Formula (I), x is 0. In some embodiments of Formula (I), x is 1. In some embodiments of Formula (I), x is 2. In some embodiments, the compound of Formula (I) is a compound of Formula (I”): a pharmaceutically acceptable salt, solvate, hydrate , , , erein: W1, W2, W3, and W4 is each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; 104 Attorney Docket No.: R2103-7054WO L is absent, a bond, -O-, -NR8-, -C(O)-, -P(O)y-, -S(O)x-, –NRBC(O)-, –C(O)NRB-, C1-C6- alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2- C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, –NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD; each of R4a and R4b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene- heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, -S(O)(=NH)RD, or –S(O)xRD, h i h lk l lk l lk l lk l h t lk l h l lk l l lk l h t rocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1- C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene- heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3- 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C1- 105 Attorney Docket No.: R2103-7054WO C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, –C(O)RD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, -P(O)yRD, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD and RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each R7 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or –ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2.In some embodiments, the compound of Formula (I) is a compound of Formula (I’): a pharmaceutically acceptable salt, solvate, hydrate erein: W1, W2, W3, and W4 is each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, -S(O)x-, –NRBC(O)-, –C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; 106 Attorney Docket No.: R2103-7054WO each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1- C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, –NRBRC, –C(O)RD, –C(O)ORD, - , P(O)yRD, , or –S(O)xRD; each of R4a and R4b is independently hydrogen, C1-C6-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene- heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, – C(O)ORD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, – NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1- C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, –C(O)RD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6-alkyl, C1-C6- 107 Attorney Docket No.: R2103-7054WO heteroalkyl, cycloalkyl, heterocyclyl, -P(O)yRD, S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R7 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or –ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2. In some embodiments, the present disclosure provides compounds of Formula (I-02): a pharmaceutically acceptable salt, solvate, hydrate ein W1, W2, W3, 4 and W is each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, -P(O)y-, -S(O)x-, –NRBC(O)-,– C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, – NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, -S(O)(=NH)RD, or each of R4a and R4b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, – 108 Attorney Docket No.: R2103-7054WO NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1- C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene- heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3- 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C1- C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, –C(O)RD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, -P(O)yRD, S(O)xRD, or –ORA, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD and RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 109 Attorney Docket No.: R2103-7054WO cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each R7 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, - NRBRC, oxo, or –ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; R9 is C1-C6-alkyl or -ORA1; RA1 is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2. In some embodiments, the compound of Formula (I) is a compound of Formula (I-01): a pharmaceutically acceptable salt, solvate, hydrate ein: W1, W2, W3, and W4 is each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, -S(O)x-, –NRBC(O)-,–C(O)NRB-, C1-C6-alkylene, or C1- C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1- C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, –NRBRC, –C(O)RD, –C(O)ORD, or – S(O)xRD; each of R4a and R4b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a 110 Attorney Docket No.: R2103-7054WO adjacent groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene- heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, – NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C1- C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, –C(O)RD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, S(O)xRD, or –ORA, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1- C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R7 is independently C1-C6-alkyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or – ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is 111 Attorney Docket No.: R2103-7054WO optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; R9 is C1-C6-alkyl or - ORA1; RA1 is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2. In some embodiments, the compound of Formula (I) is a compound of Formula (I-a): a pharmaceutically acceptable salt, solvate, hydrate erein: W1, W2, W3, and W4 is each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl or 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, -S(O)x-, –NRBC(O)-, –C(O)NRB-, C1-C6-alkylene, or C1-C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring); each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2- C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, – NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD; each of R4a and R4b is independently hydrogen, C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene- heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, – C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, – 112 Attorney Docket No.: R2103-7054WO NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6- haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, – NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C1- C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, –C(O)RD, or –S(O)xRD; each of RB and RC is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, or –ORA; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R7 is independently C1-C6-alkyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or – ORA; R8 is hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and x is 0, 1, or 2. In some embodiments, the compound of Formula (I) is a compound of Formula (I-b): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, L, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-c): 113 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, rein each of W1, A, B, L, and R4a are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-d): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, A, B, L, R4a, and R4b, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-e): a pharmaceutically acceptable salt, solvate, hydrate, each of X, A, B, L, R4a, 4b and R , are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-f): a pharmaceutically acceptable salt, solvate, hydrate, n each of X, A, B, L, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-g): 114 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, B, and R4a, are as defined herein, and each of Z1, Z2, Z3, and Z4 is independently N or CR4b. In some embodiments, the compound of Formula (I) is a compound of Formula (I-h): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, B, R4a, and R5, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-h’): ate, in. In some embodiments, the compound of Formula (I) is a compound of Formula (I-i): a pharmaceutically acceptable salt, solvate, , , , erein each of W1, X, A, B, L, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-i’): 115 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, rein each of W1, X, B, L, and R4a, are as defined herein, and A’ is a 5-membered heteroaryl optionally substituted with one or more R6. In some embodiments, the compound of Formula (I) is a compound of Formula (I-j): O 1 B O W L a pharmaceutically acceptable salt, solvate, herein each of W1, X, A, B, L, R4a, and RA, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-j’): a pharmaceutically acceptable salt, solvate, hydrate, V1 is halogen, and each 1 4a of W , X, A, B, L, and R are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-j”): a pharmaceutically acceptable salt, solvate, hydrate, V2 is C1-C6-haloalkyl, and each of W1, X, A, B, L, and R4a are as defined herein. 116 Attorney Docket No.: R2103-7054WO In some embodiments, the compound of Formula (I) is a compound of Formula (I-k): a pharmaceutically acceptable salt, solvate, hydrate, rein each of W1, X, A, B, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-k’): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-l): a pharmaceutically acceptable salt, solvate, hydrate, rein each of W1, X, A, B, and 4a R , are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-l’): O R4a W1 a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-m): 117 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, ein each of W1, X, A, B, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-m’): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, and R4a, are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-n): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, B, and R4a, are as defined herein, and wherein each of Z5 and Z6 is independently N, NR5, O, or CR5. In some embodiments, the compound of Formula (I) is a compound of Formula (I-n’): a pharmaceutically acceptable salt, solvate, hydrate, ach of W1, X, B, and R4a, are as defined herein, and wherein each of Z5 and Z6 is independently N, O, or CR4b. In some embodiments, the compound of Formula (I) is a compound of Formula (I-o): 118 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, B, R4a, and R5 are as defined herein, and wherein Z2 is independently N or CR5. In some embodiments, the compound of Formula (I) is a compound of Formula (I-p): O R4a W1 Z2 NH a pharmaceutically acceptable salt, solvate, hydrate, ein each of W1, X, B, R4a, and R5 are as defined herein, and wherein Z2 is independently N or CR5. In some embodiments, the compound of Formula (I) is a compound of Formula (I-q): a pharmaceutically acceptable salt, solvate, hydrate, 1 4a 5 ach of W , X, B, R , and R are as defined herein, and wherein Z7, Z8, and Z9 form part of an aromatic ring and are each independently C, N, CR5, NR5, O, or S. In some embodiments, the compound of Formula (I) is a compound of Formula (I-r): a pharmaceutically acceptable salt, solvate, hydrate, , , ein each of W1, X, B, R4a, and R5 are as defined herein, 119 Attorney Docket No.: R2103-7054WO and wherein Z7’, Z8, and Z9 form part of an aromatic ring and are each independently C, N, CR5, NR5, O, or S. In some embodiments, the compound of Formula (I) is a compound of Formula (I-s): a pharmaceutically acceptable salt, solvate, rein each of W1, X, A, R4a, R5, and RA are as defined herein. In some embodiments, the compound of Formula (I) is a compound of Formula (I-t): a pharmaceutically acceptable salt, solvate, erein each of W1, X 4a 5 , A, R , and R are as defined herein, and wherein V3 is halogen or C1-C6 alkyl. In some embodiments, the compound of Formula (I) is a compound of Formula (I-u): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, R4a, and R5 are as defined herein, and wherein ZD is N or CR5. In some embodiments, the compound of Formula (I) is a compound of Formula (I-v): 120 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, rein each of W1, X, A, R4a, and R5 are as defined herein, and wherein ZA, ZB, and ZC form part of an aromatic ring and are each independently C, N, CR5, NR5, O or S. In some embodiments, the compound of Formula (I) is a compound of Formula (I-w): O R4a W1 ZC NH ZB a pharmaceutically acceptable salt, solvate, ein each of 1 4a 5 W , X, A, R , and R are as defined herein, and wherein ZA, ZB, and ZC form part of an aromatic ring and are each independently C, N, CR5, NR5, O, or S. In some embodiments, the compound of Formula (I) is selected from a compound in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. Table 1: Exemplary compounds of Formula (I) # Structure # Structure 121 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 127 Attorney Docket No.: R2103-7054WO # Structure # Structure 12 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure O O F Attorney Docket No.: R2103-7054WO # Structure # Structure 131 Attorney Docket No.: R2103-7054WO # Structure # Structure 132 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure O Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 139 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 141 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 144 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 146 Attorney Docket No.: R2103-7054WO # Structure # Structure F Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 151 Attorney Docket No.: R2103-7054WO # Structure # Structure 152 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure O Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 158 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO # Structure # Structure 168 Attorney Docket No.: R2103-7054WO # Structure # Structure Attorney Docket No.: R2103-7054WO Pharmaceutical Compositions, Kits, and Administration The present invention provides pharmaceutical compositions comprising a compound of Formula (I) e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, as described herein, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of Formula (I) (the “active ingredient”) into association with a carrier 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. Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, 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, for example, 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 of the invention 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. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient. 170 Attorney Docket No.: R2103-7054WO The term “pharmaceutically acceptable excipient” refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention are any of those that are well known in the art of pharmaceutical formulation and 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. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Compositions of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and/or orally. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or 171 Attorney Docket No.: R2103-7054WO solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained/delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A provided compound can also be in micro-encapsulated form. Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions or in an ointment such as petrolatum. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. 172 Attorney Docket No.: R2103-7054WO Although the descriptions of pharmaceutical 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. Compounds provided herein are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending 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 exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be 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. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, 173 Attorney Docket No.: R2103-7054WO 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. In certain embodiments, the compounds of Formula (I) may be 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. It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. The compound or composition can be 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. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered 174 Attorney Docket No.: R2103-7054WO together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized 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. Exemplary additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. 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. Also encompassed by the invention are kits (e.g., pharmaceutical packs). The inventive kits may be useful for preventing and/or treating a proliferative disease or a non-proliferative disease, e.g., as described herein. The kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one-unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit 175 Attorney Docket No.: R2103-7054WO of the disclosure includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits are useful in preventing and/or treating a disease, disorder, or condition described herein in a subject (e.g., a proliferative disease or a non-proliferative disease). In certain embodiments, the kits further include instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof, to a subject to prevent and/or treat a proliferative disease or a non-proliferative disease. Methods of Use Described herein are compounds useful for modulating cyclin dependent kinase (CDK) activity (e.g., CDK12 activity) and/or cyclin protein expression (e.g., Cyclin K). In some embodiments, a compound of Formula (I) modulates the activity of a CDK and/or cyclin. The compounds and compositions described herein may also be useful for treating a disease, disorder, or condition described herein (e.g., cancer). Cyclin K Degradation Cyclins are a family of genes that regulate the enzymatic activity of cyclin dependent kinases (CDKs). Every CDK must be complexed with a partner cyclin to be catalytically active. Cyclin K plays a role as an important regulator of gene transcription by activating the cyclin dependent kinases CDK12 and CDK13. In the absence of Cyclin K, both CDK12 and CDK13 are functionally inactive. Cyclin K therefore plays a pivotal role in regulating cellular processes downstream of CDK12 and CDK13 activity, including gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression, and cell proliferation. It has been demonstrated that Cyclin K protein levels can be modulated by small molecule compounds, such as molecular glue degraders (molecular glues). Molecular glues result in proteasome mediated degradation of Cyclin K by inducing ternary complex formation between CDK12 (or CDK13) and the ubiquitin ligase scaffolding protein DDB1. DDB1 positions the CDK12/Cyclin K (or CDK13/Cyclin K) complex in the proximity of an E2 176 Attorney Docket No.: R2103-7054WO ubiquitin ligase for efficient ubiquitination of Cyclin K, which results in the degradation of Cyclin K by the proteasome. In an embodiment, the compound of Formula (I) or pharmaceutically acceptable salt thereof is capable of modulating an activity of Cyclin K. The compound of Formula (I) may inhibit the activity of Cyclin K. In an embodiment, the compound of Formula (I) inhibits the activity of Cyclin K, e.g., by about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%.8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%....90%, 95%, 99%, or more, e.g., relative to a reference standard. In an embodiment, the compound of Formula (I) inhibits the activity of Cyclin K between about 1% and 50%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 15%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 20%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 25%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 50%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 75%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 90%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 95%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by at least 99%. In some embodiments, the compound of Formula (I) slows the activity of Cyclin K by more than 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K, e.g., in a cell or sample. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 5%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 10%. In 177 Attorney Docket No.: R2103-7054WO some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 20%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 30%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 40%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 50%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 75%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 90%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 95%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by at least 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of Cyclin K by more than 99%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 5%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 10%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 20%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 30%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 40%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 50%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 75%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 90%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 95%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by at least 178 Attorney Docket No.: R2103-7054WO 99%. In some embodiments, the compound of Formula (I) is capable of increasing the rate of Cyclin K degradation by more than 99%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 0.5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 1%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 2%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 10%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 15%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 20%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 25%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 50%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 75%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 90%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to Cyclin K by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound 179 Attorney Docket No.: R2103-7054WO of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 0.5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 1%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 2%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 50%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for Cyclin K by more than about 95%. CDK12/13 Inhibition The cell cycle is a highly regulated process governing cell division and is controlled by several cyclins and cyclin-dependent kinases (CDKs), a group of serine/threonine protein kinases. Cyclins phosphorylate CDKs, forming complexes that play crucial roles in cell cycle regulation and gene transcription (see, e.g., Ding, L. et al. International Journal of Molecular Sciences. (2020) 21:65-78). While cyclins activate CDKs, there are other regulatory molecules that can inhibit their function. Under normal conditions, the activation and inhibition of CDK complexes controls the behavior of the cell at many important cell cycle checkpoints to regulate healthy division. However, this process can become dysregulated and promote uncontrolled division of cells, leading to cancer. In fact, in many human cancers, CDKs are overactive or CDK-inhibiting proteins are not functional. Inhibiting CDKs can promote cell cycle arrest and 180 Attorney Docket No.: R2103-7054WO attenuate cell proliferation (Malumbres, M., et al. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer (2009) 9:153–166). CDKs are divided into two subfamilies, including cell cycle-associated CDKs and transcription-associated CDKs. Cell cycle-associated CDKs mainly contain CDK1, CDK2, CDK4 and CDK6, which directly regulate the cell cycle progression. The transcription- associated CDKs, consisting of CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13, control gene transcription. Cyclin-dependent kinase 12 (CDK12) is known to regulate gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression, and cell proliferation. CDK12 complexes with cyclin K to regulate gene transcription elongation via phosphorylating RNA polymerase II (RNAP II) and additionally regulates translation. CDK12 is mainly composed of three domains: a central Cdc2-related protein kinase domain (KD), an N-terminal “arm”, about 700 amino acids, and a C-terminal “arm”, about 500 amino acids. The central KD is composed of 300 amino acids, and its main function is to mediate phosphorylation of the C-terminal domain of RNAP II. The RS domain, which is enriched arginine and serine, is a prominent feature of CDK12. There are 21 RS motifs in the first 400 amino acids of CDK12, and one RS motif in the rest of the approximately 1000 amino acids. In CDK12, the RS domain mainly functions to target CDK12 to the nuclear speckles. The central KD and the RS domain give CDK12 the capacity to directly link transcription with splicing machinery. Proline-rich motifs (PRM) are located between the RS domain and the central KD and are also found in the C-terminal region. The PRM contains the consensus binding sites for Src homology 3 (SH3) and tryptophan (WW) regions, which mediate protein–protein interactions by binding proline-rich modules in ligands. The presence of the RS domain and PRM domain indicates that CDK12 can take part in numerous protein–protein interactions. When CDK12 is bound to cyclin K, the complex functions as an RNA polymerase II (RNAP II) C-terminal domain kinase. Inhibition of CDK12 reduces RNAP II processivity and is correlated with defective transcription elongation (Chirackal Manavalan A.P., et al. EMBO Rep. (2019) 20:e47592). Additionally, CDK12 phosphorylates 4E-BP1 (the mRNA 5’ cap-binding repressor) 181 Attorney Docket No.: R2103-7054WO at Ser65 and Thr70 and is known to suppress intronic polyadenylation (Krajewska M., et al. Nat. Commun. (2019) 10:1757). The closest human homologue of CDK12 is CDK13. While their KD sequences are highly homologous (sharing 43% sequence identity), their C- and N-terminal regions differ. CDK12/13 phosphorylate Ser5 and Ser2 of the RNAP II C-terminal domain when complexed with cyclin K. CDK13 has been shown to be involved in alternative splicing (R. Berro, et al. J. Virol., (2008) 82:7155-7166), and also capable of direct phosphorylation of two key components of the protein translation machinery, e.g., 4E-BP1 at Thr6 and eIF4B at Ser422. In some embodiments, CDK12 comprises the amino acid sequence of SEQ ID NO 1: MPNSERHGGKKDGSGGASGTLQPSSGGGSSNSRERHRLVSKHKRHKSKHSKDMGLVTP EAASLGTVIKPLVEYDDISSDSDTFSDDMAFKLDRRENDERRGSDRSDRLHKHRHHQHR RSRDLLKAKQTEKEKSQEVSSKSGSMKDRISGSSKRSNEETDDYGKAQVAKSSSKESRS SKLHKEKTRKERELKSGHKDRSKSHRKRETPKSYKTVDSPKRRSRSPHRKWSDSSKQD DSPSGASYGQDYDLSPSRSHTSSNYDSYKKSPGSTSRRQSVSPPYKEPSAYQSSTRSPSPY SRRQRSVSPYSRRRSSSYERSGSYSGRSPSPYGRRRSSSPFLSKRSLSRSPLPSRKSMKSRS RSPAYSRHSSSHSKKKRSSSRSRHSSISPVRLPLNSSLGAELSRKKKERAAAAAAAKMDG KESKGSPVFLPRKENSSVEAKDSGLESKKLPRSVKLEKSAPDTELVNVTHLNTEVKNSSD TGKVKLDENSEKHLVKDLKAQGTRDSKPIALKEEIVTPKETETSEKETPPPLPTIASPPPPL PTTTPPPQTPPLPPLPPIPALPQQPPLPPSQPAFSQVPASSTSTLPPSTHSKTSAVSSQANSQP PVQVSVKTQVSVTAAIPHLKTSTLPPLPLPPLLPGDDDMDSPKETLPSKPVKKEKEQRTR HLLTDLPLPPELPGGDLSPPDSPEPKAITPPQQPYKKRPKICCPRYGERRQTESDWGKRCV DKFDIIGIIGEGTYGQVYKAKDKDTGELVALKKVRLDNEKEGFPITAIREIKILRQLIHRSV VNMKEIVTDKQDALDFKKDKGAFYLVFEYMDHDLMGLLESGLVHFSEDHIKSFMKQL MEGLEYCHKKNFLHRDIKCSNILLNNSGQIKLADFGLARLYNSEESRPYTNKVITLWYRP PELLLGEERYTPAIDVWSCGCILGELFTKKPIFQANLELAQLELISRLCGSPCPAVWPDVI KLPYFNTMKPKKQYRRRLREEFSFIPSAALDLLDHMLTLDPSKRCTAEQTLQSDFLKDV ELSKMAPPDLPHWQDCHELWSKKRRRQRQSGVVVEEPPPSKTSRKETTSGTSTEPVKNS SPAPPQPAPGKVESGAGDAIGLADITQQLNQSELAVLLNLLQSQTDLSIPQMAQLLNIHS 182 Attorney Docket No.: R2103-7054WO NPEMQQQLEALNQSISALTEATSQQQDSETMAPEESLKEAPSAPVILPSAEQTTLEASSTP ADMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTPTMPQEEAAACPPHILPP EKRPPEPPGPPPPPPPPPLVEGDLSSAPQELNPAVTAALLQLLSQPEAEPPGHLPHEHQAL RPMEYSTRPRPNRTYGNTDGPETGFSAIDTDERNSGPALTESLVQTLVKNRTFSGSLSHL GESSSYQGTGSVQFPGDQDLRFARVPLALHPVVGQPFLKAEGSSNSVVHAETKLQNYGE LGPGTTGASSSGAGLHWGGPTQSSAYGKLYRGPTRVPPRGGRGRGVPY. In some embodiments, CDK12 comprises an amino acid sequence having at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or greater) sequence identity to SEQ ID NO: 1. In some embodiments, CDK13 comprises the amino acid sequence of SEQ ID NO 2: MPSSSDTALGGGGGLSWAEKKLEERRKRRRFLSPQQPPLLLPLLQPQLLQPPPPPPPLLFL AAPGTAAAAAAAAAASSSCFSPGPPLEVKRLARGKRRAGGRQKRRRGPRAGQEAEKRR VFSLPQPQQDGGGGASSGGGVTPLVEYEDVSSQSEQGLLLGGASAATAATAAGGTGGS GGSPASSSGTQRRGEGSERRPRRDRRSSSGRSKERHREHRRRDGQRGGSEASKSRSRHS HSGEERAEVAKSGSSSSSGGRRKSASATSSSSSSRKDRDSKAHRSRTKSSKEPPSAYKEPP KAYREDKTEPKAYRRRRSLSPLGGRDDSPVSHRASQSLRSRKSPSPAGGGSSPYSRRLPR SPSPYSRRRSPSYSRHSSYERGGDVSPSPYSSSSWRRSRSPYSPVLRRSGKSRSRSPYSSRH SRSRSRHRLSRSRSRHSSISPSTLTLKSSLAAELNKNKKARAAEAARAAEAAKAAEATKA AEAAAKAAKASNTSTPTKGNTETSASASQTNHVKDVKKIKIEHAPSPSSGGTLKNDKAK TKPPLQVTKVENNLIVDKATKKAVIVGKESKSAATKEESVSLKEKTKPLTPSIGAKEKEQ HVALVTSTLPPLPLPPMLPEDKEADSLRGNISVKAVKKEVEKKLRCLLADLPLPPELPGG DDLSKSPEEKKTATQLHSKRRPKICGPRYGETKEKDIDWGKRCVDKFDIIGIIGEGTYGQ VYKARDKDTGEMVALKKVRLDNEKEGFPITAIREIKILRQLTHQSIINMKEIVTDKEDAL DFKKDKGAFYLVFEYMDHDLMGLLESGLVHFNENHIKSFMRQLMEGLDYCHKKNFLH RDIKCSNILLNNRGQIKLADFGLARLYSSEESRPYTNKVITLWYRPPELLLGEERYTPAID VWSCGCILGELFTKKPIFQANQELAQLELISRICGSPCPAVWPDVIKLPYFNTMKPKKQY RRKLREEFVFIPAAALDLFDYMLALDPSKRCTAEQALQCEFLRDVEPSKMPPPDLPLWQ DCHELWSKKRRRQKQMGMTDDVSTIKAPRKDLSLGLDDSRTNTPQGVLPSSQLKSQGS 183 Attorney Docket No.: R2103-7054WO SNVAPVKTGPGQHLNHSELAILLNLLQSKTSVNMADFVQVLNIKVNSETQQQLNKINLP AGILATGEKQTDPSTPQQESSKPLGGIQPSSQTIQPKVETDAAQAAVQSAFAVLLTQLIKA QQSKQKDVLLEERENGSGHEASLQLRPPPEPSTPVSGQDDLIQHQDMRILELTPEPDRPRI LPPDQRPPEPPEPPPVTEEDLDYRTENQHVPTTSSSLTDPHAGVKAALLQLLAQHQPQDD PKREGGIDYQAGDTYVSTSDYKDNFGSSSFSSAPYVSNDGLGSSSAPPLERRSFIGNSDIQ SLDNYSTASSHSGGPPQPSAFSESFPSSVAGYGDIYLNAGPMLFSGDKDHRFEYSHGPIA VLANSSDPSTGPESTHPLPAKMHNYNYGGNLQENPSGPSLMHGQTWTSPAQGPGYSQG YRGHISTSTGRGRGRGLPY. In an embodiment, the compound of Formula (I) or pharmaceutically acceptable salt thereof is capable of modulating an activity of a CDK, e.g., CDK12 and/or CDK13. The compound of Formula (I) may inhibit the activity of a CDK, e.g., CDK12 and/or CDK13. In an embodiment, the compound of Formula (I) inhibits the activity of a CDK, e.g., CDK12 and/or CDK13 by about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%.8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%....90%, 95%, 99%, or more, e.g., relative to a reference standard. In an embodiment, the compound of Formula (I) inhibits the activity of a CDK, e.g., CDK12 and/or CDK13 between about 1% and 50%. In an embodiment, the compound of Formula (I) does not substantially inhibit the activity of CDK13. In some embodiments, the compound of Formula (I) slows the activity of a CDK, e.g., CDK12 and/or CDK13. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 15%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 20%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 25%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 50%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 75%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 90%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by at least 95%. In some embodiments, the compound of 184 Attorney Docket No.: R2103-7054WO Formula (I) slows the activity of CDK12 by at least 99%. In some embodiments, the compound of Formula (I) slows the activity of CDK12 by more than 99%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 10% (e.g., at least 15%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 15%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 20%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 25%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 50%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 75%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 90%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 95%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by at least 99%. In some embodiments, the compound of Formula (I) slows the activity of CDK13 by more than 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 5%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 10%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 20%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 30%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 40%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 50%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation 185 Attorney Docket No.: R2103-7054WO of RNAP II by CDK12 by at least 75%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 90%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 95%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by at least 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK12 by more than 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 5%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 10%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 20%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 30%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 40%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 50%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 75%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 90%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 95%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by at least 99%. In some embodiments, the compound of Formula (I) is capable of reducing the level of phosphorylation of RNAP II by CDK13 by more than 99%. 186 Attorney Docket No.: R2103-7054WO In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 5%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 10%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 20%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 30%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 40%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 50%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 75%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 90%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 95%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by at least 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK12 by more than 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 1% (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 5%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 10%. In some 187 Attorney Docket No.: R2103-7054WO embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 20%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 30%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 40%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 50%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 75%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 90%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 95%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by at least 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by more than 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 10% (e.g., about 25%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 25%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 50%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 75%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 90%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 95%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by about 99%. In some embodiments, the compound of Formula (I) is capable of slowing the rate of phosphorylation of RNAP II by CDK13 by more than 99%. 188 Attorney Docket No.: R2103-7054WO In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 1%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 2%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 10%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 15%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 20%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 25%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 50%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 75%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 90%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK12 to RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding 189 Attorney Docket No.: R2103-7054WO of CDK13 to RNAP II by about 1%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 2%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 5%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 10%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 15%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 20%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 25%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 50%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 75%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 90%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by about 95%. In some embodiments, the compound of Formula (I) is capable of modulating the binding of CDK13 to RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 1%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 2%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity 190 Attorney Docket No.: R2103-7054WO of CDK12 for RNAP II by about 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 50%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK12 for RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 0.1% (e.g., by about 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 0.5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 1%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 2%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 50%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by about 95%. In some embodiments, the 191 Attorney Docket No.: R2103-7054WO compound of Formula (I) reduces the binding affinity of CDK13 for RNAP II by more than about 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 0.1% (e.g., 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 0.5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 1%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 2%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 50%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by at least 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK12 by more than 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 0.1% (e.g., 0.5%.1%, 2%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 0.5%. In some embodiments, 192 Attorney Docket No.: R2103-7054WO the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 1%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 2%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 5%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 10%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 15%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 20%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 25%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 50%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 75%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 90%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by at least 95%. In some embodiments, the compound of Formula (I) reduces the binding affinity of RNAP II for CDK13 by more than 95%. Methods of Treatment The present disclosure also provides methods for the treatment or prevention of a disease, disorder, or condition. In an embodiment, the disease, disorder or condition is related to (e.g., caused by) modulation of a phosphorylation event, such as an unwanted, aberrant, or alternative phosphorylation event. In an embodiment, the disease, disorder or condition comprises a proliferative disease (e.g., cancer, benign neoplasm, or inflammatory disease) or non- proliferative disease. Such methods comprise the step of administering to the subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the methods described herein include administering to a subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or 193 Attorney Docket No.: R2103-7054WO a pharmaceutical composition thereof. In certain embodiments, the disease or disorder to be treated or prevented using the compounds of Formula (I) is cancer. As used herein, the term “cancer” refers to a malignant neoplasm (Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the disclosure. 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); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), e.g., adenoid cystic carcinoma (ACC)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell 194 Attorney Docket No.: R2103-7054WO lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. 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. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of 195 Attorney Docket No.: R2103-7054WO the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva). In an embodiment, the cancer is breast cancer, gastroesophageal cancer, salivary cancer, bladder cancer, colorectal cancer, uterine cancer, ovarian cancer, or lung cancer. In some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. For example, in some embodiments, the cancer is a carcinoma. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is a lymphoma. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is a melanoma. In some embodiments, the cancer is a mesothelioma. In some embodiments, the cancer is a multiple myeloma. In some embodiments, the cancer is a seminoma. In some embodiments, the disease or disorder is associated with a benign neoplasm. For example, a benign neoplasm may include adenoma, fibroma, hemangioma, tuberous sclerosis, and lipoma. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In some embodiments, the disease or disorder is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the disclosure. 196 Attorney Docket No.: R2103-7054WO In some embodiments, a compound of Formula (I) may slow progression of tumor growth, reduce tumor size, slow and/or prevent cell division, accelerate cell death, prevent metastasis, enhance immune recognition of the tumor, and/or reduce inflammation. For example, in some embodiments, a compound of Formula (I) slows progression of tumor growth. In some embodiments, a compound of Formula (I) reduces tumor size. In some embodiments, a compound of Formula (I) slows and/or prevents cell division. In some embodiments, a compound of Formula (I) accelerates cell death. In some embodiments, a compound of Formula (I) slows and/or prevents metastasis. In some embodiments, a compound of Formula (I) enhances immune recognition of the tumor. In some embodiments, a compound of Formula (I) reduces inflammation. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type- matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type- matched cancer cell, by at least 95%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer 197 Attorney Docket No.: R2103-7054WO cell, by at least 99%. In some embodiments, the compound of Formula (I) promotes slow growth of a cancer cell, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 95%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 99%. In some embodiments, the compound of Formula (I) results in reduced angiogenesis, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more). For example, in some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 20%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 30%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., 198 Attorney Docket No.: R2103-7054WO relative to a reference, e.g., a type-matched cancer cell, by at least 40%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 50%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 75%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 90%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by at least 95%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type- matched cancer cell, by at least 99%. In some embodiments, the compound of Formula (I) results in reduction of a tumor, e.g., relative to a reference, e.g., a type-matched cancer cell, by more than 99%. In some embodiments, the compound of Formula (I) results in the death of a cancer cell. A compound of Formula (I) may be used to treat a subject having or diagnosed having a cancer. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a a neurological disease, autoimmune disorder, immunodeficiency disorder, lysosomal storage disease, cardiovascular condition, metabolic disorder, respiratory condition, inflammatory disease, renal disease, or infectious disease. In certain embodiments, the disease is a neurological disease. In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a neurological disease, disorder, or condition. A neurological disease, disorder, or condition may include a neurodegenerative disease, a psychiatric condition, or a musculoskeletal disease. Exemplary neurological diseases, disorders, and conditions include Alzheimer’s disease, Huntington’s chorea, a prion disease (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), a mental retardation disorder (e.g., a disorder caused by a 199 Attorney Docket No.: R2103-7054WO SETD5 gene mutation, e.g., intellectual disability-facial dysmorphism syndrome, autism spectrum disorder), Lewy Body disease, diffuse Lewy body disease (DLBD), dementia, progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick’s disease, primary progressive aphasia, corticobasal dementia, Parkinson’s disease, Down’s syndrome, multiple system atrophy, spinal muscular atrophy (SMA), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase- associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler’s disease, Krabbe’s disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder’s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh’s syndrome, a demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), autism, Machado-Joseph disease, or a combination thereof. In some embodiments, the neurological disease comprises Friedrich’s ataxia or Sturge Weber syndrome. In some embodiments, the neurological disease comprises Huntington’s disease. In some embodiments, the neurological disease comprises spinal muscular atrophy. All types of neurological diseases disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the disease is an autoimmune disorder or an immunodeficiency disorder. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat an autoimmune disease, disorder, or condition, or an immunodeficiency disease, disorder, or condition. Exemplary autoimmune and 200 Attorney Docket No.: R2103-7054WO immunodeficiency diseases, disorders, and conditions include arthritis (e.g., rheumatoid arthritis, osteoarthritis, gout), Chagas disease, chronic obstructive pulmonary disease (COPD), dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture’s syndrome, Graves’ disease, Guillain-Barrė syndrome (GBS), Hashiomoto’s disease, Hidradenitis suppurativa, Kawasaki disease, ankylosing spondylitis, IgA nephropathy, idiopathic thrombocytopenic purpura, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, infective colitis, indeterminate colitisinterstitial cystitis, lupus (e.g., systemic lupus erythematosus, discoid lupus, drug-induced lupus, neonatal lupus), mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, scleroderma, Sjögren’s syndrome, Stiff person syndrome, vasculitis, vitiligo, a disorder caused by a GATA2 mutation (e.g., GATA2 deficiency; GATA2 haploinsufficiency; Emberger syndrome; monocytopenia and mycobacterium avium complex/dendritic cell, monocyte, B and NK lymphocyte deficiency; familial myelodysplastic syndrome; acute myeloid leukemia; chronic myelomonocytic leukemia), neutropenia, aplastic anemia, and Wegener’s granulomatosis. In some embodiments, the autoimmune or immunodeficiency disorder comprises chronic mucocutaneous candidiasis. All types of autoimmune disorders and immunodeficiency disorders disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the disease is a cardiovascular condition. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a cardiovascular disease, disorder, or condition. A cardiovascular disease, disorder, or condition may include a condition relating to the heart or vascular system, such as the arteries, veins, or blood. Exemplary cardiovascular diseases, disorders, or conditions include angina, arrhythmias (atrial or ventricular or both), heart failure, arteriosclerosis, atheroma, atherosclerosis, cardiac hypertrophy, cardiac or vascular aneurysm, cardiac myocyte dysfunction, 201 Attorney Docket No.: R2103-7054WO carotid obstructive disease, endothelial damage after PTCA (percutaneous transluminal coronary angioplasty), hypertension including essential hypertension, pulmonary hypertension and secondary hypertension (renovascular hypertension, chronic glomerulonephritis), myocardial infarction, myocardial ischemia, peripheral obstructive arteriopathy of a limb, an organ, or a tissue; peripheral artery occlusive disease (PAOD), reperfusion injury following ischemia of the brain, heart or other organ or tissue, restenosis, stroke, thrombosis, transient ischemic attack (TIA), vascular occlusion, vasculitis, and vasoconstriction. All types of cardiovascular diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the disease is a metabolic disorder. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a metabolic disease, disorder, or condition. A metabolic disease, disorder, or condition may include a disorder or condition that is characterized by abnormal metabolism, such as those disorders relating to the consumption of food and water, digestion, nutrient processing, and waste removal. A metabolic disease, disorder, or condition may include an acid-base imbalance, a mitochondrial disease, a wasting syndrome, a malabsorption disorder, an iron metabolism disorder, a calcium metabolism disorder, a DNA repair deficiency disorder, a glucose metabolism disorder, hyperlactatemia, a disorder of the gut microbiota. Exemplary metabolic conditions include obesity, diabetes (Type I or Type II), insulin resistance, glucose intolerance, lactose intolerance, eczema, hypertension, Hunter syndrome, Krabbe disease, sickle cell anemia, maple syrup urine disease, Pompe disease, and metachromatic leukodystrophy. All types of metabolic diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the disease is a respiratory condition. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a respiratory disease, disorder, or condition. A respiratory disease, disorder, or condition 202 Attorney Docket No.: R2103-7054WO can include a disorder or condition relating to any part of the respiratory system, such as the lungs, alveoli, trachea, bronchi, nasal passages, or nose. Exemplary respiratory diseases, disorders, or conditions include asthma, allergies, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), lung cancer, oxygen toxicity, emphysema, chronic bronchitis, and acute respiratory distress syndrome. All types of respiratory diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the disease is a renal disease. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat a renal disease, disorder, or condition. A renal disease, disorder, or condition can include a disease, disorder, or condition relating to any part of the waste production, storage, and removal system, including the kidneys, ureter, bladder, urethra, adrenal gland, and pelvis. Exemplary renal diseases include acute kidney failure, amyloidosis, Alport syndrome, adenovirus nephritis, acute lobar nephronia, tubular necrosis, glomerulonephritis, kidney stones, urinary tract infections, chronic kidney disease, polycystic kidney disease, and focal segmental glomerulosclerosis (FSGS). In some embodiments, the renal disease, disorder, or condition comprises HIV-associated nephropathy or hypertensive nephropathy. All types of renal diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the disease is an infectious disease. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof, is used to prevent or treat an infectious disease, disorder, or condition. An infectious disease may be caused by a pathogen such as a virus or bacteria. Exemplary infectious diseases include human immunodeficiency syndrome (HIV), acquired immunodeficiency syndrome (AIDS), meningitis, African sleeping sickness, actinomycosis, pneumonia, botulism, chlamydia, Chagas disease, Colorado tick fever, cholera, typhus, giardiasis, food poisoning, ebola hemorrhagic fever, diphtheria, Dengue fever, gonorrhea, streptococcal infection (e.g., Group A or Group B), 203 Attorney Docket No.: R2103-7054WO hepatitis A, hepatitis B, hepatitis C, herpes simplex, hookworm infection, influenza, Epstein-Barr infection, Kawasaki disease, kuru, leprosy, leishmaniasis, measles, mumps, norovirus, meningococcal disease, malaria, Lyme disease, listeriosis, rabies, rhinovirus, rubella, tetanus, shingles, scarlet fever, scabies, Zika fever, yellow fever, tuberculosis, toxoplasmosis, or tularemia. In some embodiments, the infectious disease comprises cytomegalovirus. All types of infectious diseases, disorders, or conditions disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig. In certain embodiments, the methods described herein comprise the additional step of administering one or more additional pharmaceutical agents in combination with the compound of Formula (I), a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof. Such additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. The additional pharmaceutical agent(s) may synergistically augment the modulation of CDK activity induced by the inventive compounds or compositions of this disclosure in the biological sample or subject. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating, for example, a cancer or other disease, disorder, or condition resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions. ENUMERATED EMBODIMENTS 204 Attorney Docket No.: R2103-7054WO 1. A compound of Formula (I): a pharmaceutically acceptable salt, solvate, hydrate, rein: W1, W2, W3, and W4 are each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl, 5-membered heteroaryl, or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, –NRBC(O)-, –C(O)NRB-, C1-C6-alkylene, or C1- C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, –NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, or –S(O)xRD; each R4a is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, - P(O)yRD, -S(O)(=NH)RD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7- membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; 205 Attorney Docket No.: R2103-7054WO each R4b is independently hydrogen, C1-C6-alkyl, cycloalkyl, heterocyclyl, or halo, wherein each alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, - P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, – NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1- C6 alkylene-heteroaryl, –C(O)RD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, -P(O)yRD, -S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD and RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene- 206 Attorney Docket No.: R2103-7054WO aryl, C1-C6 alkylene-heteroaryl, or -N(RB1)(RC1), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each R7 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NRB1RC1, oxo, –ORA1, –C(O)NRB1RC1, or – C(O)RD1, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; each R9 is independently C1-C6-alkyl, cycloalkyl, heterocyclyl, oxo, -ORA1, or - N(RB1)(RC1); each RA1 is independently hydrogen or C1-C6-alkyl; each of RB1, RC1, and RD1 is independently hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2. 2. The compound of embodiment 1, wherein Ring A is 6-membered aryl (e.g., phenyl) optionally substituted with one or more R5. 3. The compound of any one of the preceding embodiments, wherein Ring A is 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. 4. The compound of any one of the preceding embodiments, wherein Ring A is a nitrogen- containing 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. 207 Attorney Docket No.: R2103-7054WO 5. The compound of any one of the preceding embodiments, wherein Ring A is selected bed 6. The compound of any one of the preceding embodiments, wherein Ring A is selected from 1. Attorney Docket No.: R2103-7054WO 7. The compound of any one of the preceding embodiments, wherein Ri , wherein R5 is as described in embodiment 1. 8. The compound of any one of the preceding embodiments, wherein Ring A is selected , Attorney Docket No.: R2103-7054WO 9. The compound of any one of the preceding embodiments, wherein Ring A is selected from . y one of the preceding embodiments, wherein Ring A 11. The compound of any one of the preceding embodiments, wherein L is absent, a bond, - O-, -NR8-, -C(O)-, or -S(O)x-. 12. The compound of any one of the preceding embodiments, wherein L is a bond. 13. The compound of any one of the preceding embodiments, wherein Ring B is aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more R5. 14. The compound of any one of the preceding embodiments, wherein Ring B is a nitrogen- containing heteroaryl or heterocyclyl, each of which is optionally substituted with one or more R5. 15. The compound of any one of the preceding embodiments, wherein Ring B is a 5- membered or 6-membered nitrogen-containing heteroaryl or heterocyclyl, each of which is optionally substituted with one or more R5. 210 Attorney Docket No.: R2103-7054WO 16. The compound of any one of the preceding embodiments, wherein Ring B is selected from (R5)0-4 N nd 17. The compound of any one of the preceding embodiments, wherein Ring B is selected from (R5)0-4 , wherein R5 is as described in embodiment 18. The compound of any one of the preceding embodiments, wherein Ring B is selected , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO 20. The compound of any one of the preceding embodiments, wherein A-L-B is selected , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO nd 21. The compound of any one of the preceding embodiments, wherein A-L-B is selected , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , , 221 Attorney Docket No.: R2103-7054WO 22. The compound of any one of embodiments 1-19, wherein L is absent. 23. The compound of embodiment 22, wherein L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5. 24. The compound of embodiment 22-23, wherein L is absent and A and B are fused together to form a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5. 25. The compound of embodiment 22-24, wherein when A and B are fused together, A and B , Attorney Docket No.: R2103-7054WO , , , . Attorney Docket No.: R2103-7054WO 26. The compound of embodiment 22-25, wherein when A and B are fused together, A and B , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO , 226 Attorney Docket No.: R2103-7054WO , 27. The compound of any one of the preceding embodiments, wherein W1 is N or CR4a. 28. The compound of any one of the preceding embodiments, wherein W2 is N or CR4a. 29. The compound of any one of the preceding embodiments, wherein W3 is N or CR4a. 30. The compound of any one of the preceding embodiments, wherein W4 is N or CR4a. 31. The compound of any one of the preceding embodiments, wherein one of W1, W2, W3 and W4 is independently N. 32. The compound of any one of the preceding embodiments, wherein two of W1, W2, W3 and W4 is independently N. 33. The compound of any one of the preceding embodiments, wherein W1 is N and each of W2, W3, and W4 is independently CR4a. 227 Attorney Docket No.: R2103-7054WO 34. The compound of any one of the preceding embodiments, wherein W2 is N and each of W1, W3, and W4 is independently CR4a. 35. The compound of any one of the preceding embodiments, wherein W3 is N and each of W1, W2, and W4 is independently CR4a. 36. The compound of any one of the preceding embodiments, wherein W4 is N and each of W1, W2, and W3 is independently CR4a. 37. The compound of any one of the preceding embodiments, wherein W4 is N and each of W1, W2, and W3 is independently CR4a. 38. The compound of any one of the preceding embodiments, wherein each of W1, W2, W3 and W4 is independently CR4a. 39. The compound of any one of the preceding embodiments, wherein each R4a is hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, –ORA, or cycloalkyl. 40. The compound of any one of the preceding embodiments, wherein each R4a is hydrogen, C1-C6-alkyl, halo, or –ORA. 41. The compound of any one of the preceding embodiments, wherein R4a is hydrogen. 42. The compound of any one of the preceding embodiments, wherein X is N. 43. The compound of any one of embodiments 1-41, wherein X is CR4b. 44. The compound of any one of the preceding embodiments, wherein R4b is hydrogen. 228 Attorney Docket No.: R2103-7054WO 45. The compound of any one of the preceding embodiments, wherein n is 1. 46. The compound of any one of the preceding embodiments, wherein RA is C1-C6-alkyl (e.g., -CH3). 47. The compound of any one of the preceding embodiments, wherein the compound comprises 1 or 2 R5. 48. The compound of any one of the preceding embodiments, wherei is , 49. The compound of any one of the preceding embodiments, wherei is selected , 229 Attorney Docket No.: R2103-7054WO , Attorney Docket No.: R2103-7054WO , , Attorney Docket No.: R2103-7054WO nd 50. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-b): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, L, and R4a are as defined in embodiment 1. 51. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-c): a pharmaceutically acceptable salt, solvate, hydrate, , , rein each of W1, A, B, L, and are as defined in embodiment 1. 232 Attorney Docket No.: R2103-7054WO 52. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-d): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, A, B, L, R4a, and R4b, are as defined in embodiment 1. 53. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-e): a pharmaceutically acceptable salt, solvate, hydrate, each of X, A, B, L, R4a, and R4b, are as defined in embodiment 1. 54. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-f): a pharmaceutically acceptable salt, solvate, hydrate, n each of X, A, B, L, and R4a, are as defined in embodiment 1. 55. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-g): 233 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, B, and R4a, are as defined in embodiment 1, and each of Z1, Z2, Z3, and Z4 is independently N or CR5b. 56. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-h): a pharmaceutically acceptable salt, solvate, hydrate, each of W1 4a 5 , X, B, R , and R , are as defined in embodiment 1. 57. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-i): a pharmaceutically acceptable salt, solvate, erein each of W1, X, A, B, L, and R4a, are as defined in embodiment 1. 58. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-j): 234 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, erein each of W1, X, A, B, L, R4a, and RA, are as defined in embodiment 1. 59. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-j’): a pharmaceutically acceptable salt, solvate, hydrate, V1 is halogen, 1 4a and each of W , X, A, B, L, R , and RA, are as defined in embodiment 1. 60. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-j”): a pharmaceutically acceptable salt, solvate, hydrate, V2 is C1-C6-haloalkyl, and each of W1, X, A, B, L, R4a, and RA, are as defined in embodiment 1. 61. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-k): 235 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, in each of W1, X, A, B, and R4a are as defined in embodiment 1. 62. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-k’): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, and R4a are as defined in embodiment 1. 63. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-l): a pharmaceutically acceptable salt, solvate, hydrate, herein each of W1, X, A, B, and R4a are as defined in embodiment 1. 64. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-l’): 236 Attorney Docket No.: R2103-7054WO a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, and R4a are as defined in embodiment 1. 65. The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (I-m): a pharmaceutically acceptable salt, solvate, hydrate, ein each of W1, X, A, B, and R4a are as defined in embodiment 1. 66. The compound of any one of the preceding embodiments, wherein one of R3a and R3b is H, and the other is selected from H, C1-C6-alkyl, and C1-C6-heteroalkyl. 67. The compound of any one of the preceding embodiments, wherein the compound is selected from a compound listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. 68. A pharmaceutical composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable excipient. 69. A method of modulating the rate of degradation of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) as described in any one of embodiments 1-67. 237 Attorney Docket No.: R2103-7054WO 70. The method of embodiment 69, wherein the compound increases the rate of degradation of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 71. A method of modulating the level of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) as described in any one of embodiments 1-67. 72. The method of embodiment 71, wherein the compound reduces the level of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 73. A method of modulating the activity of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) as described in any one of embodiments 1-67. 74. The method of embodiment 73, wherein the compound inhibits the activity of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 75. A method of modulating the rate of degradation of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) as described in any one of embodiments 1-67. 238 Attorney Docket No.: R2103-7054WO 76. The method of embodiment 75, wherein the compound increases the rate of degradation of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 77. A method for treating a disease or disorder in a subject comprising administering to the subject a compound of Formula (I) according to any one of embodiments 1-67 or the pharmaceutical composition of embodiment 68. 78. The method of embodiment 77, wherein the disease or disorder comprises a proliferative disease (e.g., cancer, a benign neoplasm, or angiogenesis). 79. The method of any one of embodiments 77-78, wherein the disease or disorder comprises cancer. 80. The method of embodiment 79, wherein the cancer is selected from breast cancer, prostate cancer, lung cancer, skin cancer, blood cancer, or ovarian cancer. 81. The method of embodiment 77, wherein the disease or disorder comprises a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease. 82. A composition for use in treating a disease or disorder in a subject comprising a compound of Formula (I) according to any one of embodiments 1-67 or the pharmaceutical composition of embodiment 68. EXAMPLES 239 Attorney Docket No.: R2103-7054WO In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. Reactions can be purified or analyzed according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1H or 13C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrome (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Proton NMR: 1H NMR spectra were recorded in CDCl3 solution in 5-mm o.d. tubes (Wilmad) at 24 °C and were collected on a BRUKER AVANCE NEO 400 at 400 MHz for 1H. The chemical shifts (δ) are reported relative to tetramethylsilane (TMS = 0.00 ppm) and expressed in ppm. LC/MS: Liquid chromatography-mass spectrometry (LC/MS) was performed on Shimadzu-2020EV using column: Shim-pack XR-ODS (C18, Ø4.6 x 50 mm, 3 μm, 120 Å, 40 °C) 240 Attorney Docket No.: R2103-7054WO operating in ESI(+) ionization mode; flow rate = 1.2 mL/min. Mobile phase = 0.05% TFA in water or CH3CN; or on Shimadzu-2020EV using column: Poroshell HPH-C18 (C18, Ø4.6 x 50 mm, 3 μm, 120 Å, 40 °C) operating in ESI(+) ionization mode; flow rate = 1.2 mL/min. Mobile phase A: Water/5mM NH4HCO3, Mobile phase B: CH3CN). Analytical chiral HPLC: Analytical chiral HPLC was performed on a Agilent 1260 using column: CHIRALPAK IG-3, CHIRALPAK IC-3 or CHIRALPAK OJ-3, with flow rate = 1.2 mL/min. Mobile phase = MTBE(DEA):EtOH=50:50). Preparative HPLC Prep-HPLC was performed using one of the following conditions: Condition 1: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(20mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient 1: 18% B to 69% B in 9 min; Gradient 2: Flow rate: 35 mL/min, 15% B to 72% B in 8 min; Gradient 3: Flow rate: 35 mL/min, 21% B to 49% B in 8 min; Gradient 4: Flow rate: 35 mL/min, 5% B to 31% B in 8 min; Gradient 5: Flow rate: 35 mL/min, 31% B to 51% B in 8 min; Gradient 6: Flow rate: 35 mL/min, 24% B to 62% B in 8 min; Condition 2: Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; Mobile Phase A: Water (0.05% NH3.H2O); Mobile Phase B: ACN; Gradient 1: 35% B to 70% B in 10 min; Gradient 2: 15% B to 65% B in 12 min; Gradient 3: 30% B to 70% B in 7 min; Condition 3: Column: Xtimate C18 30*150 mm, 10μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O); Mobile Phase B: ACN; Flow rate: 35 mL/min; Gradient 1: 24% B to 96% B in 7 min; Gradient 2: 28% B to 75% B in 7 min, Mobile Phase A: water (0.1% NH3.H2O+10mmol/L NH4HCO3); Gradient 3: 9% B to 76% B in 7 min, Mobile Phase A: water (0.1% NH3.H2O+10mmol/L NH4HCO3); Gradient 4: 40% B to 52% B in 7 min, Mobile Phase A: Water(10mmol/L NH4HCO3+0.1%NH3·H2O); Gradient 5: 40% B to 52% B in 13 min, Mobile Phase A: Water(0.1% NH3.H2O); Condition 4: Column: Ultimate-XB-C18 Column, 50*250 mm, 10μm; Mobile Phase A: Water (10mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 90 mL/min; Gradient 1: 20% B to 60% B in 12 min; Gradient 2: Mobile Phase A: Water (10mmol/L NH4HCO3+0.1%NH3.H2O), 241 Attorney Docket No.: R2103-7054WO 33% B to 70% B in 20 min; Gradient 3: Mobile Phase A: Water(10mmol/L NH4HCO3+0.1%NH3·H2O), 50% B to 65% B in 20 min; Gradient 4: Mobile Phase A: Water (10mmol/L NH4HCO3+0.1%NH3H2O), 35% B to 65% B in 20 min; Condition 5: Column: XBridge Prep OBD Column 19 x 150mm 8μm; Mobile Phase A: water (0.1% NH3.H2O); Mobile Phase B: MeCN; Flow rate: 12 mL/min; Gradient 1: 35% B to 60% B in 12 min; Gradient 2: 25% B to 50% B in 8 min; Gradient 3: 45% B to 70% B in 12 min; Gradient 4: Flow rate: 10 mL/min, 35% B to 70% B in 15 min; Gradient 5: Flow rate: 10 mL/min, 40% B to 65% B in 12 min; Gradient 6: Flow rate: 10 mL/min, 25% B to 50% B in 8 min; Gradient 7: 35% B to 65% B in 15 min; Gradient 8: Flow rate: 10 mL/min, 30% B to 55% B in 12 min; Gradient 9: Flow rate: 10 mL/min, 35% B to 60% B in 15 min; Gradient 10: Flow rate: 15 mL/min, 40% B to 80% B in 12 min; Gradient 11: Flow rate: 10 mL/min, 25% B to 50% B in 12 min; Gradient 12: Flow rate: 10 mL/min, 15% B to 40% B in 12 min; Gradient 13: Flow rate: 10 mL/min, 30% B to 70% B in 12 min; Gradient 14: Flow rate: 15 mL/min, 25% B to 50% B in 12 min; Gradient 15: Flow rate: 10 mL/min, 45% B to 70% B in 12 min; Gradient 16: Flow rate: 10 mL/min, 45% B to 80% B in 12 min; Gradient 17: Flow rate: 10 mL/min, 35% B to 60% B in 8 min; Gradient 18: 20% B to 45% B in 12 min; Gradient 19: 40% B to 65% B in 10 min; Gradient 20: 45% B to 60% B in 8 min; Gradient 21: 35% B in 60% B in 8 min; Gradient 22: Flow rate: 10 mL/min, 35% B to 60% B in 12 min; Gradient 23: 45% B to 55% B in 8 min; Gradient 24: 40% B to 70% B in 12 min; Gradient 25: 30% B to 50% B in 8 min; Gradient 26: 30% B to 50% B in 10 min; Gradient 27: 20% B to 55% B in 10 min; Gradient 28: 20% B to 60% B in 8 min; Gradient 29: 20% B to 60% B in 12 min; Gradient 30: 20% B to 45% B in 8 min; Gradient 31: 30% B to 80% B in 8 min; Condition 6: Welch Ultimate XB-C18 (30*250 mm); Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O); Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient 1: 25% B to 55% B in 16 min; Gradient 2: 35% B to 65% B in 16 min; Gradient 3: 35% B to 55% B in 16 min; Gradient 4: mobile phase A: Water (0.05%NH3.H2O), 5% B to 45% B in 16 min; Condition 7: Column: Xtimate C1830*150 mm, 10μm; Mobile Phase A: Water (0.1% TFA); Mobile Phase B: ACN; Flow rate: 35 mL/min; Gradient 1: 6% B to 36% B in 9 min; 242 Attorney Docket No.: R2103-7054WO Condition 8: Column: XBridge Prep RP C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O); Mobile Phase B: ACN; Flow rate: 35mL/min; Gradient 1: 35% B to 65% B in 10 min; Gradient 2: 10% B to 62% B in 7 min; Gradient 3: 30% B to 60% B in 10 min, Mobile Phase A: Water(0.05%NH3.H2O); Gradient 4: 35% B to 55% B in 9 min, Mobile Phase A: Water (10mmol/L NH4HCO3); Gradient 5: 50% B to 62% B in 10 min; Gradient 6: 30% B to 95% B in 7 min; Gradient 7: 29% B to 73% B in 7 min; Gradient 8: 35% B to 61% B in 7 min; Gradient 9: 62% B to 97% B in 7 min; Gradient 10: 22% B to 57% B in 8 min, Mobile Phase A: Water(10mmol/L NH4HCO3); Gradient 11: Mobile Phase A: Water (0.05%NH3.H2O), 10% B to 32% B in 10 min; Gradient 12: 3% B to 46% B in 8 min; Gradient 13: 31% B to 52% B in 8 min; Condition 9: Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% NH3•H2O), Mobile Phase B: ACN; Flow rate: 35 mL/min; Gradient 1: 20% B to 60% B in 12 min; Gradient 2: 30% B to 55% B in 12 min; Gradient 3: Mobile Phase A: Water (0.1% NH4HCO3), 22% B to 75% B in 7 min; Gradient 4: 10% B to 45% B in 10 min; Condition 10: Column: Triart Diol 100x4.6mm 3.0um Mobile Phase B: MeOH (10 mM NH3); Flow rate: 3mL/min; Gradient 1: 100% B; Condition 11: Column YMC-ActusTriart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient 1: 25% B to 55% B in 7 min; Gradient 2: 29% B to 69% B in 7 min; Condition 12: Column: XBridge Prep OBD Column 19*150mm 8μm; Mobile Phase A: water (0.1% HCl), Mobile Phase B: MeCN; Flow rate: 10 mL/min; Gradient 1: 30% B to 55% B in 12 min; Gradient 2: Mobile Phase A: water (0.05% HCl), 30% B to 70% B in 7 min; Gradient 3: Mobile Phase A: water (0.05% HCl), 20% B to 60% B in 8 min; Gradient 4: Flow rate: 20 mL/min, Mobile Phase A: water (0.05% HCl), 20% B to 50% B in 8 min; Gradient 5: Mobile Phase A: water (0.05% HCl), 15% B to 75% B in 10 min; Gradient 6: Mobile Phase A: water (0.05% HCl), 30% B to 45% B in 8 min; Gradient 7: Flow rate: 20 mL/min, Mobile Phase A: water (0.05% HCl), 35% B to 60% B in 8 min; Gradient 8: Flow rate: 20 mL/min, Mobile Phase A: water (0.05% HCl), 10% B to 50% B in 8 min; Gradient 9: 25% B to 50% B in 12 min; Gradient 10: 243 Attorney Docket No.: R2103-7054WO 35% B to 60% B in 12 min; Gradient 11: Flow rate: 12 mL/min, 30% B to 50% B in 8 min; Gradient 12: Flow rate: 12 mL/min, 35% B to 60% B in 12 min; Gradient 13: 25% B to 60% B in 12 min; Gradient 14: 35% B to 60% B in 8 min; Gradient 15: 10% B to 30% B in 10 min; Gradient 16: 5% B to 40% B in 10 min; Gradient 17: 20% B to 60% B in 10 min; Gradient 18: 15% B to 40% B in 10 min; Gradient 19: 30% B to 65% B in 10 min; Gradient 20: Flow rate: 12 mL/min, 30% B to 80% B in 8 min; Condition 13: Column: XBridge Prep OBD Column 19 x 150mm 8um; Mobile Phase A: water (0.05% NH3‧H2O), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient 1: 30% B to 60% B in 8 min; Gradient 2: 40% B to 70% B in 8 min; Gradient 3: 30% B to 70% B in 8 min; Gradient 4: 10% B to 50% B in 8 min; Gradient 5: 60% B to 90% B in 8 min; Gradient 6: 20% B to 60% B in 8 min; Gradient 7: 20% B to 70% B in 8 min; Gradient 8: 35% B to 60% B in 8 min; Gradient 9: 35% B to 70% B in 8 min; Gradient 10: 33% B to 51% B in 8 min; Gradient 11: 30% B to 51% B in 8 min; Gradient 12: 20% B to 51% B in 8 min; Condition 14: Column: XBridge Prep OBD Column 19 x 150mm 8um; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN, Gradient 1: 30% B to 70% B in 7 min; Condition 15: Column: Welch Ultimate AQ-C18(50*250); Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 90 mL/min; Gradient 1: 15% B to 50% B in 16 min; Condition 16: Column: Xtimate C1830*150 mm, 10μm; Mobile Phase A: Water (0.05% HCl), Mobile Phase B: ACN; Flow rate: 35 mL/min; Gradient 1: 13% B to 51% B in 8 min; Gradient 2: 20% B to 47% B in 8.5 min; Gradient 3: 3% B to 38% B in 8 min; Gradient 4: 20% B to 51% B in 8 min; Condition 17: Column: XBridge C1830*150 mm, 5μm; Mobile Phase A: Water (0.05% HCl), Mobile Phase B: ACN; Flow rate: 35 mL/min; Gradient 1: 30% B to 53% B in 8 min; Gradient 2: 35% B to 61% B in 7 min; Gradient 3: 29% B to 73% B in 7 min; Gradient 4: Mobile Phase A: Water (0.5% HCl), 35% B to 65% B in 8.5 min; Condition 18: Column, C18 silica gel, XBridge, 19x150 mm; Mobile Phase A: Water (0.05% NH4HCO3), Mobile Phase B: ACN; Gradient 1: 30% B to 70% B in 7 min; Gradient 2: 244 Attorney Docket No.: R2103-7054WO 10% B to 50% B in 8 min; Gradient 3: Mobile Phase A: Water (0.1% NH4HCO3), 20% B to 60% B in 12 min; Condition 19: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% NH3H2O), Mobile Phase B: CH3CN; Flow rate: 35 mL/min; Gradient 1: 15% B to 38% B in 9 min; Gradient 2: 25% B to 70% B in 10 min with 50 mL/min flow rate; Gradient 3: 10% B to 50% B in 10 min with 70 mL/min flow rate; Condition 20: Column: CHIRALPAK IM, 2*25 cm, 5 μm; Mobile Phase A: Hexanes:DCM (1:2); Mobile Phase B: EtOH (0.1% 2M NH3-MeOH); Flow rate: 35 mL/min; Gradient 1: 30% B isocratic; Condition 21: Column: CHIRALPAK-IK, 3*25mm, 5μm; Mobile Phase A: Hexanes:DCM (3:1); Mobile Phase B: EtOH (0.1% 2M NH3-MeOH); Flow rate: 35 mL/min; Gradient 1: 50% B isocratic; Condition 22: Column: XBridge C18 Column, 5μm, 19*150 mm; Mobile Phase A: Water (0.05% HCl); Mobile Phase B: ACN; Gradient 1: 30% B to 70% B in 7 min; Condition 23: Column: XBridge BEH Shield RP18, 5μm, 30*150 mm; Mobile Phase A: Water (20 mmol/L NH4HCO3); Mobile Phase B: ACN; Gradient 1: 44% B to 55% B in 9 min; Gradient 2: 39% B to 50% B in 9 min; Condition 24: Column: XSelect CSH C18, 5μm, 30*150 mm; Mobile Phase A: Water (0.05% HCl); Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient 1: 15% B to 50% B in 12 min; Gradient 2: 15% B to 45% B in 8 min; Condition 25: Column: XBridge Prep OBD, 19 x 250mm 5μm; Mobile Phase A: water (20 mmol/L NH4HCO3); Mobile Phase B: MeCN; Flow rate: 40 mL/min; Gradient 1: 28% B to 38% B in 10 min; Condition 26: Column: XBridge C18, 30 x 150mm 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: MeCN; Flow rate: 45 mL/min; Gradient 1: 35% B to 65% B in 10 min; Gradient 2: Flow rate: 35 mL/min, 5% B to 77% B in 8 min; Condition 27: Column: XBridge Prep OBD, 19 x 250mm 5μm; Mobile Phase A: water (0.05% NH3-H2O; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient 1: 32% B to 42% B 245 Attorney Docket No.: R2103-7054WO in 10 min; Condition 28: Column: XSelect CSH C18, 5μm, 30*150 mm; Mobile Phase A: Water (0.1% NH4HCO3); Mobile Phase B: ACN; Flow rate: 35 mL/min; Gradient 1: 30% B to 35% B in 8 min; Reversed-Phase Flash Chromatography purification Reversed-phase flash purification was performed using one of the following conditions: Condition 1: SunFire Prep C18 OBD Column 19*150 mm, 5μm 10 nm; Mobile Phase A: Water (0.05% FA); Mobile Phase B: MeCN; Gradient 1: 10% B to 20% B in 7 min; Gradient 2: 10% B to 35% B in 7 min; Gradient 3: 10% B to 55% B in 12 min; Gradient 4: 10% B to 50% B in 7 min; Gradient 5: 3% B to 5% B in 2 min; Gradient 6: Mobile Phase A: Water (0.1% FA), 20% B to 60% B in 7 min; Gradient 7: 25% B to 30% B in 7 min; Gradient 8: 20% B to 35% B in 7 min; Gradient 9: 15% B to 25% B in 10 min; Gradient 10: 15% B to 25% B in 7 min; Condition 2: Column, C18 silica gel; Mobile Phase A: Water (0.1% NH3•H2O); Mobile Phase B: CH3CN; Gradient 1: 25% B to 50% B in 10 min; Gradient 2: 20% B to 60% B in 12 min; Gradient 3: 15% B to 60% B in 12 min; Gradient 4: 30% B to 80% B in 12 min; Gradient 5: 30% B to 50% B in 10 min; Gradient 6: 45% B to 70% B in 10 min; Gradient 7: 30% B to 60% B in 10 min; Gradient 8: 55% B to 70% B in 10 min; Gradient 9: 45% B to 55% B in 10 min; Gradient 10: 10% B to 55% B in 12 min; Gradient 11: 20% B to 60% B in 10 min; Gradient 12: 40% B to 65% B in 10 min; Gradient 13: 15% B to 60% B in 10 min; Gradient 14: 30% B to 70% B in 12 min; Gradient 15: 10% B to 40% B in 10 min; Gradient 16: 25% B to 50% B in 7 min; Gradient 17: 20% B to 70% B in 12 min; Gradient 18: 10% B to 70% B in 10 min; Gradient 19: 10% B to 50% B in 10 min; Gradient 20: 60% B to 75% B in 10 min; Gradient 21: 50% B to 60% B in 10 min; Gradient 22: 30% B to 70% B in 10 min; Gradient 23: 25% B to 95% B in 10 min; Gradient 24: 5% B to 45% B in 12 min; Gradient 25: 30% B to 80% B in 10 min; Gradient 26: 35% B to 60% B in 12 min; Gradient 27: 40% B to 100% B in 10 min; Gradient 28: 20% B to 40% B in 10 min; Gradient 29: 40% B to 50% B in 10 min; Gradient 30: 25% B to 35% B in 10 min; Gradient 31: 45% B to 65% B in 12 min; Gradient 32: 45% B to 75% B in 12 min; Gradient 33: 40% B to 55% B in 10 min; Gradient 34: 30% B to 40% B in 10 min; Gradient 35: 37% B to 67% B in 12 min; 246 Attorney Docket No.: R2103-7054WO Gradient 36: 30% B to 60% B in 3.5 min; Gradient 37: 35% B to 65% B in 5 min; Gradient 38: 40% B to 60% B in 12 min; Gradient 39: 20% B to 75% B in 10 min; Gradient 40: 35% B to 45% B in 10 min; Gradient 41: 20% B to 50% B in 10 min; Gradient 42: 50% B to 80% B in 3 min; Gradient 43: 25% B to 45% B in 12 min; Gradient 44: 30% B to 80% B in 15 min; Gradient 45: 15% B to 90% B in 10 min; Gradient 46: 20% B to 55% B in 12 min; Gradient 47: Mobile Phase A: Water (0.1% NH3.H2O+10mmol/L NH4HCO3), 10% B to 50% B in 10 min; Gradient 48: 0% B to 100% B in 15 min; Gradient 49: 15% B to 70% B in 10 min; Gradient 50: 50% B to 70% B in 3 min; Gradient 51: 65% B to 68% B in 10 min; Gradient 52: 20% B to 60% B in 15 min; Gradient 53: 30% B to 60% B in 15 min; Gradient 54: Mobile Phase A: Water (0.05% NH3•H2O), 30% B to 95% B in 10 min; Gradient 55: 20% B to 70% B in 10 min; Gradient 56: 15% B to 45% B in 2 min; Gradient 57: 20% B to 45% B in 10 min; Gradient 58: 30% B to 60% B in 12 min; Gradient 59: 40% B to 80% B in 12 min; Gradient 60: 10% B to 55% B in 10 min; Gradient 61: 50% B to 70% B in 10 min; Gradient 62: 35% B to 70% B in 10 min; Gradient 63: 5% B to 55% B in 10 min; Gradient 64: 30% B to 65% B in 10 min; Gradient 65: 20% B to 30% B in 10 min; Gradient 66: 45% B to 55% B in 10 min; Gradient 67: 55% B to 60% B in 10 min; Gradient 68: 50% B to 55% B in 10 min; Gradient 69: 45% B to 51% B in 10 min; Gradient 70: 55% B to 59% B in 10 min; Gradient 71: 35% B to 42% B in 10 min; Gradient 72: 5% B to 45% B in 10 min; Gradient 73: 0% B to 30% B in 10 min; Gradient 74: 10% B to 45% B in 10 min; Gradient 75: 20% B to 55% B in 10 min; Gradient 76: 33% B to 42% B in 10 min; Gradient 77: 40% B to 48% B in 10 min; Gradient 78: 45% B to 85% B in 10 min; Gradient 79: 55% B to 66% B in 10 min; Condition 3: SunFire Prep C18 OBD Column 19*150 mm, 5μm 10 nm; Mobile Phase A: water (0.1% NH3•H2O); Mobile Phase B: MeCN; Gradient 1: 10% B to 50% B in 7 min; Gradient 2: 10% B to 20% B in 7 min; Gradient 3: 30% B to 75% B in 10 min; Condition 4: Column: (R,R) WHELK-O1, 4.6*100 mm, 3.5 μm; Mobile Phase A: 10 mmol NH4HCO3+0.05% NH3.H2O, Mobile Phase B: ACN; Gradient 1: 20% B to 50% B in 7 min; Gradient 2: 30% B to 60% B in 7 min; Condition 5: Column, C18 silica gel; Mobile Phase A: Water (0.1% FA); Mobile Phase B: CH3CN; Gradient 1: 20% B to 60% B in 10 min; Gradient 2: 10% B to 50% B in 10 min; 247 Attorney Docket No.: R2103-7054WO Gradient 2a: 10% B to 50% B in 12 min; Gradient 3: 15% B to 60% B in 10 min; Gradient 4: 25% B to 95% B in 10 min; Gradient 5: 10% B to 60% B in 12 min; Gradient 6: 10% B to 45% B in 10 min; Gradient 7: 15% B to 55% B in 12 min; Gradient 8: 20% B to 90% B in 12 min; Gradient 9: 20% B to 60% B in 12 min; Gradient 10: 30% B to 80% B in 10 min; Gradient 11: 35% B to 60% B in 10 min; Gradient 12: Flow Rate: 90 mL/min, 10% B to 100% B in 15 min; Gradient 13: Flow Rate: 20 mL/min, 10% B to 100% B in 10 min; Gradient 14: 5% B to 20% B in 10 min; Gradient 15: 30% B to 95% B in 12 min; Gradient 16: 5% B to 40% B in 12 min; Gradient 17: 5% B to 30% B in 10 min; Gradient 18: 15% B to 65% B in 12 min; Gradient 19: 0% B to 30% B in 12 min; Gradient 20: 5% B to 45% B in 10 min; Gradient 21: 0% B to 30% B in 10 min; Gradient 22: Mobile Phase A: water (0.5% FA), 0% B to 90% B in 15 min; Gradient 23: 10% B to 30% B in 10 min; Condition 6: Column, C18 silica gel; Mobile Phase A: water (0.5% TFA); Mobile Phase B: MeCN; Gradient 1: 10% B to 50% B in 10 min; Gradient 2: Mobile Phase A: water (0.1% TFA), 10% B to 90% B in 10 min; Gradient 3: Mobile Phase A: water (0.1% TFA), 10% B to 50% B in 10 min; Condition 7: Column, C18 silica gel; Mobile Phase A: water (0.5% NH4HCO3); Mobile Phase B: MeCN; Gradient 1: 10% B to 50% B in 10 min; Gradient 2: 25% B to 55% B in 15 min; Condition 8: Column, C18 silica gel; Mobile Phase A: Water (0.1% HCl); Mobile Phase B: MeCN; Gradient 1: 10% B to 50% B in 10 min; Gradient 2: 5% B to 45% B in 12 min; Gradient 3: Mobile Phase A: water (0.3% HCl), 25% B to 95% B in 10 min; Gradient 4: Mobile Phase A: water (0.5% HCl), 10% B to 50% B in 10 min; Gradient 5: 10% B to 40% B in 10 min; Gradient 6: 20% B to 60% B in 12 min; Gradient 7: 25% B to 85% B in 12 min; Gradient 8: 10% B to 40% B in 12 min; Gradient 9: 10% B to 50% B in 12 min; Gradient 10: 10% B to 30% B in 10 min; Gradient 11: 10% B to 55% B in 10 min; Gradient 12: 20% B to 40% B in 10 min; Gradient 13: 20% B to 90% B in 12 min; Gradient 14: 20% B to 85% B in 10 min; Gradient 15: 20% B to 50% B in 3 min; Gradient 16: 30% B to 80% B in 12 min; Gradient 17: 30% B to 95% B in 10 min; Gradient 18: 30% B to 60% B in 3 min; Gradient 19: 30% B to 100% B in 15 min; Gradient 20: 35% B to 65% B in 2 min; Gradient 21: 40% B to 70% B in 3 min; Gradient 22: 55% B to 70% B 248 Attorney Docket No.: R2103-7054WO in 10 min; Gradient 23: 45% B to 55% B in 10 min; Gradient 24: 45% B to 65% B in 12 min; Gradient 25: 15% B to 45% B in 3 min; Gradient 26: Mobile Phase A: water (0.05% HCl), 25% B to 45% B in 12 min; Gradient 27: Mobile Phase A: water (0.05% HCl), 30% B to 50% B in 12 min; Gradient 28: Mobile Phase A: water (0.05% HCl), 10% B to 50% B in 10 min; Gradient 29: Mobile Phase A: water (0.05% HCl), 25% B to 55% B in 12 min; Gradient 30: Mobile Phase A: water (0.05% HCl), 40% B to 60% B in 12 min; Gradient 31: Mobile Phase A: water (0.05% HCl), 35% B to 55% B in 12 min; Gradient 32: 30% B to 75% B in 10 min; Gradient 33: 20% B to 50% B in 10 min; Gradient 34: 0% B to 100% B in 15 min; Gradient 35: 30% B to 95% B in 10 min; Gradient 36: Mobile Phase A: water (0.05% HCl), 30% B to 50% B in 3 min; Gradient 37: 50% B to 58% B in 10 min; Gradient 38: Mobile Phase A: water (0.05% HCl), 30% B to 95% B in 10 min; Gradient 39: 35% B to 55% B in 2 min; Gradient 40: 50% B to 60% B in 12 min; Gradient 41: Mobile Phase A: water (0.05% HCl), 40% B to 70% B in 3 min; Gradient 42: Mobile Phase A: water (0.05% HCl), 30% B to 60% B in 12 min; Gradient 43: Mobile Phase A: water (0.05% HCl), 15% B to 35% B in 12 min; Gradient 44: 5% B to 36% B in 10 min; Gradient 45: 20% B to 70% B in 10 min; Gradient 46: 30% B to 70% B in 12 min; Gradient 47: 5% B to 45% B in 10 min; Gradient 48: Mobile Phase A: water (0.05% HCl), 10% B to 50% B in 12 min; Gradient 49: Mobile Phase A: water (0.05% HCl), 20% B to 60% B in 12 min; Condition 9: Column: Welch Ultimate AQ-C18(50*250); Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 90mL/min; Gradient 1: 20% B to 50% B in 16 min; Gradient 2: 15% B to 50% B in 16 min. Condition 10: SunFire Prep C18 OBD Column 19*150 mm, 5μm 10 nm, Mobile Phase A: Water (0.05% HCl), Mobile Phase B: MeCN; Gradient 1: 10% B to 20% B in 7 min; Gradient 2: 45% B to 55% B in 7 min; Gradient 3: 10% B to 30% B in 7 min; Gradient 4: 40% B to 52% B in 7 min; Chiral HPLC Purification by chiral HPLC was performed on a Gilson-GX 281 with the following conditions: Condition 1: Column: CHIRALPAK IM, 2*25 cm, 5 μm; Mobile Phase A: Hex/DCM=1: 249 Attorney Docket No.: R2103-7054WO 2, Mobile Phase B: EtOH (0.1% 2M NH3-MeOH); Flow rate: 35 mL/min; Gradient 1: 30% B isocratic; Condition 2: Column: XA-CHIRALPAK IF, 3*25 cm, 5 μm; Mobile Phase A: Hex/DCM=3:1, Mobile Phase B: EtOH(0.5% 2M NH3-MeOH); Flow rate: 25 mL/min; Gradient 1: 50% B isocratic; Condition 3: Column: XA-CHIRALPAK IK, 3*25 cm, 5 μm; Mobile Phase A: Hex/DCM=3:1, Mobile Phase B: MeOH/EtOH=1:1; Flow rate: 35 mL/min; Gradient 1: 50% B isocratic; Condition 4: Column: XA-CHIRAL ART Cellulose SB, 3*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH/DCM=2:1; Flow rate: 35 mL/min; Gradient 1: 40% B isocratic; Condition 5: Column: XA-CHIRALPAK IF, 3*25 cm, 5 μm; Mobile Phase A: Hex/DCM=3:1, Mobile Phase B: MeOH/EtOH=1:1; Flow rate: 30 mL/min; Gradient 1: 50% B isocratic; General Schemes Scheme A1: ion A1-1b (see Compound 230): 250 Attorney Docket No.: R2103-7054WO Exemplary Protocol: Example 1: Synthesis of Compound 127 Synthesis of A1 py y p y g, . in DMF (5 mL) was added T3P (50 wt. % in EtOAc) (1.55 g, 4.9 mmol) and pyridine (641 mg, 8.1 mmol), and the reaction was stirred at room temperature for 30 min.2-amino-5-methoxy-benzonitrile (240 mg, 1.62 mmol) was then added, and the reaction was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc (150 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure 251 Attorney Docket No.: R2103-7054WO and purified by silica gel column chromatography (17-33% EtOAc in PE) to afford N-(2-cyano- 4-methoxy-phenyl)-2-(4-pyrrol-1-ylphenyl)acetamide (A1, 220 mg, 663.9 μmol, 41% yield) as a solid. LCMS (ES, m/z): 332 [M+H]+. Synthesis of Compound 127 e (A1, 240 mg, 724.3 μmol) in EtOH (5 mL) and 3M NaOH (0.5 mL) was added H2O2 (123.2 mg, 3.62 mmol), and the reaction was stirred at 70°C for 1 h. The resulting mixture was cooled to room temperature and diluted with EtOAc (150 mL). The resulting mixture was washed with sat. Na2S2O3 (50 mL), brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC (Condition 1, Gradient 1) to afford 6-methoxy- 2-[(4-pyrrol-1-ylphenyl)methyl]-3H-quinazolin-4-one (Compound 127, 26.4 mg, 79.7 μmol, 11% yield) as a solid. LCMS (ES, m/z): 332 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.06 (brs, 1H), 7.56-7.43 (m, 6H), 7.39-7.36 (m, 1H), 7.31 (s, 2H), 6.24 (s, 2H), 3.93 (s, 2H), 3.96 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Materials Characterization The filtrate was concentrated under reduced 4 Attorney Docket No.: R2103-7054WO Gradient 18) to afford 2-[(4-pyrrol-1- ylphenyl)methyl]-3H-quinazolin-4-one 1 1 1 l 2 , - 3 , ). - 4- 2 δ 8- m . l- δ Attorney Docket No.: R2103-7054WO (m, 2H), 7.48-7.40 (m, 3H), 7.32-7.17 (m, 3H), 6.25 (t, J = 2.1 Hz, 2H), 3.94 (s, 2H). h i ifi g, 6 m . - - 87 )- Attorney Docket No.: R2103-7054WO (ES, m/z): 237.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.07 (d, J = H 1H 1H d J 8- C ), 7 z, 6 - 4- 0 ), m, , 255 Attorney Docket No.: R2103-7054WO Modifications: Step 1 was ran at room temperature for 2 h. Step 2 was ran at room f 2 h - 5 = t e - 3, , , - - = 256 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran for 16 h at room temperature. Step 2 was ran at room f 2 h 4- 8 d, , - g, , , ), 5 257 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 4 h. Step 2 was ran at room f 2 h ) - 7 5 ), , 6 d ), , , r - J 1 = Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran in DMF for 16 h. Step 2 was ran at room temperature for 16 h - J ). ) g, J .6 d, J m - 3 5- = Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran in DMF for 16 h. Step 2 was ran at room temperature for 16 h g, J 3 7 g, J 9 5 m Attorney Docket No.: R2103-7054WO Gradient 9) to afford 6-methoxy-2-[(4- pyrrol-1-ylphenyl)methyl]-3H-pyrido-[3,4- d i idi 4 1 2 g, , 6 4 d 5 , l- J C d % Attorney Docket No.: R2103-7054WO [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.92 dd = 24 H 1H 1 4 H), , at e l- 5 ), , .2 5 8, = ). - Attorney Docket No.: R2103-7054WO [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 2H), 8.21 (d, J = 2.4 Hz, 1H), 7.96- 2 1H d = H 1H 4- - e 4 = h - 8 9 1 , o- n- , 0 263 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 16 h. Step 2 was ran at room f 1 h J - J h. . ), J 2 l- J , 54 ), Attorney Docket No.: R2103-7054WO 7.37 (dd, J = 9.0, 3.0 Hz, 1H), 4.03 (s, 2H), 3.86 (s, 3H). ifi i f h p 4 J , r - g, z, , - 7 265 Attorney Docket No.: R2103-7054WO Modifications: Step 1 was ran without DMF. Step 2 was ran for 2 h. Th id ifid b d h e - z, 1- g, , ]- 4 , at Attorney Docket No.: R2103-7054WO methoxy-2-((4-methoxy-6-(3-methyl-1H- pyrrol-1-yl)pyridin-3-yl)methyl)-quinazolin- 4 H 2 1 , m ), d d Attorney Docket No.: R2103-7054WO 347, 14 mg, 39.9 μmol, 47% yield) as a solid. LCMS (ES, m/z): 352 [M+H]+.1H MR MH DM d δ dd = 0 J d - Attorney Docket No.: R2103-7054WO 3H-quinazolin-4-one (Compound 454, 11.8 mg, 25.5 μmol, 61% yield) as a solid. LCMS ES / 464 M+H + 1H NMR ), e ), , The general protocol in Scheme A1 can also be prepared using an amide starting material, as shown in Scheme A2. Scheme A2: : 269 Attorney Docket No.: R2103-7054WO Exemplary Example 2: Synthesis of Compound 356 Synthesis of A89 To y , , , y y )acetic acid hydrochloride (A88, 0.2 g, 974.4 μmol) and 2-amino-5-methoxy-benzamide (194 mg, 1.17 mmol) in DMF (2 mL) were added pyridine (231 mg, 2.9 mmol, 235.5 μL) and T3P (1.9 g, 2.92 mmol, 50 wt.% in EtOAc), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (10 mL) and filtered. The filter cake was dried to afford 5-methoxy-2-[[2-(1- methyl-3,4-dihydro-2H-quinolin-6-yl)acetyl]amino]benzamide (A89, 0.14 g, 396.1 μmol, 41% yield) as a solid. LCMS (ES, m/z): 354 [M+H]+. 270 Attorney Docket No.: R2103-7054WO Synthesis of Compound 356 acetyl]- amino]benzamide (A89, 0.14 g, 396.1 μmol) in MeOH (2 mL) was added NaOH (2 M, 2 mL), and the reaction was stirred for 16 h at 80 °C. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 7) to afford 6- methoxy-2-[(1-methyl-3,4-dihydro-2H-quinolin-6-yl)methyl]-3H-quinazolin-4-one (Compound 356, 16 mg, 47.7 μmol, 12% yield) as a solid. LCMS (ES, m/z): 336 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 3.0 Hz, 1H), 7.36 (dd, J = 8.9, 3.0 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.89 (s, 1H), 6.50 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 2H), 3.17-3.07 (m, 2H), 2.77 (s, 3H), 2.65 (t, J = 6.5 Hz, 2H), 1.85 (p, J = 6.1 Hz, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization The residue was purified by reversed-phase nt 4- g, S, z, .9 , J ), (s, (s, .1 271 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran for 2 h. Step 2 was ran in EtOH at room temperature for 4 h. Th i idifid H 7 ih 1M d- 2, 1- H- g, S, z, 66 = 35 ), m C 7- 4- ol, z): 6) m, (s, (s, m °C C 7- l- ol, 91 δ m, = .1 z, 272 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 4 h. Step 2 was ran at room f 1 h se nt l- % 95 δ .4 (s, ), m se nt 3- % 62 δ 23 ), = ), ). m C se nt l]- % 65 δ ), z, ), z, 273 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 1 h. Step 2 was ran at 70 °C f h C 7- g, S, z, 31 ), ), se 0, H- g, S z, 44 (s, se nt 3- % 07 δ .3 = s, (t, ), C 7- g, S, z, Attorney Docket No.: R2103-7054WO DMSO-d6) δ 12.71-11.20 (d, J = 460.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 2.6 H 1H 741 1H 729 J = 17 Hz, ), ), C 7- g, S z, .9 ), 12 88 ). 6 C 7- .6 S, z, 08 ), z, ), m at M as 2, 5- a H ), ), 275 Attorney Docket No.: R2103-7054WO 7.41 (s, 1H), 7.17 (tt, J = 9.2, 2.3 Hz, 1H), 7.06 (s, 1H), 3.91-3.81 (m, 8H). ifi i m at M ke 2, 5- a H = s, (s, ), m m M re er d- 2, 5- % 91 δ 42 ), 32 C 5- 10 ): O- .0 , J z, .0 Attorney Docket No.: R2103-7054WO Hz, 1H), 6.98 (s, 1H), 4.06 (s, 2H), 3.82 (d, J = 6.0 Hz, 6H). h i iifi ih M re (5 sh 2) l)- g, S, z, ), ), ). se nt H- 40 d. R z, 67 7- 81 m m C 7- % 90 δ ), ), = z, z, 277 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran for 8 h. The residue was purified by reversed-phase fl h h h dii 2 dint 3- % 07 δ 41 (s, ). 6 C 2- % 00 δ m, ), 16 C 6- 8 S z, .2 , J - 90 m m n ed hy 4- Attorney Docket No.: R2103-7054WO pyridyl]methyl]-6,7-dimethoxy-3H- quinazolin-4-one (Compound 458, 6 mg, 14 l 2 ild lid L M ES, z, 88 ), 11 (s, m se nt 4- .7 ): O- ), .9 m m N re 10 sh to l- 4- ol, ): O- ), = .1 , J se nt 3- g, S, Attorney Docket No.: R2103-7054WO m/z): 504 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (d, J = 2.2 Hz, 1H), 8.32 (s, 1H 4 d = 1 H 1H dd = 5- 90 2 C 7- g, S, z, (s, m, ), z, m se nt l)- .3 S, z, 07 z, ), ), m m se nt l)- .0 S, z, Attorney Docket No.: R2103-7054WO DMSO-d6) δ 12.31 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H dd = 2 22 H 1H 74 23 se 0, 8- g, S z, (s, ), 85 m se nt 2- )- .0 S z, ), ), ), ), se nt 5- d a H ), ), m, (s, 281 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 2 h. Step 2 was ran at room f 2 h se nt 5- d S z, .2 z, 76 05 m se nt 4- 4, d. R 6- 12 42 J 2 se nt 8- 5, d. R 19 72 41 (s, 282 Attorney Docket No.: R2103-7054WO Modification: Step 2 was ran at 70 °C for 2 h. Th id ifid b P HPLC 7- - g, S, z, 46 ), z, ), 2 C 7- g, S, z, 98 ), .4 (s, m se nt y- % 78 δ d, z, ), 86 m C Attorney Docket No.: R2103-7054WO The mixture was acidified to pH 8 with 1 M HCl, and poured into water (20 mL). The ii d lid ll d by nd l- % 95 δ 66 08 ), se nt H- % 07 4) 99 z, d, m se nt H- .8 z): O- 76 16 2 se nt 3- g, Attorney Docket No.: R2103-7054WO 11.2 μmol, 9% yield) as a solid. LCMS (ES, m/z): 362 [M+H]+. 1H NMR (300 MHz, DM d δ 1242 1H 2 1H 87 ), (s, ), m m se nt 3- )- .4 S 00 J 1, ), ), z, m ng 16 C 4- 16 S z, .0 = 9, 23 m m N re er 3- Attorney Docket No.: R2103-7054WO quinazolin-4-one (Compound 531, 0.005 g, 13.3 μmol, 19% yield) as a solid. LCMS (ES, / M H + 1H MR MHz, .1 z, ), 85 ), m C se nt 5- )- g, S z, ), ), 87 m m er nd 1- % 51 δ = 83 ), 2 se nt l- 81 Attorney Docket No.: R2103-7054WO μmol, 67% yield) as a solid. LCMS (ES, m/z): 351 [M+H]+. 1H NMR (300 MHz, DM d δ 4 d = 2 H 1H 09 ), z, ), m m se nt 7- % 86 δ m, 1, ), m C C 2- % 87 δ = z, (s, m C N re (5 sh 4) 5- d Attorney Docket No.: R2103-7054WO 551, 12.6 mg, 27.5 μmol, 13% yield) as a solid. LCMS (ES, m/z): 458 [M+H]+. 1H MR MH DM d δ 12 1H), z, 6- 2 se nt n- 3, d. R z, z, = ), z, se 0, 4- .0 S, z, .1 J ), 86 ). C 7- % 92 δ 3, = ), .9 Attorney Docket No.: R2103-7054WO The residue was purified by reversed-phase flash chromatography (Condition 8, Gradient ff d di h 2 hl15- 9, d. R (s, ), 90 m m se nt 2- e % M- δ d, z, ), m m he h al se nt 3- )- g, S, z, .2 , J 6- z, ), 4- Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 30 min. Step 2 was ran at f 1 h N re (5 sh to H- de % 69 δ z, ), z, m at se nt H- de % 85 δ 99 z, m se nt 6- 4- g, S, z, 87 (s, ). 290 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 16 h. Step 2 was ran at 70 °C f 1 h C 6- - 10 z): O- ), z, m on m se nt 3- ne % 22 δ z, 77 ), 67 z, = 6, m C se nt 2- g, S, z, ), 03 291 Attorney Docket No.: R2103-7054WO (s, 1H), 4.33 (s, 2H), 3.86 (d, J = 5.4 Hz, 6H), 2.47 (s, 3H), 2.32 (s, 3H). ifi i m m he at ct. se nt 3- - ol, 57 δ 07 z, ), 07 = 05 z, m m se nt ]- % 73 δ (s, m m he at ct. se nt 3- Attorney Docket No.: R2103-7054WO (Compound 611, 0.01 g, 13.8 μmol, 19% yield) as a solid. LCMS (ES, m/z): 508 M H + 1H MR MH DM d δ z, 77 90 (s, = 54 z, m m on m se nt l)- 2, d. H ), (s, m, ), 73 ), 9- 04 m m se nt 2- )- .8 S 00 = d, Attorney Docket No.: R2103-7054WO J = 8.2 Hz, 2H), 7.40-7.28 (m, 2H), 4.16 (s, 2H), 4.00 (d, J = 2.1 Hz, 2H), 3.94-3.83 (m, H 122 d = 2 H H m m se nt l)- de % M- δ .1 J .2 z, m se nt 2- g, S z, .8 z, (s, 3 ep ne al se nt H- .8 S, z, Attorney Docket No.: R2103-7054WO DMSO-d6) δ 7.65-7.56 (m, 2H), 7.44 (s, 1H), 7.32 (d, J = 9.3 Hz, 1H), 7.06 (s, 1H), 4.21 (s, 2H d = 12 H H 6 Cl 50 re er te nd 2, H- % 23 δ .8 , J 7, 15 m C in h se nt H- d a H = ), 86 m C C 7- - Attorney Docket No.: R2103-7054WO one (Compound 651, 22 mg, 60.2 μmol, 33% yield) as a solid. LCMS (ES, m/z): 366 M H + 1H MR MH DM d δ 41 J m m se nt 2- % 49 δ 98 .1 , J m m N ed ). l- 2- - ol, 66 δ 42 (s, C 6- - ol, 85 δ 48 (s, Attorney Docket No.: R2103-7054WO Modification: Step 2 was ran at room temperature for 2 h. Th i idifid H ih 2 N ed ). se nt 7- de % M- δ 83 ), in . ed ca in 7- % 79 δ 24 J .8 m N d- 2, 7- g, S, z, 77 (s, = ), Attorney Docket No.: R2103-7054WO 2.26 (s, 3H), 2.17 (s, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H). ifi i m N by hy 7- g, S, z, 69 = (s, ), H 2 nd ed ca in o- % 05 δ 88 (s, m m se nt 5- 03 S z, 42 (s, Attorney Docket No.: R2103-7054WO 2H), 3.86 (d, J = 4.3 Hz, 6H), 2.44 (s, 3H), 2.29 (s, 3H). ifi i m er H ic ed he ed sh 7) 7- ne g, S z, 20 78 (s, m m M as 3, 5- 60 d. nd H by hy he 5- .1 80 δ ), Attorney Docket No.: R2103-7054WO 7.41 - 7.33 (m, 2H), 7.18 - 7.09 (m, 2H), 4.05 (dd, J = 9.9, 7.4 Hz, 1H), 3.91 (s, 3H), 3.88 H dd = H 1H 03 ), = m n to 3- ol, 56 m se nt 5- 40 z): se M ed rd 5, C 2- .7 ): O- 60 – 300 Attorney Docket No.: R2103-7054WO 6.20 (m, 1H), 4.73 – 4.40 (m, 1H) 3.85 (d, J = 8.6 Hz, 6H). h li ifi hse nt 7- )- 16 S, z, 15 z, = ), se nt 6- - % 49 δ d, .8 (s, re h. ed m ct C 6- )- % 2- 13 45 66 δ 42 (s, 301 Attorney Docket No.: R2103-7054WO The crude product mixture was purified by reversed-phase flash chromatography di i di 12 he 6- - % H ), z, .9 .9 nd as 6- ol, 44 ne th m n to 2- ol, 77 by L) 2- g, S, z, 73 (s, ), 302 Attorney Docket No.: R2103-7054WO The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 2 ff d 2 fl hyl- % 69 δ 74 z, ), M re 10 rd g, S nd as 3- 3, d. p- to o- % 73 δ 60 303 Attorney Docket No.: R2103-7054WO Modifications: Step 2 used 5 equiv. K3PO4 base in EtOH/H2O (1:1) solvent mixture for h ds th 6- 00 S se nt 6- e % 85 (s, ), 31 se nt 2- 1, S, z, 06 (s, H N- m C 7- - ol, 52 δ ), (s, Attorney Docket No.: R2103-7054WO 1H), 7.08 (s, 1H), 4.08 (s, 2H), 3.87 (d, J = 3.6 Hz, 6H), 2.29 (d, J = 1.1 Hz, 3H). ifi i i h of N- m p- 2- - ol, 66 δ 07 J C 6- a H N- C n to 7- % 80 δ 07 ), 305 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used 1.5 equiv. TCFH as amide coupling reagent and 3 equiv. N- h li id l b i M ºC. n to n- - ol, 72 δ 53 ), z, H N- m v. by to 6- 2- % 06 δ J 07 ). m m N re 10 6- - 1, d. 306 Attorney Docket No.: R2103-7054WO The mixture was acidified to pH 5 with 1 N HCl (aq.). The precipitated solids were ll d b fil i d hd ih ter 6- .0 S, d- 2, 7- - ol, 97 δ 42 (s, ), se 2, 8- - ol, 97 δ 69 J 87 er re (1 ed - ol, 43 307 Attorney Docket No.: R2103-7054WO Modifications: Step 1 was performed at 70 ºC over 2 h. Step 2 used LiOH‧H2O in THF at 2 h er 30 es nd 8- 6, S ºC 70 n to l- )- .6 S, re he gh re N re 10 o- - nd 9) % 18 308 Attorney Docket No.: R2103-7054WO Modification: Step 1 and Step 2 were each ran for 2 h. Th i idifid H 5 ih 2 N as er 7- 3- ne S m nd as 7- ]- - 80 d. se nt H- % 65 δ 68 ), 31 ), .9, 309 Attorney Docket No.: R2103-7054WO The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 1 ff d 2 634di hl l1- g, S, z, .2 d, ), 50 ), d, .1 re he gh re er re (8 d 6- g, S 310 Attorney Docket No.: R2103-7054WO Modification: Step 2 was run at room temperature for 6 h. Th id ifid b d hse nt 4- g, S se nt 2- a an 5 (4 ed nd n to 7, d. R 311 Attorney Docket No.: R2103-7054WO (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.26 (s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.52 (d, J = 1 H 1H 2 1H 41 2H 99 re h. ed m 6 δ 8 δ 8 312 Attorney Docket No.: R2103-7054WO Modifications: Step 1 was run for 2 h. Step 2 was run at room temperature. Th id ifid b hse 2, l- 2- % 20 δ 87 ), d, = 86 ), F n to 2- % 87 δ (s, ), F n to 2- g, S z, 98 ), 00 313 Attorney Docket No.: R2103-7054WO Modification: Step 2 used LiOH‧H2O in THF at 70 ºC over 3 h. Th i i d der nd he by L) 1- 73 S, m se nt 6- - - .7 S, z, 96 ), (t, ), 71 (s, (s, m n to 4- - 00 d. Attorney Docket No.: R2103-7054WO Modification: Step 2 was run at room temperature. Th fil d d d ed 1- - 4- as xt n. 50 n to 6- - % 98 δ 22 59 ), 87 ), (s, 70 n to 3- g, S, z, .3 d, ), 51 ), Attorney Docket No.: R2103-7054WO 2.19 (s, 3H), 2.03 (s, 3H), 1.94 (s, 2H), 1.75 (s, 2H). ifi i i ‧ i HF ed to l- a F er as er 6- 1, d. ep . n to 3- .2 S, z, .3 d, ), (s, ), d, ), z, 316 Attorney Docket No.: R2103-7054WO Modification: Step 2 was run at room temperature for 2 h. Th i i idifid H 5 ng n, to ol, 51 F er re er 3- ol, 00 at C 4- % .1 δ 43 ), (s, Scheme B: 317 Attorney Docket No.: R2103-7054WO 3b, and B-3c. Condition B-3a O O B 1 2W X B W1 L W NH HN W2 NH 3 A 3 A W W4 N W Pd cat W4 N 3 ., ligand, base R3a R b R3a R3b B-2 Common examples Pd cat. = RuPhos Pd G3 B-3 Exemplary Protocol: Example 3: Synthesis of Compound 171 Synthesis of A12 To a strre souton o -(-oopeny)acetc ac ( g, . mmo) and 2-amino-4- methoxy-benzonitrile (3.1 g, 21 mmol) in DMF (100 mL) were added T3P (18.2 g, 28.6 mmol, 50 wt. % in EtOAc) and pyridine (4.5 g, 57.2 mmol, 4.6 mL), and the reaction was stirred for 16 h at 318 Attorney Docket No.: R2103-7054WO room temperature. The resulting mixture was diluted with water (100 mL) and the precipitated solids were collected by filtration and washed with water (50 mL) to afford N-(2-cyano-5- methoxy-phenyl)-2-(4-iodophenyl)acetamide (A12, 5.2 g, 13.3 mmol, 69% yield) as a solid. LCMS (ES, m/z): 393 [M+H]+. Synthesis of A13 ide (A12, 5 g, 12.8 mmol) in EtOH (100 mL) were added 30% H2O2 (32 mL) and 2M aq. NaOH (32 mL), and the reaction was stirred for 5 h at room temperature. The mixture was acidified to pH 5 with 1 N HCl (aq.). The precipitated solids were collected by filtration and washed with water (30 mL). The solid was purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 2-[(4-iodophenyl)methyl]-7-methoxy-3H-quinazolin-4-one (A13, 2.5 g, 6.4 mmol, 50% yield) as a solid. LCMS (ES, m/z): 393 [M+H]+. Synthesis of Compound 171 [Condition B-3a] , mg, 510 μmol) and 3-methyl-1H-pyrrole (82.7 mg, 1.0 mmol) in dioxane (3 mL) were added Ruphos (20 mg, 42 μmol), Cs2CO3 (498.4 mg, 1.5 mmol) and RuPhos Pd G3 (42.6 mg, 51.0 μmol), and the reaction was stirred for 16 h at 100 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 11) to afford 7-methoxy-2-[[4-(3-methylpyrrol-1-yl)phenyl]methyl]-3H- quinazolin-4-one (Compound 171, 18.9 mg, 54.7 μmol, 11% yield) as a solid. LCMS (ES, m/z): 319 Attorney Docket No.: R2103-7054WO 346 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.01-7.92 (m, 1H), 7.44 (q, J = 8.7 Hz, 4H), 7.21 (t, J = 2.6 Hz, 1H), 7.12-6.99 (m, 3H), 6.08 (t, J = 2.3 Hz, 1H), 3.89 (d, J = 12.3 Hz, 5H), 2.06 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Materials sh to 1- % ]+. ), 21 = (s, a. Na n 2- 2, S z, z, 4- 85 z, m, .6, The general protocol in Scheme B can be prepared using the exemplary conditions described in Condition B-3b. 320 Attorney Docket No.: R2103-7054WO Exe Exa yl]-7- methoxy-3H-quinazolin-4-one (A13, 100 mg, 255 μmol) in DMF (5 mL) was treated with Cs2CO3 (249.2 mg, 764.9 μmol), CuI (9.7 mg, 51.0 μmol, 1.73 μL), DMCyDA (14.5 mg, 102 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water/Ice (30 mL) and the resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep- HPLC (Condition 6, Gradient 1) to afford 7-methoxy-2-[[4-(4-methylpyrazol-1-yl)phenyl]- methyl]-3H-quinazolin-4-one (Compound 213, 22 mg, 63.5 μmol, 25% yield) as a solid. LCMS (ES, m/z): 347 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (br, 1H), δ 8.21 (s, 1H), 7.98- 7.95 (m, 1H), 7.74-7.71 (m, 2H), 7.53 (s, 1H), 7.47-7.44 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 3.93 (s, 2H), 3.87 (s, 3H), 2.09 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization 321 Attorney Docket No.: R2103-7054WO Step 3 was ran using Condition B-3b. The residue was purified by Prep-HPLC dii di 1 ff d h 2- - .5 z): δ ), m, 87 b. m ep sh to d) H 31 J = (s, b. m ep sh to 1- % ]+. ), z, m, z, b. m ep Attorney Docket No.: R2103-7054WO The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to ff d h 2 4 hl l1- d) H 59 .0 (s, b. m ep C 3- 6, d. 00 8- m, 9- m, C 4- 7, d. 00 ), ), ), (s, b. m ep C 5- 9, S Attorney Docket No.: R2103-7054WO (ES, m/z): 342 [M+H]+. 1H NMR (300 MHz, DMSO-d) δ8.27 (s, 1H), 7.72-7.63 (m, 2H), 7.58- H 21 1H 4 2H), ), b. . n 2- - g, S, O- 08 .3 ), ), b. ad C o- e d) H 06 0, 6, m, 7, b. ad C 1- .2 z): δ 75 ), m, ), Attorney Docket No.: R2103-7054WO Step 3 was ran using Condition B-3b. Modification: Step 3 was ran for 16 h. Th id ifi d b P HPLC 2- g, S, O- z, = = 36 28 b. m ep p- 4- 1, S z, ), , J b. m ep C 4- 6- 3, S z, ), z, b. C 4- 7- 5, 3 Attorney Docket No.: R2103-7054WO 9.6 mg, 26.4 μmol, 7% yield) as a solid. LCMS (ES, m/z): 364 [M+H]+. 1H NMR (300 MHz, DM d δ d = 4 H 1H 93 ), 92 ng C 4- 8, S z, z, = 9, b. C 4- % ]+. ), .3 (s, b. m ep sh to 3- % ]+. .8 = 94 326 Attorney Docket No.: R2103-7054WO (dd, J = 6.4, 2.6 Hz, 2H), 3.95 (s, 2H), 3.83 (s, 3H), 2.26 (s, 3H). i ii ed on 1- d. 00 m, (t, b. sh to - .8 ): δ 59 10 ), 5, = .9 b. m ep C % 2- g, S, O- 7- .1 B- n ed to Attorney Docket No.: R2103-7054WO afford 6-methoxy-2-[[6-(5-methyl-2-oxo-1- pyridyl)-3-pyridyl]methyl]-3H-quinazolin-4-one 2 1 4 l 14 i ld) H 57 ), J 97 b. C 7- .5 ): δ (s, m, 9- (s, b. sh 2- % ]+. .7 = (s, .7 b. sh to 1- d) H 47 7- Attorney Docket No.: R2103-7054WO 7.66 (m, 2H), 7.50-7.37 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.07 (s, 1H), 6.55 (t, J = 2.1 Hz, 1H), 2H d = H H sh to 1- % ]+. ), m, 85 h. C 4- - 36 28 44 5, ), ), . C 4- d d. 00 d, ), ), ), 329 Attorney Docket No.: R2103-7054WO Step 3 was ran using Condition B-3b. Modification: Step 3 was ran at 110 °C for 16 h. Th id ifid b P HPLC 7- de % ]+. ), d, 62 ), , J b. in C H- de % ]+. .1 ), 81 44 32 330 Attorney Docket No.: R2103-7054WO Modification: Steps 1 and 2 were omitted. Step 3 was run in dioxane solvent for 16 h. Th d d ifid b d- 7, 4- % +. ), ), ), ), ), 82 .1 3 d- 7, 4- % +. ), ), m, 65 82 ), ), 331 Attorney Docket No.: R2103-7054WO Modification: Steps 1 and 2 were omitted. Step 3 was run in dioxane solvent for 16 h. Th id ifid b hse nt 4- - .8 22 04 .6, ), = ), , J z, 4- . C 7- d) H ), m, 57 . C 3- e d) H 72 d, ), (s, 332 Attorney Docket No.: R2103-7054WO Modification: Step 3 was ran in dioxane for 2 h. The residue was purified by Prep-HPLC C di i 26 G di 1 ff d 2 6 (4- e d) H ), 00 41 (s, . C 3- e d. The general protocol in Scheme B can be prepared using exemplary conditions for Step 3 as described in Condition B-3c. plary conditions for Step 3 as described in Condition B-3d (see intermediate C91) or Condition B-3e (see Compound 517 and Compound 546). 333 Attorney Docket No.: R2103-7054WO Ex Exa p e : y es s o o pou , one (A70, 150 mg, 354.4 μmol) and 3-fluoropyrrolidine hydrochloride (67.2 mg, 531.7 μmol) in dioxane (3 mL) were added Cs2CO3 (346.4 mg, 1.1 mmol) and Pd-PEPPSI-IPentCl (28.1 mg, 35.4 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 ℃ under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 25) to afford 2-[[6-(3-fluoropyrrolidin-1-yl)-3-pyridyl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 313, 17.7 mg, 46.1 μmol, 13% yield) as a solid. LCMS (ES, m/z): 385 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 2.4 Hz, 1H), 7.52 (dd, J = 8.6, 2.4 Hz, 1H), 7.37 (s, 1H), 7.00 (s, 1H), 6.45 (d, J = 8.6 Hz, 1H), 5.42 (d, J = 53.3 Hz, 1H), 3.84 (d, J = 9.7 Hz, 6H), 3.71 (s, 2H), 3.72-3.38 (m, 4H), 2.27-2.19 (m, 2H). 334 Attorney Docket No.: R2103-7054WO An analogous method was followed using Scheme B-3c, to obtain the following compounds. Compound Starting Characterization Material se nt )- g, S, z, 2 s, .3 ), c. n ), 3, 3- d d. 0 J m, z, s, ), z, c. n ), 3, 6- Attorney Docket No.: R2103-7054WO quinazolin-4-one (Compound 323, 20.4 mg, 57.9 μmol, 23% yield) as a solid. LCMS (ES, z, z, 0 8 m, c. 6 C 6- g, S, z, .4 9 ), z, z, m, .0 c. C 5- ]- % 7 δ 1, z, 9 ), 336 Attorney Docket No.: R2103-7054WO Step 3 was ran using Condition B-3c. Modification: Step 3 was ran for 16 h. C 6- g, S z, 55 s, .1 84 m, ep p- 6- % 91 δ 85 d, ), d, ), 59 ). Scheme C1: 337 Attorney Docket No.: R2103-7054WO Scheme C2: Exempl me C2 are described in Conditions C-3a and C-3b. The general protocol in Scheme C can be prepared using exemplary conditions for Step 3 as described in Condition C-3a. 338 Attorney Docket No.: R2103-7054WO Exe Example 6: Synthesis of Compound 179 Synthesis of A14 To a minobenzonitrile (1.9 g, 16.7 mmol) in pyridine (20 mL) were added T3P (20 mL), and the reaction was stirred for 2 h at 80°C. The mixture was quenched with water (100 mL). The resulting solid was collected by filtration, washed with water (40 mL), and dried to afford 2-(4-bromophenyl)-N-(2-cyanophenyl)- acetamide (A14, 3.8 g, 12.1 mmol, 86% yield) as a solid. LCMS (ES, m/z): 315 [M+H]+. Synthesis of A15 To a sou o o - - o opey - - -cyaopey acea e , . g, 12.1 mmol) in EtOH (40 mL) were added NaOH (2.5 mL, 2 M) and H2O2 solution (2 g, 60.3 mmol, 1.9 mL), and the reaction was stirred for 2 h at 70°C. The mixture was allowed to cool down to room temperature and diluted with water (30 mL). The resulting solid was collected by filtration and 339 Attorney Docket No.: R2103-7054WO washed with water (20 mL). The solid was dried to afford 2-[(4-bromophenyl)methyl]-3H- quinazolin-4-one (A15, 2.7 g, 8.6 mmol, 71% yield) as a solid. LCMS (ES, m/z): 315 [M+H]+. Synthesis of Compound 179 150 mg, 475.9 μmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (149.9 mg, 713.9 μmol) in dioxane (6 mL) and H2O (1.5 mL) were K3PO4 (303.0 mg, 1.43 mmol), Pd(dppf)Cl2 (69.6 mg, 95.2 μmol), and the reaction was stirred for 6 h at 100°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 2-[[4-(3,6-dihydro-2H-pyran-4-yl)- phenyl]methyl]-3H-quinazolin-4-one (Compound 179, 16 mg, 50.3 μmol, 11% yield) as a solid. LCMS (ES, m/z): 319 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.07 (dd, J = 8.0, (q, ds. d- on 6- l, ): z, = 59 ), ), Attorney Docket No.: R2103-7054WO 3.92 (s, 2H), 3.80 (t, J = 5.5 Hz, 2H), 2.42 (s, 2H). m at as d- n )- e l, ): z, = .6 J 3, .2 d, s, m at an d- n y- .2 d. R ), m, .6 6 C C 2- Attorney Docket No.: R2103-7054WO pyridyl]methyl]-6-methoxy-3H- quinazolin-4-one (Compound 286, 17 d. R ), ), ), 9, ), C d- on 2- .7 S, z, = d, z, J s, C C 2- 23 d. R ), .9 ), 2, z, 40 ), Attorney Docket No.: R2103-7054WO Modification: Step 3 was ran at 110 °C for 16 h. C 6- 30 d. R ), .2 = ), s, m at as C 6- .5 d. H s, .0 2- z, s, m at an O d- on 6- 5, 34 Attorney Docket No.: R2103-7054WO 9.6 mg, 22.2 μmol, 24% yield) as a solid. LCMS (ES, m/z): 406 [M+H]+.1H NMR H), ), z, = m at an d- on 6- % 24 O- J ), 76 49 z, ng 16 C 6- % 38 O- J 7- ), ), 344 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at room temperature for 16 h. Step 2 was ran at an d- n o- l, ): z, ), m, 1 ), .8 or d- n 3- l, ): z, = t, ), J 0- ), z, C C 2- Attorney Docket No.: R2103-7054WO dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 392, 380 mg, d. R .2 = ), d, J or C 2- n- - d a H s, J z, 3 z, .1 z, or C 2- .6 d. R ), ), 5, ), ), 0 Attorney Docket No.: R2103-7054WO (s, 2H), 3.83 (d, J = 5.4 Hz, 6H), 2.19 (s, 3H). or C 6- .6 d. R ), 2, z, ), ), ), C C 6- 23 d. R ), ), J = .6 C d- on o- - a H 34 Attorney Docket No.: R2103-7054WO NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.03 (d, J ), .1 4 or C 7- l, ): z, = .2 ), ), ), or C 5- g, S 0 z, J z, s, z, C 2- n- - Attorney Docket No.: R2103-7054WO 4(3H)-one hydrochloride (Compound 422, 392 mg, 883.2 μmol, 25% yield) as +. 4 d, .1 6, = J d- n o- 6 d. R .2 2 z, s, z, C C 6- 2 d. R ), z, J = ), 349 Attorney Docket No.: R2103-7054WO Modification: Step 3 was ran at 110 °C for 16 h. d- on o- - a H s, s, 80 ), .0 C 6- .9 d. R ), .5 ), s, z, J C 4- 24 d. R ), .4 87 35 Attorney Docket No.: R2103-7054WO Modification: Step 3 was ran at 110 °C for 2 h. d- n l- - .2 d. R .2 J ), s, s, J C 2- - .5 d. R ), m, s, s, z, C 2- de l, ): z, ), .7 Attorney Docket No.: R2103-7054WO Hz, 2H), 4.25 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.33 (s, 6H). C 2- de l, ): z, ), 5, ), m, z, C 2- - g, S 0 d, ), ), ), H, h. C 2- .5 d. R Attorney Docket No.: R2103-7054WO (400 MHz, DMSO-d6) δ 8.97 (s, 2H), 8.19 (d, J = 2.4 Hz, 1H), 7.41 (s, 1H), s, s, C 2- - d as +. 2 2 z, J ), ), or d- n o- g, S 0 s, s, J ), C C 2- Attorney Docket No.: R2103-7054WO quinazolin-4-one (Compound 581, 30 mg, 69.1 μmol, 29% yield) as a solid. R ), 4, ), ), .5 z, 24 d- on o- - .1 S, z, = ), ), ), 59 d, C 2- .2 d. R .2 ), ), 4, s, 35 Attorney Docket No.: R2103-7054WO Modification: Step 2 was ran with LiOH and without H2O2 at room temperature v. C 2- g, S 00 (s, 6- (s, H re v. C he o- .9 S, z, m, z, s, th 16 v. e- on 3- 02 S 35 Attorney Docket No.: R2103-7054WO (ES, m/z): 427 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J = 9.0 Hz, 62 ), ), th 16 v. e- on 5- 4 S, z, = ), s, z, Scheme C, Condition C-3b The general protocol in Scheme C can be prepared using a stannane starting material in step 3, as shown in Condition C-3b. Exe mpary ro oco : Example 7: Synthesis of Compound 180 356 Attorney Docket No.: R2103-7054WO mg, 475.9 μmol) and tributyl(2-furyl)stannane (203.9 mg, 571.1 μmol, 179.9 μL) in dioxane (3 mL) were added Pd(PPh3)4 (55.0 mg, 47.6 μmol), and the reaction was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 2-[[4-(2-furyl)phenyl]methyl]-3H- quinazolin-4-one (Compound 180, 40.3 mg, 133.3 μmol, 28% yield) as a solid. LCMS (ES, m/z): 303 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.08 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (ddd, J = 15.8, 8.5, 1.7 Hz, 2H), 7.64 (dd, J = 14.9, 8.1 Hz, 3H), 7.53-7.39 (m, 3H), 6.90 (d, J = 3.4 Hz, 1H), 6.58 (dd, J = 3.4, 1.8 Hz, 1H), 3.96 (s, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material ) = = - .2 357 Attorney Docket No.: R2103-7054WO 314 [M-TFA+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.53 (brs, 1 H), 8.67 (d, J=5.2 Hz, 1H), 8.10- - ) R J - . e . z, 2 358 Attorney Docket No.: R2103-7054WO = 7.7 Hz, 2H), 3.93 (s, 2H), 3.80 (s, 3H), 2.53 (s, 3H). . R . ]- ), = d, ). g, Attorney Docket No.: R2103-7054WO Hz, 1H), 7.75 (s, 1H), 7.46 (t, J = 9.1 Hz, 3H), 7.14 (d, J = 5.0 Hz, 1H), 3.93 (s, 2H), 2.36 (s, . - R J = = , . d. z, = 360 Attorney Docket No.: R2103-7054WO Modification: Step 3 was ran at 120 °C for 4 h. The residue was purified by Prep-HPLC = c eme : Compound 601) and D-3b (see Compound 609). 361 Attorney Docket No.: R2103-7054WO Scheme E: Compounds 679, 680, 778, and 784), E-2b (see Compound 359), and E-2c (see Compounds 478, 440, and 512). Attorney Docket No.: R2103-7054WO E- 2a, E-2b, and E-2c). Exemplary Protocol: Example 8: Synthesis of Compound 108 Synthesis of A27 To a solution o -met y- -qu nazo n- -one ( mg, . mmol) in DMF (10 mL) was added NBS (800 mg, 4.5 mmol), and the reaction was stirred overnight at 40 °C. The system was filtered, and the filter cake was washed with DMF (0.5 mL) and PE (2 mL) to afford 2- 363 Attorney Docket No.: R2103-7054WO (bromomethyl)-3H-quinazolin-4-one (A27, 400 mg, 1.7 mmol, 45% yield) as a solid. LCMS (ES, m/z): 238.7 [M+H]+. Synthesis of Compound 108 To a s -(bromomethyl)- 3H-quinazolin-4-one (A27, 140 mg, 585.8 μmol) in CH3CN (2 mL) was added K2CO3 (221 mg, 1.6 mmol), and the reaction was stirred for 4 h at 50 °C. The solvent was filtered, and the filter cake was washed with DMF (5 mL). The filtrate was purified by reversed-phase flash chromatography (Condition 2, Gradient 23) to afford 2-[(4-pyrrol-1-yl-1-piperidyl)methyl]-3H- quinazolin-4-one (Compound 108, 27 mg, 87.6 μmol, 16% yield) as a solid. LCMS (ES, m/z): 309.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 6.75 (s, 2H), 5.89 (s, 2H), 3.92-3.88 (m, 1H), 3.43 (s, 2H), 2.93-2.91 (m, 2H), 2.23-2.22 (m, 2H), 1.83-1.81 (m, 4H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization M i l sh to .6 .2 J 8 9 m, 364 Attorney Docket No.: R2103-7054WO The residue was purified by reversed-phase flash chromatography (Condition 5, Gradient 2) to afford 2- .1 08 δ .6 58 4- ), Sc eme : Example 9: Synthesis of Compound 342 Synthesis of A97 To a souton o -(-odopeny)acetc acd (3 g, .5 mmo) and -amno-5-methoxy- benzonitrile (2 g, 13.7 mmol) in pyridine (15 mL) were added T3P (15 mL), and the reaction was 365 Attorney Docket No.: R2103-7054WO stirred for 16 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water (100 mL). The resulting solid was collected by filtration and washed with water (30 mL). The solid was dried to afford N-(2-cyano-4-methoxy-phenyl)-2-(4- iodophenyl)acetamide (A97, 3.5 g, 8.9 mmol, 78% yield) as a solid. LCMS (ES, m/z): 393 [M+H]+. Synthesis of A98 97, 3.5 g, 8.9 mmol) in EtOH (30 mL) and H2O (10 mL) were added NaOH (1.7 g, 44.6 mmol) and 30% H2O2 (1.5 g, 44.6 mmol, 1.4 mL), and the reaction was stirred for 2 h at 70°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and purified by reversed- phase flash chromatography (Condition 2, Gradient 1) to afford 2-[(4-iodophenyl)methyl]-6- methoxy-3H-quinazolin-4-one (A98, 2.6 g, 6.6 mmol, 74% yield) as a solid. LCMS (ES, m/z): 393 [M+H]+. Synthesis of A99 p y y y q 98, 4 g, 10.2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (3.9 g, 15.3 mmol) in dioxane (80 mL) were added KOAc (3.0 g, 30.6 mmol) and Pd(dppf)Cl2 (1.49 g, 2.04 mmol), and the reaction was stirred for 16 h at 100°C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (33% EtOAc in PE) to afford 6-methoxy-2-[[4-(4,4,5,5-tetramethyl-1,3,2- 366 Attorney Docket No.: R2103-7054WO dioxaborolan-2-yl)phenyl]methyl]-3H-quinazolin-4-one (A99, 2 g, 4.38 mmol, 43% yield) as a solid. LCMS (ES, m/z): 393 [M+H]+. Synthesis of Compound 342 To a stirred mixture of 6-methoxy-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]-3H-quinazolin-4-one (A99, 0.15 g, 382.4 μmol) and 4-bromo-2-methyl- pyrimidine (99 mg, 573.6 μmol) in dioxane (3 mL) and H2O (0.3 mL) were added K3PO4 (243 mg, 1.15 mmol) and Pd(dppf)Cl2 (55 mg, 76.5 μmol), and the reaction was stirred for 16 h at 100°C. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC (Condition 2, Gradient 8) to afford 6-methoxy-2-[[4-(2-methylpyrimidin-4-yl)phenyl]methyl]-3H- quinazolin-4-one (Compound 342, 0.03 g, 83.7 μmol, 22% yield) as a solid. LCMS (ES, m/z): 359 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.1 (s, 1H), 8.72 (d, J = 5.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 5.4 Hz, 1H), 7.52 (dd, J = 8.6, 2.3 Hz, 3H), 7.46 (d, J = 3.0 Hz, 1H), 7.33 (dd, J = 8.9, 3.1 Hz, 1H), 3.98 (s, 2H), 3.84 (s, 3H), 2.67 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization C y- d d. 0 = d, ), .1 Attorney Docket No.: R2103-7054WO Hz, 1H), 3.98 (s, 2H), 3.84 (s, 3H), 2.67 (s, 3H). Modification: Step 1 was ran at room m C 00 n ) 1, 4- d a R d, .2 ), 46 88 Scheme K: e pay ooco: Example 10: Synthesis of Compound 136, 221-222 Synthesis of A29 368 Attorney Docket No.: R2103-7054WO To a and 2-(4-bromo- phenyl)acetyl chloride (1.04 g, 4.4 mmol) in NMP (4 mL), and the reaction was irradiated with microwave radiation for 4 h at 200 °C. The resulting mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with water (2 x 5 mL), brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to afford 3-[(4-bromophenyl)methyl]isochromen-1-one (A29, 260 mg, 825 μmol, 37% yield) as a solid. LCMS (ES, m/z): 315 [M+H]+. Synthesis of A30 To a so u o o - - o op e y e y soc o e - -o e , g, 666.3 μmol) in DMF (4 mL) were added NH3 (4.0 M in methanol) (0.5 mL) at 0 oC, and the reaction was stirred for 16 h at 130 oC under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% THF in PE) to 3-[(4-bromophenyl)methyl]-2H-isoquinolin-1-one (A30, 150 mg, 477.4 μmol, 72% yield) as a solid. LCMS (ES, m/z): 314 [M+H]+. Synthesis of A31 369 Attorney Docket No.: R2103-7054WO To a solution of 3-[(4-bromophenyl)methyl]-2H-isoquinolin-1-one (A30, 100 mg, 318.3 μmol) and N’,N’-dimethylethane-1,2-diamine (6 mg, 63.7 μmol) in DMF (2 mL) were added Cs2CO3 (207 mg, 636.6 μmol), CuI (12 mg, 63.7 μmol) and NaI (238 mg, 1.6 mmol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 40 mL), brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (75% EtOAc in PE) to afford 3-[(4-iodophenyl)methyl]-2H- isoquinolin-1-one (A31, 60 mg, 166.1 μmol, 52% yield) as a solid. LCMS (ES, m/z): 362 [M+H]+. Synthesis of Compound 136 , mg, 138.4 μmol) and pyrrole (11 mg, 166.1 μmol) in dioxane (1 mL) were added CuI (5 mg, 27.7 μmol) and Cs2CO3 (90 mg, 276.9 μmol), and the reaction was stirred for 16 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 40 mL), brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (75% EtOAc in PE) to afford 3-[(4-pyrrol-1-ylphenyl)methyl]-2H-isoquinolin-1-one (Compound 136, 23 mg, 76.6 μmol, 55% yield) as a solid. LCMS (ES, m/z): 301 [M+H]+. 1H NMR (400 MHz, 370 Attorney Docket No.: R2103-7054WO DMSO-d6, ppm) δ 8.13 (d, J = 8.0 Hz, 1H), 7.67-7.62 (m, 1H), 7.59-7.50 (m, 3H), 7.47-7.38 (m, 3H), 7.35-7.32 (m, 2H), 6.35 (s, 1H), 6.24 (s, 2H), 6.06 (s, 1H), 3.86 (s, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Materials n 4- a 00 ), m, ), 2- an on l- as 00 ), 21 2- an on 1- d d. z, 42 m, ), Individual Protocols Example 11: Synthesis of Compound 102 Synthesis of A20 371 Attorney Docket No.: R2103-7054WO To a stir edioate (1.7 g, 11.8 mmol) in MeOH (15 mL), and the reaction was stirred for 6 h at reflux. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford dimethyl (E)-2-anilinobut-2-enedioate (A20, 1.5 g, 6.4 mmol, 59% yield) as an oil. LCMS (ES, m/z): 236 [M+H]+. Synthesis of A21 To a stirr 1.4 g, 5.95 mmol) in PPA (10 mL), and the reaction was stirred for 4 h at 120 °C. The resulting mixture was neutralized to pH 8 with NaHCO3 (aq.) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford methyl 4-oxo-1H-quinoline-2-carboxylate (A21, 1.1 g, 5.4 mmol, 91% yield) as a solid. LCMS (ES, m/z): 204 [M+H]+. Synthesis of A22 Attorney Docket No.: R2103-7054WO To a stirred mixture of methyl 4-oxo-1H-quinoline-2-carboxylate (A21, 1.0 g, 4.9 mmol) in DCM (10 mL) and MeOH (10 mL) was added NaBH4 (931 mg, 24.6 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 15 mL), brine (15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-(hydroxymethyl)-1H-quinolin-4-one (A22, 500 mg, 2.85 mmol, 58% yield) as a solid. LCMS (ES, m/z): 176 [M+H]+. Synthesis of A23 To a stirred , 200 mg, 1.1 mmol) in DCM (4 mL) was added SOCl2 (204 mg, 1.7 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (3 mL) and extracted with DCM (3 x 3 mL). The combined organic layers were washed with water (2 x 5 mL), brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-(chloromethyl)-1H-quinolin- 4-one (A23, 150 mg, 774.7 μmol, 68% yield) as a solid. LCMS (ES, m/z): 194 [M+H]+. Synthesis of A24 o a st rred m xture o -( -bromop eny )pyrro e ( 00 mg, 900.6 μmo ) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (252 mg, 990.6 μmol) in dioxane (4 mL) were added NaOAc (185 mg, 2.3 mmol, 120.9 μL) and Pd(dppf)Cl2 (132 373 Attorney Docket No.: R2103-7054WO mg, 180.1 μmol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 40 mL), brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (75% EtOAc in PE) to afford 1-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrole (A24, 200 mg, 743.1 μmol, 83% yield) as a solid. LCMS (ES, m/z): 270 [M+H]+. Synthesis of Compound 102 6 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrole (A24, 61 mg, 227.2 μmol) in Dioxane (1.6 mL) and H2O (0.4 mL) were added Na2CO3 (66 mg, 619.7 μmol, 26 μL) and Pd(dppf)Cl2 (30 mg, 41.3 μmol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to afford 2-[(4-pyrrol-1-ylphenyl)methyl]-1H-quinolin-4-one (Compound 102, 22 mg, 73.3 μmol, 35% yield) as a solid. LCMS (ES, m/z): 301 [M+H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 12.49 (brs, 1H), 8.11 (s, 1H), 7.79-7.65 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 3H), 7.36-7.34 (m, 3H), 6.27-6.25 (m, 3H), 4.11 (s, 2H). Example 12: Synthesis of Compound 106 Synthesis of Compound 106 374 Attorney Docket No.: R2103-7054WO py y p y y q 4-one (Compound 190, 260 mg, 683.8 μmol) and Zn(CN)2 (241 mg, 2.1 mmol) in DMF (3 mL) was added Pd(PPh3)4 (39 mg, 34.2 μmol) in portions, and the reaction was stirred for 16 h at 90 °C. The reaction was quenched with Water/Ice and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 19) to afford 4-oxo-2-[(4-pyrrol-1-ylphenyl)methyl]-3H-quinazoline-6-carbonitrile (Compound 106, 9 mg, 29.7 μmol, 4% yield) as a solid. LCMS (ES, m/z): 327 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 12.86 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.14 (dd, J = 8.4, 2.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 2.4 Hz, 2H), 6.25 (t, J = 2.4 Hz, 2H), 4.00 (s, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: The reaction was p- 7) 4- de .8 d. H δ z, ), = 03 = 375 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran at 120 °C for 5 h. by 6, 7- de .7 d. +. O- ), 0 = 7, 8 J as y sh 2, 7- 0, d) ): 0 s, ), 3 .7 s, 376 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran at 80 ºC. by sh 8, 7- d % S, R 6 s, ), .5 n v. 0 ed 5, 7- 4, % S, R 9 d, d, d, s, ), 0 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran at 100 ºC. by 8, 7- 8, % S, R 5 ), s, ), 2 as y 2, he 7- e- d % S, H δ 4 z, ), 7 Example 13: Synthesis of Compound 137 Synthesis of A32 378 Attorney Docket No.: R2103-7054WO (200 mg, 616.4 μmol) and 2-aminobenzonitrile (87.4 mg, 739.6 μmol) in THF (3 mL) were added LiHMDS (2.5 mL, 2.5 mmol, 1 M in THF), and the reaction was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with NH4Cl water (5 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-[4-[2-[tert- butyl(dimethyl)silyl]oxyethoxy]phenyl]-N-(2-cyanophenyl)acetamide (A32, 130 mg, 316.6 μmol, 51% yield) as a solid. LCMS (ES, m/z): 411 [M+H]+. Synthesis of A33 no- phenyl)acetamide (A32, 120 mg, 292.3 μmol) in EtOH (2 mL) was added H2O2 (1 mL) and 2 M NaOH (1 mL), and the reaction was stirred for 2 h at room temperature. The mixture was acidified to pH 5 with 1N HCl (aq.). The precipitated solids were collected by filtration and washed with water (5 mL). The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]phenyl]-N-(2-cyanophenyl)- acetamide (A33, 120 mg, 292.3 μmol) as a solid. LCMS (ES, m/z): 411 [M+H]+. Synthesis of Compound 137 379 Attorney Docket No.: R2103-7054WO -3H- quinazolin-4-one (A33, 100 mg, 243.6 μmol) in DCM (2 mL) was added TFA (0.2 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and adjusted to pH 8 with NH3 (g) in MeOH. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 10) to afford 2-[[4-(2-hydroxyethoxy)phenyl]methyl]-3H-quinazolin-4- one (Compound 137, 66.5 mg, 224.4 μmol, 92% yield) as a solid. LCMS (ES, m/z): 297 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.10-8.01 (m, 1H), 7.75 (td, J = 7.7, 7.0, 1.6 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.50-7.39 (m, 1H), 7.27 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.81 (t, J = 5.5 Hz, 1H), 3.92 (t, J = 5.0 Hz, 2H), 3.83 (s, 2H), 3.66 (q, J = 5.2 Hz, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: The first two Steps or by sh 2, o- - g, . ]+. 6) 02 = 380 Attorney Docket No.: R2103-7054WO 8.2, 2.3 Hz, 1H), 7.84 -7.74 (m, 3H), 7.29 (tt, J = 9.2, 2.4 Hz, 1H), (s, ), s, , J ). ps ed 5, he o- .1 d. ]+. 6) (s, ), z, ), d, .9 (s, Example 14: Synthesis of Compound 187, 214 Attorney Docket No.: R2103-7054WO To a solution of 8-bromo-2-[(4-pyrrol-1-ylphenyl)methyl]-3H-quinazolin-4-one (A37, 150 mg, 394.5 μmol) and morpholine (103.1 mg, 1.2 mmol) in dioxane (2 mL) were added RuPhos Pd G3 (33 mg, 39.5 μmol), Cs2CO3 (257.1 mg, 789 μmol) and Ruphos (36.8 mg, 78.9 μmol), and the reaction was stirred for 16 h at 100°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 10) to afford 8-morpholino-2-[(4-pyrrol-1-ylphenyl)methyl]-3H-quinazolin-4-one (Compound 187, 3.6 mg, 9.3 μmol, 2% yield) as a solid. LCMS (ES, m/z): 387 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ12.24 (s, 1H), δ 7.64 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.37-7.24 (m, 3H), 7.12 (d, J = 7.8 Hz, 1H), 6.25 (t, J = 2.1 Hz, 2H), 3.97 (s, 2H), 3.59 (t, J = 4.2 Hz, 4H), 3.11 (t, J = 4.4 Hz, 4H). An analogous method was followed to obtain the following compound. Compound Starting Material Characterization Modification: The reaction was or ca % 3- ne .2 d. ]+. 6) = m, 39 d, , J z, .5 ), 382 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran in DMF at 70 °C for 16 h. Th i ifi d by sh 8, 5- n- de .6 d. ]+. 6) .0 8- 9- 20 = .2 .6 as 3 e- hy to 2- - n- .7 d. ]+. 6) 14 87 z, 73 ), ), ), 383 Attorney Docket No.: R2103-7054WO 3.11 (d, J = 13.8 Hz, 2H), 2.24 - 2.01 (m, 4H). ifi i h i as nd by sh 8, a 3- 6- .9 d. ]+. 6) z, 32 (s, ), ), ). as nd as sh 8, he 5- .3 d. ]+. 6) z, 32 ), (s, = m, Attorney Docket No.: R2103-7054WO 5H), 2.27 (s, 1H), 2.00 (s, 3H), 1.75 (s, 1H). ifi i h i as as by sh 2, 7- .7 d. ]+. 6) 63 ), z, ), z, (s, m, ), as as ed 2, he 6- .7 d. ]+. 6) .2 z, 89 40 93 Attorney Docket No.: R2103-7054WO (s, 1H), 6.79 (s, 1H), 4.34 (s, 2H), 4.25 (s, 1H), 3.94 (s, 3H), 3.68 dd = 1 H 1H 24 dd, = = as as ed 2, he 6- .7 d. ]+. 6) .1 87 39 86 ), 67 d, 57 6 C . ed 5, 6- .3 d. ]+. 6) Attorney Docket No.: R2103-7054WO δ 12.61 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), dd = 22 H 1H), dt, = .3 = d, .3 = I- p- 4) 5- d d) 82 z, 65 = ), tt, = (s, I- in p- 7) 5- n- g, d. ]+. 6) .2 ), ), Attorney Docket No.: R2103-7054WO 7.86 (s, 1H), 7.85-7.77 (m, 2H), 7.36-7.27 (m, 1H), 6.64 (s, 1H), d = H 1H 4 (s, = 4, z, 15 = I- in p- 7) 5- .1 d. ]+. 6) .2 ), ), ), 65 ), J 99 64 0- ), 6 C . ed 5, 6- Attorney Docket No.: R2103-7054WO (Compound 774, 11 mg, 21.7 μmol, 6% yield) as a solid. L M E / 44 M H]+. 6) ), ), = m, 32 (s, 18 ). I- e, re ed 5, o- - g, d. ]+. 6) 05 93 ), z, 83 = (s, ), ), 19 .0 389 Attorney Docket No.: R2103-7054WO Modifications: The reaction was ran with GPhos Pd G6 as catalyst d B ON b 80 ºC ed 5, o- .4 S, 00 ), d, .2, .8, z, ), q, .8 z, z, z, as as by sh 2, 2- nd d) 63 z, 26 ), (s, .5 (s, 390 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran with Pd-PEPPSI-IPentCl as l d B b 80 p- 4) 7- d d) 51 z, 26 = d, 04 02 ). as 6 at p- 4) 7- .1 d. ]+. 6) 69 = z, 68 ), , J 6, .6 ), 391 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran with Pd-PEPPSI-IPentCl as l d B b 80 p- 4) 7- .2 te ]+. 6) 86 ), ), (s, 27 = as as p- 7) 4- d d) 78 z, 7- 4, z, 01 ), (s, 03 . 392 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran with GPhos Pd G6 as catalyst d B b º - 0 , d, as st p- 4) alt 7- .2 d. ]+. 6) ), (s, 18 = (t, 51 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran with Pd-PEPPSI-IPentCl as l h by sh 0, he 7- 2- e .5 d. M- z, 55 = ), , J z, ), z, ), (s, , J m, ed st by sh 8, he 6- .4 d. M- z, 49 Attorney Docket No.: R2103-7054WO (d, J = 2.2 Hz, 1H), 8.29 (s, 1H), 7.96 (dd, J = 8.6, 2.3 Hz, 1H), d = H 1H 2 (d, .1 (s, = ), 5, .1 ed st ed 1, 2- - n- g, d. ]+. 6) 85 45 67 ), J .2 99 z, (t, ed st ed 5, 4- n- 4, d) 96 Attorney Docket No.: R2103-7054WO [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.37 1H 1H 4 1H), z, ), z, .1 ed F ed 5, o- n- .2 d. ]+. 6) ), z, = .1 (s, 29 = ed st p- 7) 4- n- g, d. ]+. 6) .2 Attorney Docket No.: R2103-7054WO Hz, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.88 (dd, J = 8.4, 2.3 Hz, 1H 778 d J = 84 H 1H 679 ), (s, 20 ), d, .5 ). ed st p- 7) 1- .5 id. ]+. 6) 09 ), (s, ), (s, ), (t, 397 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with a mixture of D18 and D1 i i l Pd d ca hy by sh 8, he 2- - % S, 6) .9 ), d, 34 ), z, ), z, as as 70 by n 2, o- d % S, 00 ), d, Attorney Docket No.: R2103-7054WO J = 2.4 Hz, 1H), 7.86 (s, 1H), 6.65 (s, 1H), 5.63 (d, J = 8.1 Hz, 1H), 41 2H 42 d = Hz, ), q, = = ), as st, as ed 1, 2- n- .9 d. 6) 89 = .0 ), (s, z, z, z, 24 as as er p- 3) 1- ]- Attorney Docket No.: R2103-7054WO (Compound 826, 11 mg, 23.0 μmol, 10% yield) as a solid. LCMS ES / 462 M+H]+. 6) 88 49 = – z, (s, .2 as as by sh 2, 6- 7, as 76 z, 26 ), ), (s, = m, ), as as p- 3) 1- - 8, d) Attorney Docket No.: R2103-7054WO as a solid. LCMS (ES, m/z): 476 [M+H]+. 1H NMR (300 MHz, DM d δ 12 1H 26 ), d, 73 ), – 52 . an st p- 9) 4- d % S, 00 ), (s, = .5 (s, .8 = d, m, ), 401 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with a mixture of D46 and D47 i il d Pd- ca hy al- 1) 7- - 25 d) - 25 as S, 00 ), (s, ), (s, ), (s, ). S, 00 ), (s, .9 54 33 (s, 402 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with Pd-PEPPSI-IPentCl as l d DMF l - ]- ) ), , - - g, d. ) ), , – Attorney Docket No.: R2103-7054WO = 13.1, 6.5 Hz, 1H), 0.50 – 0.41 (m, 2H), 0.11 – 0.04 (m, 2H). ifi i h i C. by sh 8, he 2- - .7 d. M- z, .8 29 78 = (s, ), = ), as as C. by sh 8, he 6- .5 d. M- z, 52 = Attorney Docket No.: R2103-7054WO 7.2 Hz, 1H), 7.93 (d, J = 5.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 6.94 d = 122 H 1H d = .6 ), m, z, 28 (s, as as ed 5, 7- - g, d. ]+. 6) – z, 38 ), = z, .9 ), 60 as as ed 5, 7- - g, . ]+. 6) Attorney Docket No.: R2103-7054WO δ 12.07 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 5.1 Hz, 2H), d = H 1H 1 , J z, = .2 ), ), d, .0 ), as as ed 5, 2- n- g, d. 6) .2 ), , J z, .3 = (s, (s, (s, dt, (s, = 406 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with Pd-PEPPSI-IPentCl as l i DMF l - n- , . 6) .3 ), q, 80 ), (s, m, – 01 = as as h. p- 2) 4- 7- d % S, 00 ), (s, z, (s, ), (s, .4 407 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with Pd-PEPPSI-IPentCl as l i DMF l p- nt 4- n- g, d. ]+. 6) .2 J m, ), ), (s, = 08 = m, as as C. ed 1, 2- - d % S, 00 ), d, .2 = (s, ), z, 408 Attorney Docket No.: R2103-7054WO 5H), 1.86 (d, J = 12.2 Hz, 2H), 1.62 (s, 1H), 1.59 (s, 1H). ifi i h i as as p- nt 4- - n- g, d. 6) .2 (s, z, 79 ), d, m, 85 = as as p- nt 4- n- g, d. ]+. 6) .3 (s, z, 74 ), d, Attorney Docket No.: R2103-7054WO J = 9.1 Hz, 3H), 2.69 – 2.54 (m, 2H), 2.44 (q, J = 7.1 Hz, 2H), 2.29 3H 220 3H 203 d J = z, as as p- nt 4- n- g, d. ]+. 6) .3 (s, z, 74 ), (s, – z, (s, ), as as - - n- , d. ]+. 6) .3 , J 41 Attorney Docket No.: R2103-7054WO = 8.5, 2.4 Hz, 1H), 7.64 – 7.50 (m, 2H), 7.41 (d, J = 2.6 Hz, 1H), 6.74 1H 1 dd = 1 Hz, 15 54 29 ), z, as as C. p- 4) 4- d % S, 00 ), (s, ), d, .6 ), q, m, ), as as 7 by sh 2, 2- 3- d % S, Attorney Docket No.: R2103-7054WO m/z): 506 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), d = 22 H 1H 2 (s, = .5 (s, ), = 11 ), .9 as as . ca y, 6- - d % S, 00 ), d, 5, z, .6 = z, .8 z, .5 z, z, 412 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with Pd-PEPPSI-IPentCl as l i DMF l f h. ca hy 7- 2- n- g, d. ]+. 6) .6 ), ), (s, z, 99 = – .9 ). as as in by sh 2, 7- - g, . ]+. 6) m, = 5, (s, = 11 Attorney Docket No.: R2103-7054WO (d, J = 10.7 Hz, 6H), 2.02 (d, J = 0.9 Hz, 4H), 1.69 (t, J = 10.9 Hz, 2H 14 H as as in ed 1, 2- 3- .2 d. ]+. 6) .2 82 ), z, .5 = (s, ), as as C. by n 2, o- n- g, d. 6) 86 56 z, .0 Attorney Docket No.: R2103-7054WO Hz, 1H), 3.80 (s, 2H), 3.43 (s, 1H), 2.83 (d, J = 11.0 Hz, 2H), 232 J = 72 H 2H 210- .1 z, as as C. by n 2, o- - - .5 d. ]+. 6) .6 ), .7 53 ), (s, d, = m, - by sh 2, 7- 2- 4 Attorney Docket No.: R2103-7054WO a]pyrimidin-2-yl)methyl)-7-((1- methylpyrrolidin-3-yl)amino)-6- ifl h l i li d: d) as C to g, d. ]+. 6) m, ), z, ), .4 19 ). as as e, F ed 5, 4- n- g, d. ]+. 6) .2 (s, z, 61 ), z, 416 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with Pd-PEPPSI-IPentCl as l 12 i i d 3 p- nt de 2- - 2 a 55 z, (s, = .5 (s, ), d, as as 3 p- 1) 7- n- g, d. ]+. 6) 08 ), z, ), – z, ), – 417 Attorney Docket No.: R2103-7054WO 1.54 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H). ifi i h i as as 3 p- 3) 3- - n- g, S R (s, 52 ), ), (s, 77 ), d, .1 ), 5- z, Example 15: Synthesis of Compound 215 Synthesis of A38 T o a souton o -(-pyrro--ypeny)acetc ac ( g, mmo) an -amino-5-iodo- benzonitrile (1.2 g, 5 mmol) in pyridine (10 mL) was added T3P (10 mL), and the reaction was stirred for 3 h at room temperature. The resulting mixture was diluted with water (50 mL). The 418 Attorney Docket No.: R2103-7054WO precipitated solids were collected by filtration and washed with water (10 mL) to afford N-(2- cyano-4-iodo-phenyl)-2-(4-pyrrol-1-ylphenyl)acetamide (A38, 1 g, 2.2 mmol, 44% yield) as a solid. LCMS (ES, m/z): 428 [M+H]+. Synthesis of A39 38, 900 mg, 2.1 mmol) in EtOH (18 mL) was added 30% H2O2 (9.9 mL) and 2 M aq. NaOH (9.9 mL), and the reaction was stirred for 4 h at room temperature. The mixture was acidified to pH 5 with 1 N HCl (aq.). The precipitated solids were collected by filtration and purified by reversed-phase flash chromatography (Condition 2, Gradient 10) to afford 6-iodo-2-[(4-pyrrol-1-ylphenyl)methyl]-3H- quinazolin-4-one (A39, 650 mg, 1.2 mmol, 59% yield) as a solid. LCMS (ES, m/z): 428 [M+H]+. Synthesis of Compound 215 O O O I N N mg, 1.2 mmol) in dioxane (15 mL) was added Pd2(dba)3 (214.3 mg, 234 μmol) and CataCXium A (84.0 mg, 234 μmol) in a pressure tank. The mixture was purged with nitrogen for 1 min and then was pressurized to 10 atm with carbon monoxide and 10 atm with NH3 at 100 °C for 16 h. The mixture was allowed to cool down to room temperature, concentrated under reduced pressure, and purified by reversed-phase flash chromatography (Condition 2, Gradient 24) to afford 4-oxo-2- [(4-pyrrol-1-ylphenyl)methyl]-3H-quinazoline-6-carboxamide (Compound 215, 57.7 mg, 165.4 μmol, 14% yield) as a solid. LCMS (ES, m/z): 345 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 419 Attorney Docket No.: R2103-7054WO 8.63 (d, J = 2.1 Hz, 1H), 8.25-8.15 (m, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.4 Hz, 3H), 7.32 (t, J = 2.3 Hz, 2H), 6.24 (t, J = 2.2 Hz, 2H), 3.97 (s, 2H). Example 16: Synthesis of Compound 220, 209 O O O N HO N NH NH n-4-one (Compound 127, 100 mg, 301.8 μmol) in DCE (2.3 mL) was added BBr3 (0.5 mL) dropwise, and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and basified to pH 8 with 7 M NH3(g) in MeOH. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 2) to afford 6-hydroxy-2-[(4-pyrrol-1-ylphenyl)methyl]-3H-quinazolin-4- one (Compound 220, 30 mg, 93.6 μmol, 31% yield) as a solid. LCMS (ES, m/z): 318 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 8.8 Hz, 1H), 7.55 (s, 4H), 7.41 (d, J = 2.8 Hz, 1H), 7.38-7.29 (m, 3H), 6.25 (t, J = 2.2 Hz, 2H), 4.08 (s, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: The reaction was ran at 50 d- 2, 4- n- ol, 18 6) ), 32 24 Example 17: Synthesis of Compound 231 Synthesis of A56 420 Attorney Docket No.: R2103-7054WO To , 300 mg, 1.23 mmol) and 2-aminobenzonitrile (145.7 mg, 1.23 mmol) in DMF (6 mL) were added T3P (50 wt.% in EtOAc) (1.17 g, 1.85 mmol) and pyridine (195.1 mg, 2.5 mmol), and the reaction was stirred for 2 h at room temperature. The resulting mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 4) to afford N-(2-cyanophenyl)-2-[3-methoxy-4-(2- pyridyl)phenyl]acetamide (A56, 200 mg, 582.5 μmol, 47% yield) as a solid. LCMS (ES, m/z): 344 [M+H]+. Synthesis of A57 cetamide (A56, 200 mg, 582.5 μmol) in EtOH (4 mL) were added NaOH (2 M, 2 mL) and H2O2 (30%, 2 mL), and the reaction was stirred for 2 h at 70 °C. The mixture was acidified to pH 5 with 2 N HCl. The precipitated solids were collected by filtration and washed with water (5 mL). The solid was purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 2-[[3- methoxy-4-(2-pyridyl)phenyl]methyl]-3H-quinazolin-4-one (A57, 150 mg, 436.8 μmol, 75% yield) as a solid. LCMS (ES, m/z): 344 [M+H]+. Synthesis of Compound 231 421 Attorney Docket No.: R2103-7054WO A ne (A57, 100 mg, 291.2 μmol) and sodium thiomethoxide (204.1 mg, 2.9 mmol) in DMF (2 mL) was stirred at 120 °C for 2 h. The resulting mixture was diluted with water (2 mL) and adjusted PH to 6 with 1 N aq.HCl. The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 4) to afford 2-[[3-hydroxy-4-(2-pyridyl)phenyl]methyl]-3H-quinazolin-4- one (Compound 231, 25.3 mg, 76.8 μmol, 26% yield) as a solid. LCMS (ES, m/z): 330 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 14.07 (s, 1H), 8.60 (dd, J = 4.7, 1.6 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.08-7.94 (m, 2H), 7.95 (d, J = 8.7 Hz, 1H), 7.73-7.62 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.46-7.31 (m, 2H), 6.97-6.89 (m, 2H), 3.87 (s, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: Ste 3 was ran for 16 h d- 2, o- % 38 6) z, m, = 99 Example 18: Synthesis of Compound 359 422 Attorney Docket No.: R2103-7054WO Synthesis of A90 A solution o - romo- -pyrazo e ( g, . mmo ), ( - uorop enyl)boronic acid (5.71 g, 40.8 mmol), X-Phos (1.3 g, 2.7 mmol), X-Phos Pd G2 (2.14 g, 2.7 mmol) and K3PO4 (11.6 g, 54.4 mmol) in dioxane/H2O (4:1, 60 mL) was stirred at 100°C for 3 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (17% EtOAc in PE) to afford 3-(3-fluorophenyl)-1H-pyrazole (A90, 4.6 g, 26.9 mmol, 99% yield) as an oil. LCMS (ES, m/z): 163 [M+H]+. Synthesis of Compound 359 g, 890.3 μmol) and 3-(3-fluorophenyl)-1H-pyrazole (A90, 173 mg, 1.07 mmol) in DMF (2 mL) was added t-BuOK (300 mg, 2.67 mmol) in portions, and the reaction was stirred at room temperature for 3 h. The reaction was quenched with NH4Cl (15 mL) at 25 °C. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC (Condition 9, Gradient 3), followed by Prep-HPLC (Condition 10, 423 Attorney Docket No.: R2103-7054WO Gradient 1) to afford 2-[[3-(3-fluorophenyl)pyrazol-1-yl]methyl]-6-methoxy-3H-quinazolin-4- one (Compound 359, 22 mg, 62.2 μmol, 7% yield) as a solid. LCMS (ES, m/z): 351 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.68-7.48 (m, 4H), 7.47- 7.35 (m, 2H), 7.11 (td, J = 8.3, 2.5 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 5.33 (s, 2H), 3.86 (s, 3H). Example 19: Synthesis of Compound 349 Synthesis of A103 To a stirred solution of 2-[[6-(4-fluoropyrazol-1-yl)-3-pyridyl]methyl]-7-methoxy-3H- quinazolin-4-one (Compound 347, 0.1 g, 284.6 μmol) in DMF (5 mL) was added MeSNa (398.4 mg, 5.7 mmol), and the reaction was stirred for 4 h at 120 °C. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 2, Gradient 19) to afford 2-[[6-(4-fluoropyrazol-1-yl)-3-pyridyl]methyl]-7-hydroxy-3H-quinazolin- 4-one (A103, 0.04 g, 118.6 μmol, 42% yield) as a solid. LCMS (ES, m/z): 338 [M+H]+. Synthesis of A104 3H- quinazolin-4-one (A103, 0.05 g, 148.2 μmol) and tert-butyl-(2-iodoethoxy)-dimethyl-silane (50.9 mg, 177.9 μmol) in DMSO (3 mL) was added Cs2CO3 (53.1 mg, 163.1 μmol), and the reaction was stirred for 1 h at 50 °C. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 27) to afford 7-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-2-[[6-(4-fluoropyrazol-1-yl)-3-pyridyl]methyl]-3H- quinazolin-4-one (A104, 0.03 g, 60.5 μmol, 41% yield) as a solid. LCMS (ES, m/z): 496 [M+H]+. Synthesis of Compound 349 424 Attorney Docket No.: R2103-7054WO ol- 1-yl)-3-pyridyl]methyl]-3H-quinazolin-4-one (A104, 0.03 g, 60.5 μmol) in DCM (2 mL) was added HCl (4.0 M in 1,4-dioxane) (0.02 mL), and the reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 5) to afford 2-[[6-(4-fluoropyrazol- 1-yl)-3-pyridyl]methyl]-7-(2-hydroxyethoxy)-3H-quinazolin-4-one (Compound 349, 6 mg, 15.7 μmol, 26% yield) as a solid. LCMS (ES, m/z): 382 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 4.5 Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.10-7.96 (m, 2H), 7.96-7.86 (m, 2H), 7.10 (d, J = 6.8 Hz, 2H), 4.12 (d, J = 3.8 Hz, 4H), 3.74 (t, J = 4.8 Hz, 2H). Example 20: Synthesis of Compound 303 Synthesis of A108 To a stirred solu , .6 mmol) in morpholine (78 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 48 h at 130°C under nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was poured into ice/water (100 mL). The PH value was adjusted to about 7 with con. HCl. The solid was collected by filtration and dried under infrared light to afford 3-morpholino-2-nitrobenzoic acid (A108, 10.7 g, 42.4 mmol, 85% yield) as a solid. LCMS (ES, m/z): 253 [M+H]+. Synthesis of A109 425 Attorney Docket No.: R2103-7054WO To a stirred sol 08, 10.6 g, 42.0 mmol) in DMF (110 mL) were added K2CO3 (11.6 g, 84.1 mmol) was added MeI (11.9 g, 84.1 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The residue was poured in ice/water (100 mL). The solid was collected by filtration and dried under infrared light to afford methyl 3-morpholino-2-nitrobenzoate (A109, 10 g, 42.3 mmol, 99.8% yield) as a solid. LCMS (ES, m/z): 267 [M+H]+. Synthesis of A110 To a stirred sol A109, 10 g, 37.6 mmol) in MeOH (115 mL) were added Pd/C (4.0 g, 37.6 mmol) at room temperature. The flask was evacuated and flushed with nitrogen (x3), followed by flushing with hydrogen. The mixture was stirred 2 h at room temperature under an atmosphere of hydrogen. The solid was filtered out. The filtrate was concentrated under reduced pressure to afford methyl 2-amino-3-morpholinobenzoate (A110, 6.5 g, 27.5 mmol, 73% yield) as a solid. LCMS (ES, m/z): 237 [M+H]+. Synthesis of A111 426 Attorney Docket No.: R2103-7054WO To a stirred so A110, 6.5 g, 27.5 mmol) in HOAc (65 mL) were added Br2 (5.28 g, 33.0 mmol) at 0°C. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction mixture was slowly poured into ice/water (100 mL) and stirred for 30 minutes. The resulting mixture was extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford methyl 2-amino-5-bromo-3- morpholinobenzoate (A111, 5.6 g, 17.8 mmol, 65% yield) as a solid. LCMS (ES, m/z): 237 [M+H]+. Synthesis of A112 y p , g, 1.3 mmol) and 2-(6-(1H-pyrrol-1-yl)pyridin-3-yl)acetic acid (197.4 mg, 976.3 mmol) in DMF (6 mL) were added T3P (1.2 mL) and pyridine (1.2 mL) at room temperature under N2 atmosphere. The resulting mixture was stirred for 16 h at room temperature. The residue was poured in ice/water (10 mL). The solid was collected by filtration and dried under infrared light to afford methyl 2-(2- (6-(1H-pyrrol-1-yl)pyridin-3-yl)acetamido)-5-bromo-3-morpholino-benzoate (A112, 300 mg, crude) as a solid. LCMS (ES, m/z): 499 [M+H]+. 427 Attorney Docket No.: R2103-7054WO Synthesis of A113 pyridyl)- acetyl]amino]benzoate (A112, 300 mg, 600.8 μmol) in ammonium hydroxide (2.11 g, 60.1 mmol, 2.3 mL) at room temperature, and the reaction was stirred for 16 h at 110°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, quenched with water (10 mL), and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 6-bromo-8-morpholino-2-[(6-pyrrol-1-yl-3-pyridyl)methyl]-3,1-benzoxazin-4- one (A113, 140 mg, crude) as a solid. Synthesis of Compound 303 ) was added AlMe3 (1M in toluene, 0.45 mL, 0.25 mmol, 3 equiv.) in portions, and the reaction was stirred at room temperature for 1 h under nitrogen atmosphere. To the above mixture was added 6- bromo-8-morpholino-2-[(6-pyrrol-1-yl-3-pyridyl)methyl]-3,1-benzoxazin-4-one (A113, 80 mg, 171.2 μmol) in portion, and the reaction was stirred at 110°C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was quenched by addition of water (10 mL) at 0°C and extracted with EtOAc (3 x 5 mL). The combined organic phase was washed with brine (5 mL), and dried over anhydrous Na2SO4, and filtered. The filtrate 428 Attorney Docket No.: R2103-7054WO was concentrated under reduced pressure and purified by Prep-HPLC (Condition 15, Gradient 1) to afford 6-bromo-8-morpholino-2-[(6-pyrrol-1-yl-3-pyridyl)methyl]-3H-quinazolin-4-one (Compound 303, 15 mg, 32.2 μmol, 19% yield) as a solid. LCMS (ES, m/z): 466 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (d, J=1.8 Hz, 1H), 7.84-7.80 (dd, J = 8.4, 1.8 Hz, 1H), 7.66- 7.61 (m, 4H), 6.84 (d, J = 2.4 Hz, 1H), 6.28 (t, J = 2.1 Hz, 2H), 3.83 (s, 2H), 3.58 (t, J = 4.5 Hz, 4H), 3.15 (d, J = 4.5 Hz, 4H). Example 21: Synthesis of Compound 353 Synthesis of A115 100 mg, 254.3 μmol) and tert-butyl piperazine-1-carboxylate (95 mg, 510.1 μmol) in dioxane (2 mL) was added Cs2CO3 (249 mg, 764.2 μmol) and Pd-PEPPSI-IPentCl (22 mg, 26.2 μmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100°C for 16 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford tert-butyl 4-[5-[(6-methoxy-4-oxo- 3H-quinazolin-2-yl)methyl]-2-pyridyl]piperazine-1-carboxylate (A115, 70 mg, 155.0 μmol, 61% yield) as a solid. LCMS (ES, m/z): 452 [M+H]+. Synthesis of Compound 353 y y q y hyl]-2- pyridyl]piperazine-1-carboxylate (A115, 50 mg, 11.1 μmol) in DCM (0.2 mL) was added HCl in dioxane (4 M, 0.2 mL), and the reaction was stirred for 2 h at room temperature under nitrogen 429 Attorney Docket No.: R2103-7054WO atmosphere. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (Condition 12, Gradient 4) to afford 6-methoxy-2-((6-(piperazin-1-yl)pyridin-3-yl)methyl)- quinazolin-4(3H)-one hydrochloride (Compound 353, 32 mg, 82.5 μmol, 57% yield) as a solid. LCMS (ES, m/z): 352 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 2H), 8.29 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 9.4 Hz, 1H), 7.51-7.43 (m, 2H), 7.30 (d, J = 9.2 Hz, 1H), 4.11 (s, 2H), 3.97-3.90 (m, 4H), 3.85 (s, 3H), 3.19 (p, J = 4.6 Hz, 4H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: Step 1 was ran by sh 8, 1- - - d % S, R 96 (s, ), 25 (s, ), ), ), an by sh 8, 6- - n- Attorney Docket No.: R2103-7054WO 2-yl)amino)-6- methoxyquinazolin-4(3H)-one 9, as 7 z, 8 ), 0 s, ), z, = = .4 as y 9, 2- g, d. +. 6) 7 J 7 ), z, ), 8 ), ), 7, .9 Attorney Docket No.: R2103-7054WO Hz, 1H), 2.11 (dt, J = 21.3, 11.1 Hz, 2H), 1.44 (d, J = 12.4 Hz, = as 6 y 6, he 6- g, d. +. 6) ), 1 = m, 1 s, = 5 s, = as y sh 2, 5- Attorney Docket No.: R2103-7054WO (Compound 720, 14 mg, 27.9 μmol, 17% yield) as a solid. +. 6) δ d, m, 4 J .2 z, ), d, = m, Example 22: Synthesis of Compound 394 A mixture of 6-bromo-7-methoxy-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H- quinazolin-4-one (Compound 365, 0.2 g, 470.3 μmol) and cyclopropylboronic acid (101 mg, 1.2 mmol), K3PO4 (299 mg, 1.4 mmol) and Pd(dppf)Cl2 (69 mg, 94 μmol) in dioxane (6 mL) and water (1 mL) was stirred at 80 °C for 16 h. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 6, Gradient 2), followed by Prep- HPLC (Condition 14, Gradient 1) to afford 6-cyclopropyl-7-methoxy-2-[[6-(3-methylpyrrol-1-yl)- 3-pyridyl]methyl]-3H-quinazolin-4-one (Compound 394, 19 mg, 51.8 μmol, 11% yield) as a solid. LCMS (ES, m/z): 387 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.39(s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.6, 2.4 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 2.6 Hz, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.01 (s, 1H), 6.16-6.08 (m, 1H), 3.95 (s, 2H), 3.92 (s, 3H), 2.17-2.09 (m, 1H), 2.07 (s, 3H), 1.02-0.90 (m, 2H), 0.66 (td, J = 6.0, 4.1 Hz, 2H). 433 Attorney Docket No.: R2103-7054WO An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: The reaction was ran p- to 3- de .5 S R = J z, 4 .4 7- an y sh 8, 8- de l, S, R = J m, 7 = z, 434 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran at 80 °C. ed as ed as sh 2, 4- .4 S R s, 1 = = z, 5 ), .2 an ca / 4- g, S, of )2 he O y sh 8, he Attorney Docket No.: R2103-7054WO hydrochloride salt of 2-((7- cyclopropyl-6-methylimidazo[1,2- l, S, R s, 4 ), ), 5, z, n ca / 6- 2, as 6 z, s, 6 .1 . n ca y 6- - g, d. Example 23: Synthesis of Compound 632 436 Attorney Docket No.: R2103-7054WO , 4.5 mmol) in DMAC (8 mL) were added NiCl2 (195 mg, 1.5 mmol) and picolinimidamide hydrochloride (71 mg, 450.9 μmol) under nitrogen atmosphere, and the reaction was stirred for 4 h at 60°C under nitrogen atmosphere. To the above mixture were added 3-bromo-6-isopropoxy- quinoline (400 mg, 1.50 mmol) and Zinc (295 mg, 4.51 mmol) at room temperature under nitrogen atmosphere, and the resulting mixture was stirred for an additional 16 h at 60°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 13) to afford 2-[(6-isopropoxy-3-quinolyl)methyl]-6,7- dimethoxy-3H-quinazolin-4-one (Compound 632, 46.6 mg, 114.9 μmol, 8% yield) as a solid. LCMS (ES, m/z): 406 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.42 (s, 1H), 7.38-7.28 (m, 2H), 7.04 (s, 1H), 4.77 (p, J = 6.0 Hz, 1H), 4.12 (s, 2H), 3.86 (d, J = 2.8 Hz, 6H), 1.33 (d, J = 6.0 Hz, 6H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization by sh 2, 6- - .5 a 2 z, 437 Attorney Docket No.: R2103-7054WO DMSO-d6) δ 12.36 (s, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.10 (d, J = z, m, = = z, y sh 8, 6- d % S, R s, = 1- 9 s, . y n c) 3- g, a 6 z, 1 s, = 438 Attorney Docket No.: R2103-7054WO The residue was purified by silica gel column c) 3- g, a 6 z, 5 = 7 = 9 y sh 2, 7- - g, a 6 z, 0 7 s, ), z, . y n / he 8- g, Attorney Docket No.: R2103-7054WO 121.7 μmol, 8% yield) as a solid. LCMS (ES, m/z): 408 z, z, ), z, ), 7 y sh 2, 7- - - 0 a 8 z, 9 = 3 s, ), 5 y sh 2, 8- - - 0 a 8 z, 7 = z, ), 1 440 Attorney Docket No.: R2103-7054WO (s, 2H), 3.94 (d, J = 3.0 Hz, 6H), 3.85 (d, J = 2.7 Hz, 6H). by n / 7- n- g, as 9 z, 1 = = .5 .2 s, = n he ed M m y sh 2, 7- g, a 2 z, m, – 6 = Attorney Docket No.: R2103-7054WO The residue was purified by reversed-phase flash 7, 3- n- .0 d. ]+. 6) 35 ), 90 ), Example 24: Synthesis of Compound 379 Synthesis of A127 , 7, 500 mg, 1.83 mmol) and 2-amino-4,5-dimethoxy-benzonitrile (326 mg, 1.83 mmol) in THF (10 mL) was added LiHMDS (1 M in THF, 4.6 mL), and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford N-(2-cyano-4,5- dimethoxy-phenyl)-2-(5,6-dichloro-1H-benzimidazol-2-yl)acetamide (A127, 300 mg, 740.3 μmol, 40% yield) as a solid. LCMS (ES, m/z): 405 [M+H]+. 442 Attorney Docket No.: R2103-7054WO Synthesis of Compound 379 ro-1H- benzimidazol-2-yl)-acetamide (120 mg, 296.1 μmol) in DMSO (3 mL) were added NaOH (2 M, 1 mL) and 30% H2O2 (1 mL), and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched with saturated sodium thiosulfate solution at 0°C. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 9) to afford 2-((5,6-dichloro-1H-benzo[d]imidazol-2- yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 379, 9 mg, 20.4 μmol) as a solid. LCMS (ES, m/z): 405 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 2H), 7.43 (s, 1H), 7.02 (s, 1H), 4.50 (s, 2H), 3.84 (d, J = 8.0 Hz, 6H). Example 25: Synthesis of Compound 478 Synthesis of A130 N O HN Br O Br To a stirred mixture of 2-(chloromethyl)-6,7-dimethoxy-3H-quinazolin-4-one (A129, 1 g, 3.93 mmol) and 4-bromo-2H-triazole (581.0 mg, 3.93 mmol) in DMF (10 mL) was added Cs2CO3 (3.8 g, 11.78 mmol), and the reaction was ran at room temperature for 16 h. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash 443 Attorney Docket No.: R2103-7054WO chromatography (Condition 2, Gradient 42) to afford 2-[(4-bromotriazol-2-yl)methyl]-6,7- dimethoxy-3H-quinazolin-4-one (A130, 72 mg, 196.6 μmol, 5% yield) as a solid. LCMS (ES, m/z): 366 [M+H]+. Synthesis of Compound 478 -4-one (A130, 88 mg, 241.1 μmol) and (3,5-difluorophenyl)boronic acid (38.1 mg, 241.1 μmol) and XPhos Pd G3 (5.8 mg, 6.8 μmol), K3PO4 (153.3 mg, 723 μmol) in dioxane (2 mL) were stirred for 16 h at 100°C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature, concentrated under reduced pressure, and purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 2-[[4-(3,5-difluorophenyl)triazol-2- yl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 478, 4.2 mg, 10.5 μmol, 15% yield). LCMS (ES, m/z): 400 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.49 (s, 1H), 7.64-7.58 (m, 2H), 7.44 (s, 1H), 7.36-7.25 (m, 1H), 6.97 (s, 1H), 5.66 (s, 2H), 3.86 (s, 6H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization M ifi i 1 i t- 16 el in p- to )- 0, d. R 444 Attorney Docket No.: R2103-7054WO (400 MHz, DMSO-d6) δ 7.84 (d, J = 1.2 Hz, 1H), 7.78 (s, 1H), 7.49-7.41 (m, 2H), (s, t- 16 C 2- l- de ol, ): z, d, ), d, (s, s, Example 26: Synthesis of Compound 495 n-4-one (Compound 423, 170 mg, 441.1 umol) and NaH (141.1 mg, 3.53 mmol) in THF (3 mL) was added Ac2O (270.2 mg, 2.65 mmol) dropwise, and the reaction was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 21) to afford 2-[(9-acetylcarbazol-2-yl)methyl]-6,7-dimethoxy-3H-quinazolin-4-one hydrochloride 445 Attorney Docket No.: R2103-7054WO (Compound 495, 10 mg, 23.4 μmol, 2% yield) as a solid. LCMS (ES, m/z): 428 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 2.9 Hz, 1H), 8.15 (d, J = 3.3 Hz, 1H), 7.51 (td, J = 7.7, 5.4 Hz, 2H), 7.45-7.39 (m, 2H), 7.14 (s, 1H), 4.16 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.91 (s, 3H). Example 27: Synthesis of Compound 393 so ut on o 6-bromo-7-met oxy- -[[6-(3-met y pyrro - -y )-3-pyrdy ]met y ]-3H- quinazolin-4-one (Compound 365, 0.2 g, 470.3 μmol), 1M diisopropylzinc in toluene (0.94 mL, 940.6 μmol), Pd-PEPPSI-IPentCl (75 mg, 94.1 μmol) and Cs2CO3 (307 mg, 940.6 μmol) in dioxane (5 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 6, Gradient 3), followed by Prep-HPLC (Condition 2, Gradient 3) to afford 6-isopropyl- 7-methoxy-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H-quinazolin-4-one (Compound 393, 0.032 g, 82.4 μmol, 18% yield) as a solid. LCMS (ES, m/z): 389 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.88-7.74 (m, 2H), 7.63-7.50 (m, 2H), 7.41 (s, 1H), 7.00 (s, 1H), 6.12 (dd, J = 3.0, 1.7 Hz, 1H), 3.94 (s, 2H), 3.89(s, 3H), 3.25 (q, J = 6.8 Hz, 1H), 2.07 (d, J = 1.0 Hz, 3H), 1.20 (d, J = 6.9 Hz, 6H). Example 28: Synthesis of Compound 547 A mixture of 7-bromo-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6-methoxy-3H- quinazolin-4-one (Compound 551, 130 mg, 283.7 μmol) and methylsulfinyloxysodium (57.9 mg, 567.4 μmol) and N,N’-dimethylethane-1,2-diamine (5 mg, 56.7 μmol) in DMF (2 mL) were added 446 Attorney Docket No.: R2103-7054WO CuI (11 mg, 56.7 μmol) and stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 30) to afford 2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6-methoxy-7- methylsulfonyl-3H-quinazolin-4-one (Compound 547, 14.8 mg, 32.4 μmol, 9% yield) as a solid. LCMS (ES, m/z): 458 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.96 (s, 2H), 7.85-7.79 (m, 2H), 7.74 (s, 1H), 7.43-7.27 (m, 1H), 4.10 (s, 2H), 4.05 (s, 3H), 3.33 (s, 3H). Example 29: Synthesis of Compound 451 To a solution of 6-bromo-2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-7-methoxy- quinazolin-4(3H)-one (Compound 433, 0.15 g, 0.43 mmol) in 2 M MeNH2 in THF (3 mL) were added BrettPhos Pd G3 (0.03 g, 0.03 mmol), NaOt-Am (0.11 g, 0.98 mmol), and the reaction was stirred for 16 h at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 4) to afford 2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-7-methoxy-6- (methylamino)quinazolin-4(3H)-one (Compound 451, 12.1 mg, 0.03 mmol, 9% yield) as a solid. LCMS (ES, m/z): 409 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.85-7.75 (m, 2H), 7.32 (ddd, J = 9.2, 6.8, 2.4 Hz, 1H), 7.07 (s, 1H), 6.89 (s, 1H), 4.17 (s, 2H), 3.92 (s, 3H), 2.77 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Attorney Docket No.: R2103-7054WO Modification: The reaction was ran using Me2N in THF. by 2, 8- 0, d) 91 z, 22 = z, ), s, ), (s, Example 30: Synthesis of Compound 577 xo- 3H-quinazoline-7-carboxylic acid (A156, 100 mg, 236.2 μmol) and O-methyl hydroxyl lamine hydrochloride (59 mg, 708.6 μmol) in DMF (2 mL) were added TEA (71 mg, 708.6 μmol) and HOBT (54 mg, 354.3 μmol) and EDCI (67 mg, 354.3 μmol) in portions, and the reaction was stirred at room temperature for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 36) to afford 2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-N,6-dimethoxy-4-oxo-3H- 448 Attorney Docket No.: R2103-7054WO quinazoline-7-carboxamide (Compound 577, 3.5 mg, 7.7 μmol, 3% yield) as a solid. LCMS (ES, m/z): 391 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.53 (s, 1H), 8.69 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.93-7.88 (m, 1H), 7.85-7.77 (m, 2H), 7.62 (s, 1H), 7.55 (s, 1H), 7.36- 7.27 (m, 1H), 4.04 (s, 2H), 3.91 (s, 3H), 3.71 (s, 3H). Example 31: Synthesis of Compound 465 3H- quinazolin-4-one (Compound 466, 100 mg, 259.5 μmol) in tetrahydropyran-4-ol (2 mL) was added t-BuOK (116.4 mg, 1.04 mmol), and the reaction was stirred for 12 h at 100℃. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 16) to afford 2-((6-(3,5-difluorophenyl)pyridin-3- yl)methyl)-6-fluoro-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(3H)-one hydrochloride (Compound 465, 20 mg, 39.7 μmol, 15% yield) as a solid. LCMS (ES, m/z): 468 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 2.0 Hz, 1H), 8.12 (q, J = 8.3 Hz, 2H), 7.73 (dd, J = 9.3, 5.5 Hz, 3H), 7.30 (t, J = 8.9 Hz, 2H), 4.77 (dt, J = 9.7, 5.0 Hz, 1H), 3.80 (dt, J = 11.5, 4.5 Hz, 2H), 3.53-3.39 (m, 2H), 2.51 (s, 1H), 2.03-1.93 (m, 2 ), 1.60 (dtd, J = 13.0, 9.1, 8.6, 3.7 Hz, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization on ed sh 7) 6- - 449 Attorney Docket No.: R2103-7054WO 3H-quinazolin-4-one hydrochloride g, a ): R δ ), = m, z, ), ), m, z, d, Example 32: Synthesis of Compound 521 oxy- 3H-quinazolin-4-one (Compound 500, 400 mg, 966.6 μmol) in MsOH (10 mL) was added DL- methionine (1.5 g, 9.6 mmol), and the reaction was stirred for 16 h at 120 ℃. The resulting mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 25) to afford 6- chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7-hydroxy-3H-quinazolin-4-one (Compound 521, 150 mg, 375.2 μmol, 39% yield) as a solid. LCMS (ES, m/z): 400 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.01-7.91 (m, 2H), 7.86-7.77 (m, 2H), 7.40-7.27 (m, 1H), 7.12 (s, 1H), 4.07 (s, 2H). Example 33: Synthesis of Compound 562 450 Attorney Docket No.: R2103-7054WO so ut on o 6-bromo-7-met oxy- -[[6-(3-met y pyrro - -y )-3-pyrdy ]met y ]-3H- quinazolin-4-one (Compound 365, 0.2 g, 470.3 μmol), 1-vinyloxybutane (141 mg, 1.41 mmol), TEA (143 mg, 1.41 mmol), Pd(AcO)2 (21 mg, 94.1 μmol) and dppp (39 mg, 94.1 μmol) in Ethylene glycol, 99% (4 mL) was stirred at 120 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 3 with 1 M HCl (1.5 mL). The mixture was stirred at room temperature for 1 h. The mixture was poured into ice water. The resulting mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC (Condition 2, Gradient 3) to afford 6-acetyl-7-methoxy-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H-quinazolin-4-one (Compound 562, 0.006 g, 15.5 μmol, 3% yield) as a solid. LCMS (ES, m/z): 389 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.47(s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.86 (d, J = 10.6 Hz H), 7.64-7.51 (m, 2H), 7.41 (s, 1H), 7.14 (s, 1H), 6.13 (s, 1H), 3.98 (s, 5H), 2.56 (s, 3H), 2.08 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Th id ifi d by n c p- nt 6- - d % S, R δ .3 Attorney Docket No.: R2103-7054WO Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 8.2, 2.3 Hz, 62 4 s, To the solution of 6-acetyl-7-methoxy-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H- quinazolin-4-one (Compound 562, 0.1 g, 257.5 μmol) in MeOH (2 mL) was added NaBH4 (29 mg, 772 μmol) at 0 °C, and the reaction was stirred at room temperature for 2 h. The reaction was quenched with water and purified by reversed-phase flash chromatography (Condition 8, Gradient 7) to afford 6-(1-hydroxyethyl)-7-methoxy-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H- quinazolin-4-one (Compound 561, 0.012 g, 30.7 μmol, 12% yield) as a solid. LCMS (ES, m/z): 391 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 0.8 Hz, 1H), 7.85 (dd, J = 8.6, 2.4 Hz, 1H), 7.64-7.50 (m, 2H), 7.41 (s, 1H), 6.99 (s, 1H), 6.16- 6.09 (m, 1H), 5.20 (d, J = 4.6 Hz, 1H), 5.03-4.93 (m, 1H), 3.95 (s, 2H), 3.89 (s, 3H), 2.07 (d, J = 1.1 Hz, 3H), 1.28 (d, J = 6.3 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization by g 8, 1- g, a 2 Attorney Docket No.: R2103-7054WO [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 23 z, = ), .2 ), 0 a p e : y es s o o pou hoxy- 3H-quinazolin-4-one (Compound 551, 130 mg, 283.7 μmol), methylphosphonoylmethane (22.1 mg, 283.7 μmol) and Xantphos (16.4 mg, 28.4 μmol) in DMF (2 mL) were added TEA (86.1 mg, 851.1 μmol), and the reaction was stirred for 16 h at 110°C under a nitrogen atmosphere. The reaction was allowed to cool down to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 43) to afford 2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7-dimethyl-phosphoryl-6-methoxy-3H- quinazolin-4-one (Compound 572, 12.6 mg, 27.7 μmol, 10% yield) as a solid. LCMS (ES, m/z): 454 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.98-7.89 (m, 2H), 7.85-7.77 (m, 2H), 7.58 (d, J = 5.2 Hz, 1H), 7.31 (tt, J = 9.3, 2.4 Hz, 1H), 4.07 (s, 2H), 3.97 (s, 3H), 1.71 (s, 3H), 1.67 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization 453 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran using Cs2CO3 in place of by sh 8, 6- 4- de .6 d. ]+. δ s, .8 s, ), Example 36: Synthesis of Compound 595 , oxo- 3H-quinazoline-7-carboxylic acid (A156, 120 mg, 283.4 μmol) and NH4Cl (15.2 mg, 283.4 μmol) in DMF (2 mL) were added HATU (323.3 mg, 850.3 μmol) and DIEA (54.9 mg, 425.2 μmol), and the reaction was ran for 2 h at room temperature. The reaction solution was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 9) to afford 2-((6-(3,5-difluorophenyl)pyridin-3- yl)methyl)-6-methoxy-4-oxo-3,4-dihydroquinazoline-7-carboxamide hydrochloride (Compound 454 Attorney Docket No.: R2103-7054WO 595, 11.5 mg, 27.2 μmol, 10% yield) as a solid. LCMS (ES, m/z): 423 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.87-7.78 (m, 4H), 7.73 (s, 1H), 7.59 (s, 1H), 7.33 (t, J = 9.3 Hz, 1H), 4.13 (s, 2H), 3.95 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: The reaction was h. by 2, 7- de .7 d. ]+. 6) ), 5- 2, 79 ), 85 an by 3, o- - n- .7 d. ]+. 6) ), z, Attorney Docket No.: R2103-7054WO 1H), 7.25 (s, 1H), 7.09 (d, J = 2.4 Hz, 1H), 4.06 (s, 2H), 3.32 s, ), = ed y 3, o- - d % S, 6) ), 1 = z, ), .4 J .1 ), 6 = .9 ), 5 z, 456 Attorney Docket No.: R2103-7054WO Modification: The reaction used 3 equiv. of DIEA. by 3, o- r n- - g, a 50 z, 30 J 07 ), .0 J .1 z, .1 Example 37: Synthesis of Compound 617 , thoxy- 3H-quinazolin-4-one (Compound 551, 200 mg, 436.4 μmol) and methanesulfonamide (124 mg, 1.3 mmol) in DMF (6 mL) were added BrettPhos Pd G3 (39 mg, 43.6 μmol) and K2CO3 (181 mg, 1.3 mmol) in portions, and the reaction was stirred at 80°C for 16 h under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted 457 Attorney Docket No.: R2103-7054WO with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 36) to afford N-[2-[[6-(3,5-difluorophenyl)-3- pyridyl]methyl]-6-methoxy-4-oxo-3H-quinazolin-7-yl]methanesulfonamide (Compound 617, 14 mg, 29.6 μmol, 7% yield) as a solid. LCMS (ES, m/z): 473 [M+H]+.1H NMR (300 MHz, DMSO- d6) δ 12.42 (s, 1H), 9.37 (s, 1H), 8.70 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.51 (d, J = 1.7 Hz, 2H), 7.37-7.28 (m, 0H), 4.03 (s, 2H), 3.93 (s, 3H), 3.12 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: The reaction was y sh 2, 6- .9 d. +. 6) .1 ), = ), z, ), 458 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran at 70 °C using tBuBrettPhos e. y sh 8, he 6- .2 d. +. 6) .2 ), 6 s, s, .7 ). as os e. 7- . 6) Attorney Docket No.: R2103-7054WO 1H), 7.42 (s, 1H), 7.00 (s, 1H), 4.21 (s, 2H), 3.85 (d, J = 1.2 Hz, as 3 y o- g 8, 6- e 7, as 7 z, 9 ), ), - 5 s, = .0 .9 ). as st y sh 8, he 6- - Attorney Docket No.: R2103-7054WO (Compound 780, 8 mg, 17.1 μmol, 5% yield) as a solid. +. 6) ), s, ), z, ), a p e : y es s o o pou no]-5- methoxy-benzamide (A258, 10 mg, 19.9 μmol) and 2 M NaOH (0.5 mL) in MeOH (0.5 mL) was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 23) to afford 7-benzyloxy-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6-methoxy-3H-quinazolin-4-one (Compound 457, 8.2 mg, 16.9 μmol) as a solid. LCMS (ES, m/z): 486 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.70~12.0 (br, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.87 (dd, J = 8.2, 2.3 Hz, 1H), 7.83-7.74 (m, 2H), 7.49-7.24 (m, 7H), 7.10 (s, 1H), 5.20 (s, 2H), 3.98 (s, 2H), 3.85 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization by sh 2, 7- Attorney Docket No.: R2103-7054WO quinolyl)methyl]-3H-quinazolin- 4-one (Compound 552, 12 mg, d. H δ 3- .0 .5 .3 ), s, xamp e : yn es s o ompoun Synthesis of A188 xy-3H- quinazolin-4-one (Compound 457, 500 mg, 1.03 mmol), N,N-diphenylcarbamoyl chloride (477 mg, 2.06 mmol) and DIEA (266 mg, 2.06 mmol) in pyridine (10 mL) was stirred for 1 h at 100°C. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 12) to afford [7-benzyloxy-2-[[6-(3,5- difluorophenyl)-3-pyridyl]methyl]-6-methoxy-quinazolin-4-yl]-N,N-diphenylcarbamate (A188, 300 mg, 440.7 μmol, 43% yield) as a solid. LCMS (ES, m/z): 681 [M+H]+. Synthesis of A189 462 Attorney Docket No.: R2103-7054WO hyl]-6- methoxy-quinazolin-4-yl]-N,N-diphenylcarbamate (A188, 250 mg, 367.3 μmol) in MeOH (5 mL) was added Pd/C (100 mg, 939.7 μmol) in portions. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 1 h at room temperature. The resulting mixture was filtered through a Celite pad, the filter cake was washed with MeOH (2 x 20 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford [2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7-hydroxy-6-methoxy- quinazolin-4-yl]-N,N-diphenylcarbamate (A189, 150 mg, 254 μmol, 69% yield) as a solid. LCMS (ES, m/z): 591 [M+H]+. Synthesis of A190 , y y y y y y ethoxy- quinazolin-4-yl]-N,N-diphenylcarbamate (A189, 150 mg, 254.0 μmol), tetrahydropyran-4-ol (51 mg, 499.4 μmol) and CMBP (122 mg, 505.5 μmol) in toluene (2 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 13) to afford [2-[[6-(3,5- difluorophenyl)-3-pyridyl]methyl]-6-methoxy-7-tetrahydropyran-4-yloxy-quinazolin-4-yl]-N,N- 463 Attorney Docket No.: R2103-7054WO diphenylcarbamate (A190, 90 mg, 133.4 μmol, 53% yield) as a solid. LCMS (ES, m/z): 675 [M+H]+. Synthesis of Compound 499 -7- ol) and HSiEt3 (0.1 mL) in DCE (1 mL) was added TFA (45.6 mg, 400.2 μmol), and the reaction was stirred for 4 h at 80°C. The resulting mixture was concentrated under reduced pressure and purified by HPLC (Condition 12, Gradient 8) to afford 2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6- methoxy-7-tetrahydropyran-4-yloxy-3H-quinazolin-4-one (Compound 499, 33.8 mg, 70.5 μmol, 53% yield) as a solid. LCMS (ES, m/z): 480 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 8.3, 2.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.44 (s, 1H), 7.33 (tt, J = 9.1, 2.4 Hz, 1H), 7.19 (s, 1H), 4.78 (dt, J = 9.0, 4.7 Hz, 1H), 4.06 (s, 2H), 3.90-3.80 (m, 5H), 3.51 (td, J = 11.6, 10.7, 2.6 Hz, 2H), 2.00-1.98 (m, 2H), 1.69-1.57 (m, 2H). An analogous method was followed to obtain the following compounds. Compounds Starting Characterization C 2- - .7 S R ), = Attorney Docket No.: R2103-7054WO 8.2 Hz, 1H), 7.99 (dd, J = 8.3, 2.3 Hz, 1H), 7.87-7.77 (m, 2H), 7.45 (s, 1H), s, s, ), ), = ), d- y 2- - 5 S, 0 .2 3 7 m, ), 8- 2 = .5 ut d- y 2- - 1 S R ), ), ), Attorney Docket No.: R2103-7054WO 7.33 (s, 3H), 5.27 (s, 2H), 4.21 (s, 3H), 3.88 (s, 5H), 3.56 (s, 1H), 3.35 (s, 2H), ), C d- y 2- .1 d. H .3 7 2, 8 ), 3 7 1 0 4 d- y 7- de l, ): z, J J .3 s, 9 6 Attorney Docket No.: R2103-7054WO (d, J = 5.9 Hz, 2H), 0.92 (d, J = 5.9 Hz, 2H). ut d- y 2- .4 S R ), ), 3 6 2 1 .3 ut e- y 2- - n- .5 S, 0 .2 7 4 m, 2 8 7 467 Attorney Docket No.: R2103-7054WO Modification: Step 4 was ran without Et3SiH. p- to 3- - 4- .4 S R = ), 3- z, ), = ), m, m, ut d- y 2- 4- .5 S R ), = 4 1- s, s, 468 Attorney Docket No.: R2103-7054WO Modification: Step 4 was ran without Et3SiH, for 2 h. d- y rd )- 2, S R ), = ), ), d- y 2- 0 S R ), ), = ), 9 3 = z, t d- y 7- 6- Attorney Docket No.: R2103-7054WO methyl]-6-methoxy-3H-quinazolin-4- one (Compound 647, 6.3 mg, 9.9 ): z, ), = ), 05 83 01 m, ), ). ut d- 6- 5 ), 0 Example 40: Synthesis of Compound 610 Synthesis of A191 470 Attorney Docket No.: R2103-7054WO ethoxy- quinazolin-4-yl]-N,N-diphenylcarbamate (A189, 100 mg, 169.3 μmol), tert-butyl 4- iodopiperidine-1-carboxylate (105 mg, 337.5 μmol) and K2CO3 (50 mg, 361.8 μmol) in CH3CN (1 mL) was stirred for 1 h at 60°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 13) to afford tert-butyl 4-[2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-4- (diphenylcarbamoyloxy)-6-methoxy-quinazolin-7-yl]oxypiperidine-1-carboxylate (A191, 30 mg, 38.8 μmol, 23% yield) as a solid. LCMS (ES, m/z): 735 [M+H]+. Synthesis of Compound 610 To a mixture of tert-butyl 4-[2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-4- (diphenylcarbamoyloxy)-6-methoxy-quinazolin-7-yl]oxypiperidine-1-carboxylate (A191, 30 mg, 38.8 μmol) and triethylsilane (9 mg, 77.4 μmol) in DCE (0.5 mL) was added TFA (25 mg, 219.3 μmol), and the reaction was stirred for 4 h at 80°C. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC (Condition 12, Gradient 8) to afford 2-((6-(3,5- 471 Attorney Docket No.: R2103-7054WO difluorophenyl)pyridin-3-yl)methyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4(3H)-one hydrochloride (Compound 610, 7.4 mg, 14.4 μmol, 37% yield) as a solid. LCMS (ES, m/z): 735 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.84 (d, J = 13.1 Hz, 2H), 8.71 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.92 (dd, J = 8.3, 2.2 Hz, 1H), 7.86-7.78 (m, 2H), 7.46 (s, 1H), 7.33 (tt, J = 9.2, 2.4 Hz, 1H), 7.24 (s, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.06 (s, 2H), 3.87 (s, 3H), 3.22 (s, 2H), 3.08 (s, 2H), 2.13 (d, J = 14.0 Hz, 2H), 1.86 (d, J = 9.5 Hz, 2H). Example 41: Synthesis of Compound 620 Synthesis of A192 oxy- 3H-quinazolin-4-one (Compound 551, 200 mg, 436.4 μmol) and tert-butyl 3-aminopyrrolidine- 1-carboxylate (162 mg, 872.9 μmol) in DMF (4 mL) were added Ruphos (102 mg, 218.2 μmol), RuPhos Pd G3 (73 mg, 87.3 μmol) and Cs2CO3 (426 mg, 1.3 mmol) in portions, and the reaction was stirred at 100°C for 16 h under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc) to afford tert-butyl 3-[[2-[[6-(3,5-difluorophenyl)-3- pyridyl]methyl]-6-methoxy-4-oxo-3H-quinazolin-7-yl]amino]pyrrolidine-1-carboxylate (A192, 150 mg, 266.2 μmol, 61% yield) as a solid. LCMS (ES, m/z): 564 [M+H]+. Synthesis of Compound 620 Attorney Docket No.: R2103-7054WO To a stirred solution of tert-butyl3-[[2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6- methoxy-4-oxo-3H-quinazolin-7-yl]amino]pyrrolidine-1-carboxylate (A192, 140 mg, 248.4 μmol) in DCM (3 mL) was added 4M HCl (gas) in dioxane (6 mL) dropwise, and the reaction was stirred for 2 h at room temperature. The reaction solution was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 18) to afford 2-((6- (3,5-difluorophenyl)pyridin-3-yl)methyl)-6-methoxy-7-(pyrrolidin-3-ylamino)quinazolin-4(3H)- one dihydrochloride (Compound 620, 35 mg, 75.5 μmol, 30% yield) as a solid. LCMS (ES, m/z): 464 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 9.23 (d, J = 37.4 Hz, 2H), 8.85 (s, 1H), 8.11 (s, 2H), 7.90-7.77 (m, 2H), 7.40-7.29 (m, 2H), 6.84 (s, 1H), 6.61 (s, 1H), 4.23 (s, 3H), 3.93 (s, 3H), 3.59-3.42 (m, 1H), 3.29 (s, 3H), 2.28 (dd, J = 13.2, 7.3 Hz, 1H), 2.02 (s, 1H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material se 8, 3- g, S 00 (s, 81 z, ), 9- se 8, alt 6- - % ): O- = ), Attorney Docket No.: R2103-7054WO 7.34 (d, J = 6.3 Hz, 2H), 6.79 (s, 1H), 4.18 (s, 2H), 3.87 (s, 3H), 3.82(m,1H),3.57 (m, 4H 22 1H 2 1H se 8, 3- .1 S, z, m, ), 21 - ng at se 8, 5- - g, S 00 (s, = 33 - (s, ng at se 8, de 3- - ol, 82 Attorney Docket No.: R2103-7054WO [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.70 (s, 1H), 8.83 (t, J = 1.5 H 1H 14 1 2H m, 39 ), m, ng at se 8, de 3- n- ol, 82 δ d, ), z, ), 93 ng in C 1- % 96 4) .0 z, ), 50 = 475 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used GPhos Pd G6 as catalyst and tBuONa as base in dioxane l 2 d TFA/D M 1:2 m se 8, de 1- - % z): O- ), ), ), (s, ), I- nt. ic to se 2, 1- o- % 68 δ z, d, ), ), 20 476 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used XantPhos Pd G3 as catalyst and tBuONa as base in dioxane l C he 6- ol, ): z, 92 (s, (s, J .6 ), ), J as :2 m se 2, 1- o- % 31 δ z, = ), .4 z, 477 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used Pd-PEPPSI- IPentCl as catalyst. Step 2 used TFA/DCM 12 l i i 2 h om se 2, 5- a H = 90 ), ), .4 z, 3- 71 I- °C p- rd - g, S 00 , J 93 .5 = 87 ), .0 63 ), z, 478 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used Pd-PEPPSI- IPentCl as catalyst at 90 ºC over 2 h. Th id ifid b d hse 2, o- - % 41 δ 26 z, 34 I- % 479 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used Pd-PEPPSI- IPentCl as catalyst at 80 ºC. Step 2 used TFA/D M 1 l i i 2 h se 2, 5- )- ol, 10 δ z, 1- 01 (s, 3- , J ), I- ed he 7- - a ep S, 480 Attorney Docket No.: R2103-7054WO Modifications: Step 1 used Pd-PEPPSI- IPentCl as catalyst. Th i i ed he 7- - 55 in er 50 I- ed o- - ), ep n. 481 Attorney Docket No.: R2103-7054WO Modification: Step 1 used Pd-PEPPSI- IPentCl as catalyst. Th li i ed o- - ), ep n. I- ed o- % ic n. 482 Attorney Docket No.: R2103-7054WO Modification: Step 1 used Pd-PEPPSI- IPentCl as catalyst. Th li i ed o- % ic n. I- ed o- ), ep n. 483 Attorney Docket No.: R2103-7054WO Modification: Step 1 used Pd-PEPPSI- IPentCl as catalyst. Th li i ed o- d), ep n. I- ed o- d), ep n. 484 Attorney Docket No.: R2103-7054WO Modification: Step 1 used Pd-PEPPSI- IPentCl as catalyst. Th li i ed o- d), ep n. I- ed 7- - .8 xt er 78 485 Attorney Docket No.: R2103-7054WO Modification: Step 1 used Pd-PEPPSI- IPentCl as catalyst. Th i i ed 7- a ic n. I- ed 7- a ic n. Example 42: Synthesis of Compound 604 Synthesis of A193 486 Attorney Docket No.: R2103-7054WO lin-4- one (150 mg, 351.9 μmol) and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrazole (146.8 mg, 527.8 μmol) in dioxane (3 mL) and H2O (0.6 mL) were added K3PO4 (224.0 mg, 1.06 mmol) and Pd(dppf)Cl2 (25.7 mg, 35.2 μmol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 6,7- dimethoxy-2-[[8-(1-tetrahydropyran-2-ylpyrazol-4-yl)-3-quinolyl]methyl]-3H-quinazolin-4-one (A193, 100 mg, 201 μmol, 57% yield) as a solid. LCMS (ES, m/z): 498 [M+H]+. Synthesis of Compound 604 , y y y y y -4-yl)-3- quinolyl]methyl]-3H-quinazolin-4-one (A193, 100 mg, 201 μmol) in DCM (1 mL) was added TFA (1 mL), and the reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC (Condition 12, Gradient 12) to afford 2-((8-(1H-pyrazol-4-yl)quinolin-3-yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 604, 40.9 mg, 90.9 μmol, 45% yield) as a solid. LCMS (ES, m/z): 414 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 9.10 (d, J = 2.6 Hz, 1H), 8.53-8.46 (m, 2H), 8.47 (s, 487 Attorney Docket No.: R2103-7054WO 1H), 8.06 (dd, J = 7.3, 1.4 Hz, 1H), 7.90-7.81 (m, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.45 (s, 1H), 7.18 (s, 1H), 4.36 (s, 2H), 3.88 (d, J = 1.2 Hz, 6H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization The residue was purified by Prep- to 5- 22 d. H 37 .2 z, ), = J s, Example 43: Synthesis of Compound 570 Synthesis of A194 , y-6- methoxy-3H-quinazolin-4-one (85 mg, 215.0 μmol) and tert-butyl 4-(iodomethyl)piperidine-1- carboxylate (105 mg, 322.9 μmol) in DMSO (1 mL) was added Cs2CO3 (140 mg, 429.7 μmol), and the reaction was stirred for 1 h at 60 °C. The residue was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 8) to afford tert-butyl 4-[[2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6-methoxy-4-oxo-3H-quinazolin-7- 488 Attorney Docket No.: R2103-7054WO yl]oxymethyl]piperidine-1-carboxylate (A194, 60 mg, 101.2 μmol, 47% yield) as a solid. LCMS (ES, m/z): 593 [M+H]+. Synthesis of Compound 498 -4- oxo-3H-quinazolin-7-yl]oxymethyl]piperidine-1-carboxylate (A194, 60 mg, 101.2 μmol) in HCl (0.6 mL, 4.0 M in 1,4-dioxane), and the reaction was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 14) to afford 2-[[6-(3,5-difluorophenyl)-3-pyridyl]- methyl]-6-methoxy-7-(4-piperidylmethoxy)-3H-quinazolin-4-one (Compound 570, 14.6 mg, 29.6 μmol, 29% yield) as a solid. LCMS (ES, m/z): 493 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 9.13 (d, J = 11.1 Hz, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.72 (d, J = 11.1 Hz, 1H), 8.12 (t, J = 1.6 Hz, 2H), 7.84 (dt, J = 7.5, 2.2 Hz, 2H), 7.46 (s, 1H), 7.35 (tt, J = 9.1, 2.4 Hz, 1H), 7.28 (s, 1H), 4.24 (s, 2H), 4.00 (d, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.27 (s, 2H), 2.90 (q, J = 12.2, 11.8 Hz, 2H), 2.55 (s, 1H), 1.93 (d, J = 13.3 Hz, 1H), 1.55 (d, J = 11.0 Hz, 2H), 1.49 (d, J = 10.8 Hz, 2H). Example 44: Synthesis of Compound 615 Synthesis of A197 , y y y y y 3H- quinazolin-4-one (Compound 551, 520 mg, 1.13 mmol) and MeNaS (119.3 mg, 1.7 mmol) and DIEA (733.3 mg, 5.7 mmol) and XantPhos (196.9 mg, 340.4 μmol) and Pd2(dba)3 (311.7 mg, 340.4 μmol) in dioxane (5 mL) were stirred for 16 h at 110 °C under nitrogen atmosphere. The 489 Attorney Docket No.: R2103-7054WO reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6-methoxy-7- methylsulfanyl-3H-quinazolin-4-one (A197, 100 mg, 235.1 μmol, 21% yield) as a solid. LCMS (ES, m/z): 426 [M+H]+. Synthesis of Compound 615 o a st rred m xture o -[[6-(3,5-d uorop eny )-3-pyrdy ]met y ]-6-met oxy-7-methyl- sulfanyl-3H-quinazolin-4-one (A197, 100 mg, 235.1 μmol) in EtOH (1 mL) was added PhI(OAc)2 (227.1 mg, 705.1 μmol) and NH4OAc (72.5 mg, 940.2 μmol) were stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure and purified by reversed- phase flash chromatography (Condition 8, Gradient 31) to afford 2-[[6-(3,5-difluorophenyl)-3- pyridyl]methyl]-6-methoxy-7-(methylsulfonimidoyl)-3H-quinazolin-4-one (Compound 615, 13.1 mg, 28.7 μmol, 12% yield) as a solid. LCMS (ES, m/z): 457 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.1 Hz, 1H), 8.16-8.05 (m, 2H), 8.05-7.97 (m, 1H), 7.88-7.79 (m, 3H), 7.42-7.29 (m, 1H), 4.16 (s, 2H), 4.11 (d, J = 5.6 Hz, 3H), 3.89 (d, J = 6.0 Hz, 3H). Example 45: Synthesis of Compound 528 Synthesis of A201 Attorney Docket No.: R2103-7054WO To a stirred solution of 8-bromo-7-fluoro-quinoline (1 g, 4.42 mmol) in HOAc (13 mL) was added NIS (1.09 g, 4.87 mmol), and the reaction was stirred for 2 h at 100 °C. The resulting mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (20% EtOAc in PE) to afford 8-bromo-7-fluoro-3-iodo-quinoline (A201, 1 g, 2.84 mmol, 64% yield) as a solid. LCMS (ES, m/z): 352 [M+H]+. Synthesis of A202 To a mol) and bromo- (2-tert-butoxy-2-oxo-ethyl)zinc (1.78 g, 6.82 mmol) in THF (16 mL) was added QPhos Pd G3 (244.7 mg, 227.3 μmol), and the reaction was stirred for 16 h at 70 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-(8-bromo-7-fluoro-3-quinolyl)acetate (A202, 450 mg, 1.32 mmol, 58% yield) as a solid. LCMS (ES, m/z): 340 [M+H]+. Synthesis of A203 A so u o o e - u y - - o o- - uo o- -qu o y ace a e , 450 mg, 1.32 mmol) and TFA (5 mL) in DCM (5 mL) was stirred for 2 h at room temperature. The mixture was neutralized to pH 7 with NH3 (g) in MeOH. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 10) to afford 491 Attorney Docket No.: R2103-7054WO 2-(8-bromo-7-fluoro-3-quinolyl)acetic acid (A203, 300 mg, 1.06 mmol, 80% yield) as a solid. LCMS (ES, m/z): 284 [M+H]+. Synthesis of A204 mg, 1.06 mmol) and 2-amino-4,5-dimethoxy-benzamide (248.6 mg, 1.27 mmol) in DMF (6 mL) were added T3P (50 wt. % in EtOAc) (1.01 g, 1.58 mmol) and pyridine (167.1 mg, 2.11 mmol), and the reaction was stirred for 4 h at room temperature. The resulting mixture was diluted with water (10 mL). The precipitated solids were collected by filtration and washed with water (15 mL) to afford 2-[[2- (8-bromo-7-fluoro-3-quinolyl)acetyl]amino]-4,5-dimethoxy-benzamide (A204, 400 mg, 865.3 μmol, 82% yield) as a solid. LCMS (ES, m/z): 462 [M+H]+. Synthesis of A205 , hoxy- benzamide (A204, 400 mg, 865.3 μmol) in MeOH (8 mL) was added NaOH solution (4 mL, 2 M), and the reaction was stirred for 2 h at 70 ℃. The mixture was acidified to pH 5 with 1 N aqueous HCl. The precipitated solids were collected by filtration and washed with water (10 mL) to afford 2-[(4-bromo-3-fluoro-phenyl)methyl]-3H-quinazolin-4-one (A205, 380 mg, 1.14 mmol, 73% yield) as a solid. LCMS (ES, m/z): 444 [M+H]+. Synthesis of Compound 528 492 Attorney Docket No.: R2103-7054WO -3H- quinazolin-4-one (A205, 100 mg, 225.1 μmol) and methylboronic acid (67.3 mg, 1.13 mmol) in dioxane (4 mL) and H2O (1 mL) were added K3PO4 (143.3 mg, 675.3 μmol) and Pd(dppf)Cl2 (16.5 mg, 22.5 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 70 ℃ under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 6) to afford 2-[(7-fluoro-8-methyl-3-quinolyl)methyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 528, 15 mg, 39.5 μmol, 18% yield) as a solid. LCMS (ES, m/z): 380 [M-HCl+H]+.1H NMR (300 MHz, DMSO-d6) δ 9.05 (d, J = 2.2 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 9.1, 6.3 Hz, 1H), 7.55 (t, J = 9.2 Hz, 1H), 7.43 (s, 1H), 7.07 (s, 1H), 4.26 (s, 2H), 3.86 (s, 6H), 2.63 (d, J = 2.4 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material d. as as el A, 3- .1 S 00 29 z, d, s, Attorney Docket No.: R2103-7054WO 3H), 3.45 (d, J = 9.3 Hz, 1H), 2.82 (d, J = 11.1 Hz, 2H), 2.55 (s, 3H), 2.32 (q, ), 1 To a stirred solution of methyl 3-[(6,7-dimethoxy-4-oxo-3H-quinazolin-2-yl)methyl]- quinoline-8-carboxylate (100 mg, 246.7 μmol) in THF (2 mL) were added LiBH4 (10.7 mg, 493.3 μmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by sat. NH4Cl (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with DCM/MeOH (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC (Condition 12, Gradient 1) to afford 2-((8- (hydroxymethyl)quinolin-3-yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 554, 20.3 mg, 49.0 μmol, 20% yield) as a solid. LCMS (ES, m/z): 378 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 9.12 (d, J = 2.2 Hz, 1H), 8.66 (s, 1H), 8.02-7.88 (m, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 5.15 (s, 2H), 4.36 (s, 2H), 3.86 (d, J = 1.8 Hz, 6H). Example 47: Synthesis of Compound 579 , y y y q y ethyl]-3H- quinazolin-4-one (Compound 556, 100 mg, 255.5 μmol) in H2O (3 mL) was added HCl (1 M, 0.5 mL), and the reaction was stirred for 2 h at room temperature. The resulting mixture was 494 Attorney Docket No.: R2103-7054WO lyophilized to afford 2-((4-hydroxy-8-methylquinolin-3-yl)methyl)-6,7-dimethoxyquinazolin- 4(3H)-one hydrochloride (Compound 579, 16.6 mg, 40.1 μmol, 16% yield) as a solid. LCMS (ES, m/z): 378 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 11.52 (d, J = 6.4 Hz, 1H), 8.12 (d, J = 6.2 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 7.1 Hz, 1H), 7.46 (s, 1H), 7.26 (dd, J = 8.1, 7.1 Hz, 1H), 7.12 (s, 1H), 4.00 (s, 2H), 3.88 (s, 6H), 2.53 (s, 3H). Example 48: Synthesis of Compound 535 Synthesis of A227 To a stirred mixture of (3-bromo-5-fluorophenyl)methanamine hydrochloride (1.5 g, 6.24 mmol) and Boc2O (2.72 g, 12.48 mmol, 2.86 mL) in DCM (15 mL) was added Et3N (630 mg, 6.22 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford tert-butyl N-[(3-bromo-5-fluoro-phenyl)methyl]carbamate (A227, 1.6 g, 5.26 mmol, 84% yield) as a solid. LCMS (ES, m/z): 304 [M+H]+. Synthesis of A228 To a s e u e o e - u y - - o o- - uo o-p e y e y ca amate (A227, 1 g, 3.29 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.67 g, 6.58 mmol) in dioxane (10 mL) were added KOAc (968 mg, 9.86 mmol) and Pd(dppf)Cl2 (240 mg, 328.0 μmol) under nitrogen atmosphere, and the reaction was stirred for 16 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced 495 Attorney Docket No.: R2103-7054WO pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford tert-butyl N-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (A228, 1 g, 2.85 mmol, 87% yield) as a solid. LCMS (ES, m/z): 352 [M+H]+. Synthesis of A229 -one (100 mg, 236.3 μmol) and tert-butyl (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)carbamate (A228, 125 mg, 355.9 μmol) in Dioxane (1.6 mL) and H2O (0.4 mL) were added K3PO4 (150 mg, 706.7 μmol) and Pd(dppf)Cl2 (18 mg, 24.6 μmol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford tert-butyl N-[[3-[5-[(6,7-dimethoxy-4-oxo-3H-quinazolin-2-yl)methyl]-2-pyridyl]-5- fluorophenyl]methyl]carbamate (A229, 75 mg, 144.1 μmol, 61% yield) as a solid. LCMS (ES, m/z): 521 [M+H]+. Synthesis of Compound 535 y , y n-2- yl)methyl]-2-pyridyl]-5-fluoro-phenyl]methyl]carbamate (A229, 50 mg, 96.1 μmol) in DCM (1.0 mL) were added 4M HCl (gas) in dioxane (4 M, 0.5 mL), and the reaction was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and purified by Prep- 496 Attorney Docket No.: R2103-7054WO HPLC (Condition 17, Gradient 2) to afford 2-((6-(3-(aminomethyl)-5-fluorophenyl)pyridin-3- yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 535, 21 mg, 46 μmol, 48% yield) as a solid. LCMS (ES, m/z): 421 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 13.76 (s, 1H),8.76 (s, 1H), 8.46 (s, 3H), 8.23 (s, 1H), 8.09-7.95 (m, 2H), 7.92 (d, J = 10.3 Hz, 1H), 7.45 (d, J = 12.0 Hz, 2H), 7.10 (s, 1H), 4.19-4.08 (m, 4H), 3.88 (d, J = 5.3 Hz, 6H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material h. C 2- - g, S, z, z, (s, 13 = Example 49: Synthesis of Compound 609 Synthesis of A243 O O NH N To e so u on o -( -pyrazo - -y )ace c ac ( g, . mmo ), 2-amino-4,5- dimethoxybenzamide (6.22 g, 31.7 mmol) and pyridine (7.53 g, 95.2 mmol, 7.66 mL) in DMF (40 mL) was added T3P (50 wt. % in EtOAc) (30.28 g, 47.6 mmol, 50% purity), and the reaction was stirred at 25 °C for 3 h. The reaction was quenched with water and purified by flash 497 Attorney Docket No.: R2103-7054WO chromatography (Condition 2, Gradient 2) to afford 4,5-dimethoxy-2-[[2-(1H-pyrazol-4- yl)acetyl]amino]benzamide (A243, 2 g, 6.57 mmol, 21% yield) as a solid. LCMS (ES, m/z):327 [M+Na]+. Synthesis of A244 To hoxy-2-[[2-(1H-pyrazol-4-yl)acet l]amino]benzamide (A243, 4.2 g, 13.8 mmol) in MeOH (42 mL) was added (4.2g NaOH in 42 mL water), and the reaction was stirred for 6 h at 25 °C. The mixture was acidified to pH 8 with 1 M HCl. After filtration, the filtrate cake was drying to afford 6,7-dimethoxy-2-(1H-pyrazol-4-ylmethyl)-3H-quinazolin-4-one (A244, 2 g, 6.99 mmol, 51% yield) as a solid. LCMS (ES, m/z):287 [M+H]+. Synthesis of Compound 609 A solution of 6,7-dimethoxy-2-(1H-pyrazol-4-ylmethyl)-3H-quinazolin-4-one (A244, 0.1 g, 349.3 μmol), (3-fluoro-2-hydroxy-5-methyl-phenyl)boronic acid (59 mg, 349.3 μmol), Pyridine (83 mg, 1.05 mmol) and Cu(OAc)2 (95 mg, 524.0 μmol) in DMSO (2 mL) was stirred at 25 °C for 16 h under oxygen atmosphere. The crude product was purified by Prep-HPLC (Condition 12, Gradient 2) to afford 2-[[1-(3-fluoro-2-hydroxy-5-methyl-phenyl)pyrazol-4-yl]methyl]-6,7- dimethoxy-3H-quinazolin-4-one hydrochloride (Compound 609, 0.022 g, 53.6 μmol, 15% yield) as a solid. LCMS (ES, m/z): 411[M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.80(s, 1H), 10.48(s, 1H)), 8.45 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 7.02 (dd, J = 11.6, 2.2 Hz, 1H), 3.98 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.26 (s, 3H). 498 Attorney Docket No.: R2103-7054WO An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material p- to y- l, ): z, s, s, s, J ). p- to y- l, ): z, s, d, m, .6 p- to 5- - .2 d. H s, s, m, z, Attorney Docket No.: R2103-7054WO 244, 0.1 g, 349.3 μmol), 2-chloro-4-methyl-thiazole (70 mg, 524.0 μmol) and TsOH (30 mg, 174.7 μmol) in IPA (2 mL) was stirred for 16 h at 100°C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (Condition 8, Gradient 16) to afford 6,7-dimethoxy-2- [[1-(4-methylthiazol-2-yl)pyrazol-4-yl]methyl]-3H-quinazolin-4-one hydrochloride (Compound 601, 0.017 g, 44.3 μmol, 13% yield) as a solid. LCMS (ES, m/z): 384 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.60-8.54 (m, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 7.08 (q, J = 1.1 Hz, 1H), 4.12 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 2.33 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization M difi ti n Th r ti n as by sh 2, 5- - d % S, R 08 21 .3 z, 500 Attorney Docket No.: R2103-7054WO 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.80 (s, 2H). as by sh 8, 3- ol d % S, R 44 (s, 8- 90 ), 85 Example 51: Synthesis of Compound 441 Synthesis of A254 T , . l) and (3,5- difluorophenyl)boronic acid (468 mg, 2.96 mmol) in dioxane (2.5 mL) and H2O (0.5 mL) were added K3PO4 (945 mg, 4.45 mmol) and Pd(dppf)Cl2 (121 mg, 148.2 μmol), and the reaction was stirred at 100 °C for 3 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to 501 Attorney Docket No.: R2103-7054WO afford 2-[5-(3,5-difluorophenyl)-2-thienyl]acetonitrile (A254, 260 mg, 1.11 mmol, 74% yield) as a solid. LCMS (ES, m/z): 237 [M+H]+. Synthesis of Compound 441 80 mg, 340.1 μmol) and methyl 2-amino-4,5-dimethoxybenzoate (36 mg, 170.4 μmol) in 4M HCl (gas) in dioxane (2 mL), and the reaction was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC (Condition 8, Gradient 7) to afford 2-[[5-(3,5-difluorophenyl)-2-thienyl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 441, 11 mg, 26.5 μmol, 8% yield) as a solid. LCMS (ES, m/z): 415 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.55 (d, J = 3.7 Hz, 1H), 7.42 (s, 1H), 7.40-7.28 (m, 2H), 7.20-7.11 (m, 2H), 7.09 (d, J = 3.7 Hz, 1H), 4.16 (s, 2H), 3.88 (d, J = 15.0 Hz, 6H). Example 52: Synthesis of Compound 412 Synthesis of A263 o a s rre m x ure o -[( - o o- -pyr y )me y ]- , - me oxy- -qu nazo n-4-one (4 g, 9.5 mmol) and 2-[3-fluoro-2-(methoxymethoxy)-5-methyl-phenyl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (A262, 4.20 g, 14.2 mmol) in dioxane (40 mL) and H2O (8 mL) were 502 Attorney Docket No.: R2103-7054WO added K3PO4 (6.02 g, 28.4 mmol) and Pd(dppf)Cl2 (691.5 mg, 945.2 μmol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in DCM) to afford 2-[[6-[3-fluoro-2-(methoxymethoxy)-5-methyl-phenyl]-3-pyridyl]methyl]-6,7-dimethoxy- 3H-quinazolin-4-one (A263, 2 g, 4.30 mmol, 45% yield) as a solid. LCMS (ES, m/z): 466 [M+H]+. Synthesis of Compound 412 yl]-3- pyridyl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (A263, 2 g, 4.30 mmol) in DCM (20 mL) was added 4M HCl (gas) in dioxane (20 mL), and the reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was lyophilized to afford 2-((6-(3-fluoro-2-hydroxy-5-methylphenyl)pyridin-3- yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 412, 215 mg, 469.6 μmol, 99% yield) as a solid. LCMS (ES, m/z): 422 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 1.5 Hz, 2H), 7.61 (s, 1H), 7.44 (s, 1H), 7.20 (s, 1H), 7.15 (dd, J = 11.8, 2.0 Hz, 1H), 4.27 (s, 2H), 3.89 (d, J = 5.4 Hz, 6H), 2.30 (s, 3H). An analogous method was followed to obtain the following compound. Compound Starting Material Characterization p- to 5- - e .1 d. H 7 2 503 Attorney Docket No.: R2103-7054WO (s, 3H), 8.23 (dd, J = 8.6, 2.1 Hz, 1H), 8.16-8.06 (m, 2H), 7.95 (s, 1H), 7.44 07 z, p- to 3- .1 d. H 7 2 ), ), 9 ), ), p- to 3- l, S, 0 ), ), = 5, J 6 2 Example 53: Synthesis of Compound 626 Synthesis of A284 504 Attorney Docket No.: R2103-7054WO To a solution of 3-bromo-4,5-dimethoxy-benzaldehyde (20 g, 81.61 mmol) in Ac2O (200 mL) was added H2SO4 (98%, 0.2 mL), and the reaction was stirred for 1 h at room temperature. To the above mixture was added HNO3 (65-68%, 100 mL) dropwise at 0°C. The resulting mixture was stirred for an additional 16 h at room temperature. The resulting mixture was diluted with water/ice (300 mL). The precipitated solids were collected by filtration and washed with (2 x 50 mL). The residue was purified by trituration with 9% EtOAc in PE (200 mL) to afford 3-bromo- 4,5-dimethoxy-2-nitro-benzaldehyde (A284, 18 g, 62.05 mmol, 76% yield) as a solid. LCMS (ES, m/z): 290 [M+H]+. Synthesis of A285 To a solution of 3-bromo-4,5-dimethoxy-2-nitro-benzaldehyde (A284, 10 g, 34.47 mmol) in CHOOH (100 mL) was added HCOONa (5.86 g, 86.19 mmol) and hydroxylamine hydrochloride (3.11 g, 44.82 mmol), and the reaction was stirred at 100°C for 3 h. The resulting mixture was diluted with water (500 mL). The precipitated solids were collected by filtration and washed with (2 x 50 mL) to afford 3-bromo-4,5-dimethoxy-2-nitro-benzonitrile (A285, 7 g, 24.38 mmol, 71% yield) as a solid. LCMS (ES, m/z): 287 [M+H]+. Synthesis of A286 505 Attorney Docket No.: R2103-7054WO To a so g, 24.38 mmol) in EtOH (70 mL) and H2O (30 mL) was added Fe (5.10 g, 91.25 mmol) and acetic acid (17.57 g, 292.6 mmol), and the reaction was stirred at 80°C for 16 h. The resulting mixture was diluted with water (200 mL). The mixture was basified to pH 8 with NH3.H2O. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-amino-3-bromo-4,5-dimethoxy-benzamide (A286, 4.5 g, 16.36 mmol, 67% yield) as a solid. LCMS (ES, m/z): 275 [M+H]+. Synthesis of A287 , , , . mol) and pyridine (3.45 g, 43.6 mmol, 3.5 mL) in DMF (15 mL) was added 2-[6-(3,5-difluorophenyl)-3- pyridyl]acetic acid (3.62 g, 14.5 mmol) and T3P (6.94 g, 21.8 mmol, 50 wt. % in EtOAc), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL). The precipitated solids were collected by filtration and washed with water (2 x 30 mL) to afford 3-bromo-2-[[2-[6-(3,5-difluorophenyl)-3-pyridyl]acetyl]amino]-4,5-dimethoxy- benzamide (A287, 4.5 g, 8.9 mmol, 61% yield) as a solid. LCMS (ES, m/z): 506 [M+H]+. Synthesis of A288 506 Attorney Docket No.: R2103-7054WO ]-4,5- dimethoxy-benzamide (A287, 4 g, 7.90 mmol) in MeOH (5 mL) was added 2 M NaOH (aq.) (12 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL) to afford 8-bromo-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6,7-dimethoxy-3H- quinazolin-4-one (A288, 3.5 g, 7.17 mmol, 91% yield) as a solid. LCMS (ES, m/z): 488 [M+H]+. Synthesis of Compound 626 thyl]-6,7- dimethoxy-3H-quinazolin-4-one (A288, 120 mg, 245.8 μmol) and 3-amino-2,2-difluoro-propan- 1-ol (82 mg, 737.3 μmol) in dioxane (1.5 mL) was added t-BuONa (71 mg, 737.3 μmol) and Pd- PEPPSI-IPentCl (21 mg, 24.6 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100 °C. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (Condition 19, Gradient 1) to afford 8-[(2,2-difluoro-3-hydroxy- propyl)amino]-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6,7-dimethoxy-3H-quinazolin-4- one (Compound 626, 23 mg, 44.4 μmol, 18% yield) as a solid. LCMS (ES, m/z): 519 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.71-8.64 (m, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.2, 2.2 Hz, 1H), 7.84-7.71 (m, 2H), 7.29 (tt, J = 9.2, 2.4 Hz, 1H), 6.94 (s, 1H), 5.49 (dt, 507 Attorney Docket No.: R2103-7054WO J = 12.1, 6.6 Hz, 2H), 4.02 (s, 2H), 3.91 (q, J = 7.9 Hz, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 3.52 (td, J = 13.7, 6.3 Hz, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material C 6- )- 32 d. R 64 ), ), 67 01 Example 54: Synthesis of Compound 586 Synthesis of A299 T y , y , p y y acetic acid (A298, 220 mg, 1.07 mmol) and HATU (608 mg, 1.60 mmol) in DMF (4 mL) were added DIEA (689 mg, 5.33 mmol) and 2-amino-4,5-dimethoxybenzamide (419 mg, 2.13 mmol), and the reaction was stirred for 6 h at 90°C. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 2, Gradient 40) to afford 4,5- dimethoxy-2-[[2-(8-methyl-6,7-dihydro-5H-1,8-naphthyridin-3-yl)acetyl]amino]benzamide (A299, 200 mg, 520.3 μmol, 49% yield) as a solid. LCMS (ES, m/z): 385 [M+H]+. 508 Attorney Docket No.: R2103-7054WO Synthesis of Compound 586 yridin-3- yl)acetyl]amino]benzamide (A299, 100 mg, 260.1 μmol) in MeOH (2.00 mL) was added 2M NaOH (aq.) (0.5 mL), and the reaction was stirred for 4 h at room temperature. The resulting mixture was diluted with water (5 mL) and extracted with DCM/ MeOH (10/1) (3 x 10 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to afford 6,7-dimethoxy-2-[(8- methyl-6,7-dihydro-5H-1,8-naphthyridin-3-yl)methyl]-3H-quinazolin-4-one (Compound 586, 75 mg, 204.7 μmol, 79% yield) as a solid. LCMS (ES, m/z): 367 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.39 (s, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.07 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.68 (s, 2H), 3.28 (t, J = 5.7 Hz, 2H), 2.98 (s, 3H), 2.66 (t, J = 6.4 Hz, 2H), 1.93-1.74 (m, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization M difi i S 1 m at d- y 2- .8 S R s, 3 Attorney Docket No.: R2103-7054WO (s, 1H), 7.04 (s, 1H), 4.16 (s, 2H), 3.86 (d, J = 4.8 Hz, 6H), 2.35 (s, 3H), ethyl]-3,4- dihydro-2H-1,5-naphthyridine-1-carboxylate (A300, 100 mg, 221.0 μmol) in THF (2.0 mL) was added LAH (2.0 M in THF) (0.3 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 0.5 h. The mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was quenched with sat. NH4Cl (50 mL), and then the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford 6,7-dimethoxy-2-[(5-methyl-7,8-dihydro-6H-1,5-naphthyridin-3- yl)methyl]-3H-quinazolin-4-one (Compound 587, 11.6 mg, 31.7 μmol, 14% yield) as a solid. LCMS (ES, m/z): 367 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.40 (s, 1H), 7.08 (s, 1H), 6.92 (d, J = 1.7 Hz, 1H), 3.87 (d, J = 13.0 Hz, 6H), 3.78 (s, 2H), 3.22-3.15 (m, 2H), 2.81 (s, 3H), 2.75 (t, J = 6.5 Hz, 2H), 1.97-1.90 (m, 2H). Example 56: Synthesis of Compound 496 Attorney Docket No.: R2103-7054WO To a stirred mixture of 4-(3,5-difluorophenyl)-2-[(6,7-dimethoxy-4-oxo-3H-quinazolin-2- yl)methyl]-N,N-dimethyl-imidazole-1-sulfonamide (A305, 60 mg, 118.7 μmol) in DCM (1 mL) was added 4M HCl (gas) in dioxane (1 mL), and the reaction was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC (Condition 12, Gradient 12) to afford 2-((5-(3,5- difluorophenyl)-1H-imidazol-2-yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 496, 5.7 mg, 13.1 μmol, 11% yield) as a solid. LCMS (ES, m/z): 399 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.74 (s, 2H), 8.21 (s, 1H), 7.65 (d, J = 7.1 Hz, 2H), 7.44 (s, 1H), 7.30 (t, J = 9.3 Hz, 1H), 7.00 (s, 1H), 4.45 (s, 2H), 3.86 (d, J = 6.4 Hz, 6H). Example 57: Synthesis of Compound 447 Synthesis of A305 To a solution of l) in DMSO (100 mL) were added K2CO3 (4.21 g, 30.45 mmol) and 30% H2O2 Solution (40 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 4) to afford 2-amino-6-bromo-benzamide (A305, 3 g, 13.95 mmol, 55% yield) as a solid. LCMS (ES, m/z): 215 [M+H]+. Synthesis of A306 Attorney Docket No.: R2103-7054WO To a stirred solution of 2-[6-(3,5-difluorophenyl)-3-pyridyl]acetic acid (300 mg, 1.20 mmol) and 2-amino-6-bromo-benzamide (A305, 284.7 mg, 1.32 mmol) in DMF (6 mL) were added T3P (1151.1 mg, 1.81 mmol, 50 wt.% in EtOAc) and Pyridine (285.6 mg, 3.61 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (10 mL). The precipitated solids were collected by filtration and washed with water (5 mL) to afford 2-bromo-6-[[2-[6-(3,5-difluorophenyl)-3-pyridyl]acetyl]amino]benzamide (A306, 300 mg, 672.3 μmol, 56% yield) as a solid. LCMS (ES, m/z): 446 [M+H]+. Synthesis of A307 ]amino]- benzamide (A306, 300 mg, 672.3 μmol) in MeOH (8 mL) was added 2 M NaOH (3 mL), and the reaction was stirred for 16 h at room temperature. The mixture was acidified to pH 5 with 1N HCl (aq.). The resulting mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 25) to afford 5-bromo-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-3H-quinazolin-4- one (A307, 200 mg, 467.0 μmol, 69% yield) as a solid. LCMS (ES, m/z): 428 [M+H]+. Synthesis of Compound 447 o a so u o o - o o- - - , - uo op e y - -py y e y - -qu azolin-4- one (A307, 100 mg, 233.5 μmol) and NH3•H2O (1 mL) in NMP (2.0 mL) was added Cu2O (10.0 mg, 70.1 μmol), and the reaction was stirred for 12 h at 80 ℃ under nitrogen atmosphere. The resulting mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 4) 512 Attorney Docket No.: R2103-7054WO to afford 5-amino-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-3H-quinazolin-4-one (Compound 447, 15 mg, 41.2 μmol, 18% yield) as a solid. LCMS (ES, m/z): 365 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.08-7.99 (m, 1H), 7.88 (dd, J = 8.2, 2.3 Hz, 1H), 7.87-7.72 (m, 2H), 7.37-7.19 (m, 2H), 7.09 (s, 2H), 6.51 (dd, J = 7.9, 1.1 Hz, 1H), 6.44 (dd, J = 8.1, 1.1 Hz, 1H), 3.91 (s, 2H). Example 58: Synthesis of Compound 405 Synthesis of A318 ol) and 2- amino-5-bromo-3-iodo-benzamide (427.0 mg, 1.25 mmol) in DMF (4 mL) were added T3P (996.2 mg, 1.57 mmol, 50 wt. % in EtOAc) and Pyridine (165.1 mg, 2.09 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (10 mL). The precipitated solids were collected by filtration and washed with water (10 mL) to afford 5-bromo- 3-iodo-2-[[2-(4-pyrrol-1-ylphenyl)acetyl]amino]benzamide (A318, 350 mg, 667.8 μmol, 64% yield) as a solid. LCMS (ES, m/z): 524 [M+H]+. Synthesis of A319 o a st rre so ut on o - romo- - o o- -[[ -( -pyrro - -y p eny )acety ]amino]- benzamide (A318, 350 mg, 667.8 μmol) in MeOH (7 mL) was added 2 M NaOH (3 mL), and the reaction was stirred for 8 h at room temperature. The mixture was acidified to pH 5 with 2 M HCl 513 Attorney Docket No.: R2103-7054WO (aq.). The precipitated solids were collected by filtration and washed with water (5 mL) to afford 6-bromo-8-iodo-2-[(4-pyrrol-1-ylphenyl)methyl]-3H-quinazolin-4-one (A319, 210 mg, 414.9 μmol, 62% yield) as a solid. LCMS (ES, m/z): 506 [M+H]+. Synthesis of Compound 405 n-4-one (A319, 210 mg, 414.9 μmol) and KOH (46.6 mg, 829.8 μmol) in (R)-2-aminobutan-1-ol (4 mL) was added CuCl (4.1 mg, 41.5 μmol), and the reaction was stirred for 20 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 25) to afford 6-bromo-8- [[(1R)-1-(hydroxymethyl)propyl]amino]-2-[(4-pyrrol-1-ylphenyl)methyl]-3H-quinazolin-4-one (Compound 405, 43 mg, 90.9 μmol, 22% yield) as a solid. LCMS (ES, m/z): 467 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.32 (t, J = 2.2 Hz, 2H), 7.21 (d, J = 2.1 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.25 (t, J = 2.2 Hz, 2H), 5.93 (d, J = 8.3 Hz, 1H), 4.82 (t, J = 5.3 Hz, 1H), 3.96 (s, 2H), 3.57-3.34 (m, 3H), 1.74-1.59 (m, 1H), 1.49 (dt, J = 14.0, 7.1 Hz, 1H), 0.88 (t, J = 7.4 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization ep se 8, 5- 0, d. R Attorney Docket No.: R2103-7054WO (300 MHz, DMSO-d6) δ 13.2 (s, 1H), 8.74 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.06 (s, m, 2 .8 .4 y -7-[1- (hydroxymethyl)propylamino]-3H-quinazolin-4-one (Compound 470, 0.08 g, 155.2 μmol) and TEA (47 mg, 465.7 μmol) in DCM (3 mL) were added DMAP (4 mg, 31.1 μmol) and Ac2O (24 mg, 232.9 μmol), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 12) to afford N-(6-bromo-2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)- 4-oxo-3,4-dihydroquinazolin-7-yl)-N-(1-hydroxybutan-2-yl)acetamide hydrochloride (Compound 484, 0.01 g, 16.8 μmol, 11% yield) as a solid. LCMS (ES, m/z): 557 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.14-7.97 (m, 2H), 7.93 (d, J = 8.5 Hz, 1H), 7.86-7.74 (m, 2H), 7.38-7.29 (m, 1H), 6.79 (s, 1H), 5.53 (s, 1H), 4.26-3.93 (m, 3H), 3.89 (s,2H), 1.97 (s, 3H), 1.70-1.57 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). Example 60: Synthesis of Compound 491 Synthesis of A326 515 Attorney Docket No.: R2103-7054WO A solution of 6-bromo-7-methoxy-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H- quinazolin-4-one (Compound 365, 3 g, 7.05 mmol), DIEA (9.12 g, 70.5 mmol) and bromo- (methoxy)methane (3.53 g, 28.2 mmol, 2.3 mL) in DMF (30 mL) was stirred at room temperature for 2 days. The crude product was purified by Prep-HPLC (Condition 18, Gradient 1) to afford 6- bromo-7-methoxy-4-(methoxymethoxy)-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]- quinazoline (A326, 1 g, 2.13 mmol, 30% yield) as a solid. LCMS (ES, m/z): 471 [M+H]+. Synthesis of A327 )-3- pyridyl]methyl]quinazoline (A326, 1 g, 2.13 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.08 g, 4.26 mmol), K3PO4 (1.36 g, 6.39 mmol) and Pd(dppf)Cl2 (155.9 mg, 213.1 μmol) in Dioxane (20 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the solution was added H2O2 Solution (0.25 mL, 30% purity) at room temperature and the reaction was stirred at room temperature for 2 h. The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 47) to afford 7-methoxy-4-(methoxymethoxy)-2-[[6-(3-methylpyrrol-1- yl)-3-pyridyl]methyl]quinazolin-6-ol (A327, 0.56 g, 1.38 mmol, 65% yield) as a solid. LCMS (ES, m/z): 407 [M+H]+. Synthesis of A328 516 Attorney Docket No.: R2103-7054WO -yl)-3- pyridyl]methyl]quinazolin-6-ol (A327, 0.15 g, 369.1 μmol), EtOH (51 mg, 1.11 mmol) and PPh3 (145 mg, 553.6 μmol) in THF (3 mL) was added DIAD (97 mg, 479.8 μmol), and the reaction was stirred at room temperature for 3 h. The mixture was quenched with saturated NH4Cl (aq.) (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% THF in PE) to afford 6-ethoxy-7-methoxy-4- (methoxymethoxy)-2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]quinazoline (A328, 0.13 g, 299.2 μmol, 81% yield) as a solid. LCMS (ES, m/z): 435 [M+H]+. Synthesis of Compound 491 rrol-1-yl)- 3-pyridyl]methyl]quinazoline (A328, 0.1 g, 230.2 μmol) in DCM (1 mL) was added TFA (1 mL), and the reaction was stirred at room temperature for 16 h. The mixture was acidified to pH 7 with Na2CO3 (aq.) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 6) to afford 6-ethoxy-7-methoxy- 2-[[6-(3-methylpyrrol-1-yl)-3-pyridyl]methyl]-3H-quinazolin-4-one hydrochloride (Compound 491, 0.005 g, 12.8 μmol, 6% yield) as a solid. LCMS (ES, m/z): 391 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J = 2.3 Hz, 1H), 7.92 (dd, J = 8.5, 2.3 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.55 517 Attorney Docket No.: R2103-7054WO (t, J = 2.6 Hz, 1H), 7.41 (s, 2H), 7.15 (s, 1H), 6.16-6.09 (m, 1H), 4.12 (q, J = 6.9 Hz, 2H), 4.05 (s, 2H), 3.89 (s, 3H), 2.07 (d, J = 1.0 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H). Example 61: Synthesis of Compound 510 Synthesis of A333 To a stirre mol) and (COCl)2 (3 mL) in DCM (38 mL) were added DMF (236.0 mg, 3.23 mmol, 0.25 mL) for 1 min at 0°C, and the reaction was stirred for 1 h at 0 °C. The resulting mixture was concentrated under reduced pressure to afford 2-(6-iodo-3-pyridyl)acetyl chloride (A333, 1.7 g, 6.04 mmol, 42% yield) as a solid. Synthesis of A334 To a 33, 1.7 g, 6.04 mmol) and (6,7-dimethoxyisochromane-1,3-dione (2 g, 9.0 mmol) in CH3CN (25 mL) were added pyridine (2.46 g, 31.04 mmol, 2.5 mL) at 0℃, and the reaction was stirred for 16 h at 25°C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% THF in PE) to afford 3-[(6-iodo-3-pyridyl)methyl]-6,7-dimethoxy- isochromen-1-one (A334, 1.8 g, 4.25 mmol, 70% yield) as a solid. LCMS (ES, m/z): 424 [M+H]+. Synthesis of A335 518 Attorney Docket No.: R2103-7054WO A omen-1-one (A334, 1.5 g, 3.54 mmol) and NH3 (7.0 M in methanol) (150 mL) was stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% THF in PE) to afford 3-[(6-iodo-3-pyridyl)methyl]-6,7-dimethoxy-2H- isoquinolin-1-one (A335, 350 mg, 829.0 μmol, 23% yield) as a solid. LCMS (ES, m/z): 423 [M+H]+. Synthesis of Compound 510 n-1-one (A335, 85 mg, 201.3 μmol) and (2-hydroxy-5-methyl-phenyl)boronic acid (60 mg, 394.9 μmol) in Dioxane/H2O (2 mL) was added K3PO4 (120 mg, 565.3 μmol) and Xphos Pd G3 (20 mg, 23.6 μmol), and the reaction was stirred for 1 h at 110 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (Condition 8, Gradient 22) to afford 3-((6-(2- hydroxy-5-methylphenyl)pyridin-3-yl)methyl)-6,7-dimethoxyisoquinolin-1(2H)-one hydrochloride (Compound 510, 30 mg, 68.4 μmol, 34% yield) as a solid. LCMS (ES, m/z): 403 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.72 (s, 1H), 8.28-8.18 (m, 2H), 7.68 (d, J = 2.1 Hz, 1H), 7.51 (s, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 7.07 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.29 (s, 1H), 3.99 (s, 2H), 3.84 (d, J = 4.3 Hz, 6H), 2.29 (s, 3H). Example 62: Synthesis of Compound 477 519 Attorney Docket No.: R2103-7054WO -1-one (A335, 110 mg, 260.5 μmol) in dioxane (2.2 mL) was added 3,4-dimethyl-1H-pyrazole (50 mg, 520.1 μmol), Pd-PEPPSI-IHEPTCl (25 mg, 25.7 μmol), potassium tert-butoxide (59 mg, 525.8 μmol), and the reaction was stirred for 6 h at 120 °C under nitrogen. The resulting solution was filtered and purified by Prep-HPLC (Condition 12, Gradient 5) to afford 3-((6-(3,4-dimethyl-1H- pyrazol-1-yl)pyridin-3-yl)methyl)-6,7-dimethoxyisoquinolin-1(2H)-one hydrochloride (Compound 477, 34 mg, 79.6 μmol, 31% yield) as a solid. LCMS (ES, m/z): 391 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.41-8.36 (m, 1H), 8.28 (s, 1H), 7.85 (dd, J = 8.5, 2.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.06 (s, 1H), 6.22 (s, 1H), 3.87-3.81 (m, 8H), 2.19 (s, 3H), 2.03 (s, 3H). Example 63: Synthesis of Compound 456 To a solution of 3-[(6-chloro-3-pyridyl)methyl]-6,7-dimethoxy-2H-isoquinolin-1-one (A336, 100 mg, 302.3 μmol) in dioxane (1.5 mL) and H2O (0.15 mL) were added (3,5- difluorophenyl)boronic acid (200 mg, 1265.8 μmol), Pd(dppf)Cl2 (11 mg, 15.1 μmol), K2CO3 (125 mg, 907.0 μmol), and the reaction was stirred for 2 h at 90 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 44) to afford 3-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6,7-dimethoxy-2H-isoquinolin-1-one (Compound 456, 7 mg, 17.1 μmol, 6% yield) as a solid. LCMS (ES, m/z): 409 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.88 (dd, J = 8.2, 520 Attorney Docket No.: R2103-7054WO 2.3 Hz, 1H), 7.82 (dt, J = 7.6, 2.2 Hz, 2H), 7.50 (s, 1H), 7.32 (tt, J = 9.2, 2.4 Hz, 1H), 7.06 (s, 1H), 6.23 (s, 1H), 3.90 (s, 2H), 3.84 (d, J = 1.8 Hz, 6H), 1.24 (s, 1H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: The reaction was ed sh 7, 7- g, d. ]+. δ 63 ), ), 5, ), (s, ), d, .8 ). Example 64: Synthesis of Compound 576 521 Attorney Docket No.: R2103-7054WO To a stirred mixture of 3-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-6,7-dimethoxy- isoquinolin-1(2H)-one (Compound 456, 100 mg, 244.9 μmol) in CH3CN (2 mL) was added 1- (chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (66 mg, 186.3 μmol), and the reaction was stirred for 16 h at 25 °C. The resulting mixture was diluted with DMSO (10 mL) and purified by reversed-phase flash chromatography (Condition 8, Gradient 7) to afford 3-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-4-fluoro-6,7-dimethoxyisoquinolin- 1(2H)-one hydrochloride (Compound 576, 9.1 mg, 19.7 μmol, 8% yield) as a solid. LCMS (ES, m/z): 427 [M+H-HCl]+.1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.86-7.75 (m, 3H), 7.56 (d, J = 1.9 Hz, 1H), 7.36-7.27 (m, 1H), 7.13 (s, 1H), 4.01 (d, J = 2.7 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H). Example 65: Synthesis of Compound 520 To a stirred solution of 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7-hydroxy- 3H-quinazolin-4-one (Compound 521, 100 mg, 250.1 μmol) and 4-iodotetrahydropyran (106 mg, 500.3 μmol) in DMF (2 mL) was added K2CO3 (69 mg, 500.3 μmol), and the reaction was stirred for 16 h at 60 ℃. The resulting mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 25) to afford 6-chloro-2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-7- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(3H)-one hydrochloride (Compound 520, 15 mg, 31.0 μmol, 12% yield) as a solid. LCMS (ES, m/z): 484 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.97 (dd, J = 8.3, 2.3 Hz, 1H), 7.83 (dt, J = 7.5, 2.2 Hz, 2H), 7.42-7.27 (m, 2H), 4.94 (p, J = 4.0 Hz, 1H), 4.09 (s, 2H), 3.90-3.77 (m, 2H), 3.54 (ddd, J = 11.6, 8.6, 3.0 Hz, 2H), 2.00 (d, J = 13.3 Hz, 2H), 1.65 (dtd, J = 12.5, 8.2, 3.8 Hz, 2H). Example 66: Synthesis of Compound 548 Synthesis of A344 522 Attorney Docket No.: R2103-7054WO l)methyl]- piperidine-1-carboxylate (A343, 450 mg, 1.09 mmol) and 2-[6-(3,5-difluorophenyl)-3-pyridyl]- acetic acid (271.9 mg, 1.09 mmol) in DMF (4.5 mL) were added T3P (1.04 g, 3.27 mmol, 50% in EtOAc) and pyridine (129.4 mg, 1.64 mmol) dropwise, and the reaction was stirred for 72 h at 50℃. The reaction solution was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 4-[[5-bromo- 3-carbamoyl-2-[[2-[6-(3,5-difluorophenyl)-3-pyridyl]acetyl]amino]phenyl]methyl]piperidine-1- carboxylate (A344, 0.14 g, 217.6 μmol) as a solid. LCMS (ES, m/z): 643 [M+H]+. Synthesis of A345 o a s e so u o o - -a o- - e y - u y - - o o- - 2-[6-(3,5- difluorophenyl)-3-pyridyl]acetyl]amino]benzamide (A344, 140 mg, 263.5 μmol) in EtOH (2 mL) was added 2 M NaOH (aq.) (1.4 mL), and the reaction was stirred for 16 h at room temperature. The mixture was acidified to pH 4 with 1 N HCl (aq.). The precipitated solids were collected by 523 Attorney Docket No.: R2103-7054WO filtration, washed with water (15 mL), and air dried to afford tert-butyl 4-[[6-bromo-2-[[6-(3,5- difluorophenyl)-3-pyridyl]methyl]-4-oxo-3H-quinazolin-8-yl]methyl]piperidine-1-carboxylate (A345, 120 mg, 191.9 μmol, 73% yield) as a solid. LCMS (ES, m/z): 625 [M+H]+. Synthesis of Compound 548 To a stirred solution of tert-butyl 4-[[6-bromo-2-[[6-(3,5-difluorophenyl)-3-pyridyl]- methyl]-4-oxo-3H-quinazolin-8-yl]methyl]piperidine-1-carboxylate (A345, 120 mg, 191.9 μmol) in DCM (4 mL) was added 4M HCl (gas) in dioxane (4 mL) dropwise at 0°C. The resulting mixture was stirred for 1 h at 0 °C. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 24) to afford 6- bromo-2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-8-(piperidin-4-ylmethyl)quinazolin- 4(3H)-one hydrochloride (Compound 548, 6.3 mg, 11.2 μmol, 6% yield) as a solid. LCMS (ES, m/z): 525 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.68- 8.21 (m, 2H), 8.12 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.87- 7.78 (m, 3H), 7.39-7.29 (m, 1H), 4.10 (s, 2H), 3.07 (d, J = 12.6 Hz, 2H), 2.71 (d, J = 6.8 Hz, 2H), 1.67 (s, 1H), 1.42 (d, J = 13.4 Hz, 2H), 1.26 (d, J = 12.0 Hz, 3H). Example 67: Synthesis of Compound 460 Synthesis of A356 Attorney Docket No.: R2103-7054WO To a stirred solution of [4-bromo-3-(methoxymethoxy)phenyl]acetic acid (A355, 300 mg, 1.09 mmol) and pyridine (259 mg, 3.27 mmol) in DMF (6 mL) were added T3P (1388 mg, 2.18 mmol, 50% wt. in EtOAc) and 2-amino-4,5-dimethoxybenzamide (236 mg, 1.2 mmol), and the reaction was stirred at room temperature for 16 h. The mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 4) to afford 2-{2-[4-bromo-3-(methoxymethoxy)- phenyl]acetamido}-4,5-dimethoxybenzamide (A356, 250 mg, 51%yield) as a solid. LCMS (ES, m/z): 453 [M+H]+. Synthesis of A357 ido}-4,5- dimethoxybenzamide (A356, 250 mg, 0.55 mmol, 1 equiv) in MeOH (5 mL) was added and 2 M NaOH (aq.) (1.38 mL, 2.76 mmol), and the reaction was stirred for 4 h at room temperature. The reaction was quenched by the addition of water (20 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL) to afford 2-{[4-bromo-3-(methoxymethoxy)phenyl]- methyl}-6,7-dimethoxy-3H-quinazolin-4-one (A357, 180 mg, 75% yield) as a solid. LCMS (ES, m/z): 435 [M+H]+. Synthesis of A358 o a s rre so u on o -{[ - romo- -(me oxyme oxy)p eny ]me y }- , - methoxy- 3H-quinazolin-4-one (A357, 180 mg, 0.41 mmol) and 4-fluoro-2-methyl-6-(trimethylstannyl)- pyridine (139 mg, 0.54 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (48 mg, 0.04 mmol), and 525 Attorney Docket No.: R2103-7054WO the reaction was stirred at 120 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (80% EtOAc in PE) to afford 2-{[4-(4-fluoro-6-methylpyridin-2-yl)-3-(methoxymethoxy)phenyl]- methyl}-6,7-dimethoxy-3H-quinazolin-4-one (A358, 75 mg, 39% yield) as a solid. LCMS (ES, m/z): 466 [M+H]+. Synthesis of Compound 460 ethoxy)- phenyl]methyl}-6,7-dimethoxy-3H-quinazolin-4-one (A358, 75 mg, 0.16 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.7 mL), and the reaction was stirred for 4 h at room temperature. The mixture was basified to pH 9 with saturated NaHCO3 (aq.), and extracted with DCM:MeOH (10:1) (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 11) to afford 2-{[4-(4-fluoro-6- methylpyridin-2-yl)-3-hydroxyphenyl]methyl}-6,7-dimethoxy-3H-quinazolin-4-one hydrochloride (Compound 460, 4 mg, 5% yield) as a solid. LCMS (ES, m/z): 422 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.90-7.75 (m, 2H), 7.62 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J = 9.1 Hz, 2H), 4.21 (s, 2H), 4.00 (d, J = 13.2 Hz, 6H), 2.74 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization h. 3 )4 an ed y Attorney Docket No.: R2103-7054WO HPLC (Condition 12, Gradient 8) to afford 2-[[6-(4,6-dimethyl-2-pyridyl)-5- l, ): z, = m, s, s, Example 68: Synthesis of Compound 580 Synthesis of A359 hoxy- 3H-quinazolin-4-one (A357, 160 mg, 0.37 mmol) and 3,4-dimethyl-1H-pyrazole (54 mg, 0.55 mmol) in 1,4-dioxane (3 mL) were added Cs2CO3 (360 mg, 1.10 mmol) and EPhos Pd G4 (34 mg, 0.04 mmol), and the reaction was stirred at 120 °C for 24 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-{[4-(3,4-dimethylpyrazol-1-yl)-3- (methoxymethoxy)phenyl]methyl}-6,7-dimethoxy-3H-quinazolin-4-one (A359, 75 mg, 45% yield) as a solid. LCMS (ES, m/z): 451 [M+H]+. Synthesis of Compound 580 527 Attorney Docket No.: R2103-7054WO )phenyl]- methyl}-6,7-dimethoxy-3H-quinazolin-4-one (A359, 75 mg, 0.17 mmol) in DCM (3 mL) was added trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 2 h. The mixture was basified to pH 9 with saturated NaHCO3 (aq.) and extracted with DCM:MeOH (10:1) (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 9) to afford 2-{[4-(3,4- dimethylpyrazol-1-yl)-3-hydroxyphenyl]methyl}-6,7-dimethoxy-3H-quinazolin-4-one hydrochloride (Compound 580, 25 mg, 34% yield) as a solid. LCMS (ES, m/z): 407 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.15 (s, 1H), 7.02 (d, J = 1.9 Hz, 1H), 6.92 (dd, J = 8.3, 1.9 Hz, 1H), 3.92 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.19 (s, 3H), 2.02 (s, 3H). Example 69: Synthesis of Compound 518 Synthesis of A372 - - - - - y y y y y p py amino]- 4,5-dimethoxy-benzamide (A371, 1.44 g, 3.63 mmol) and 2-[6-(3-fluorophenyl)-3-pyridyl]acetic acid (700 mg, 3.03 mmol) in DMF (10 mL) were added T3P (2.89 g, 4.54 mmol, 50% purity) and pyridine (718 mg, 9.08 mmol), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined 528 Attorney Docket No.: R2103-7054WO organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford 3-[1-[[tert-butyl(dimethyl)silyl]oxymethyl]- propylamino]-2-[[2-[6-(3-fluorophenyl)-3-pyridyl]acetyl]amino]-4,5-dimethoxy-benzamide (A372, 600 mg, 982.3 μmol, 32% yield) as a solid. LCMS (ES, m/z): 611 [M+H]+. Synthesis of A373 2-[6- (3-fluorophenyl)-3-pyridyl]acetyl]amino]-4,5-dimethoxy-benzamide (A372, 100 mg, 163.7 μmol) in MeOH (1 mL) was added NaOH (2 M, 1 mL), and the reaction was stirred for 2 h at room temperature. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 8-[1-[[tert- butyl(dimethyl)silyl]oxymethyl]propylamino]-2-[[6-(3-fluorophenyl)-3-pyridyl]methyl]-6,7- dimethoxy-3H-quinazolin-4-one (A373, 80 mg, 135.0 μmol, 82% yield) as a solid. LCMS (ES, m/z): 593 [M+H]+. Synthesis of Compound 518 [[6-(3- fluorophenyl)-3-pyridyl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (A373, 80 mg, 135.0 μmol) in THF (1 mL) was added TBAF (45 mg, 162.0 μmol), and the reaction was stirred for 16 h at 529 Attorney Docket No.: R2103-7054WO room temperature. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 23) to afford 2-((6-(3- fluorophenyl)pyridin-3-yl)methyl)-8-((1-hydroxybutan-2-yl)amino)-6,7-dimethoxyquinazolin- 4(3H)-one hydrochloride (Compound 518, 14 mg, 27.2 μmol, 20% yield) as a solid. LCMS (ES, m/z): 479 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.82-8.74 (m, 1H), 8.19-8.09 (m, 2H), 7.94- 7.84 (m, 2H), 7.60 (td, J = 8.1, 6.0 Hz, 1H), 7.36 (tt, J = 8.4, 1.6 Hz, 1H), 7.19 (s, 1H), 4.15 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.62 (s, 1H), 3.5-3.27 (m, 2H), 1.59-1.39 (m, 1H), 1.29 (tq, J = 12.2, 6.1, 5.2 Hz, 1H), 0.70 (t, J = 7.4 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modifications: Step 2 used F as p- 6) H- d % S, 00 ), 43 ), z, Example 70: Synthesis of Compound 656 530 Attorney Docket No.: R2103-7054WO -3H- quinazolin-4-one (Compound 551, 0.1 g, 218.2 μmol), (R)-1-ethylpyrrolidin-3-amine dihydrochloride (61 mg, 327.3 μmol), Pd-PEPPSI™-IPent catalyst (17 mg, 21.8 μmol) and t- BuONa (63 mg, 654.7 μmol) in Dioxane (2.5 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC (Condition 12, Gradient 2) to afford (R)-2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-7-((1-ethylpyrrolidin-3-yl)amino)- 6-methoxyquinazolin-4(3H)-one hydrochloride (Compound 656, 0.063 g, 119.3 μmol, 55% yield) as a solid. LCMS (ES, m/z): [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.09 (s, 2H), 7.81 (dd, J = 8.3, 2.8 Hz, 2H), 7.33 (d, J = 1.4 Hz, 2H), 6.77 (d, J = 7.2 Hz, 1H), 4.49-4.15 (m, 1H), 3.94 (d, J = 6.2 Hz, 5H), 3.71 (m, 1H), 3.42-3.07 (m, 4H), 2.58 (dd, J = 8.9, 4.1 Hz, 1H), 2.43-2.25 (m, 1H), 2.04 (m, 1H), 1.25 (td, J = 7.3, 2.7 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization M t i l C 6- - g, S z, 1 z, m, ), z, 531 Attorney Docket No.: R2103-7054WO 1H), 2.43-2.25 (m, 1H), 2.04 (m, 1H), 1.25 (td, J = 7.3, 2.7 Hz, 3H). d C 6- - g, S 0 J ), m, s, ), m, 7 g he n or se 8, 1- - g, S 0 s, ), .1 s, m, Example 71: Synthesis of Compound 683 532 Attorney Docket No.: R2103-7054WO hyl]- 3H-quinazolin-4-one (Compound 454, 150 mg, 324.2 μmol) and 1-ethylpiperidin-4-amine (42 mg, 327.6 μmol) in DMF (3 mL) were added Cs2CO3 (320 mg, 982.1 μmol) and Pd-PEPPSI- IPentCl (28 mg, 33.3 μmol), and the reaction was stirred for 16 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 17) to afford 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7-[(1- ethyl-4-piperidyl)amino]-3H-quinazolin-4-one (Compound 683, 69 mg, 135.3 μmol, 42% yield) as a solid. LCMS (ES, m/z): 510 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.69 J = Hz, (m, as Cl or d- y 6- % 08 z, Attorney Docket No.: R2103-7054WO DMSO-d6) δ 12.20 (s, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), = .4 ), ), as re ed re d x rs ), d ed ed sh 2, 6- 3, a +. δ = 0 = z, d, z, ), = 534 Attorney Docket No.: R2103-7054WO Modification: The reaction was performed using GPhos Pd G6. d- y rd - l, S, 0 7 5 2, 2 s, d, s, d- y 6- }- d d. H 5 6 ), s, (t, q, z, J z, 535 Attorney Docket No.: R2103-7054WO Modification: After the reaction, the protecting group was removed upon as re C 7- e l, S, 0 7 z, = = ), ), ). e l, 7 J Attorney Docket No.: R2103-7054WO Example 72: Synthesis of Compound 641 quinazolin-4-one (Compound 519, 18 mg, 44.3 μmol) was purified by Chiral-HPLC (Condition 21, Gradient 1) to afford 2-[(1R)-1-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-methylpropyl]-6,7- dimethoxy-3H-quinazolin-4-one (B35, 5.5 mg, 13.5 μmol, 31% yield) as a solid and 2-[(1S)-1- (5,6-dimethyl-1H-benzimidazol-2-yl)-2-methylpropyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 641, 3.8 mg, 9.4 μmol, 21% yield) as a solid. Compound 641: LCMS (ES, m/z): 407 [M+H]+.1H NMR (300 MHz, Methanol-d4) δ 7.54 (s, 1H), 7.33 (s, 2H), 7.30 (s, 1H), 3.96 (d, J = 21.8 Hz, 6H), 2.70 (dt, J = 9.9, 6.6 Hz, 1H), 2.35 (s, 6H), 1.29 (s, 1H), 0.97 (dd, J = 33.0, 6.6 Hz, 6H). Example 73: Synthesis of Compound 652 Synthesis of B52 0 mg, 2.07 mmol) and 2-amino-4,5-dimethoxybenzamide (610 mg, 3.1 mmol) in DMF (10 mL) were added T3P (50 wt. % in EtOAc) (2 g, 3.1 mmol) and pyridine (0.5 g, 6.2 mmol), and the reaction was stirred for 2 h at room temperature. The resulting mixture was diluted with water (20 mL). The precipitated solids were collected by filtration and washed with water (5 mL). The solid was dried to afford 4-bromo-2-(2-(6-(3,5-dimethylphenyl)pyridin-3-yl)acetamido)-5-methoxybenzamide (B52, 0.65 g, 1.39 mmol, 67% yield) as a solid. LCMS (ES, m/z): 468 [M+H]+. 537 Attorney Docket No.: R2103-7054WO Synthesis of B53 do)-5- methoxybenzamide (B52, 0.65 g, 1.39 mmol) in MeOH (15 mL) was added 2 M NaOH (aq.) (6 mL), and the reaction was stirred for 2 h at room temperature. The mixture was acidified to pH 5 with 1 M HCl (aq.). The precipitated solids were collected by filtration and washed with H2O (20 mL). The solid was dried to afford 7-bromo-2-((6-(3,5-dimethylphenyl)pyridin-3-yl)methyl)-6- methoxyquinazolin-4(3H)-one (B53, 450 mg, 1.0 mmol, 72% yield) as a solid. LCMS (ES, m/z): 450 [M+H]+. Synthesis of B54 l)-6- methoxyquinazolin-4(3H)-one (B53, 150 mg, 0.33 mmol) and tert-butyl (R)-3-aminopyrrolidine- 1-carboxylate (90 mg, 0.5 mmol) in DMF (3 mL) were added BrettPhos Pd G3 (60 mg, 0.06 mmol) and Cs2CO3 (330 mg, 1.0 mmol), and the reaction was stirred for 2 h at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl (R)-3-((2-((6-(3,5-dimethylphenyl)-pyridin-3-yl)methyl)-6- methoxy-4-oxo-3,4-dihydroquinazolin-7-yl)amino)-pyrrolidine-1-carboxylate (B54, 100 mg, 0.18 mmol, 55% yield) as a solid. LCMS (ES, m/z): 555 [M+H]+. 538 Attorney Docket No.: R2103-7054WO Synthesis of Compound 652 methoxy-4-oxo-3,4-dihydroquinazolin-7-yl)amino)pyrrolidine-1-carboxylate (B54, 100 mg, 0.18 mmol) and TFA (0.5 mL) in DCM (2 mL) was stirred for 2 h at room temperature. The mixture was neutralized to pH 7 with NH3 (g) in MeOH. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 6) to afford (R)-2-((6-(3,5-dimethylphenyl)pyridin-3-yl)methyl)-6-methoxy-7-(pyrrolidin-3- ylamino)quinazolin-4(3H)-one hydrochloride (Compound 652, 17.3 mg, 0.038 mmol, 21% yield) as a solid. LCMS (ES, m/z): 456 [M-HCl+H]+.1H NMR (300 MHz, DMSO-d6) δ 9.31 (d, J = 41.5 Hz, 2H), 8.90 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.71 (s, 2H), 7.31 (s, 1H), 7.16 (s, 1H), 6.85 (s, 1H), 6.62 (s, 1H), 4.29 (s, 2H), 4.24 (s, 1H), 3.93 (s, 3H), 3.53- 3.41 (m, 1H), 3.28 (s, 3H), 2.36 (s, 6H), 2.26 (p, J = 7.5 Hz, 1H), 2.01 (s, 1H). An analogous method was followed to obtain the following compound. Compound Starting Characterization Material n - = ), ), 539 Attorney Docket No.: R2103-7054WO (m, 1H), 3.28 (s, 3H), 2.36 (s, 6H), 2.26 (p, J = 7.5 Hz, 1H), 2.01 (s, 1H). t n 0 - , d, , a p e : y es s o o pou thyl]-7- fluoro-3H-quinazolin-4-one (110 mg, 308.3 μmol) and 1,1-dioxothian-4-ol (92 mg, 616.6 μmol) in NMP (2 mL) were added NaH (60% dispersion in oil) (24.6 mg, 616.6 μmol) under nitrogen atmosphere, and the reaction was stirred for 16 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (2 mL) and purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to 540 Attorney Docket No.: R2103-7054WO afford 6-chloro-2-[(6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl]-7-(1,1-dioxothian-4-yl)oxy- 3H-quinazolin-4-one (Compound 695, 80 mg, 164.3 μmol, 53% yield) as a solid. LCMS (ES, m/z): 487 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 14.50 (s, 1H), 12.65 (s, 1H), 8.72 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.36 (s, 1H), 5.05 (p, J = 4.8 Hz, 1H), 4.36 (s, 2H), 3.18 (qd, J = 13.8, 7.3 Hz, 4H), 2.47 (s, 3H), 2.33 (s, 3H), 2.25 (q, J = 5.5 Hz, 4H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization The residue was purified by reversed- hy 6- - - .3 S 00 26 40 5- , J .1 (s, in A al Cl ic d- 7- 1 Attorney Docket No.: R2103-7054WO (d, J = 8.2 Hz, 1H), 7.98 (dd, J = 8.3, 2.3 Hz, 1H), 7.84 (qd, J = 6.8, 3.4 Hz, 2H 4 1H = 2 2.4 , = fluoro- 3H-quinazolin-4-one (150 mg, 373.4 μmol) and 1-ethylpiperidin-4-ol (96 mg, 746.7 μmol) in THF (3 mL) was added NaH (60% dispersion in oil) (30 mg, 746.7 μmol) under nitrogen atmosphere, and the reaction was stirred for 16 h at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (4 mL) and extracted with EtOAc (3 x 6 mL). The combined organic layers were washed with water (2 x 4 mL) and brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 10, Gradient 1) to afford 6-chloro-2-((6-(3,5-difluorophenyl)pyridin-3-yl)methyl)-7-((1- ethylpiperidin-4-yl)oxy)quinazolin-4(3H)-one hydrochloride (Compound 684, 60 mg, 109.6 μmol, 29% yield) as a solid. LCMS (ES, m/z): 511 [M-HCl+H]+.1H NMR (400 MHz, Methanol- d4) δ 8.89 (d, J = 2.1 Hz, 1H), 8.41 (t, J = 7.6 Hz, 1H), 8.26-8.17 (m, 2H), 7.69 (ddt, J = 6.2, 3.7, 2.0 Hz, 2H), 7.33-7.21 (m, 2H), 5.09 (s, 1H), 4.32 (d, J = 6.7 Hz, 2H), 3.63 (dd, J = 61.1, 12.7 Hz, 2H), 3.32-3.16 (m, 4H), 2.52-2.31 (m, 2H), 2.28-1.96 (m, 2H), 1.40 (td, J = 7.3, 4.3 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization 42 Attorney Docket No.: R2103-7054WO Modification: The reaction used 1.5 equiv. of alcohol and 3 equiv. of NaH h p- to 6- 4- ol, S, 00 70 ), dt, ), (t, z, z, , J 68 H 30 le . d- hy to o- 08 S un C el hy 2- - 0, a . Attorney Docket No.: R2103-7054WO un ºC el hy 2- - 6, a . Example 76: Synthesis of Compound 668 Synthesis of B41 -3H- quinazolin-4-one (Compound 637, 0.2 g, 473.5 μmol) and 2-bromoethoxy-tert-butyl-dimethyl- silane (339 mg, 1.42 mmol) in DMF (4 mL) was added Cs2CO3 (462 mg, 1.42 mmol), and the reaction was stirred for 16 h at room temperature. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford 2-[[5- [2-[tert-butyl(dimethyl)silyl]oxyethyl]-6,8-difluoro-pyrido[3,2-b]indol-3-yl]methyl]-6,7- dimethoxy-3H-quinazolin-4-one (B41, 0.05 g, 86.1 μmol, 18% yield) as a solid. LCMS (ES, m/z): 580 [M+H]+. Synthesis of Compound 668 544 Attorney Docket No.: R2103-7054WO -difluoro- pyrido [ , - ]n o - -y ]me y ]- , - me oxy- -qu nazo n- -one ( , . g, .1 μmol) in THF (2 mL) was added TBAF (36 mg, 129.2 μmol), and the reaction was stirred for 16 h at room temperature. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 5) to afford 2-((6,8-difluoro-5-(2-hydroxyethyl)-5H- pyrido[3,2-b]indol-3-yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one hydrochloride (Compound 668, 0.015 g, 29.8 μmol, 35% yield) as a solid. LCMS (ES, m/z): 467 [M-HCl+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.75 (s, 1H), 8.23 (dd, J = 8.0, 2.4 Hz, 1H), 7.68 (ddd, J = 12.2, 9.5, 2.4 Hz, 1H), 7.42 (s, 1H), 7.15 (s, 1H), 4.61 (t, J = 5.3 Hz, 2H), 4.46 (s, 2H), 3.86 (d, J = 7.3 Hz, 6H), 3.81 (t, J = 5.2 Hz, 2H). Example 77: Synthesis of Compound 671 , -3H- quinazolin-4-one (A42, 100 mg, 196.2 μmol) and trans-4-amino-1-methyl-pyrrolidin-3-ol (27 mg, 235.4 μmol) in dioxane (2 mL) were added t-BuONa (57 mg, 588.6 μmol) and GPhos Pd G6 (18 mg, 19.6 μmol), and the reaction was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by Prep-HPLC (Condition 5, Gradient 20) to afford 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-8-[[trans-4- 545 Attorney Docket No.: R2103-7054WO hydroxy-1-methylpyrrolidin-3-yl]amino]-3H-quinazolin-4-one (Compound 671, 5.9 mg, 11.9 μmol, 6% yield) as a solid. LCMS (ES, m/z): 498 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 8.2, 2.3 Hz, 1H), 7.81 (dt, J = 7.6, 2.1 Hz, 2H), 7.31 (tt, J = 9.2, 2.4 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 5.86 (d, J = 7.0 Hz, 1H), 5.29 (d, J = 4.9 Hz, 1H), 4.06 (s, 2H), 3.86 (s, 1H), 3.59 (s, 1H), 2.91-2.77 (m, 2H), 2.33 (dd, J = 9.5, 3.8 Hz, 1H), 2.22 (dd, J = 9.7, 3.9 Hz, 1H), 2.17 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization OH Modification: The reaction was S. p- to 5- - .0 S R s, z, ), = ), ), ), p- to 5- - d d) 99 z, s, 94 .8 Attorney Docket No.: R2103-7054WO Hz, 2H), 7.55-7.44 (m, 1H), 7.44- 7.26 (m, 1H), 7.08 (d, J = 2.7 Hz, 40 0 .5 . p- 1) 5- - .8 S R s, .8 ), 0 tt, .8 .3 an p- to 5- - .9 S R s, 7 1, 1 0 .1 ), .0 Attorney Docket No.: R2103-7054WO Hz, 1H), 2.68 (dd, J = 9.5, 6.5 Hz, 1H), 2.59 (td, J = 8.3, 5.1 Hz, 1H), ), m, as I- he th d p- to 7- - d d) 8 z, d, z, ), 4, ), = s, 4 .2 z, 8 as d p- 4) 5- Attorney Docket No.: R2103-7054WO hydrochloride (Compound 669, 5.5 mg, 10.8 μmol, 6% yield) as a solid. H 0 .4 ), ), = 7 z, as I- p- to 3- .4 S R s, 6 0 .9 ), 6 as I- p, ed at y sh 8, 1- - Attorney Docket No.: R2103-7054WO (pyrrolidin-3-ylamino)quinazolin- 4(3H)-one hydrochloride .4 S R s, z, 3 ), 4- s, 2, ), .2 as I- p- to 5- - - d d) ): z, d, z, 7 ), ), 550 Attorney Docket No.: R2103-7054WO Modification: The reaction was performed using Pd-PEPPSI- d y sh 2, 2- d d. H 6 6 m, ), = ), z, 6 .9 ), J y nt 5- - - 7, a 4 z, s, 3 .5 z, 3 ), Attorney Docket No.: R2103-7054WO 1.48 (d, J = 9.7 Hz, 1H), 1.28 (d, J = 9.9 Hz, 1H). A 150 mg, 589.0 μmol), 5,6-dimethyl-2H-indazole (111.9 mg, 765.7 μmol) and Cs2CO3 (767.6 mg, 2.36 mmol) in DMF (1.5 mL) was stirred at room temperature for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prep- HPLC (Condition 12, Gradient 2) to afford 2-[(5,6-dimethylindazol-2-yl)methyl]-6,7-dimethoxy- 3H-quinazolin-4-one (Compound 697, 35 mg, 96.1 μmol, 16% yield) as a solid. LCMS (ES, m/z): 506 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.33 (d, J = 1.0 Hz, 1H), 7.47 (s, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 6.98 (s, 1H), 5.53 (s, 2H), 3.85 (d, J = 6.3 Hz, 6H), 2.33- 2.25 (m, 6H). Example 79: Synthesis of Compound 665 Synthesis of B61 o a s rre so u on o [ -( , - me y m azo[ , -a]pyr n- -y )ace y ]oxylithium (B60, 2 g, 9.52 mmol) and 2-amino-3-bromo-4,5-dimethoxybenzamide (3.9 g, 14.2 mmol) in DMF (20 mL) was added T3P (9 g, 14.1 mmol, 50 wt. % in EtOAc) and pyridine (2.3 g, 29.1 mmol), 552 Attorney Docket No.: R2103-7054WO and the reaction was stirred for 5 h at 60°C. The product was precipitated by the addition of water (30 mL). The precipitated solids were collected by filtration and washed with water (5 mL) to afford 3-bromo-2-[[2-(6,7-dimethyl-imidazo[1,2-a]pyridin-2-yl)acetyl]amino]-4,5-dimethoxy- benzamide (B61, 400 mg, 867.1 μmol, 9% yield) as a solid. LCMS (ES, m/z): 461 [M+H]+. Synthesis of B62 yl)acetyl]- amino]-4,5-dimethoxy-benzamide (400 mg, 867.1 μmol) in THF (4 mL) was added LiOH (80 mg, 3.34 mmol), and the reaction was stirred for 16 h at room temperature. The mixture was acidified to pH 4 with 2M HCI. The precipitated solids were collected by filtration and washed with water (10 mL) to afford 8-bromo-2-[(6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl]-6,7-dimethoxy- 3H-quinazolin-4-one (B62, 280 mg, 631.6 μmol, 73% yield) as a solid. LCMS (ES, m/z): 443 [M+H]+. Synthesis of Compound 665 , , thyl]-6,7- dimethoxy-3H-quinazolin-4-one (B62, 100 mg, 225.6 μmol) and cyclopropyl(piperazin-1- yl)methanone (100 mg, 648.5 μmol) in dioxane (2 mL) were added Pd-PEPPSI-IPentCl (20 mg, 23.8 μmol) and t-BuONa (70 mg, 728.4 μmol) under nitrogen atmosphere, and the reaction was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under 553 Attorney Docket No.: R2103-7054WO reduced pressure and purified by Prep-HPLC (Condition 8, Gradient 7) to afford 8-[4- (cyclopropanecarbonyl)piperazin-1-yl]-2-[(6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl]-6,7- dimethoxy-3H-quinazolin-4-one (Compound 665, 5 mg, 9.7 μmol, 4% yield) as a solid. LCMS (ES, m/z): 517 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.26 (s, 1H), 7.66 (s, 1H), 7.25 (d, J = 7.6 Hz, 2H), 4.02 (s, 2H), 3.86 (s, 3H), 3.73 (s, 4H), 3.45 (d, J = 18.8 Hz, 4H), 3.16 (d, J = 18.0 Hz, 3H), 2.24 (s, 3H), 0.76-0.65 (m, 4H). Example 80: Synthesis of Compound 670 To a stirred solution of 7-bromo-6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]- 3H-quinazolin-4-one (Compound 454, 150 mg, 324.2 μmol) and potassium trifluoro(morpholinomethyl)borate (81 mg, 389.0 μmol) in dioxane (4.8 mL) and H2O (0.8 mL) were added Cs2CO3 (317 mg, 972.6 μmol), CataCXium A (butyldi(1-adamantyl)phosphine, 23.3 mg, 64.8 μmol) and diacetoxypalladium (8 mg, 32.4 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 49) to afford 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7- (morpholinomethyl)-3H-quinazolin-4-one (Compound 670, 28.4 mg, 58.8 μmol, 18% yield) as a solid. LCMS (ES, m/z): 483 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.02 (s, 1H), 7.91 (dd, J = 8.2, 2.3 Hz, 1H), 7.81 (dtd, J = 8.7, 6.7, 2.2 Hz, 2H), 7.68 (s, 1H), 7.31 (tt, J = 9.2, 2.4 Hz, 1H), 4.06 (s, 2H), 3.63 (s, 2H), 3.59 (t, J = 4.6 Hz, 4H), 2.45 (t, J = 4.6 Hz, 4H). An analogous method was followed to obtain the following compounds. 554 Attorney Docket No.: R2103-7054WO Compound Starting Material Characterization Modifications: The reaction was ran at 90 º f h f h i he th at er p- to 3- .7 d. R .4 d, ), ), ), at he th at se 2, 4- % 35 6) ), ), 08 . d- on 6- - - .4 S, z, Attorney Docket No.: R2103-7054WO DMSO-d6) δ 12.59 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 8.00 1H 2 dd = 2 2 H 1H), tt, (s, J z, d- on 7- 15 d. R ), ), ), 46 (s, 4 up Cl m ed 6- )- ol, ): z, 28 .3 (s, , J ), 556 Attorney Docket No.: R2103-7054WO Modifications: The reaction was ran at 80 ºC for 4 h. After the reaction, the i d ith nd h. ed 6- .4 as ly S, xamp e 8 : Synt es s o Compound 688 Synthesis of B69 -(4- piperidyloxy)-3H-quinazolin-4-one (150 mg, 310.6 μmol) and tert-butyl-(2-iodoethoxy)dimethyl- silane (177 mg, 621.2 μmol) in DMF (2 mL) was added DIEA (120 mg, 931.9 μmol), and the reaction was stirred for 6 h at 50°C. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to afford 7-[[1-[2- [tert-butyl(dimethyl)silyl]oxyethyl]-4-piperidyl]oxy]-6-chloro-2-[[6-(3,5-difluorophenyl)-3- pyridyl]methyl]-3H-quinazolin-4-one (B69, 145 mg, 226.1 μmol, 73% yield) as a solid. LCMS (ES, m/z): 641 [M+H]+. Synthesis of Compound 688 Attorney Docket No.: R2103-7054WO To a solution of 7-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-piperidyl]oxy]-6-chloro-2- [[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-3H-quinazolin-4-one (B69, 145 mg, 226.1 μmol) in MeOH (2 mL) was added 2 M NaOH (2 mL), and the reaction was stirred for 2 h at 80°C. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 2, Gradient 1) to afford 6-chloro-2-[[6-(3,5-difluorophenyl)-3- pyridyl]methyl]-7-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-3H-quinazolin-4-one (Compound 688, 35 mg, 66.4 μmol, 29% yield) as a solid. LCMS (ES, m/z): 527 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 8.02 (s, 1H), 7.91 (dd, J = 8.2, 2.3 Hz, 1H), 7.86-7.78 (m, 2H), 7.32 (tt, J = 9.1, 2.3 Hz, 1H), 7.23 (s, 1H), 4.75 (s, 1H), 4.35 (t, J = 5.4 Hz, 1H), 4.04 (s, 2H), 3.49 (q, J = 6.0 Hz, 2H), 2.65 (s, 2H), 2.39 (t, J = 6.3 Hz, 2H), 2.36 (s, 2H), 1.94 (d, J = 12.9 Hz, 2H), 1.75-1.66 (m, 2H). Example 82: Synthesis of Compound 699 Synthesis of B73 , g, 722.3 μmol) and 2-amino-4-bromo-5-(difluoromethoxy)benzamide (B72, 223.3 mg, 794.5 μmol) in DMF (3.6 mL) were added pyridine (114.3 mg, 1.44 mmol) and T3P (50 wt. % in EtOAc) (689.4 mg, 1.08 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was purified by reversed-phase flash chromatography (Condition 2, Gradient 4) to afford 4-bromo- 5-(difluoromethoxy)-2-[[2-[6-(3,5-difluorophenyl)-3-pyridyl]acetyl]amino]benzamide (B73, 180 mg, 351.4 μmol, 49% yield) as a solid. LCMS (ES, m/z): 512 [M+H]+. Synthesis of B74 558 Attorney Docket No.: R2103-7054WO yl)-3- pyridyl]acetyl]amino]benzamide (B73, 180 mg, 351.4 μmol) in MeOH (3.6 mL) was added 2 M NaOH (1.8 mL), and the reaction was stirred for 2 h at room temperature. The mixture was acidified to pH 5 with 1 N HCl (aq.). The precipitated solids were collected by filtration and washed with water (5 mL). The solid was dried to afford 7-bromo-6-(difluoromethoxy)-2-[[6-(3,5- difluorophenyl)-3-pyridyl]methyl]-3H-quinazolin-4-one (B74, 150 mg, 303.5 μmol, 86% yield) as a solid. LCMS (ES, m/z): 494 [M+H]+. Synthesis of Compound 699 )-3- pyridyl]methyl]-3H-quinazolin-4-one (B74, 100 mg, 202.3 μmol) and 1-ethylpiperidin-4-amine (31.1 mg, 242.8 μmol) in DMF (2 mL) were added Pd-PEPPSI-IPentCl (17.0 mg, 20.2 μmol) and Cs2CO3 (197.8 mg, 607.0 μmol), and the reaction was stirred for 16 h at 80 °C. The mixture was diluted with water (60 mL) and extracted with DCM/MeOH (10/1) (3 x 6 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 9) to afford 6-(difluoromethoxy)-2-((6-(3,5- difluorophenyl)pyridin-3-yl)methyl)-7-((1-ethylpiperidin-4-yl)amino)quinazolin-4(3H)-one hydrochloride (Compound 699, 25.4 mg, 43.9 μmol, 22% yield) as a solid. LCMS (ES, m/z): 542 [M-HCl+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.80 (d, J = 2.1 Hz, 1H), 8.15-8.00 (m, 2H), 7.81 (dt, J = 7.5, 2.2 Hz, 2H), 7.62 (d, J = 5.9 Hz, 1H), 7.53-6.98 (m, 2H), 6.92 (d, J = 4.6 Hz, 1H), 559 Attorney Docket No.: R2103-7054WO 4.18 (d, J = 5.0 Hz, 1H), 3.80-3.64 (m, 2H), 3.50 (s, 2H), 3.29-2.97 (m, 4H), 2.55 (s, 2H), 2.14- 1.80 (m, 4H), 1.25 (td, J = 7.3, 4.1 Hz, 3H). Example 83: Synthesis of Compound 679 Synthesis of B77 A 312 mg, 1.23 mmol), NiCl2 (16 mg, 122.8 μmol) and 2-(2-pyridyl)pyridine (19 mg, 122.8 μmol) in DMAc (5 mL) was stirred for 4 h at 60 °C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature.6-bromo-2,3-dimethyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2- b]pyridine (B76, 250 mg, 613.8 μmol) and Zn (117 mg, 1.84 mmol) were added into the mixture, and the resulting mixture was stirred for 16 h at 60 °C. The mixture was allowed to cool down to room temperature and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 18, Gradient 3) to afford 2-((1-(mesitylsulfonyl)-2,3-dimethyl-1H-pyrrolo[3,2- b]pyridin-6-yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one (B77, 42 mg, 76.8 μmol, 13% yield) as a solid. LCMS (ES, m/z): 547 [M+H]+. Synthesis of Compound 679 Attorney Docket No.: R2103-7054WO To a stirred mixture of 2-[[2,3-dimethyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2- b]pyridin-6-yl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (B77, 40 mg, 73.2 μmol) and NaOH (15 mg, 365.9 μmol) in water (0.2 mL) and MeOH (1 mL) was stirred for 36 h at 70 °C. The mixture was acidified to pH 5 with HCl in dioxane. The mixture was concentrated under pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 2-[(2,3- dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 679, 3.8 mg, 10.4 μmol, 14% yield) as a solid. LCMS (ES, m/z): 365 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.81 (s, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.37 (s, 1H), 7.05 (s, 1H), 3.94 (s, 2H), 3.84 (d, J = 8.9 Hz, 6H), 2.75-2.66 (m, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 2.14 (s, 3H). Example 84: Synthesis of Compound 680 T e (639.0 mg, 2.5 mmol) in DMAc (1.98 mL) were added NiCl2 (54 mg, 418.2 μmol) and 4,4’-di-tert-butyl-2,2’- bipyridine (112 mg, 418.2 μmol) under nitrogen atmosphere, and the reaction was stirred at 60°C for additional 4 h. 5-bromo-1,2,3-trimethyl-pyrrolo[2,3-b]pyridine (B80, 200 mg, 836.4 μmol) and Zn (547 mg, 8.36 mmol) were then added, and the resulting mixture was stirred at 60°C for additional 16 h. The reaction was quenched by the addition of water (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 6,7-dimethoxy-2-[(1,2,3- trimethylpyrrolo[2,3-b]pyridin-5-yl)methyl]-3H-quinazolin-4-one (Compound 680, 5.8 mg, 15.2 561 Attorney Docket No.: R2103-7054WO μmol, 2% yield) as a solid. LCMS (ES, m/z): 379 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.37 (s, 1H), 7.04 (s, 1H), 3.96 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.65 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material 2- d- hy he y- 8) 79 z, ), ), ), nd ed (5 by y rd 5- 7- ol, 13 z, 53 ), ). Example 85: Synthesis of Compound 681 562 Attorney Docket No.: R2103-7054WO Synthesis of B81 4.2 μmol), picolinimidamide hydrochloride (13.6 mg, 86.5 μmol) and Ni(DME)Cl2 (19.0 mg, 86.5 μmol) in DMA (2 mL) was stirred at 40 °C for 4 h under nitrogen atmosphere.7-bromo-6-chloro- 2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-3H-quinazolin-4-one (Compound 464, 100 mg, 216.1 μmol) and Zn (28.3 mg, 432.3 μmol) were added, and the resulting mixture was stirred at 60oC for additional 16 h. The operation was repeated 2 times. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (90% EtOAc in PE) to afford tert-butyl (3R)-3-[[6-chloro-2-[[6-(3,5-difluorophenyl)-3- pyridyl]methyl]-4-oxo-3H-quinazolin-7-yl]methyl]pyrrolidine-1-carboxylate (B81, 93 mg, 164.0 μmol, 38% yield) as a solid. LCMS (ES, m/z): 567 [M+H]+. Synthesis of B82 y , p yl)-3- pyridyl]methyl]-4-oxo-3H-quinazolin-7-yl]methyl]pyrrolidine-1-carboxylate (B81, 93 mg, 164.0 μmol) in DCM (1 mL) was added 4M HCl (gas) in dioxane (1 mL), and the reaction was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-7-[[(3R)-pyrrolidin-3-yl]methyl]- 563 Attorney Docket No.: R2103-7054WO 3H-quinazolin-4-one hydrochloride (B82, 63 mg, 125.2 μmol, 76% yield) as a solid. LCMS (ES, m/z): 467 [M+H]+. Synthesis of Compound 681 l)-7- (pyrrolidin-3-ylmethyl)quinazolin-4(3H)-one hydrochloride (B82, 63 mg, 125.2 μmol) and CH3CHO (55.1 mg, 1.25 mmol) in CH3CN (2 mL), and the reaction was stirred at room temperature for 16 h. NaBH3CN (15.7 mg, 250.3 μmol) was added and the resulting mixture was stirred at room temperature for an additional 0.5 h. The mixture was basified to pH 7 with NaHCO3 (aq). The resulting mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were concentrated under reduced pressure and purified by reversed- phase flash chromatography (Condition 2, Gradient 36) to afford (R)-6-chloro-2-((6-(3,5- difluorophenyl)pyridin-3-yl)methyl)-7-((1-ethylpyrrolidin-3-yl)methyl)quinazolin-4(3H)-one hydrochloride (Compound 681, 23 mg, 43.3 μmol, 35% yield) as a solid. LCMS (ES, m/z): 495 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.40 (s, 1H), 8.71 (s, 1H), 8.08-8.05 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.85-7.79 (m, 2H), 7.65 (d, J = 5.3 Hz, 1H), 7.37-7.28 (m, 1H), 4.09 (s, 2H), 3.61 (s, 2H), 3.50 (s, 1H), 3.13 (d, J = 7.5 Hz, 3H), 2.97 (d, J = 7.4 Hz, 2H), 2.92- 2.73 (m, 1H), 2.18-1.92 (m, 1H), 1.74 (d, J = 49.2 Hz, 1H), 1.20 (td, J = 7.2, 4.5 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Characterization ’- de d- n 6- - Attorney Docket No.: R2103-7054WO 7-[(1-ethyl-4-piperidyl)methyl]-3H- quinazolin-4-one (Compound 682, 29 d. R ), .1 2, s, 6 3 z, 5 5 .1 Example 86: Synthesis of Compound 691 H- quinazolin-4-one (D73, 150 mg, 337.3 μmol) and 1-ethylpiperidin-4-amine (43.3 mg, 337.3 μmol) and Cs2CO3 (329.7 mg, 1.01 mmol) and Pd-PEPPSI-IPentCl (28.3 mg, 33.7 μmol) in dioxane (3 mL) were stirred for 16 h at 100 °C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 41) to afford 6-chloro-2-[[6-(3,4-dimethylpyrazol-1-yl)-3-pyridyl]methyl]-7-[(1-ethyl-4- piperidyl)amino]-3H-quinazolin-4-one (Compound 691, 25 mg, 50.8 μmol, 15% yield) as a solid. LCMS (ES, m/z): 492 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.28 (s, 1H), 7.91-7.84 (m, 2H), 7.82-7.73 (m, 1H), 6.70 (s, 1H), 5.66 (d, J = 8.1 Hz, 1H), 565 Attorney Docket No.: R2103-7054WO 3.92 (s, 2H), 3.45 (s, 1H), 2.82 (d, J = 11.4 Hz, 2H), 2.32 (q, J = 7.2 Hz, 2H), 2.20 (s, 3H), 2.03 (d, J = 1.0 Hz, 5H), 1.87 (d, J = 12.3 Hz, 2H), 1.58 (q, J = 10.6 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H). Example 87: Synthesis of Compound 693 Synthesis of B83 .28 g, 3.92 mmol) and 2,2’-bipyridine (613 mg, 3.92 mmol) in DMAc (40 mL) were added NiCl2 (508 mg, 3.92 mmol) under nitrogen atmosphere, and the reaction was stirred for 4 h at 60 °C under nitrogen atmosphere. 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-8-iodo-3H- quinazolin-4-one (A42, 2 g, 3.92 mmol) and Zn (255 mg, 3.92 mmol) were then added and the resulting mixture was stirred for 20 h at 60°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (33% EtOAc in PE) to afford tert-butyl 4-[[6-chloro-2-[[6-(3,5- difluorophenyl)-3-pyridyl]methyl]-4-oxo-3H-quinazolin-8-yl]methyl]piperidine-1-carboxylate (B83, 420 mg, 722.8 μmol, 18% yield) as a solid. LCMS (ES, m/z): 581 [M+H]+. Synthesis of B84 , thyl]-4- oxo-3H-quinazolin-8-yl]methyl]piperidine-1-carboxylate (B83, 420 mg, 722.8 μmol) in DCM (8 mL) was added HCl (4.0 M in 1,4-dioxane) (2 mL), and the reaction was stirred for 2 h at room 566 Attorney Docket No.: R2103-7054WO temperature. The resulting mixture was concentrated under reduced pressure and adjusted to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was diluted with water (5 mL) and extracted with DCM/MeOH (10/1) (3 x 10 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 1, Gradient 8) to afford 6-chloro-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-8-(4-piperidylmethyl)-3H-quinazolin-4- one (B84, 300 mg, 623.8 μmol, 86% yield) as a solid. LCMS (ES, m/z): 481 [M+H]+. Synthesis of Compound 693 ridyl- methyl)-3H-quinazolin-4-one (B84, 100 mg, 207.9 μmol) and DIEA (81 mg, 623.8 μmol) in DMF (2 mL) was added iodoethane (98 mg, 623.8 μmol), and the reaction was stirred for 4 h at 50°C. The resulting mixture was diluted with water (10 mL) and extracted with DCM/MeOH (10/1) (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 10, Gradient 4) to afford 6-chloro-2-((6-(3,5- difluorophenyl)-pyridin-3-yl)methyl)-8-((1-ethylpiperidin-4-yl)methyl)quinazolin-4(3H)-one hydrochloride (Compound 693, 40 mg, 73.3 μmol, 35% yield) as a solid. LCMS (ES, m/z): 509 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.34 (s, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.06 (td, J = 7.7, 7.1, 2.2 Hz, 1H), 7.89 (q, J = 3.4, 2.6 Hz, 3H), 7.73-7.65 (m, 1H), 7.37 (tt, J = 9.2, 2.4 Hz, 1H), 4.16 (s, 2H), 3.22 (d, J = 11.9 Hz, 2H), 3.11-2.79 (m, 3H), 2.70 (d, J = 6.5 Hz, 2H), 2.56 (d, J = 10.3 Hz, 1H), 1.55 (d, J = 50.2 Hz, 5H), 1.15 (t, J = 7.2 Hz, 3H).19F NMR (282 MHz, DMSO-d6) δ -108.99. An analogous method was followed to obtain the following compounds. 567 Attorney Docket No.: R2103-7054WO Compound Starting Material Characterization Modification: Step 1 was omitted. 7- by sh 2, 1- - ol, S, 00 ), s, 84 44 62 J z, 82 6. Example 88: Synthesis of Compound 686 Synthesis of B93 568 Attorney Docket No.: R2103-7054WO yrrolo[3,2- b]pyridin-2-yl]acetic acid (B92, 350 mg, 905.7 μmol) and 2-amino-4,5-dimethoxy-benzamide (213 mg, 1.09 mmol) in CH3CN (7 mL) were added NMI (297 mg, 3.62 mmol, 287.0 μL) and TCFH (381 mg, 1.36 mmol), and the reaction was stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (5% MeOH in DCM) to afford 2-[[2-[5,6-dimethyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2- b]pyridin-2-yl]acetyl]amino]-4,5-dimethoxy-benzamide (B93, 320 mg, 566.7 μmol, 63% yield) as a solid. LCMS (ES, m/z): 565 [M+H]+. Synthesis of B94 pyrrolo[3,2- b]pyridin-2-yl]acetyl]amino]-4,5-dimethoxy-benzamide (B93, 300 mg, 531.3 μmol) in THF (6 mL) were added LiOH (39 mg, 1.63 mmol) under nitrogen atmosphere, and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (50% MeOH in DCM) to afford 2-[[5,6-dimethyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2-b]pyridin-2-yl]methyl]- 6,7-dimethoxy-3H-quinazolin-4-one (B94, 200 mg, 365.9 μmol, 69% yield) as a solid. LCMS (ES, m/z): 547 [M+H]+. 569 Attorney Docket No.: R2103-7054WO Synthesis of Compound 686 ridin-2- yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one (B94, 200 mg, 365.9 μmol) in THF (2 mL) was added TBAF (1.0 M in THF) (1 M, 1 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by Prep- HPLC (Condition 13, Gradient 5) to afford 2-((5,6-dimethyl-1H-pyrrolo[3,2-b]pyridin-2- yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one (Compound 686, 31.3 mg, 85.9 μmol, 23% yield) as a solid. LCMS (ES, m/z): 365 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 10.98-10.92 (m, 1H), 7.41 (s, 2H), 7.04 (s, 1H), 6.27 (d, J = 1.9 Hz, 1H), 4.07 (s, 2H), 3.84 (d, J = 2.2 Hz, 6H), 2.41 (s, 3H), 2.28 (s, 3H). Example 89: Synthesis of Compound 704 To a stirred mixture of 3-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-4-iodo-6,7- dimethoxy-2H-isoquinolin-1-one (C1, 100 mg, 187.2 μmol) in DMF (2.0 mL) was added CuI (7.0 mg, 36.8 μmol), DMCyDA (11 mg, 77.3 μmol), morpholine (100 mg, 1.15 mmol) and Cs2CO3 (183 mg, 561.7 μmol) at r.t. under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 80 °C under nitrogen atmosphere and then allowed to cool down to r.t. and diluted with water (10 mL). The solid was collected by filtration and washed with water (10 mL). The solid was 570 Attorney Docket No.: R2103-7054WO purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, CH3CN in water (0.1% HCl), 20% to 60% gradient in 10 min; detector, UV 254 nm). The product was 60% purity. The residue was purified by reversed-phase flash chromatography with the following conditions (Condition 2, Gradient 11) to afford 3-[[6-(3,5- difluorophenyl)-3-pyridyl]methyl]-6,7-dimethoxy-4-morpholino-2H-isoquinolin-1-one (Compound 704, 6.7 mg, 13.6 μmol, 7% yield) as a solid. LCMS (ES, m/z): 494 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.83 – 7.76 (m, 2H), 7.72 (dd, J = 8.3, 2.3 Hz, 1H), 7.60 (s, 1H), 7.33 – 7.25 (m, 2H), 4.10 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.78 – 3.69 (m, 2H), 3.63 (dd, J = 10.1, 6.9 Hz, 2H), 3.29 (d, J = 11.4 Hz, 2H), 2.78 (d, J = 11.6 Hz, 2H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization O Modification: The reaction was h. ed sh 7, 7- - g, d. +. 6) .6 ), ), s, ), ), s, ), (t, .4 z, 571 Attorney Docket No.: R2103-7054WO 2H), 1.24 (s, 1H), 0.99 (t, J = 7.1 Hz, 3H). as . p- 8) 1- - 24 a 03 δ 51 = m, .0 43 z, .1 ), q, .1 Example 90: Synthesis of Compound 716 y - - ,- y-- - -q --y hyl] thiazol-2-yl] amino] pyridine-2-carboxylate (C91, 100 mg, 220.5 μmol) in MeOH (1 mL) and THF (1 mL) were added NaBH4 (42 mg, 1.10 mmol) and CaCl2 (147 mg, 1.32 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h and then diluted 572 Attorney Docket No.: R2103-7054WO with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The solid was purified by reversed-phase flash chromatography (Condition 8, Gradient 20) to afford the hydrochloride salt of 2-[[2-[[6-(hydroxymethyl)-2-pyridyl] amino] thiazol-4-yl] methyl]-6,7-dimethoxy-3H- quinazolin-4-one (Compound 716, 26 mg, 61.1 μmol, 28% yield) as a solid. LCMS (ES, m/z): 426 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.48 (s, 1H) 727 (s 1H), 7.06 (d, J = 7.4 Hz, 1H), 7.00 - 6.93 (m, 2H), 4.59 (s, 2H), 4.19 (s, 2H), 3.91 (d, J = 5.1 Hz, 6H). Example 91: Synthesis of Compound 722 To a stirred solution of 2-((8-bromoquinolin-3-yl)methyl)-6,7-dimethoxyquinazolin- 4(3H)-one (C12, 100 mg, 0.23 mmol) and 1H-imidazole (133 mg, 1.95 mmol) in DMF (3.5 mL) was added CuI (166 mg, 0.87 mmol) and Pd(OAc)2 (33 mg, 0.14 mmol) at room temperature. After stirring for 3 h at 140 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 8, Gradient 6) to afford the hydrochloride salt of 2-((8-(1H-imidazol-2-yl)quinolin-3-yl)methyl)-6,7- dimethoxyquinazolin-4(3H)-one (Compound 722, 2.3 mg, 5 µmol, 2% yield) as a solid. LCMS (ES, m/z): 414 [M-HCl+H]+.1H NMR (300 MHz, DMSO-d6) δ 14.79 (s, 2H), 12.48 (s, 1H), 9.13 (d, J = 2.2 Hz, 1H), 8.61-8.50 (m, 2H), 8.30 (dd, J = 8.3, 1.3 Hz, 1H), 7.87 (d, J = 1.7 Hz, 3H), 7.41 (s, 1H), 6.97 (s, 1H), 4.28 (s, 2H), 3.83 (d, J = 3.8 Hz, 6H). Example 92: Synthesis of Compound 725 573 Attorney Docket No.: R2103-7054WO To a solution of 7-benzyloxy-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6-methoxy- 3H-quinazolin-4-one (Compound 457, 50 mg, 103.0 μmol) in MeOH (1 mL) was added Pd/C (10% on carbon, wetted with ~55% water) (11 mg, 103.0 μmol). The resulting mixture was hydrogenated at room temperature for 2 h under 1 atm hydrogen atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Condition 16, Gradient 3) to afford the hydrochloride salt of 2-((6-(3,5- difluorophenyl)pyridin-3-yl)methyl)-7-hydroxy-6-methoxyquinazolin-4(3H)-one (Compound 725, 22 mg, 54.9 μmol, 53% yield) as a solid. LCMS (ES, m/z): 396 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 11.0(s, 1H), 8.86 (s, 1H), 8.12 (s, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 7.34 (t, J = 9.2 Hz, 2H), 4.28 (s, 2H), 3.89 (s, 3H). Example 93: Synthesis of Compound 750 Synthesis of C36 , 6,7- dimethoxy-3H-quinazolin-4-one (C32, 320 mg, 745.5 μmol) in MeOH (7 mL) was added TEA (377 mg, 3.73 mmol) and Pd(dppf)Cl2 (61 mg, 74.6 μmol) in a pressure tank. The mixture was purged with nitrogen for 2 min and then was pressurized to 20 atm with carbon monoxide at 80 °C for 16 h. The reaction mixture was cooled to room temperature, filtered to remove insoluble solids, and purified by silica gel column chromatography (DCM / MeOH, 10:1) to afford methyl 2-[(6,7- dimethoxy-4-oxo-3H-quinazolin-2-yl)methyl]-6-methyl-imidazo[1,2-a]pyridine-7-carboxylate (C36, 160 mg, 391.8 μmol, 53% yield) as a solid. LCMS (ES, m/z): 409 [M+H]+. 574 Attorney Docket No.: R2103-7054WO Synthesis of Compound 750 ]-6- methyl-imidazo[1,2-a]pyridine-7-carboxylate (C36, 160 mg, 391.8 μmol) in THF (3.2 mL) was added LiAlH4 (2.4 M in THF) (0.35 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Condition 8, Gradient 2) to afford hydrochloride salt of 2-[[7-(hydroxymethyl)- 6-methyl-imidazo[1,2-a]pyridin-2-yl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 750, 12.3 mg, 32.3 μmol, 8% yield) as a solid. LCMS (ES, m/z): 381 [M-HCl+H]+.1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.44 (s, H), 4.37 (s, 2H), 3.86 (d, J = 4.3 Hz, 6H), 2.55 (s, 2H), 2.28 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization The residue was urified b Prep- nt de 7- - e .8 d. - z, 80 ), s, .5 575 Attorney Docket No.: R2103-7054WO The residue was purified by silica gel column chromatography rd - d % S, 00 ), s, .7 ), z, as by sh 2, 6- e .9 d. ]+. 6) 80 ), z, ), z, Example 94: Synthesis of Compound 756 576 Attorney Docket No.: R2103-7054WO ,7- dimethoxy-3H-quinazolin-4-one (Compound 753, 0.42 g, 978.4 μmol) and Pd(PPh3)4 (113 mg, 97.8 μmol) in THF (8 mL) was added diethylzinc (1 M in hexanes, 2 mL, 1.96 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Condition 12, Gradient 18) to afford the hydrochloride salt of 2-((7-ethyl- 6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-6,7-dimethoxyquinazolin-4(3H)-one (Compound 756, 0.07 g, 168.7 μmol, 17% yield) as a solid. LCMS (ES, m/z): 379 [M-HCl+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.21 (s, 1H), 7.68 (s, 1H), 7.44 (s, 1H), 7.07 (s, 1H), 4.39 (s, 2H), 3.86 (d, J = 5.6 Hz, 6H), 2.80 (q, J = 7.4 Hz, 2H), 2.35 (d, J = 1.0 Hz, 3H), 1.26 (t, J = 7.4 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization M difi i Pd PEPPSI- in by sh 2, 6- - d % S, 577 Attorney Docket No.: R2103-7054WO 1H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.77 (d, J = 2.5 ), s, .4 ), Example 95: Synthesis of Compound 757 S)- 4,4-difluoropyrrolidin-3-yl]amino]-3H-quinazolin-4-one (C45, 50 mg, 99.2 μmol) in DCE (1 mL) was added formaldehyde (30 mg, 992.3 μmol) at room temperature. The resulting mixture was stirred for 1.5 h at room temperature. Then NaBH3CN (19 mg, 297.7 μmol) was added and the mixture was stirred for 1 h at room temperature. The reaction was quenched with water (80 mL) at 0°C. The resulting mixture was extracted with DCM (4 x 50 mL). The combined organic layers were washed with water (1 x 100 mL) and brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 11) to afford 6-chloro-7-[[(3S)-4,4-difluoro-1- methyl-pyrrolidin-3-yl]amino]-2-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-3H-quinazolin-4- one (Compound 757, 5 mg, 9.7 μmol, 10% yield) as a solid. LCMS (ES, m/z): 518 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 5.3 Hz, 2H), 7.85-7.77 (m, 2H), 7.32 (t, J = 9.2 Hz, 1H), 6.84 (s, 1H), 5.98 (d, J = 8.2 Hz, 1H), 4.41 (s, 1H), 4.00 (s, 2H), 3.27-3.12 (m, 2H), 2.82-2.70 (m, 2H), 2.30 (s, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization 578 Attorney Docket No.: R2103-7054WO Modification: The reaction ran for 4 h. The residue was purified by reversed- h fl h h hy 7- e as ]+. in d- hy 2- ol, z): z, J J .1 29 6- 93 J z, z, d, d- hy 6- - ol, S, 00 26 25 Attorney Docket No.: R2103-7054WO (s, 1H), 6.84 (s, 1H), 5.97 (d, J = 8.2 Hz, 1H), 4.38 (s, 1H), 3.97 (s, 2H), 24 = 4 H 1H 1 1H), ), ). in e- hy en 1) 5- - 7 6- ol, z): z, J ), (s, = d, h, z, ), m, z, z): z, J ), (s, = d, h, z, ), Attorney Docket No.: R2103-7054WO 2.10 (d, J = 9.0 Hz, 1H), 1.80-1.54 (m, 6H), 1.38 (ddd, J = 17.6, 10.5, 4.9 Hz, 2H un . e- hy to 6- - ol, S, 00 z, 4- ), ), = ), . un nd e- hy 6- - - - d as 08 O- z, ), ), = ), ), ), ), ), 581 Attorney Docket No.: R2103-7054WO 1.79-1.66 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H). ifi i h i un nd e- hy to 6- - ol, S, 00 z, ), = 74 ), z, z, 3, .2 un 3 e- hy 6- - - - d as 08 O- z, ), ), = ), ), Attorney Docket No.: R2103-7054WO 2.63 (s, 1H), 2.33 (q, J = 7.1 Hz, 2H), 2.24 (d, J = 11.7 Hz, 1H), 2.19 (s, 3H), 2 d = 11 H 1H 2 2 H), z, un 3 e- hy to 6- - n- ol, S, 00 z, ), = 74 ), z, z, 3, .2 un 3 e- hy 6- - - d as 10 O- z, 86 = = Attorney Docket No.: R2103-7054WO 8.7 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 3.93 (s, 2H), 3.91-3.79 (m, 1H), 3.09 = 11 H 1H 2 d = 11.2 19 2, z, un 3 e- hy 6- - - d as 10 O- z, ), ), ), 09 .2 24 02 z, un 3 e- hy 6- - - d a ]+. δ ), = = Attorney Docket No.: R2103-7054WO 8.8 Hz, 1H), 4.74 (td, J = 9.6, 4.8 Hz, 1H), 4.62 (td, J = 9.6, 4.9 Hz, 1H), 3.92 2H 2 d = 4 H 1H 16 = 19 .0 ), (t, un 3 e- hy 6- - d as 10 O- z, z, (s, 68 92 = ), 10 03 61 = un de e- hy 6- .8 Attorney Docket No.: R2103-7054WO μmol, 9% yield) as a solid. LCMS (ES, m/z): 506 [M+H]+.1H NMR (400 MH DM d δ 12 1H 38 1- ), ), ), 10 m, 60 45 98 un 2 by nt 6- - e ol, z): z, ), 1- 5- 0- .2 91 47 un 3 e- hy 6- e % ): z, Attorney Docket No.: R2103-7054WO DMSO-d6) δ 12.53 (s, 1H), 8.60 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 1 1H dd = 4 22 Hz, (s, z, (s, z, / .5 el hy rt- 4- d) z): un 3 e- hy 7- - .3 S 00 60 z, ), ), d, (s, 7- z, m, .1 Attorney Docket No.: R2103-7054WO F O F Modification: The reaction was run N F NH N with 5 equiv. of acetaldehyde and 3 i f N BH OA e- hy 7- - .5 S 00 60 z, ), ), z, (s, d, 8- ), ), O F F , , xy- 3H-quinazolin-4-one (D1, 0.1 g, 210.0 μmol) and 2-(difluoromethylsulfonyl)pyridine (81.1 mg, 419.9 μmol) in EtOH (2 mL) were added pyridine-2,6-bis(carboximidamide) dihydrochloride (19.8 mg, 84.0 μmol), Zn (109.8 mg, 1.68 mmol), ZnBr2 (47.2 mg, 210.0 μmol) and dichloronickel hexahydrate (9.9 mg, 42.0 μmol). After stirring for 12 h at 75 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 41) to afford 2-[[7- 588 Attorney Docket No.: R2103-7054WO (difluoromethyl)-6-methyl-imidazo[1,2-a]pyridin-2-yl]methyl]-6,7-dimethoxy-3H-quinazolin-4- one (Compound 806, 0.015 g, 37.5 μmol, 18% yield) as a solid. LCMS (ES, m/z): 401 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.44 (s, 1H), 7.86 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H), 7.05 (s, 1H), 7.17-6.87 (m, 1H), 4.05 (s, 2H), 3.85 (d, J = 3.6 Hz, 6H), 2.31 (d, J = 1.3 Hz, 3H). Example 97: Synthesis of Compound 820 , [[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino]-3H-quinazolin-4-one (D25, 50 mg, 107.3 μmol) and iodoethane (16 mg, 107.3 μmol, 8.63 μL) in DMF (2 mL) were added DIEA (13 mg, 107.3 μmol, 18.69 μL). The resulting mixture was stirred for 16 h at 50 °C under nitrogen atmosphere. The reaction was purified by Prep-HPLC (Condition 5, Gradient 30) to afford 6-chloro-2-[[6-(3,4- dimethylpyrazol-1-yl)-3-pyridyl]methyl]-8-[[(3R,4R)-1-ethyl-4-hydroxy-pyrrolidin-3-yl]amino]- 3H-quinazolin-4-one (Compound 820, 4 mg, 8.1 μmol, 8% yield) as a solid. LCMS (ES, m/z): 494 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 7.89 (dd, J = 8.5, 2.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 5.86 (d, J = 7.1 Hz, 1H), 5.26 (d, J = 4.7 Hz, 1H), 4.00 (s, 2H), 3.87 (s, 1H), 3.57 (s, 1H), 2.86 (q, J = 8.5 Hz, 2H), 2.39-2.31 (m, 4H), 2.19 (s, 3H), 2.02 (d, J = 1.0 Hz, 3H), 0.98 – 0.80 (m, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization 589 Attorney Docket No.: R2103-7054WO Modification: The reaction ran at room temperature. Th d i ifid by hy 2- - - nd a ]+. δ (s, z, (s, z, d, , J z, m e- 2, 6- H- 13 d. H 45 28 .5, ), z, (s, ), ), m, 590 Attorney Docket No.: R2103-7054WO Modification: The reaction ran at room temperature. Th d d ifid by nt )- d a H 00 .3 ), = ), m, ), z, m by hy 2- d as ]+. δ = ), 28 00 z, = . 591 Attorney Docket No.: R2103-7054WO Modification: The reaction was run in DCM at room temperature. Th id ifi d b d- hy rd o- - nd s a M- z, (s, d, (s, d, ), ), at d- hy 2- .9 S 00 44 (s, ), (s, (s, ), m, ), ), z, 592 Attorney Docket No.: R2103-7054WO Modification: The reaction was run at room temperature over 6 h. Th id ifid b d- hy 7- nd as ]+. δ ), z, = 15 ), ), – 30 = 01 Example 98: Synthesis of Compound 845 o a sou on o -[[-c oro--[(-e y--pper y)amno]--oxo- -qunazo n-2- yl]methyl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-b]pyridine-3-carbonitrile (D55, 70 mg, 115.5 μmol) in DCM (2 mL) was added HCl (4.0 M in 1,4-dioxane) (2 mL). The reaction was stirred for 2 h at room temperature and then concentrated under reduced pressure and adjusted to pH 8 with sat. NaHCO3 (aq.). The resulting mixture was diluted with water (5 mL) and extracted with DCM/MeOH (10/1) (3 x 10 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 593 Attorney Docket No.: R2103-7054WO 71) to afford 6-[[6-chloro-7-[(1-ethyl-4-piperidyl)amino]-4-oxo-3H-quinazolin-2-yl]methyl]-2- methyl-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (Compound 845, 25 mg, 52.5 μmol, 45% yield) as a solid. LCMS (ES, m/z): 476 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 2H), 8.42 (d, J = 1.8 Hz, 1H), 7.85 (s, 1H), 7.81 (d, J = 1.9 Hz, 1H), 6.69 (s, 1H), 5.65 (d, J = 8.0 Hz, 1H), 4.00 (s, 2H), 3.45 (s, 1H), 2.82 (d, J = 11.4 Hz, 2H), 2.59 (s, 3H), 2.32 (q, J = 7.2 Hz, 2H), 2.04 (t, J = 11.4 Hz, 2H), 1.87 (d, J = 12.4 Hz, 2H), 1.58 (d, J = 11.1 Hz, 2H), 1.00 (t, J = 7.1 Hz, 3H). An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization The residue was purified by reversed- hy 6- 7- 10 id. H 09 .9 .9 .1 ), = = z, (t, un er 4- 3- .2 as ly S 594 Attorney Docket No.: R2103-7054WO The filtrate was concentrated under reduced pressure to afford 2-[[6-(3- hl l1 l 3 3- .3 as ep S p- to 5- 6- e ol, S, 00 z, z, ), ), = ), ), = Example 99: Synthesis of Compound 897 Synthesis of E10 ue o - o o--c oo-- - ,- e ypyao--y --py y e y - -qu ao --one (D73, 2.0 g, 4.50 mmol), tributyl(1-ethoxyvinyl)stannane (2.4 g, 6.75 mmol), and XPhosPd G3 (381 mg, 449.7 μmol) in THF (30 mL) was stirred at 60 °C for 1 h. The reaction was cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EA (3 x 25 mL), washed with 595 Attorney Docket No.: R2103-7054WO brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/THF) to afford 6-chloro-2-[[6-(3,4- dimethylpyrazol-1-yl)-3-pyridyl] methyl]-7-(1-ethoxyvinyl)-3H-quinazolin-4-one (E10, 600 mg, 725 μmol, 16% yield) as a solid. LCMS (ES, m/z): 436 [M+H]+. Synthesis of Compound 898 -(1- ethoxyvinyl)-3H-quinazolin-4-one (E10, 100 mg, 0.230 mmol) in HCl (4.0 M in 1,4-dioxane, 6 mL) was stirred at room temperature for 6 h and then concentrated under reduced pressure. The residue was purified by Prep-HPLC (Condition 23, Gradient 2) to afford 7-acetyl-6-chloro-2-[[6- (3,4-dimethylpyrazol-1-yl)-3-pyridyl] methyl]-3H-quinazolin-4-one (Compound 898, 6.0 mg, 3.2 μmol, 6.4% yield) as a solid. LCMS (ES, m/z): 408 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.45-8.34 (m, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.95-7.84 (m, 2H), 7.81-7.73 (m, 1H), 4.02 (s, 2H), 2.61 (s, 3H), 2.19 (s, 3H), 2.03 (s, 3H). Example 100: Synthesis of Compound 912 ,7- dimethoxyquinazolin-4(3H)-one (E22, 150 mg, 0.38 mmol) in DCM (5 mL) was added DAST (305 mg, 1.89 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h and then quenched with water at room temperature. The resulting mixture was extracted with EA (3 x 15 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Condition 13, Gradient 3) to afford 2- 596 Attorney Docket No.: R2103-7054WO [[6-[3-(fluoromethyl)pyrazol-1-yl]-3-pyridyl]methyl]-6,7-dimethoxy-3H-quinazolin-4-one (Compound 912, 10 mg, 7% yield) as a white solid. LCMS (ES, m/z): 396 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.48 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 6.70 (s, 1H), 5.52 (s, 1H), 5.40 (s, 1H), 4.01 (s, 2H), 3.86 (s, 4H), 3.85 (s, 4H). Starting Materials Protocols Example 101: Synthesis of A2-A6 Synthesis of A2 To a stir mmol) in DMF (14 mL) were added Zn(CN)2 (2.13 g, 18.2 mmol) and Pd(PPh3)4 (525 mg, 454.5 μmol), and the reaction was stirred for 1 h at 130°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, quenched with water (10 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-amino-5-fluoro-4-methoxy-benzonitrile (A2, 1.2 g, 7 mmol, 77% yield) as a solid. LCMS (ES, m/z): 165 [M+H]-. An analogous method was followed to obtain the following compound. Compound Starting Material Characterization h i ifi ili l l mn 2- % n 5- ol, Attorney Docket No.: R2103-7054WO Modification: The reaction was ran at 120°C for 16 h. The residue was purified by silica gel column h h E A i PE ff d i 5- ol, n 6- ol, er nd % l- d. n 2- % to 2, S, Example 102: Synthesis of A7 To a stirred ue o -a o--c oo-py e--ca o e 1 g, 6.5 mmol) in THF (10 mL) was added MeONa (1.8 g, 32.6 mmol), and the reaction was stirred for 16 h at 50°C. The mixture was allowed to cool down to room temperature, quenched with water (10 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (10 mL), 598 Attorney Docket No.: R2103-7054WO dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (17% EtOAc in PE) to afford 2-amino-6- methoxy-pyridine-3-carbonitrile (A7, 900 mg, 5.7 mmol, 88% yield) as a solid. LCMS (ES, m/z): 150 [M+H]+. Example 103: Synthesis of A8 To a soluti mmol) in DMF (6 mL) was added CuCN (1 g, 11.4 mmol), and the reaction was stirred for 16 h at 150°C. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 2, Gradient 7) to afford 2-amino-4-fluoro-5-methoxy-benzonitrile (A8, 300 mg, 1.8 mmol, 79% yield) as a solid. LCMS (ES, m/z): 167 [M+H]+. Example 104: Synthesis of A10 Synthesis of A9 T , . -methyl-1H- pyrrole (849.9 mg, 10.5 mmol) in toluene (2.0 mL) were added CuI (1.66 g, 8.7 mmol, 296 μL), K3PO4 (1.85 g, 8.7 mmol) and DMEDA (768.3 mg, 8.7 mmol), and the reaction was stirred at 110°C for 16 h. The resulting mixture was cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford methyl 2-[4-(3-methylpyrrol-1-yl)phenyl]acetate (A9, 650 mg, 2.84 mmol, 32% yield) as a solid. LCMS (ES, m/z): 230 [M+H]+. Synthesis of A10 599 Attorney Docket No.: R2103-7054WO To a solution of methyl 2-[4-(3-methylpyrrol-1-yl)phenyl]acetate (A9, 500 mg, 2.2 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH.H2O (274.5 mg, 6.5 mmol), and the reaction was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and adjusted pH with 1 N aq. HCl. The resulting solid was collected by filtration and washed with water (10 mL) to afford 2-[4-(3-methylpyrrol-1-yl)phenyl]acetic acid (A10, 400 mg, 1.86 mmol, 85% yield) as a solid. LCMS (ES, m/z): 216 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Material Characterization Modification: Step 1 was ran in dioxane. Step 2 ed 1- .1 ): Pd C % as th 4, er 3- 2, S A at th ed ed 4- 3, Attorney Docket No.: R2103-7054WO 250 mg, 1.13 mmol, 89% yield) as a solid. LCMS (ES, m/z): 222 [M+H]+. ifi i i R)- ce an N nd 3- 1, a A 00 , A as by to 3- % ]+. Example 105: Synthesis of A18 Synthesis of A17 Ethy -etoxy--mnopropanoate yroc or e ( . g, . mmo) and 4,5-dichloro- benzene-1,2-diamine (9 g, 50.8 mmol) were dissolved in methanol (100 mL) at 0 °C. After stirring in an ice bath for 1 h the mixture was refluxed for 16 h. The hot solution was treated with activated 601 Attorney Docket No.: R2103-7054WO charcoal (0.5 g) and stirred for 1 h, while cooling slowly to room temperature. Afterwards the charcoal was filtered off by means of a small column with neutral aluminum oxide using methanol (80 mL) for rinsing. The filtrate was concentrated partially under reduced pressure. The resulting suspension was heated till the precipitate was re-dissolved. The flask was sealed under N2 with a rubber septum after cooling to room temperature and allowed to stand in the freezer (-20°C) overnight. The formed product was filtered, washed quickly with cold methanol (-20°C, 10 mL) and diethyl ether (2 x 10 mL) to afford ethyl 2-(5,6-dichloro-1H-benzimidazol-2-yl)acetate (A17, 4.8 g, 17.6 mmol, 35% yield) as a solid. LCMS (ES, m/z): 273 [M+H]+. Synthesis of A18 T 17, 2.5 g, 9.2 mmol) in THF (10 mL), EtOH (10 mL) and H2O (10 mL) was added LiOH (1.1 g, 45.8 mmol), and the reaction was stirred for 16 h at room temperature. The mixture residue was neutralized to pH 5 with 1 N of HCl (aq.) The solid was collected by filtration and washed with water (20 mL). The solid was dried to afford 2-(5,6-dichloro-1H-benzimidazol-2-yl)acetic acid (A18, 1.6 g, 4.9 mmol, 53% yield) as a solid. LCMS (ES, m/z): 245 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization M i l Cl n, 6- 0 S, 602 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran in EtOH, at 60 °C for 16 h. Step 2 was ran using TMSOK in THF at room d o- S h. .). n, 5- id d. h. .). n, 5- id d. h. or L) as er th as 6- 0 S, 1 .). d H- 4 Attorney Docket No.: R2103-7054WO mmol, 68% yield) as a solid. LCMS (ES, m/z): 213 [M+H]+. Synthesis of A25 To a solu (10 mL), was added 2,5-dimethoxytetrahydrofuran (1.04 g, 7.9 mmol) were added, and the reaction was heated to 130 °C in a closed system with microwave reactor for 0.5 h under N2.The reaction was purified by reversed-phase flash chromatography (Condition 2, Gradient 23) to afford 1-benzyl-4-pyrrol-1-yl- piperidine (A25, 200 mg, 832.2 μmol, 16% yield) as a solid. LCMS (ES, m/z): 241.2 [M+H]+. Synthesis of A26 To a mixture , , 32.2 μmol) in MeOH (4 mL) was added Pd/C (8.9 mg, 83.2 μmol), and the reaction was stirred for 12 h at room temperature under H2 atmosphere. The reaction was purified by reversed-phase flash chromatography (Condition 2, Gradient 23) to afford 4-pyrrol-1-ylpiperidine (A26, 100 mg, 665.7 μmol, 80% yield) as a solid. LCMS (ES, m/z): 151.2 [M+H]+. Example 107: Synthesis of A35 Synthesis of A34 604 Attorney Docket No.: R2103-7054WO A and tributyl(2- pyridyl)stannane (1.51 g, 4.11 mmol, 1.33 mL) in THF (10 mL) were added Pd(PPh3)4 (475.4 mg, 411.4 μmol) at 80°C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at reflux under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (17% EtOAc in PE) to afford methyl 2-[4-(2-pyridyl)phenyl]propanoate (A34, 400 mg, 1.66 mmol, 81% yield) as a solid. LCMS (ES, m/z): 242 [M+H]+. Synthesis of A35 To a 4, 400 mg, 1.66 mmol) in H2O (5 mL) and THF (5 mL) was added LiOH.H2O (208.7 mg, 4.97 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (10 mL) and the mixture was acidified to pH 4 with HCl. The precipitated solids were collected by filtration and washed with H2O (2 x 5 mL) to afford 2-[4-(2-pyridyl)phenyl]propanoic acid (A35, 300 mg, 1.32 mmol, 80% yield) as a solid. LCMS (ES, m/z): 282 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization °C. re id d. Attorney Docket No.: R2103-7054WO LCMS (ES, m/z): 232 [M+H]+. C. he ed sh rd 5, S, xamp e : ynt es s o Synthesis of A40 To a so )boronic acid (510 mg, 2.3 mmol) and 1H-pyrazole (153 mg, 2.3 mmol) in DCM (5 mL) were added Cu(OAc)2 (612 mg, 3.4 mmol) and TEA (682 mg, 6.7 mmol), and the reaction was stirred for 16 h at room temperature under N2 atmosphere. The reaction was quenched with Water/Ice and extracted with DCM (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford tert-butyl 4-pyrazol-1-yl-3,6-dihydro-2H-pyridine- 1-carboxylate (A40, 190 mg, 762.1 μmol, 34% yield) as a liquid. LCMS (ES, m/z): 194 [M+H- 56]+. Synthesis of A41 606 Attorney Docket No.: R2103-7054WO To a soluti e-1-carboxylate (A40, 190 mg, 762.1 μmol) in DCM (2 mL) was added TFA (261 mg, 2.3 mmol) dropwise at 0 °C, and the reaction was stirred for 2 h at room temperature under air atmosphere. The mixture was neutralized to pH 7 with saturated Na2CO3 (aq.) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 4-pyrazol-1-yl-1,2,3,6-tetrahydropyridine (A41, 90 mg, 603.3 μmol, 79% yield) as a solid. LCMS (ES, m/z): 150 [M+H]+. Example 109: Synthesis of A44 Synthesis of A44 To a so , ) in THF (90 mL) under N2 atmosphere was added LiHMDS (3.3 g, 19.6 mmol, 3.3 mL) dropwise with stirring at - 15°C in 10 min. The resulting solution was stirred for 10 min at -15 °C. To this was added bromo(methoxy)methane (2.5 g, 19.6 mmol, 1.6 mL) dropwise with stirring at -15 °C in 5 min. The resulting solution was stirred for 1 h at -15 °C. The reaction was then quenched by the addition of 100 mL of Sat. NH4Cl aq. The resulting solution was extracted with EtOAc (3 x 30 mL), the combined organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford in methyl 2-(4-bromophenyl)-3-methoxy-propanoate (A44, 2.8 g, 10.3 mmol, 52% yield) as an oil. Example 110: Synthesis of A50 607 Attorney Docket No.: R2103-7054WO Synthesis of A48 To a solutio utyl(2-pyridyl)stannane (2.28 g, 6.2 mmol) in Toluene (6 mL) was added Pd(PPh3)4 (477 mg, 413.3 μmol), and the reaction was stirred for 16 h at 120°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (17% EtOAc in PE) to afford 2-(4-bromo-2-thienyl)pyridine (A48, 0.7 g, 2.9 mmol, 71% yield) as a solid. LCMS (ES, m/z): 240 [M+H]+. Synthesis of A49 To a stir mmol) and bromo- (2-tert-butoxy-2-oxo-ethyl)zinc (1.63 g, 6.3 mmol) in THF (8 mL) were added XPhos (119 mg, 249.9 μmol) and Pd2(dba)3 (114 mg, 124.9 μmol), and the reaction was stirred for 8 h at 70°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (9% EtOAc in PE) to afford tert-butyl 2-[5-(2-pyridyl)-3-thienyl]acetate (A49, 0.23 g, 835.3 μmol, 67% yield) as a solid. LCMS (ES, m/z): 276 [M+H]+. Synthesis of A50 608 Attorney Docket No.: R2103-7054WO To a solution of tert-butyl 2-[5-(2-pyridyl)-3-thienyl]acetate (A49, 0.26 g, 944.2 μmol) in DCM (6 mL) was added TFA (1 mL), and the reaction was stirred for 6 h at room temperature. The resulting mixture was concentrated under reduced pressure and diluted with water (5 mL). The solid was collected by filtration and washed with water (5 mL). The solid was dried to afford 2-[5-(2-pyridyl)-3-thienyl]acetic acid (A50, 0.17 g, 775.3 μmol, 82% yield) as a solid. LCMS (ES, m/z): 220 [M+H]+. Example 111: Synthesis of A52 Synthesis of A52 A solution of 2-bromo-4-fluoro-benzonitrile (5 g, 25 mmol) in DMF (50 mL) was treated with Cs2CO3 (8.15 g, 25 mmol) at 25 °C for 30 min under nitrogen atmosphere followed by the addition of oxetan-3-ol (2.96 g, 40 mmol, 2.5 mL) dropwise, and the reaction was stirred at room temperature for 24 h under nitrogen atmosphere. The resulting mixture was diluted with water (150 mL). The precipitated solids were collected by filtration, washed with water (3 x 100 mL), and the resulting solid was dried under infrared light to afford 2-bromo-4-(oxetan-3- yloxy)benzonitrile (A52, 5.8 g, 22.8 mmol, 91% yield) as a solid. LCMS (ES, m/z): 295 [M+H+ACN]+. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization or n 3- Attorney Docket No.: R2103-7054WO bromo-6-isopropoxy-quinoline (A249, 800 mg, 3.01 mmol, 90% yield) as a solid. LCMS (ES, Synthesis of A53 -methyl- 1H-pyrrole (86.1 mg, 1.1 mmol) in dioxane (6 mL) were added XantPhos Pd G4 (102.1 mg, 106.1 μmol) and Cs2CO3 (1.04 g, 3.2 mmol), and the reaction was stirred for 4 h at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford ethyl 2-[6-(3-methylpyrrol-1- yl)pyridazin-3-yl]acetate (A53, 90 mg, 366.9 μmol, 35% yield) as an oil. LCMS (ES, m/z): 246 [M+H]+. Synthesis of A54 A y y py y py y g, 366.9 μmol) in THF (1 mL) was treated with a solution of LiOH•H2O (61.6 mg, 1.5 mmol) in H2O (1 mL), and the reaction was stirred for 2 h at room temperature. The mixture was acidified to pH 5 with 1 N HCl. The resulting mixture was concentrated under reduced pressure and purified by reversed- phase flash chromatography (Condition 5, Gradient 5) to afford 2-[6-(3-methylpyrrol-1- yl)pyridazin-3-yl]acetic acid (A54, 60 mg, 276.2 μmol, 75% yield) as a solid. LCMS (ES, m/z): 218 [M+H]+. 610 Attorney Docket No.: R2103-7054WO Example 113: Synthesis of A62 Synthesis of A60 Into a sealed tu .6 mmol), 3,4-dihydro-2H- pyran (11.1 g, 132.1 mmol, 12 mL) and TFA (582.9 mg, 5.1 mmol, 391.2 μL), and the reaction was stirred for 16 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction mixture was quenched with saturated sodium carbonate (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (2% EtOAc in PE) to afford 4-fluoro- 1-tetrahydropyran-2-yl-pyrazole (A60, 1.3 g, 7.64 mmol, 30% yield) as an oil. LCMS (ES, m/z): 171 [M+H]+. Synthesis of A61 To a solution , .3 g, 7.64 mmol) in THF (12 mL) was added dropwise n-BuLi (2.5 M in THF, 3.06 mL, 7.64 mmol) at -78°C under N2 atmosphere, and the reaction was stirred at -78°C for 1 h. Then a solution of MeI (1.63 g, 11.5 mmol) was added dropwise and the mixture was stirred for another 3 h at -78°C. The reaction was quenched with sat. NH4Cl (aq.10 mL) and Water (20 mL) at room temperature, and the reaction was extracted with ether/EtOAc (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 4-fluoro-5-methyl-1-tetrahydropyran-2-yl-pyrazole (A61, 1.1 g, 5.97 mmol, 78% yield) as an oil. LCMS (ES, m/z): 185 [M+H]+. 611 Attorney Docket No.: R2103-7054WO Synthesis of A62 A solution of (A61, 1.1 g, 5.97 mmol) and HCl (2.0 M in EtOAc) (217.7 mg, 5.97 mmol, 11 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the crude product was precipitated by the addition of ethyl ether, to afford 4-fluoro-3-methyl-1H- pyrazole (A62, 420 mg, 4.2 mmol, 70% yield) as a solid. LCMS (ES, m/z): 101 [M+H]+. Example 114: Synthesis of A64 Synthesis of A63 To a ol) and NaI (424 mg, 2.8 mmol) in ACN (5 mL) were added acetyl chloride (296 mg, 3.8 mmol) dropwise, and the reaction was stirred for 16 h at 80 °C. The reaction was quenched with Water/Ice and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford methyl 2-(6-iodo-3-pyridyl)acetate (A63, 440 mg, 1.6 mmol, 84% yield) as a solid. LCMS (ES, m/z): 278 [M+H]+. Synthesis of A64 Attorney Docket No.: R2103-7054WO To a solution of methyl 2-(6-iodo-3-pyridyl)acetate (A63, 10 g, 36.1 mmol) in H2O (50 mL), MeOH (50 mL) and THF (50 mL) was added LiOH (4.3 g, 180.5 mmol), and the reaction was stirred for 16 h at room temperature. The mixture residue was neutralized to pH 4 with 1 N of HCl (aq.). The solid was collected by filtration and washed with water (200 mL). The solid was dried to afford 2-(6-iodo-3-pyridyl)acetic acid (A64, 7 g, 26.6 mmol, 74% yield) as a solid. LCMS (ES, m/z): 264 [M+H]+. Example 115: Synthesis of A71 Synthesis of A71 To a stirred sol l) in MeCN (80 mL) was added Selectfluor (6.74 g, 46.8 mmol), and the reaction was stirred for 24 h at 80 ℃. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 25) to afford 3-chloro-4-fluoro-1H-pyrazole (A71, 100 mg, 829.8 μmol, 2% yield) as a solid. LCMS (ES, m/z): 119 [M-H]-. Example 116: Synthesis of A74 Synthesis of A73 To a so u o o - o o- - e y e o a o e g, . o n THF (6 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (2.73 g, 10.6 mmol), K3PO4 (1.12 g, 5.3 mmol), Pd(dppf)Cl2 (386.4 mg, 0.53 mmol), and the reaction was stirred for 16 h at 70°C under nitrogen atmosphere. The reaction was quenched with water (30 mL) at room temperature and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure 613 Attorney Docket No.: R2103-7054WO and purified by column chromatography (25% EtOAc in PE) to afford tert-butyl 2-(2-methyl- benzo[d]thiazol-6-yl)acetate (A73, 500 mg, 72% yield) as a solid. LCMS (ES, m/z): 264 [M+H]+. Synthesis of A74 A solution of tert-butyl 2-(2-methylbenzo[d]thiazol 00 mg, 1.90 mmol) was added HCl (4 N in dioxane, 5 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(2- methylbenzo[d]thiazol-6-yl)acetic acid (A74, 500 mg crude) as a solid. LCMS (ES, m/z): 208 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material at . ed 5- d. at in sh rd d. in H, n, 1- 4, 614 Attorney Docket No.: R2103-7054WO 200 mg, 1.05 mmol, 65% yield) as a solid. LCMS (ES, m/z): 191 [M+H]+. at in sh rd 0 S, in m er 2- d) at in he ke g 2- 3 7 in H, N y 2- 7 2 in er 2- a er Attorney Docket No.: R2103-7054WO purification.1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.71 (d, J = 8.2 Hz, = in H, he to 8, S in er 3- as in sh rd g, ): in H, re id d. in er 3- d. in H, 6 Attorney Docket No.: R2103-7054WO The resulting solid was dried under infrared light to afford 4,5-dimethoxy-2-[[2-[6-(3-methylpyrrol-1- de d. in er 3- l, in er 3- % in H, h. sh rd g, ): in H, h. 2 ed rd 4, S in ed id S, 617 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran using XPhos Pd G3 in THF at reflux for 16 h. Step 2 was ran using LiOH, 0 n. x ed 4, er )- d) in H, d ed ed as y 2, H- g, ): in H, sh rd 0 S, at H of he d 2- Attorney Docket No.: R2103-7054WO ylacetic Li salt (B14, 140 mg, 79% yield) as a solid. LCMS (ES, m/z): 189 [M+H]+. 3 sh to g, +. 3 in he d o- 7 0 3 n 2- 3 5 3 n yl g, ): 3 er 3- l, 3 619 Attorney Docket No.: R2103-7054WO Modification: In Step 1, Pd-PEPPSI-IPentCl was used as catalyst and no K3PO4 was used. n 1- l, +. as as y o- l, .1 Example 117: Synthesis of A76 Synthesis of A76 A solution of methyl 2-(2-bromothiazol-5-yl)acetate (0.9 g, 3.81 mmol) and LiOH‧H2O (320 mg, 7.62 mmol) in THF (9 mL) and H2O (1.8 mL) was stirred at room temperature for 2 h. The mixture was acidified to pH 2 with 2 M HCl. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2- (2-bromothiazol-5-yl)acetic acid (A76, 0.77 g, 3.45 mmol, 90% yield) as a solid. LCMS (ES, m/z): 222 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization 620 Attorney Docket No.: R2103-7054WO Modification: The reaction was ran for 3 h. The filtrate was concentrated under 2- 0, d. as at ds ed 5- id . 9 re e id s S Example 118: Synthesis of A82 Synthesis of A79 621 Attorney Docket No.: R2103-7054WO A mixture of S (4.6 g, 34.5 mmol) in DMF (50 mL) was stirred at 90°C for 16 h. The mixture was allowed to cool down room temperature. The mixture was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 4-chloro-2,3-difluoro-6-nitro-aniline (A79, 5 g, 24 mmol, 83% yield) as a solid.1H NMR (300 MHz, DMSO-d6) δ 8.09 (dd, J = 7.5, 2.4 Hz, 1H), 7.69 (s, 2H). Synthesis of A80 To a soluti , , , 21.6 mmol) in MeOH (45 mL) was added Raney Nickel catalyst (3.70 g, 43.2 mmol) under nitrogen atmosphere in a 100 mL Vessel. The mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The filter cake was washed with CH3OH (2 x 20 mL). The filtrate was concentrated under reduced pressure to afford 5-chloro-3,4-difluoro-benzene-1,2-diamine (A80, 3.8 g, 21.3 mmol, 99% yield) as a solid. LCMS (ES, m/z): 179 [M+H]+. Synthesis of A81 622 Attorney Docket No.: R2103-7054WO A mol) and ethyl 3-ethoxy-3-imino-propanoate (3.12 g, 19.6 mmol) in EtOH (70 mL) was stirred at 80°C for 3 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford ethyl 2-(5-chloro-6,7-difluoro-1H-benzimidazol-2- yl) acetate (A81, 4.8 g, crude) as a solid. LCMS (ES, m/z): 275 [M+H]+. Synthesis of A82 A m , te (A81, 0.4 g, 1.46 mmol) and LiOH.H2O (122 mg, 2.91 mmol) in THF (5 mL), H2O (1.5 mL) were stirred at room temperature for 1 h. The mixture was acidified to pH 2 with 2 M HCl. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-(5-chloro-6,7-difluoro-1H-benzimidazol-2-yl) acetic acid (A82, 0.32 g, crude) as a solid. LCMS (ES, m/z): 247 [M+H]+. Example 119: Synthesis of A88 Synthesis of A86 623 Attorney Docket No.: R2103-7054WO To a stirred mixture of 6-bromo-1,2,3,4-tetrahydroquinoline (3 g, 14.2 mmol) in THF (6 mL) were added NaH (678 mg, 28.3 mmol, 60% yield) in portions at 0 ℃. The resulting mixture was stirred for 0.5 h. To the above mixture was added iodomethane (6 g, 42.4 mmol, 2.6 mL), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 6-bromo- 1-methyl-3,4-dihydro-2H-quinoline (A86, 2.1 g, 9.3 mmol, 66% yield) as an oil. LCMS (ES, m/z): 226 [M+H]-. Synthesis of A87 To a s , (A86, 1.9 g, 8.4 mmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (8.75 g, 33.6 mmol) in THF (30 mL) was added XPhos Pd G3 (1.42 g, 1.68 mmol), and the reaction was stirred for 16 h at 70°C. The reaction was quenched with water (10 mL) at room temperature and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-(1-methyl-3,4-dihydro-2H-quinolin-6- yl)acetate (A87, 1 g, 3.83 mmol, 46% yield) as an oil. LCMS (ES, m/z): 262 [M+H]+. Synthesis of A88 624 Attorney Docket No.: R2103-7054WO To a te (A87, 1 g, 3.8 mmol) in DCM (10 mL) was added 4.0 M in 1,4-dioxane (10 mL), and the reaction was stirred for 16 h at room temperature. The reaction was concentrated under reduced pressure to afford 2-(1- methyl-1,2,3,4-tetrahydroquinolin-6-yl)acetic acid hydrochloride (A88, 0.76 g, crude) as a solid. LCMS (ES, m/z): 206 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material H ic y 1, 8- 2 7 Example 120: Synthesis of A106 Synthesis of A105 A solu o o - o o- - e y - e a o e g, . o , (2-(tert-butoxy)-2- oxoethyl)zinc(II) bromide (9.9 g, 37.9 mmol) and XPhos Pd G3 (802 mg, 948 μmol) in THF (20 mL) was stirred at 70°C for 3 h under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried 625 Attorney Docket No.: R2103-7054WO over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-(1- methylbenzimidazol-5-yl) acetate (A105, 1.8 g, 7.31 mmol, 77% yield) as a solid. LCMS (ES, m/z): 247 [M+H]+. Synthesis of A106 To a sti te (A105, 200 mg, 812 μmol) in DCM (2 mL) was added TFA (2.9 g, 26.1 mmol) dropwise, and the reaction was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude (A106) was used in the next step directly without further purification. LCMS (ES, m/z): 191 [M+H]+. An analogous method was followed to obtain the following compounds. Intermediate Starting Characterization Material se to 0 S, an or ed id d. Example 121: Synthesis of A114 Synthesis of A114 626 Attorney Docket No.: R2103-7054WO A solution of 3-ch NCS (781.5 mg, 5.9 mmol) in MeCN (10 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 3,4-dichloro-1H- pyrazole (A114, 400 mg, 2.92 mmol, 60% yield) as a solid. LCMS (ES, m/z):137 [M+H]+. Example 122: Synthesis of A118 Synthesis of A116 To a soluti ol) in DMF (20 mL) was added 3-methyl-1H-pyrrole (4.74 g, 58.5 mmol), Cs2CO3 (9.54 g, 29.3 mmol), and the reaction was stirred at 100℃ for 3 h. The mixture was allowed to cool down to room temperature. The reaction was diluted with H2O (15 mL), extracted with EtOAc (3 x 15 mL), and washed with brine (15 mL). The combined organic layers dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (17% EtOAc in PE) to afford 5-bromo-4-methoxy-2-(3-methyl-1H-pyrrol-1-yl)pyridine (A116, 1.8 g, 69% yield) as a solid. LCMS (ES, m/z): 267 [M+H]+. Synthesis of A117 Attorney Docket No.: R2103-7054WO To a solution of 5-bromo-4-methoxy-2-(3-methyl-1H-pyrrol-1-yl)pyridine (A116, 830 mg, 3.1 mmol) in THF (9 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (3.22 g, 12.5 mmol), Xphos Pd G3 (264 mg, 0.3 mmol), and the reaction was stirred at 70℃ for 6 h under N2 atmosphere. The resulting mixture was allowed to cool down to room temperature, concentrated under reduced pressure, and purified by purified by column chromatography (17% EtOAc in PE) to afford tert-butyl 2-(4-methoxy-6-(3-methyl-1H-pyrrol-1-yl)pyridin-3-yl)acetate (A117, 800 mg, 85% yield) as a solid. LCMS (ES, m/z): 303 [M+H]+. Synthesis of A118 To ethyl-1H-pyrrol-1-yl)p idin-3-yl)acetate (A117, 800 mg, 2.65 mmol) in 8 mL vial was added HCl (4M in dioxane, 8 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(4-methoxy-6-(3-methyl-1H-pyrrol-1-yl)pyridin-3-yl)acetic acid (A118, 620 mg crude) as a solid. LCMS (ES, m/z): 247 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization M i l an . ed 1- l, +. an ed )- ch ): Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran at 100 °C for 16 h. Step 2 was ran at 70 °C for 16 h. Step 3 was ran using LiOH, t. y 1- l, +. ep re re 3- d. Example 123: Synthesis of A123 To a , mol) and B2Pin2 (8.15 g, 32.1 mmol) in dioxane (20 mL) were added KOAc (3.67 g, 37.4 mmol) and XPhos Pd G3 (905.1 mg, 1.07 mmol), and the reaction was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford (2-amino-5-methyl-3-pyridyl)boronic acid (A123, 500 mg, 3.3 mmol, 31% yield) as a solid. LCMS (ES, m/z): 153 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization n 4- d. Attorney Docket No.: R2103-7054WO Example 124: Synthesis of A126 Synthesis of A125 To a stirre .4 mmol) in DCM (50 mL) was added DAST (5.1 g, 31.7 mmol) at 0°C under nitrogen atmosphere, and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched with saturated NaHCO3 (aq.). The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in PE) to afford 1-bromo- 3-fluoro-5-(fluoromethyl)benzene (A125, 2.7 g, 13.0 mmol, 54% yield) as an oil. LCMS (ES, m/z): 207 [M+H]+. Synthesis of A126 To a y g, 966.1 μmol) and B2Pin2 (490.7 mg, 1.93 mmol) in dioxane (4 mL) were added KOAc (284.4 mg, 2.9 mmol), Pd(dppf)Cl2 (70.7 mg, 96.6 μmol), and the reaction was stirred for 16 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography 630 Attorney Docket No.: R2103-7054WO (9% EtOAc in PE) to afford 2-[3-fluoro-5-(fluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A126, 120 mg, 472.3 μmol, 49% yield) as a solid. LCMS (ES, m/z): 255 [M+H]+. Example 125: Synthesis of A94 Synthesis of A92 A solution o ol) in THF (50 mL) was treated with 2M LiHMDS in THF (18.9 mL, 37.9 mmol) at 0 oC and stirred for 10 mins under nitrogen atmosphere. To the above mixture was added iodine (4.66 g, 32.8 mmol) in THF (10 mL) dropwise at 0 oC. The resulting mixture was stirred at 0 oC for an additional 1 h. The reaction was quenched with sat. NH4Cl (aq.) at 0 oC. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% THF in PE) to afford 5-bromo-1-methyl- imidazo[4,5-b]pyridine (A92, 1.1 g, 5.2 mmol, 21% yield) as a solid. LCMS (ES, m/z): 212 [M+H]+. Synthesis of A93 A solu o o - o o- - e y - - a o , - py e , g, 4.71 mmol), bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (4.91 g, 18.87 mmol) and Pd(PPh3)4 (545 mg, 471.5 μmol) in THF (10 mL) was stirred at 70 °C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and 631 Attorney Docket No.: R2103-7054WO filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-(3-methylimidazo[4,5-b]pyridin-5-yl) acetate (A93, 460 mg, 1.86 mmol, 39% yield) as a solid. LCMS (ES, m/z): 248 [M+H]+. Synthesis of A94 A sol te (A93, 200 mg, 809 μmol) in DCM (1 mL) was treated with 4M HCl (gas) in dioxane (0.5 mL, 2 mmol), and the reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)acetic acid (A94, 130 mg, 84% yield) as an oil. LCMS (ES, m/z): 192 [M+H]+. Example 126: Synthesis of A101 To a stirred m and 2-bromopropanedial (5.75 g, 38.1 mmol) in EtOH (80 mL) was added concentrated HCl (15 mL) at room temperature, and the reaction was stirred for 16 h at 105 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, concentrated under reduced pressure, and adjusted to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 11) to afford 6-bromothieno[3,2-b]pyridine (A101, 1 g, 4.67 mmol, 15% yield) as a solid. LCMS (ES, m/z): 214 [M+H]+. An analogous method as followed to obtain the following compounds. 632 Attorney Docket No.: R2103-7054WO Compound Starting Characterization Material n o- 6 8 p y To a st 9.5 mmol) in 4 M HCl (gas) in dioxane (20 mL) was added 2-chloroacetonitrile (1.07 g, 14.2 mmol) dropwise at room temperature, and the reaction was stirred for 2 h at room temperature. The resulting mixture was then stirred for 16 h at 60°C. The reaction was allowed to cool down to room temperature and concentrated under reduced pressure to afford 2-(chloromethyl)-6,7-dimethoxy-3H-quinazolin-4- one (A129, 2 g, 7.85 mmol, 83% yield) as a solid. LCMS (ES, m/z): 255 [M+H]+. Example 128: Synthesis of A134 Synthesis of A133 To a so u o o , - e y py - -a e . g, . o EtOH (10 mL) was added methyl 4-chloro-3-oxo-butanoate (1.36 g, 9.0 mmol, 1.04 mL), and the reaction was stirred at 80 °C for 16 h. The residue was concentrated under reduced pressure and purified by reversed- phase flash chromatography (Condition 5, Gradient 8) to afford methyl 2-(6,7-dimethylimidazo- 633 Attorney Docket No.: R2103-7054WO [1,2-a]pyridin-2-yl)acetate (A133, 800 mg, 3.67 mmol, 45% yield) as an oil. LCMS (ES, m/z): 219 [M+H]+. Synthesis of A134 To a )acetate (A133, 800 mg, 3.7 mmol) in EtOH (5 mL) was added NaOH (733 mg, 18.3 mmol) in Water (5 mL), and the reaction was stirred for 2 h at 70 °C. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The resulting mixture was acidified to pH with citric acid (aq.). The residue was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 8) to afford 2-(6,7- dimethylimidazo[1,2-a]pyridin-2-yl)acetic acid (A134, 400 mg, 1.96 mmol, 53% yield) as a solid. LCMS (ES, m/z): 205 [M+H]+. An analogous method as followed to obtain the following compounds. Compound Starting Characterization Material re l. er se a) 7- id 2- % . re Cl se 4) Attorney Docket No.: R2103-7054WO to afford 2-(6-chloro-7-methylimidazo[1,2- a]pyridin-2-yl)acetic acid (B17, 0.1 g, 445.2 μmol, 25 h. at er N er te rd d) O er N er ), he re n- % . sh to 2- 4 ): , 635 Attorney Docket No.: R2103-7054WO The residue was purified by reversed-phase flash chromatography (Condition 8, Gradient 2) to - . h ep m sh to % . C 7- id d. t. re x er 7- a Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran in MeOH solvent. The reaction mixture was concentrated under 6- id d. t. 0 in d- 1, 6- % . H sh to n- % . H th us ed 2- 9 ): n to - % . 637 Attorney Docket No.: R2103-7054WO Modification: Step 2 was ran using LiOH in H2O /EtOH/THF (1:1:1 volumetric ratio) at room n to % . O 0 d ed ), d 2- % . O 0 d 2- % . e. sh to l- g, S, Example 129: Synthesis of A146 Synthesis of A145 638 Attorney Docket No.: R2103-7054WO To a stirred solution of methyl 2-(6-chloro-3-pyridyl)acetate (12 g, 64.6 mmol) and (3- fluorophenyl)boronic acid (9.1 g, 64.6 mmol) in dioxane (200 mL) and H2O (20 mL) were added Pd(PPh3)4 (14.9 g, 12.9 mmol) and Na2CO3 (20.6 g, 194 mmol) at room temperature under N2 atmosphere. The mixture was stirred for 16 h at 100 °C. The mixture was allowed to cool down to room temperature and diluted with EtOAc (200 mL), washed with water (2 x 200 mL) and brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford methyl 2-[6-(3-fluorophenyl)-3-pyridyl]acetate (A145, 20 g, 57.1 mmol, 88% yield) as an oil. LCMS (ES, m/z): 246 [M+H]+. Synthesis of A146 T 5, 20 g, 81.5 mmol) in THF (200 mL) and H2O (200 mL) were added LiOH (9.8 g, 407.7 mmol), and the reaction was stirred for 16 h at room temperature. The mixture was diluted with EtOAc (100 mL) and extracted with water (2 x 100 mL). The water phase was adjusted to pH 8 with 2M HCl H2O solution, extracted by DCM, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-[6-(3-fluorophenyl)-3-pyridyl]acetic acid (A146, 13 g, 50.6 mmol, 62% yield) as a solid. LCMS (ES, m/z): 232 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization 639 Attorney Docket No.: R2103-7054WO Modification: Step 1 was ran using K3PO4 at 80 °C for 16 h. Step 2 was ran at room temperature Cl by ir ]- % -. ng 2 th by he 5- 3 S Example 130: Synthesis of A149 Synthesis of A148 A solution o . , . l) in DMF (20 mL) was added NIS (3.0 g, 13.5 mmol) and stirred at room temperature for 16 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford 2-amino- 5-iodo-4-methoxy-benzonitrile (A148, 2.5 g, 9.12 mmol, 68% yield) as a solid. LCMS (ES, m/z): 273 [M-H]-. Synthesis of A149 640 Attorney Docket No.: R2103-7054WO To a stirre 8, 0.5 g, 1.82 mmol) in EtOH (5 mL) was added 2 M NaOH(aq.) (12.5 mL) and H2O2 Solution (12.5 mL, 122.4 mmol) dropwise, and the reaction was stirred at room temperature for 16 h. The mixture was acidified to pH 5 with 1 N HCl (aq.). The precipitated solids were collected by filtration, washed with water (10 mL), and air dried to afford 2-amino-5-iodo-4-methoxy-benzamide (A149, 0.2 g, 719.0 μmol, 39% yield) as a solid. LCMS (ES, m/z): 293 [M+H]+. Example 131: Synthesis of A150 To a so nd NH4Cl (0.46 g, 8.5 mmol) in DMF (10 mL) were added HATU (1 g, 2.6 mmol) and DIEA (0.44 g, 3.4 mmol), and the reaction was stirred for 2 h at room temperature. The reaction mixture was quenched by water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 2-amino-4,5-dibromobenzamide (A150, 0.18 g, 0.6 mmol, 36% yield) as a solid. LCMS (ES, m/z): 293 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization sh 2- g, 641 Attorney Docket No.: R2103-7054WO 1.50 mmol, 60% yield) as a solid. LCMS (ES, m/z): 201 [M+H]+. n 5- .1 0 0 3- .5 +. xamp e : ynt es s o Synthesis of A154 To a stirr te (8.5 g, 32.7 mmol) in THF (85 mL) and water (8.5 mL) was added LiOH (2.35 g, 98.1 mmol), and the reaction was stirred for 16 h at room temperature. The mixture was acidified to pH 2 with 1 N HCl (aq.). The precipitated solids were collected by filtration, washed with water (150 mL), and air dried to afford 2-amino-4-bromo-5-methoxy-benzoic acid (A154, 5.6 g, 22.8 mmol, 70% yield) as a solid. LCMS (ES, m/z): 246 [M+H]+. Synthesis of A155 Attorney Docket No.: R2103-7054WO To a stirred solution of 2-amino-4-bromo-5-methoxy-benzoic acid (A154, 5.6 g, 22.8 mmol) and NH4Cl (1.22 g, 22.8 mmol) in DMF (56 mL) were added HATU (25.96 g, 68.3 mmol) and DIEA (4.41 g, 34.1 mmol) dropwise, and the reaction was stirred for 16 h at room temperature. The mixture was acidified to pH 7 with 1 N HCl (aq.). The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-amino-4-bromo-5-methoxy-benzamide (A155, 4.8 g, 19.6 mmol, 86% yield) as a solid. LCMS (ES, m/z): 243 [M-H]-. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material 3, 4- % Example 133: Synthesis of A157 To a stirred solution of 2-bromo-4,6-dimethyl-p y mg, 1.1 mmol) and 1,1,1,2,2,2-Hexamethyldistannane (423 mg, 1.3 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (124 mg, 107.5 μmol), and the reaction was stirred for 4 h at 110 °C under nitrogen atmosphere. The resulting mixture (A157) was used in the next step directly without further purification. LCMS (ES, m/z): 272 [M+H]+. Example 134: Synthesis of A160 Synthesis of A160 643 Attorney Docket No.: R2103-7054WO To a stirred mixture of ethyl 2-(5,6-dimethyl-1H-benzimidazol-2-yl)acetate (0.52 g, 2.24 mmol) and Cs2CO3 (1.46 g, 4.48 mmol) in DMF (5 mL) was added 2-iodopropane (494 mg, 2.91 mmol), and the reaction was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford ethyl 3-methyl-2-(5-methyl-1H-benzimidazol-2-yl)butanoate (A160, 0.25 g, 960.3 μmol, 43% yield) as a solid. LCMS (ES, m/z): 275 [M+H]+. Synthesis of A161 LiOH, H2O, THF 1 h To a , ethyl-butanoate (A160, 0.25 g, 911.2 μmol) in THF (3 mL) and H2O (1 mL) was added LiOH (109 mg, 4.6 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford lithium 2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-3- methylbutanoate (A161, 0.15 g, 609.0 μmol, crude) as a solid. LCMS (ES, m/z): 247 [M+H]+. Example 135: Synthesis of A170 Synthesis of A169 644 Attorney Docket No.: R2103-7054WO To a solution of CM (200 mL) was added m- CPBA (23.4 g, 115.2 mmol, 85% purity) in portions at 0 °C, and the reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of sat. Na2SO3 (500 mL) at room temperature for 1 h. The resulting mixture was extracted with DCM (3 x 800 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 5- methyl-1-oxido-quinolin-1-ium (A169, 16 g, 100.5 mmol, 96% yield) as a solid. LCMS (ES, m/z): 160 [M+H]+. Synthesis of A170 To the mixture g, 100.5 mmol) in CHCl3 (300 mL) was added POBr3 (23 g, 150.0 mmol) at 0 °C, and the reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of sat. Na2CO3 (500 mL) and extracted with DCM (3 x 500 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford 2-bromo-5-methyl- quinoline (A170, 5.6 g, 25.2 mmol, 25% yield) as a solid. LCMS (ES, m/z): 222 [M+H]+. An analogous method to Step 2 was ran followed to obtain the following compounds. Compound Starting Material Characterization n o- % 645 Attorney Docket No.: R2103-7054WO Example 136: Synthesis of A172 To a stirre m x ure o e y oxon o(r uoro) oranu e ( . , mL) in DME (40 mL) was added 6-bromonaphthalen-1-amine (4 g, 18.0 mmol) in DME (40 mL) at -5 °C under nitrogen atmosphere, and the reaction was stirred for 2 h at -5 °C under nitrogen atmosphere. Then tert- butyl nitrite (1.86 g, 18.0 mmol, 2.14 mL) in DME (40 mL) is dropped into the resulting mixture at -5 °C under nitrogen atmosphere, and the reaction was stirred for another 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue diluted in chlorobenzene (120 mL) was stirred for 1 h at 130 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc in PE) to afford 6-bromo-1-fluoro-naphthalene (A172, 1.8 g, 8.0 mmol, 44% yield) as an oil.1H NMR (300 MHz, DMSO-d6) δ 8.28 (q, J = 2.2 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.7-7.65 (m, 2H), 7.53 (td, J = 8.0, 5.5 Hz, 1H), 7.35 (ddd, J = 10.9, 7.8, 1.0 Hz, 1H). Example 137: Synthesis of A179 To a stirred , y g, . H (20 mL) was added 2,2,3-tribromopropanal (3.65 g, 12.4 mmol), and the reaction was stirred for 4 h at 120°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and adjusted to pH 8 with sat. NaHCO3 (aq.). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and 646 Attorney Docket No.: R2103-7054WO filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford 3-bromo-6,8-dimethyl-quinoline (A179, 900 mg, 3.81 mmol, 46% yield) as a solid. LCMS (ES, m/z): 236 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material n 3- 0 S, sh rd 8 6 of n to g, ): Example 138: Synthesis of A200 Synthesis of A198 To a stirre d m xture o 3-bromoqu no n- -am ne ( g, 7.9 mmol) in pyridine hydrofluoride (40 mL) was added NaNO2 (1.86 g, 26.90 mmol) at 0 °C under nitrogen atmosphere in batches, and the reaction was stirred for 1 h at 0 °C under nitrogen atmosphere. Then the 647 Attorney Docket No.: R2103-7054WO resulting mixture was stirred for another 16 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 3-bromo-4-fluoro-quinoline (A198, 1.4 g, 6.19 mmol, 35% yield) as a solid. LCMS (ES, m/z): 226 [M+H]+. Synthesis of A199 To a 2.65 mmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (2.77 g, 10.62 mmol) in THF (6 mL) was added QPhos Pd G3 (571 mg, 530.9 μmol), and the reaction was stirred for 4 h at reflux under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford tert-butyl 2-(4-fluoro-3-quinolyl)acetate (A199, 400 mg, 1.53 mmol, 58% yield) as an oil. LCMS (ES, m/z): 262 [M+H]+. Synthesis of A200 To a st rred m xture o tert-buty -( - uoro-3-qu no y )acetate ( 99, 400 mg, 1.53 mmol) in DCM (4 mL) was added a solution of 4M HCl (gas) in dioxane (4 mL), and the reaction was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced 648 Attorney Docket No.: R2103-7054WO pressure to afford 2-(4-fluoro-3-quinolyl)acetic acid (A200, 300 mg, 1.46 mmol, 96% yield) as a solid. LCMS (ES, m/z): 206 [M+H]+. Example 139: Synthesis of A208 Synthesis of A206 To a stirre diethylzinc (12 mL, 1 M in THF) and THF (30 mL) was added Pd(PPh3)4 (692 mg, 598.9 μmol), and the reaction was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at 0 °C, acidified to pH 6 with HOAc, and extracted with EtOAc (3 x 10 mL). The combined organics washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford 3-bromo-7-ethyl-quinoline (A206, 200 mg, 847.1 μmol, 14% yield) as a solid. LCMS (ES, m/z): 236 [M+H]+. Synthesis of A207 T y , g, . μmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (882 mg, 3.39 mmol) in THF (4 mL) was added Qphos Pd G3 (72 mg, 84.7 μmol), and the reaction was stirred for 16 h at 70 ℃ under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organics was washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography 649 Attorney Docket No.: R2103-7054WO (50% EtOAc in PE) to afford tert-butyl 2-(7-ethyl-3-quinolyl)acetate (A207, 50 mg, 184.3 μmol, 22% yield) as a solid. LCMS (ES, m/z): 272 [M+H]+. Synthesis of A208 T 45 g, 165.8 μmol) in THF (1 mL) was added a solution of LiOH•H2O (21 mg, 497.5 μmol) in H2O (1 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 2) to afford 2-(7-ethyl-3-quinolyl)acetic acid (A208, 0.03 g, 139.4 μmol, 84% yield) as a solid. LCMS (ES, m/z): 216 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Material Characterization Modifications: Step 1 was omitted Step 2 used se nt 3- 5 ): Example 140: Synthesis of A212 Synthesis of A209 T o a st rred m xture o 3-bromoqu no ne-6-carboxy c ac d ( .5 g, 5.95 mmo ) in THF (15 mL) was added CDI (2.9 g, 17.88 mmol), and the reaction was stirred for 2 h at room temperature. 650 Attorney Docket No.: R2103-7054WO To a stirred mixture of NaBH4 (675 mg, 17.84 mmol) in THF (15 mL), H2O (8 mL). A solution of crude product was added dropwise into the mixture, and the reaction was stirred for 2 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc) to afford (3-bromo-6-quinolyl)methanol (A209, 800 mg, 3.36 mmol, 56% yield) as a solid. LCMS (ES, m/z): 238 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Material Characterization The residue was purified by silica gel column 3- 0 ): Synthesis of A210 To a y , g, 3.36 mmol) in DCM (10 mL) was added DAST (1.08 g, 6.72 mmol) at 0 °C, and the reaction was stirred for 2 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 3-bromo-6-(fluoromethyl)- quinoline (A210, 320 mg, 1.33 mmol, 40% yield) as a solid. LCMS (ES, m/z): 240 [M+H]+. Synthesis of A211 651 Attorney Docket No.: R2103-7054WO 1.25 mmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (976 mg, 3.75 mmol) in THF (5 mL) was added Pd2(dba)3 (114 mg, 124.5 μmol), Q-Phos (212 mg, 249.4 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (67% EtOAc in PE) to afford tert-butyl 2-[6-(fluoromethyl)-3-quinolyl]acetate (A211, 200 mg, 726.4 μmol, 58% yield) as an oil. LCMS (ES, m/z): 276 [M+H]+ Synthesis of A212 T y y q y , 0 mg, 726.4 μmol) in DCM (2 mL) was added TFA (0.5 mL), and the reaction was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-[6- (fluoromethyl)-3-quinolyl]acetic acid (A212, 150 mg, 684.3 μmol, 94% yield) as an oil. The crude product was used directly in the next step. LCMS (ES, m/z): 220 [M+H]+. Example 141: Synthesis of A216 Synthesis of A215 652 Attorney Docket No.: R2103-7054WO To a stir l) in DCE (25 mL) was added tribromoborane (5 mL), and the reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and adjusted to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 3-bromoquinolin-6-ol (A215, 800 mg, 3.57 mmol, 85% yield) as a solid. LCMS (ES, m/z): 224 [M+H]+. Synthesis of A216 To a s iodoethane (783 mg, 5.02 mmol) in DMF (15 mL) was added Cs2CO3 (3.27 g, 10.04 mmol), and the reaction was stirred for 2 h at 100°C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford 3-bromo-6-ethoxy-quinoline (A216, 700 mg, 2.78 mmol, 83% yield) as a solid. LCMS (ES, m/z): 252 [M+H]+. Example 142: Synthesis of A222 Synthesis of A221 653 Attorney Docket No.: R2103-7054WO To a solution mmol) in THF (20 mL) was added NaH (60% dispersion in oil) (265.3 mg, 6.63 mmol) at 0 °C. The mixture was stirred for 30 min. To the above mixture was added 3-fluoro-4,5-dimethoxy-2-nitro-benzonitrile (1 g, 4.42 mmol) and the mixture was stirred for 2 h at room temperature. The reaction mixture was quenched by NH4Cl (aq.) and extracted with EtOAc (3 x 50 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford 3-(2-amino-2-methyl-propoxy)-4,5-dimethoxy-2-nitro-benzonitrile (A221, 350 mg, 1.19 mmol, 27% yield) as a solid. LCMS (ES, m/z): 296 [M+H]+. Synthesis of A222 To a y p p y , y 2-nitro-benzonitrile (A221, 310 mg, 1.05 mmol) and NH4Cl (842.3 mg, 15.75 mmol) in EtOH (6 mL) and H2O (3 mL) were added Fe (586.3 mg, 10.50 mmol), and the reaction was stirred for 2 h at 80 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford 2-amino-3-(2-amino-2- methyl-propoxy)-4,5-dimethoxy-benzamide (A222, 210 mg, 741.2 μmol, 71% yield) as a solid. LCMS (ES, m/z): 284 [M+H]+. 654 Attorney Docket No.: R2103-7054WO An analogous method as followed to obtain the following compounds. Compound Starting Material Characterization The residue was purified by silica gel column 2- 6 4 p y Synthesis of A224 To a stirre e (0.2 g, 884.3 μmol) and 1-(aminomethyl)cyclopropanol (154 mg, 1.77 mmol) in CH3CN (4 mL) was added K2CO3 (366 mg, 2.65 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (33% EtOAc in PE) to afford 3-[(1-hydroxycyclopropyl)methylamino]-4,5- dimethoxy-2-nitro-benzonitrile (A224, 0.2 g, 682.0 μmol, 77% yield) as a solids. LCMS (ES, m/z): 294 [M+H]+ Synthesis of A225 655 Attorney Docket No.: R2103-7054WO To a s imethoxy-2-nitro- benzonitrile (A224, 0.18 g, 613.8 μmol) and Boc2O (267 mg, 1.23 mmol) in THF (2 mL) were added TEA (186 mg, 1.84 mmol) and DMAP (8 mg, 61.4 μmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford [1-[(N-tert- butoxycarbonyl-5-cyano-2,3-dimethoxy-6-nitro-anilino)methyl]cyclopropyl] tert-butyl carbonate (A225, 0.24 g, 486.3 μmol, 79% yield) as a solid. LCMS (ES, m/z): 494 [M+H]+. Synthesis of A226 To a y y y , imethoxy-6-nitro- anilino)methyl]cyclopropyl] tert-butyl carbonate (A225, 0.22 g, 445.8 μmol) and NH4Cl (47 mg, 891.6 μmol) in H2O (1 mL) and EtOH (3 mL) were added Fe (248 mg, 4.46 mmol) at room temperature under nitrogen atmosphere, and the reaction was stirred for 16 h at 70 °C. The mixture was allowed to cool down to room temperature and diluted with DCM (30 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford [1-[(2-amino-N-tert-butoxycarbonyl-3-carbamoyl-5,6-dimethoxy- 656 Attorney Docket No.: R2103-7054WO anilino)methyl]cyclopropyl] tert-butyl carbonate (A226, 0.14 g, 290.7 μmol, 65% yield) as a solid. LCMS (ES, m/z): 482 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material an n t- 3- - d) 3 re 6- te as n. re 6- ), er Example 144: Synthesis of A234 Synthesis of A233 657 Attorney Docket No.: R2103-7054WO g, 13.03 mmol) and Paraformaldehyde (430 mg, 14.33 mmol) in DMSO (50 mL) was added MeONa (70 mg, 1.30 mmol), and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in PE) to afford methyl 3-hydroxy-2-[6-(3- methylpyrrol-1-yl)-3-pyridyl]propanoate (A233, 1.5 g, 5.76 mmol, 44% yield) as a solid. LCMS (ES, m/z): 261 [M+H]+. Synthesis of A234 To yl]propanoate (A233, 1 g, 3.84 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH (92 mg, 3.84 mmol), and the reaction was stirred for 16 h at room temperature. The mixture residue was adjust PH to 5 with 1 N of HCl (aq.) The resulting solid was collected by filtration, washed with water (20 mL), and dried to afford 3-hydroxy-2-[6-(3-methylpyrrol-1-yl)-3-pyridyl]propanoic acid (A234, 0.82 g, 3.33 mmol, 87% yield) as a solid. LCMS (ES, m/z): 247 [M+H]+. Example 145: Synthesis of A237 Synthesis of A235 658 Attorney Docket No.: R2103-7054WO To a stirr 3,5-difluorophenyl)- boronic acid (4.30 g, 27.2 mmol) in DCM (20 mL) were added Cu(OAc)2 (3.71 g, 20.4 mmol) and pyridine (2.15 g, 27.2 mmol, 2.2 mL), and the reaction was stirred for 48 h at room temperature. The resulting mixture was extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (20% EtOAc in PE) to afford 4-bromo-1-(3,5- difluorophenyl)pyrazole (A235, 1.04 g, crude) as a solid. LCMS (ES, m/z): 260 [M+H]+. Synthesis of A236 T .15 g, 579.0 μmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (603 mg, 2.32 mmol) in THF (4 mL) was added XPhos Pd G3 (49 mg, 57.9 μmol), and the reaction was stirred for 3 h at 70 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford tert-butyl 2-[1-(3,5- difluorophenyl)pyrazol-4-yl]acetate (A236, 0.15 g, crude) as an oil. LCMS (ES, m/z): 295 [M+H]+. Synthesis of A237 659 Attorney Docket No.: R2103-7054WO , 140 mg, 506.69 mmol) in DCM (2 mL) was added 4.0M HCl (gas) 4.0 M in 1,4-dioxane (2 mL), and the reaction was stirred for 18 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-[1-(3,5-difluorophenyl)pyrazol-4-yl]acetic acid (A237, 120 mg, crude) as a solid. LCMS (ES, m/z): 239 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material m 3 ed 3- S 3 or ed l- % or ep ed )- as ed 4- d) Attorney Docket No.: R2103-7054WO Synthesis of A238 236, 500 mg, 1.70 mmol) in THF (5 mL) was added LDA (2.0 M in THF) (2 M, 850 μL) at -70--60°C, and the reaction was stirred for 1 h at -70 ~ 60℃ under a nitrogen atmosphere. Iodomethane (241 mg, 1.70 mmol) was then added, and the reaction was stirred for 4 h at room temperature. The mixture was quenched with saturated NH4Cl(aq.) (10 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford tert-butyl 2-[1-(3,5-difluorophenyl)pyrazol-4-yl]propanoate (A238, 300 mg, 973.0 μmol, 57% yield) as an oil. LCMS (ES, m/z): 309.1 [M+H]+. Synthesis of A239 - y - - , - p y py - -y p p A238, 0.28 g, 908.1 μmol) in DCM (5 mL) was added HCl (4.0 M in 1,4-dioxane 5 mL) dropwise, and the reaction was stirred for 24 h at room temperature. The reaction solution was concentrated under reduced pressure to afford 2-[1-(3,5-difluorophenyl)pyrazol-4-yl]propanoic acid (A239, 297 mg, crude) as a solid. LCMS (ES, m/z): 253.0 [M+H]+. Example 147: Synthesis of A248 661 Attorney Docket No.: R2103-7054WO Synthesis of A246 To a s in THF (20 mL) was added bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (4.28 g, 16.43 mmol) and QPhos Pd G3 (956 mg, 821.3 μmol), and the reaction was stirred for 16 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-(8-chloro-1,5-naphthyridin-3-yl)acetate (A246, 620 mg, 2.22 mmol, 27% yield) as a solid. LCMS (ES, m/z): 279 [M+H]+. Synthesis of A247 T y , y y , 20 mg, 2.22 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.4 g, 11.15 mmol) in dioxane (6 mL) and water (1.2 mL) was added Pd(dppf)Cl2 (163 mg, 222.4 μmol) and K3PO4 (1.42 g, 6.67 mmol), and the reaction was stirred for 16 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 662 Attorney Docket No.: R2103-7054WO 2-(8-methyl-1,5-naphthyridin-3-yl)acetate (A247, 450 mg, 1.74 mmol, 78% yield) as a solid. LCMS (ES, m/z): 259 [M+H]+. Synthesis of A248 To a so 247, 450 mg, 1.74 mmol) and water (1 mL) in THF (5 mL) was added LiOH (125 mg, 5.22 mmol), and the reaction was stirred for 2 h at room temperature. The mixture was acidified to pH 6 with HCl (aq.) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 45) to afford 2-(8-methyl-1,5-naphthyridin-3-yl)acetic acid (A248, 280 mg, 1.38 mmol, 79% yield) as a solid. LCMS (ES, m/z): 203 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material o- 3 L) ed ed l- 0 S, Example 148: Synthesis of A253 Synthesis of A250 663 Attorney Docket No.: R2103-7054WO To a mixture l) and tributyl(oxazol-2- yl)stannane (1.8 g, 5.00 mmol) in THF (15 mL) was added XPhos Pd G3 (353 mg, 416.7 μmol), and the reaction was stirred at reflux for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford 2-(3,5-difluorophenyl)oxazole (A250, 400 mg, 2.21 mmol, 53% yield) as a solid. LCMS (ES, m/z): 182 [M+H]+. Synthesis of A251 To a mixtur mmol) in DMF (5 mL) was added NBS (432 mg, 2.43 mmol), and the reaction was stirred at 80°C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The precipitated solids were collected by filtration and washed with water (2 x 1 mL) to afford 5-bromo-2-(3,5-difluorophenyl)- oxazole (A251, 380 mg, 1.46 mmol, 66% yield) as a solid. LCMS (ES, m/z): 260 [M+H]+. Synthesis of A252 To a m xture o - romo- -( , - uorop eny )oxazo e ( , mg, .46 mmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (761 mg, 2.92 mmol) in THF (5 mL) was added XPhos Pd G3 (124 mg, 146.4 μmol), and the reaction was stirred at 70°C for 2 h under nitrogen atmosphere. 664 Attorney Docket No.: R2103-7054WO The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford tert-butyl 2-[2-(3,5-difluorophenyl)oxazol-5- yl]acetate (A252, 250 mg, 846.7 μmol, 58% yield) as a solid. LCMS (ES, m/z): 296 [M+H]+. Synthesis of A253 (A252, 250 mg, 846.7 μmol) in DCM (2 mL) was added 4 M HCl (gas) in dioxane (2 mL), and the reaction was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure to afford 2-[2-(3,5-difluorophenyl)oxazol-5-yl]acetic acid (A253, 200 mg, crude) as a solid. LCMS (ES, m/z): 240 [M+H]+. Example 149: Synthesis of A257 Synthesis of A256 A mixture of , , 6.54 g, 29.06 mmol) and HOAc (70 mL) was stirred at 25 °C for 16 h. The resulting mixture was concentrated under reduced pressure and purified by MPLC (Silica gel column 80 g, 0-25% EtOAc in PE in 15 min; Flow rate: 40 mL/min) to afford 5-bromo-4-chloro-2-iodo-aniline (A256, 2.5 g, 7.52 mmol, 31% yield) as a solid. LCMS (ES, m/z): 375 [M+H]+. Synthesis of A257 Attorney Docket No.: R2103-7054WO A mixture of 5-bromo-4-chloro-2-iodo-aniline (A256, 2.3 g, 6.92 mmol), Zn(CN)2, Pd2(dba)3 (633 mg, 691.3 μmol), Xantphos (400 mg, 691.3 μmol) and DMF (15 mL) was stirred at 100 °C for 2 h under a nitrogen atomosphere. The resulting mixture was concentrated and purified by MPLC (Silica gel column 40 g, 0-85% EtOAc in PE in 15 min; Flow rate: 40 mL/min) to afford 2-amino-4-bromo-5-chloro-benzonitrile (A257, 1.5 g, 6.48 mmol, 94% yield) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.19 (s, 1H), 6.46 (s, 2H). Example 150: Synthesis of A259 Synthesis of A258 To a stir (1 g, 3.70 mmol) in DMF (10 mL) were added Zn(CN)2 (870 mg, 7.41 mmol) and Pd(PPh3)4 (214 mg, 185.2 μmol), and the reaction was stirred for 16 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 2-amino-4-methoxy- 5-(trifluoromethyl)benzonitrile (A258, 600 mg, 2.78 mmol, 75% yield) as a solid. LCMS (ES, m/z): 215 [M-H]-. Synthesis of A259 To a stirr e m xture o -am no- -met oxy- -(tr uoromet y ) enzonitrile (A258, 300 mg, 1.39 mmol) in DMSO (3 mL) were added K2CO3 (575 mg, 4.16 mmol) and H2O2 (3 mL, 30% purity), and the reaction was stirred for 16 h at room temperature. The mixture was allowed to cool 666 Attorney Docket No.: R2103-7054WO down to room temperature. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2- amino-4-methoxy-5-(trifluoromethyl)benzamide (A259, 300 mg, 1.28 mmol, 92% yield), which was used in the next step directly without further purification. LCMS (ES, m/z): 235 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modification: Step 1 used Pd(dppf)Cl2 as catalyst, sh to 5 1 n yl % Example 151: Synthesis of A262 Synthesis of A260 To a stirred sol u on o - uoro- -me y -p eno ( g, . 7 mmol) in DMF (20 mL) was added NBS (28.22 g, 158.57 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified 667 Attorney Docket No.: R2103-7054WO by silica gel column chromatography (18% EtOAc in PE) to afford 2-bromo-6-fluoro-4-methyl- phenol (A260, 21 g, 102.4 mmol, 65% yield) as a solid. LCMS (ES, m/z): 203 [M-H]-. Synthesis of A261 To a stirred 0, 21 g, 102.43 mmol) and DIEA (26.48 g, 204.85 mmol, 35.68 mL) in DCM (200 mL) was added MOMBr (19.20 g, 153.6 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in PE) to afford 1-bromo-3-fluoro-2-(methoxymethoxy)-5-methyl-benzene (A261, 18 g, 72.3 mmol, 71% yield) as an oil. LCMS (ES, m/z): 249 [M+H]+. Synthesis of A262 To a stirr y y thyl-benzene (A261, 17 g, 68.3 mmol) and KOAc (23.44 g, 238.9 mmol, 14.9 mL) in dioxane (170 mL) were added B2pin2 (20.8 g, 81.90 mmol) and Pd(dppf)Cl2 (4.99 g, 6.83 mmol), and the reaction was stirred for 16 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% THF in PE) to afford 2-[3-fluoro- 2-(methoxymethoxy)-5-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A262, 10 g, 33.8 mmol, 49% yield) as a solid. LCMS (ES, m/z): 297 [M+H]+. 668 Attorney Docket No.: R2103-7054WO An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material n 2- l- % p y Synthesis of A264 To a stirred solution of 2,6-dibromo-3-methoxy-5-nitro-pyridine (4 g, 12.82 mmol) in MeOH (300 mL) was added MeONa (930 mg, 17.22 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and diluted with water (200 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL) to afford 2-bromo-5,6-dimethoxy-3-nitro-pyridine (A264, 3 g, 11.40 mmol, 89% yield) as a solid. LCMS (ES, m/z): 263 [M+H]+. Synthesis of A265 To a stir e so u o o - o o- , - e o y- - o-py e 4, 1.5 g, 5.70 mmol) in NMP (20 mL) was added CuCN (1.7 g, 18.16 mmol), and the reaction was irradiated with microwave radiation for 10 min at 170 °C. The resulting mixture was diluted with water (50 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL) to afford 669 Attorney Docket No.: R2103-7054WO crude product. The crude product was diluted with hot EtOAc (200 mL). The resulting mixture was filtered, the filter cake was washed with hot EtOAc (2 x 15 mL). The filtrate was concentrated under reduced pressure to afford 5,6-dimethoxy-3-nitro-pyridine-2-carbonitrile (A265, 600 mg, 2.87 mmol, 50% yield) as a solid. LCMS (ES, m/z): 210 [M+H]+. Synthesis of A266 To a stirr (A265, 600 mg, 2.87 mmol) and Fe (600 mg, 10.74 mmol) in EtOH (14 mL) and H2O (6 mL) was added acetic acid (2.01 g, 33.50 mmol), and the reaction was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL), basified to pH 7 with NH3•H2O (30% aq.), and extracted with EtOAc (2 x 50 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (82% EtOAc in PE) to afford 3-amino-5,6- dimethoxy-pyridine-2-carboxamide (A266, 400 mg, 2.03 mmol, 71% yield) as a solid. LCMS (ES, m/z): 198 [M+H]+. Example 153: Synthesis of A268 Synthesis of A267 To - - - y - g, . oc2O (2.70 g, 12.37 mmol) in MeOH (20 mL) were added NiCl2.6H2O (242 mg, 1.02 mmol) and NaBH4 (1.56 g, 41.23 mmolL) at -20 °C. Then the mixture was stirred for 2 h at -10 °C. The reaction solution was quenched with saturated aqueous NH4Cl (120 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, and 670 Attorney Docket No.: R2103-7054WO filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-[(3-bromo-5- methyl-phenyl)methyl]carbamate (A267, 2.5 g, 8.33 mmol, 82% yield) as a solid. LCMS (ES, m/z): 300 [M+H]+. Synthesis of A268 T mate (A267, 1 g, 3.33 mmol) and B2pin2 (1.70 g, 6.7 mmol) in dioxane (10 mL) was added Pd(dppf)Cl2 (408 mg, 499.7 μmol) and KOAc (1.14 g, 11.7 mmol), and the reaction was stirred for 16 h at 90°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in PE) to afford tert-butyl N-[[3-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (A268, 1 g, 2.88 mmol, 86% yield) as a solid. LCMS (ES, m/z): 292 [M+H]+. Example 154: Synthesis of A272 Synthesis of A269 To a stirred solution of 2-bromo-4-fluoro-6-methyl-benzoic acid (5 g, 21.5 mmol) and NH4Cl (3.4 g, 64.37 mmol) in DMF (50 mL) were added HATU (12.24 g, 32.18 mmol) and DIEA (8.32 g, 64.37 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (50 mL). The precipitated solids were collected by filtration and washed with water (2 x 20 mL) to afford 2-bromo-4-fluoro-6-methyl-benzamide (A269, 3 g, 12.93 mmol, 60% yield) as a solid. LCMS (ES, m/z): 232 [M+H]+. 671 Attorney Docket No.: R2103-7054WO Synthesis of A270 To a stirr 3 g, 12.93 mmol) in THF (30 mL) was added BH3-SMe3 (10 M, 8 mL) at room temperature, and the reaction was stirred for 16 h at 80 °C. The reaction was quenched with MeOH (50 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% MeOH in DCM) to afford (2-bromo-4-fluoro-6-methyl-phenyl)methanamine (A270, 500 mg, 2.29 mmol, 18% yield) as an oil. LCMS (ES, m/z): 218 [M+H]+. Synthesis of A271 To a stirred mixture of (2-bromo-4-fluoro-6-methyl-phenyl)methanamine (A270, 500 mg, 2.29 mmol) and TEA (465 mg, 4.60 mmol) in DCM (5 mL) was added Boc2O (1.00 g, 4.59 mmol), and the reaction was stirred for 12 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in DCM) to afford tert-butyl N-[(2-bromo-4-fluoro-6-methyl-phenyl)methyl]carbamate (A271, 530 mg, 1.67 mmol, 73% yield) as a solid. LCMS (ES, m/z): 303[M-56+41]+. Synthesis of A272 672 Attorney Docket No.: R2103-7054WO T nyl)methyl]- carbamate (A271, 250 mg, 785.7 μmol) and B2pin2 (399 mg, 1.57 mmol) in dioxane (5 mL) were added KOAc (270 mg, 2.75 mmol) and Pd(dppf)Cl2 (115 mg, 157.1 μmol), and the reaction was stirred for 16 h at 90°C under nitrogen atmosphere. The mixture was concentrated under reduced pressure to afford tert-butyl N-[[4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]carbamate (A272, 200 mg, crude) as a solid. LCMS (ES, m/z): 364 [M-H]+. Example 155: Synthesis of A283 Synthesis of A280 A , , henyl)boronic acid (853.4 mg, 7.10 mmol), K3PO4 (1.94 g, 9.15 mmol) and Pd(dppf)Cl2 (223 mg, 305.0 μmol) in dioxane (10 mL) and water (1 mL) was stirred for 16 h at 50 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-20% EtOAc in PE) to afford 4-bromo-1-(4-fluorophenyl)-2-nitro- benzene (A280, 1.56 g, 5.27 mmol, 74% yield) as an oil.1H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.3, 2.1 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.45-7.38 (m, 2H), 7.37-7.26 (m, 2H). 673 Attorney Docket No.: R2103-7054WO Synthesis of A281 To a st 280, 1.56 g, 5.27 mmol) in THF (30 mL) was added PhMgBr (7.9 mL, 15.8 mmol, 2M in THF) at 0°C under nitrogen atmosphere, and the reaction was stirred for 0.5 h at 0°C. The reaction was quenched with 10 mL of NH4Cl (aq.) at -10oC. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x100 mL) and brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford 2-bromo-7-fluoro-9H- carbazole (A281, 290 mg, 1.10 mmol, 21% yield) as a solid. LCMS (ES, m/z): 264 [M+H]+. Synthesis of A282 , , bromo-(2- tert-butoxy-2-oxo-ethyl)zinc (1.2 g, 4.39 mmol) and XPhos Pd G3 (93.0 mg, 109.8 μmol) in THF (3 mL) was stirred for 16 h at 70 °C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-(7-fluoro-9H-carbazol-2-yl)acetate (A282, 270 mg, 902.0 μmol, 82% yield) as a solid. LCMS (ES, m/z): 298 [M-H]+. 674 Attorney Docket No.: R2103-7054WO Synthesis of A283 2, 220 mg, 735.0 μmol) in DCM (2.5 mL) was added 4M HCl (gas) in dioxane (5 mL) dropwise, and the reaction was stirred for 16 h at room temperature. The reaction solution was concentrated under reduced pressure to afford 2-(7-fluoro-9H-carbazol-2-yl) acetic acid (A283, 118.0 mg, 485.1 μmol, 66% yield) as a solid. LCMS (ES, m/z): 242 [M-H]+. Example 156: Synthesis of A293 Synthesis of A289 To a stirred solution of 8-bromoquinolin-4-ol (5.5 g, 24.6 mmol) in DMF (55 mL) was added NIS (5.52 g, 24.6 mmol) in portions under nitrogen atmosphere, and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (4% MeOH in DCM) to afford 8-bromo-3-iodo- quinolin-4-ol (A289, 6.2 g, 17.7 mmol, 72% yield) as an oil. LCMS (ES, m/z): 350 [M+H]+. Synthesis of A290 675 Attorney Docket No.: R2103-7054WO To a stirred solution of 8-bromo-3-iodo-quinolin-4-ol (A289, 6.2 g, 17.7 mmol) and Ag2CO3 (7.33 g, 26.6 mmol) in DMF (60 mL) was added CH3I (3.77 g, 26.6 mmol), and the reaction was stirred for 2 h at 60 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford 8-bromo- 3-iodo-4-methoxy-quinoline (A290, 2 g, 5.49 mmol, 31% yield) as a solid. LCMS (ES, m/z): 364 [M+H]+. Synthesis of A291 To a stirred mixture of 8-bromo-3-iodo-4-methoxy-quinoline (A290, 1.3 g, 3.57 mmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (2.79 g, 10.7 mmol) in THF (15 mL) was added QPhos Pd G3 (384.4 mg, 357.2 μmol), and the reaction was stirred for 4 h at 70 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford tert-butyl 2-(8-bromo-4-methoxy-3- quinolyl)acetate (A291, 490 mg, 1.39 mmol, 39% yield) as a solid. LCMS (ES, m/z): 352 [M+H]+. Synthesis of A292 676 Attorney Docket No.: R2103-7054WO A291, 490 mg, 1.39 mmol) and methylboronic acid (166.5 mg, 2.78 mmol) in dioxane (5 mL) and H2O (1 mL) were added K3PO4 (885.9 mg, 4.17 mmol) and Pd(dppf)Cl2 (101.7 mg, 139.1 μmol), and the reaction was stirred for 16 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford tert-butyl 2-(4-methoxy-8-methyl-3-quinolyl)acetate (A292, 240 mg, 835.2 μmol, 60% yield) as a solid. LCMS (ES, m/z): 288 [M+H]+. Synthesis of A293 To a etate (A292, 240 mg, 835.2 μmol) in DCM (3 mL) was added 4M HCl (gas) in dioxane (3 mL), and the reaction was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(4-methoxy-8-methyl-3-quinolyl)acetic acid (A293, 150 mg, 648.7 μmol, 78% yield) as a solid. LCMS (ES, m/z): 232 [M+H]+. Example 157: Synthesis of A297 Synthesis of A294 Attorney Docket No.: R2103-7054WO Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromo-1,6-naphthyridine (2 g, 9.57 mmol), DMF (40 mL), NIS (2.2 g, 9.78 mmol), 4-methylbenzenesulfonic acid (0.9 g, 5.23 mmol), and the reaction was stirred for 16 h at 80 °C. The reaction was quenched by the addition of water (60 mL), extracted with DCM (3 x 100 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (20% EtOAc in PE) to afford 3-bromo-8-iodo-1,6-naphthyridine (A294, 1.2 g, 3.58 mmol, 38% yield) as a solid. LCMS (ES, m/z): 334 [M+H]+. Synthesis of A295 To a so mmol) and 2,4,6- trimethyl-1,3,5,2,4,6-trioxatriborinane (1.9 g, 15.14 mmol) in dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2 (218 mg, 297.9 μmol) and K3PO4 (1.3 g, 6.12 mmol), and the reaction was stirred for 1 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 3-bromo-8-methyl-1,6-naphthyridine (A295, 300 mg, 1.34 mmol, 45% yield) as a solid. LCMS (ES, m/z): 223 [M+H]+. Synthesis of A296 Attorney Docket No.: R2103-7054WO To a solution of 3-bromo-8-methyl-1,6-naphthyridine (A295, 300 mg, 1.34 mmol) in THF (3 mL) was added bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (1.1 g, 4.22 mmol) and XPhos Pd G3 (113 mg, 133.5 μmol), and the reaction was stirred for 4 h at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-(8-methyl-1,6-naphthyridin-3-yl)acetate (A296, 270 mg, 1.05 mmol, 78% yield) as a solid. LCMS (ES, m/z): 259 [M+H]+. Synthesis of A297 To a solution of tert-butyl 2-(8-methyl-1,6-naphthyridin-3-yl)acetate (A296, 270 mg, 1.05 mmol) in DCM (3 mL) was added TFA (3 mL), and the reaction was stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 45) to afford 2-(8-methyl-1,6- naphthyridin-3-yl)acetic acid (A297, 140 mg, 692.4 μmol, 66% yield) as a solid. LCMS (ES, m/z): 203 [M+H]+. Example 158: Synthesis of A303 Synthesis of A301 Attorney Docket No.: R2103-7054WO To a stirred solution of 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (500 mg, 2.00 mmol) and Boc2O (523 mg, 2.40 mmol) in THF (5 mL) were added DMAP (49 mg, 401.1 μmol) and Et3N (404 mg, 3.99 mmol), and the reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford tert-butyl 7-bromo-1,2,3,4-tetrahydrocarbazole-9- carboxylate (A301, 665 mg, 1.90 mmol, 95% yield) as a solid. LCMS (ES, m/z): 350 [M+H]+. Synthesis of A302 T 9-carboxylate (A301, 300 mg, 856.5 μmol) and (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (446 mg, 1.71 mmol) in THF (3 mL) were added XPhos Pd G3 (72 mg, 85.1 μmol), and the reaction was stirred for 16 h at 70°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford tert-butyl 7-(2-tert-butoxy-2-oxo-ethyl)-1,2,3,4-tetrahydrocarbazole-9-carboxylate (A302, 280 mg, 726.3 μmol, 85% yield) as a solid. LCMS (ES, m/z): 386 [M+H]+. Synthesis of A303 o a s e so u o o e - u y - -e - u o y- -o o-e yl)-1,2,3,4- tetrahydrocarbazole-9-carboxylate (A302, 300 mg, 778.2 μmol) in THF (1 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH.H2O (164 mg, 3.91 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (15 mL). The mixture was acidified to pH 5 with 2M HCl. The resulting mixture was extracted with EtOAc (3 x 10 mL). The 680 Attorney Docket No.: R2103-7054WO combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-(9-tert-butoxycarbonyl- 5,6,7,8-tetrahydrocarbazol-2-yl)acetic acid (A303, 150 mg, 455.4 μmol, 59% yield) as a solid. LCMS (ES, m/z): 230 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material e, er 3- d. xamp e 59: Synt es s o 3 0 Synthesis of A308 To a stirred mixture of 5-bromo-2-fluoro-4-methoxy-pyridine (1.2 g, 5.82 mmol) in DMF (20 mL) were added 3-methyl-1H-pyrrole (567 mg, 6.99 mmol) and Cs2CO3 (5.69 g, 17.47 mmol) at room temperature under N2 atmosphere, and the reaction was stirred for 16 h at 100°C. The mixture was allowed to cool down to room temperature and quenched with water (30 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL), washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford 5-bromo-4- methoxy-2-(3-methylpyrrol-1-yl)pyridine (A308, 800 mg, 2.99 mmol, 51% yield) as a solid. Synthesis of A309 681 Attorney Docket No.: R2103-7054WO A mmol) and 5- bromo-4-methoxy-2-(3-methylpyrrol-1-yl)pyridine (A308, 0.8 g, 2.99 mmol) in THF (20 mL) was treated with XantPhos Pd G3 (568 mg, 599.0 μmol), and the reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-[4-hydroxy-6-(3-methylpyrrol-1-yl)-3-pyridyl]acetic acid (A309, 0.39 g, 1.68 mmol, 56% yield) as a solid. Synthesis of A310 09, 0.39 g, 1.68 mmol) in DMF (5 mL) was treated with MeSNa (471 mg, 6.72 mmol), and the reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, concentrated under reduced pressure and purified by prep-HPLC (Condition 6, Gradient 4) to afford 2-[6-(3-methylpyrrol-1-yl)-4-oxo-1H-pyridin-3-yl]acetic acid (A310, 0.2 g, 861.2 μmol, 51% yield) as an oil. Example 160: Synthesis of A311 682 Attorney Docket No.: R2103-7054WO To tic acid (A142, 260 mg, 1.06 mmol) in DCE (5 mL) was added AlCl3 (703.8 mg, 5.28 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The product was precipitated by the addition of water (10 mL) and filtered, the filter cake was washed with water (2 x 10 mL). The resulting solid was dried under infrared light to afford 2- [6-(3-methylpyrrol-1-yl)-2-oxo-1H-pyridin-3-yl]acetic acid (A311, 180 mg, 775.1 μmol, 73% yield) as a solid. LCMS (ES, m/z): 233 [M+H]+. Example 161: Synthesis of A315 Synthesis of A312 To a . , . mmol) and (2,5- difluorophenyl)boronic acid (1.4 g, 9.03 mmol) in Dioxane (20 mL) were added K3PO4 (5.7 g, 27.1 mmol), H2O (2 mL) and Pd(dppf)Cl2 (660 mg, 903.3 μmol), and the reaction was stirred for 4 h at 85°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (91% EtOAc in PE) to afford 5-bromo-2-(2,5-difluorophenyl)phenol (A312, 1.2 g, 4.21 mmol, 47% yield) as a solid. LCMS (ES, m/z): 285 [M+H]+. Synthesis of A313 683 Attorney Docket No.: R2103-7054WO To a solut 2-(2,5-difluorophenyl)phenol g, 4.21 mmol) in DMF (12 mL) was added K2CO3 (1.7 g, 12.63 mmol), and the reaction was stirred for 6 h at 140°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (10 mL). The solid was collected by filtration and washed with water (10 mL). The solid was dried to afford 7-bromo-2-fluoro-dibenzofuran (A313, 500 mg, 1.89 mmol, 45% yield) as a solid. LCMS (ES, m/z): 265 [M+H]+. Synthesis of A314 To 89 mmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (1.4 g, 5.66 mmol) in THF (6 mL) were added XPhos Pd G3 (159 mg, 188.6 μmol) at room temperature under nitrogen atmosphere, and the reaction was stirred for 2 h at 70°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (75% EtOAc in PE) to afford tert-butyl 2-(8-fluorodibenzofuran-3- yl)acetate (A314, 400 mg, 1.33 mmol, 71% yield) as a solid. LCMS (ES, m/z): 301 [M+H]+. Synthesis of A315 Attorney Docket No.: R2103-7054WO To a solution of tert-butyl 2-(8-fluorodibenzofuran-3-yl)acetate (A314, 400 mg, 1.33 mmol) in DCM (2 mL) was added HCl (4.0 M in 1,4-dioxane) (2 mL), and the reaction was stirred for 16 h at room temperature. The mixture was purified by reversed-phase flash chromatography (Condition 10, Gradient 1) to afford 2-(8-fluorodibenzofuran-3-yl)acetic acid (A315, 240 mg, 982.7 μmol, 74% yield) as a solid. LCMS (ES, m/z): 245 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization Material C. ed ]- a Example 162: Synthesis of A317 To a stirred mixture of 2-amino-5-bromo-3-iodo-benzonitrile (2 g, 6.19 mmol) and K2CO3 (1.03 g, 7.43 mmol) in DMSO (40 mL) was added H2O2 (30%, 15 mL), and the reaction was stirred at room temperature for 16 h. The resulting mixture was diluted with water (40 mL). The precipitated solids were collected by filtration and washed with water (40 mL) to afford 2-amino- 5-bromo-3-iodo-benzamide (A317, 1.6 g, 4.69 mmol, 76% yield) as a solid. LCMS (ES, m/z): 341 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization 685 Attorney Docket No.: R2103-7054WO The solid was collected by filtration and washed with water (1 x 60 mL). Th lid did ff d 2- % ): un by sh 2, 4- n 26 S un by sh 2, 1- 1, as 32 Example 163: Synthesis of A322 Synthesis of A320 To a solution o me y -amno--oo-enzoae (. g, . mmol) in DMF (100 mL) was added NBS (5.91 g, 33.21 mmol) at -10 °C, and the reaction was stirred for 8 h at -10 °C. The resulting mixture was diluted with ice water (200 mL) and extracted with EtOAc (2 x 200 mL). 686 Attorney Docket No.: R2103-7054WO The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford methyl 2-amino-5-bromo-4-iodo-benzoate (A320, 9 g, 25.3 mmol, 76% yield) as a solid. LCMS (ES, m/z): 356 [M+H]+. Synthesis of A321 To a stir (A320, 8.5 g, 23.9 mmol) in THF (40 mL), MeOH (40 mL) and H2O (40 mL) was added LiOH (2.86 g, 119.4 mmol), and the reaction was stirred for 16 h at room temperature. The mixture residue was acidified to pH 5 with 1 N of HCl (aq.). The resulting solid was collected by filtration, washed with water (200 mL), and dried to afford 2-amino-5-bromo-4-iodo-benzoic acid (A321, 7.9 g, 23.1 mmol, 97% yield) as a solid. LCMS (ES, m/z): 342 [M+H]+. Synthesis of A322 To a st , 7.7 g, 22.5 mmol) and HATU (12.84 g, 33.8 mmol) in DMF (100 mL) was added DIEA (8.73 g, 67.56 mmol, 11.77 mL) and NH4Cl (6.02 g, 112.6 mmol, 3.94 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (200 mL). The solid was collected by filtration, washed with water (200 mL), and dried to afford 2-amino-5-bromo-4-iodo-benzamide (A322, 6.8 g, 19.94 mmol, 89% yield) as a solid. LCMS (ES, m/z): 341 [M+H]+. Example 164: Synthesis of A325 Synthesis of A323 687 Attorney Docket No.: R2103-7054WO To a stirr mg, 2.55 mmol) in DMF (2.5 mL) was added MeSNa (178 mg, 2.54 mmol) in H2O (0.25 μL) at 0 °C, and the reaction was stirred for 1 h at room temperature. The resulting mixture was added water (300 mL) and EtOAc (200 mL), and the mixture was filtered through a Celite pad, the cake was washed with 50 mL of EtOAc. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (75% EtOAc in PE) to afford 4-methoxy-5-methylsulfanyl-2-nitro- benzonitrile (A323, 440 mg, 1.96 mmol) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.74 (s, 1H), 4.08-3.92 (m, 3H), 2.57 (s, 3H). Synthesis of A324 To a stirred nitrile (A323, 200 mg, 891.9 μmol) and Zinc (1.74 g, 26.6 mmol) in AcOH (4 mL), and the reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% THF in PE) to afford 2-amino-4-methoxy-5- methylsulfanyl-benzonitrile (A324, 150 mg, 772.2 μmol, 87% yield) as a solid. LCMS (ES, m/z): 236 [M+H+ACN]+. Synthesis of A325 Attorney Docket No.: R2103-7054WO To a stirred solution of 2-amino-4-methoxy-5-methylsulfanyl-benzonitrile (A324, 152 mg, 782.5 μmol) and K2CO3 (324 mg, 2.34 mmol), hydrogen peroxide (1 mL) in DMSO (2 mL), and the reaction was stirred for 1 h at room temperature. The mixture was allowed to cool down to room temperature, quenched by the addition of water (10 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-amino-4-methoxy- 5-methylsulfanyl-benzamide (A325, 170 mg, 800.9 μmol) as a solid. LCMS (ES, m/z): 213 [M+H]+. Example 165: Synthesis of A331 Synthesis of A329 To a s g, 3.54 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (1.06 g, 5.31 mmol) in CH3CN (10 mL) was added K2CO3 (488 mg, 3.54 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (33% EtOAc in PE) to afford tert-butyl 3-(5-cyano-2,3- dimethoxy-6-nitro-anilino)piperidine-1-carboxylate (A329, 0.85 g, 2.09 mmol, 59% yield) as a solid. LCMS (ES, m/z): 294 [M+H]+. Synthesis of A330 689 Attorney Docket No.: R2103-7054WO To a no)piperidine-1- carboxylate (A329, 0.3 g, 738.1 μmol) and NH4Cl (157 mg, 2.95 mmol), H2O (2 mL) in EtOH (5 mL) was added Iron (248 mg, 4.46 mmol), and the reaction was stirred for 8 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with DCM (30 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 3-(2-amino-3-cyano-5,6- dimethoxy-anilino)piperidine-1-carboxylate (A330, 0.17 g, 451.6 μmol, 61% yield) as a solid. LCMS (ES, m/z): 377 [M+H]+. Synthesis of A331 To a , o)piperidine-1- carboxylate (A330, 0.15 g, 398.5 μmol) in DMSO (10 mL) were added K2CO3 (165 mg, 1.20 mmol) and H2O2 Solution (40 mg, 1.20 mmol), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl 3- (2-amino-3-carbamoyl-5,6-dimethoxy-anilino)piperidine-1-carboxylate (A331, 0.13 g, 329.6 690 Attorney Docket No.: R2103-7054WO μmol, 83% yield), which was used directly in the next step without further purification. LCMS (ES, m/z): 395 [M+H]+. Example 166: Synthesis of A339 Synthesis of A337 To a stirre .3 g, 17.64 mmol) in THF (60 mL) was added 3-bromo-5-fluoro-benzaldehyde (3 g, 14.78 mmol) and t-BuOK (4.9 g, 43.67 mmol) at 0 °C under nitrogen atmosphere, and the reaction was stirred for 0.5 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (300 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford 1-bromo-3-fluoro-5-vinyl-benzene (A337, 1.8 g, 8.95 mmol, 61% yield) as an oil. LCMS (ES, m/z): 201 [M+H]+. Synthesis of A338 To a solution of 1-bromo-3-fluoro-5-vinyl-benzene (A337, 1.8 g, 8.95 mmol) in MeOH (60 mL) was added Raney Ni (1.8 g, 21.01 mmol), and the reaction was stirred for 2 h at room temperature under hydrogen atmosphere (5 atm). The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 100 mL). The filtrate was concentrated under reduced pressure and 691 Attorney Docket No.: R2103-7054WO purified by silica gel column chromatography (20% EtOAc in PE) to afford 1-bromo-3-ethyl-5- fluoro-benzene (A338, 500 mg, 2.5 mmol, 28% yield) as an oil. LCMS (ES, m/z): 203 [M+H]+. Synthesis of A339 To l) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (750 mg, 2.95 mmol) in dioxane (5 mL) was added AcOK (483 mg, 4.92 mmol) and Pd(dppf)Cl2 (180 mg, 246.0 μmol), and the reaction was stirred for 16 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (20% EtOAc in PE) to afford 2-(3-ethyl-5-fluoro-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (A339, 220 mg, 879.6 μmol, 36% yield) as an oil. LCMS (ES, m/z): 251 [M+H]+. Example 167: Synthesis of A343 Synthesis of A341 A m ixture of 2-amino-3-iodo-benzonitrile (1 g, 4.10 mmol)，tert-butyl 4- (iodomethyl)piperidine-1-carboxylate (2 g, 6.15 mmol), Ni(DME)Cl2 (180.1 mg, 819.6 μmol) and 692 Attorney Docket No.: R2103-7054WO Zn (535.9 mg, 8.20 mmol) in DMAc (9 mL) was added TFA (233.6 mg, 2.05 mmol) in DMAc (1 mL), and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 4-[(2-amino-3- cyano-phenyl)methyl]piperidine-1-carboxylate (A341, 1.1 g, 3.49 mmol, 77% yield) as a solid. LCMS (ES, m/z): 314 [M-H]-. Synthesis of A342 To a stirred mixture of tert-butyl 4-[(2-amino-3-cyano-phenyl)methyl]piperidine-1- carboxylate (A341, 1.1 g, 3.49 mmol) and NBS (620 mg, 3.49 mmol) in DMF (11 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[(2-amino-5-bromo-3-cyano-phenyl)methyl]piperidine-1- carboxylate (A342, 0.8 g, 2.03 mmol, 58% yield) as a solid. LCMS (ES, m/z): 394 [M+H]+. Synthesis of A343 Attorney Docket No.: R2103-7054WO To a stirred solution of tert-butyl 4-[(2-amino-5-bromo-3-cyano- phenyl)methyl]piperidine-1-carboxylate (A342, 0.8 g, 2.03 mmol) in EtOH (8 mL) was added K2CO3 (841.2 mg, 6.09 mmol) and H2O2 (8 mL) at 0℃, and the reaction was stirred for 16 h at room temperature. The mixture was acidified to pH 5 with 1 N HCl (aq.). The precipitated solids were collected by filtration, washed with water (20 mL), and air dried to afford tert-butyl 4- [(2-amino-5-bromo-3-carbamoyl-phenyl)methyl]piperidine-1-carboxylate (A343, 0.5 g, 1.21 mmol, 60% yield) as a solid. LCMS (ES, m/z): 412 [M+H]+. Example 168: Synthesis of A352 Synthesis of A347 To a st 10 g, 45.46 mmol) and 3-methyl-1H-pyrrole (5.53 g, 68.18 mmol) in DMSO (100 mL) were added Cs2CO3 (29.6 g, 90.9 mmol) and H2O (3.27 g, 181.7 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h 110°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL), acidified to pH 5 with 1 N HCl (aq.), and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 5, Gradient 6) to afford 5-bromo-2-(3-methylpyrrol-1- yl)pyridine-4-carboxylic acid (A347, 1.3 g, 4.62 mmol, 10% yield) as a solid. LCMS (ES, m/z): 281 [M+H]+. Synthesis of A348 694 Attorney Docket No.: R2103-7054WO To a sol ic acid (1.3 g, 4.62 mmol) in DCM (30 mL) was added BH3 (5 mL, 1.0 M in THF), and the reaction was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure and the residue was cooled to 0° C. Methanol was carefully added until gas evolution ceased and the solution was concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc) to afford [5-bromo-2-(3-methylpyrrol-1-yl)-4-pyridyl]methanol (A348, 1.1 g, 4.12 mmol, 89% yield) as a solid. LCMS (ES, m/z): 267 [M+H]+. Synthesis of A349 To a s y py y py y (1 g, 3.74 mmol) and imidazole (305 mg, 4.49 mmol) in DCM (20 mL) was added TBSCl (620 mg, 4.12 mmol) at 0 °C, and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in PE) to afford [5-bromo-2-(3-methylpyrrol-1-yl)-4-pyridyl]methoxy-tert-butyl- dimethyl-silane (A439, 1.1 g, 2.88 mmol, 77% yield). LCMS (ES, m/z): 381 [M+H]+. Synthesis of A350 695 Attorney Docket No.: R2103-7054WO T xy-tert-butyl- dimethyl-silane (1 g, 2.62 mmol) and bromo[2-(1,1-dimethylethoxy)-2-oxoethyl]zinc (2.73 g, 10.49 mmol) in THF (20 mL) was added XPhos Pd G3 (221 mg, 262.2 μmol), and the reaction was stirred for 3 h at 70°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford tert-butyl 2-[4-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-(3-methylpyrrol-1-yl)-3-pyridyl]acetate (A350, 1 g, 2.40 mmol, 92% yield) as a solid. LCMS (ES, m/z): 417 [M+H]+. Synthesis of A351 hyl]-6-(3- methylpyrrol-1-yl)-3-pyridyl]acetate (A350, 0.8 g, 1.92 mmol) in THF (5 mL), MeOH (5 mL) and H2O (5 mL) was added LiOH•H2O (229 mg, 9.60 mmol), and the reaction was stirred for 16 h at room temperature. The mixture residue was acidified to pH 5 with 1 N of HCl (aq.) The solid was collected by filtration, washed with water (20 mL), and dried to afford 2-[4-(hydroxymethyl)-6- (3-methylpyrrol-1-yl)-3-pyridyl]acetic acid (A351, 0.4 g, 1.62 mmol, 85% yield) as a solid. LCMS (ES, m/z): 247 [M+H]+. Synthesis of A352 696 Attorney Docket No.: R2103-7054WO ic acid (0.3 g, 1.22 mmol) and imidazole (91 mg, 1.34 mmol) in DCM (6 mL) was added TBSCl (210 mg, 1.22 mmol) at 0°C, and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in PE) to afford 2-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(3- methylpyrrol-1-yl)-3-pyridyl]acetic acid (A352, 0.32 g, 887.6 μmol, 73% yield) as an oil. LCMS (ES, m/z): 361 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modifications: Ste s 1 and 2 an os ep ne by n to ol, S Example 169: Synthesis of A355 697 Attorney Docket No.: R2103-7054WO Synthesis of A353 To a stirred nd DIEA (6.49 g, 50.18 mmol) in DCM (10 mL) was added bromomethyl methyl ether (2.72 g, 21.75 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (3% EtOAc in PE) to afford 1-bromo-4-iodo-2-(methoxymethoxy)- benzene (A353, 5 g, 87% yield) as a solid. LCMS (ES, m/z): 343 [M+H]+. Synthesis of A354 To a s e so u o o - o o- -o o- - e o y e o y e e e 353, 5 g, 14.58 mmol) and (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (11.28 g, 43.74 mmol) in THF (10 mL) was added XPhos Pd G3 (1.23 g, 1.46 mmol), and the reaction was stirred at 70 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (9% EtOAc in PE) to afford tert-butyl 2-[4-bromo-3- (methoxymethoxy)phenyl]acetate (A354, 500 mg, 10% yield) as a solid. LCMS (ES, m/z): 331 [M+H]+. Synthesis of A355 698 Attorney Docket No.: R2103-7054WO tate (A354, 500 mg, 1.51 mmol) in THF (3 mL) and MeOH (3 mL) was added a solution of LiOH•H2O (317 mg, 7.55 mmol) in H2O (3 mL), and the reaction was stirred at room temperature for 6 h. The resulting mixture was purified by reversed-phase flash chromatography (Condition 5, Gradient 7) to afford [4-bromo-3-(methoxymethoxy)phenyl]acetic acid (A355, 300 mg, 72% yield) as a solid. LCMS (ES, m/z): 273 [M+H]–. An analogous method was followed to obtain the following compounds. Compound Starting Material Characterization Modifications: Steps 1 2 and 3 were ran for n er 5- id d. as to as sh to g, d. to as sh to Attorney Docket No.: R2103-7054WO trimethylsilylethoxymethyl)pyrrolo[3,2- b]pyridin-6-yl]acetic acid (D57, 310 mg, S Example 170: Synthesis of A365 Synthesis of A361 To a stirr 7 mmol) and Boc2O (9.6 g, 43.99 mmol, 10.09 mL) in toluene (15 mL) were added DMAP (359 mg, 2.94 mmol), and the reaction was stirred for 16 h at 50°C. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford tert-butyl N-(2- bromo-6-fluoro-4-methyl-phenyl)-N-tert-butoxycarbonyl-carbamate (A361, 3.5 g, 8.66 mmol, 59% yield) as a solid. LCMS (ES, m/z): 404 [M+H]+. Synthesis of A362 To a stirr y methyl-phenyl)-N-tert- butoxycarbonyl-carbamate (A361, 2 g, 4.95 mmol) and LiBr (429 mg, 4.94 mmol) in CH3CN (20 mL), and the reaction was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford tert-butyl N-(2-bromo-6-fluoro-4-methyl-phenyl)carbamate (A362, 1.1 g, 3.62 mmol, 73% yield) as a solid. LCMS (ES, m/z): 304 [M+H]+. 700 Attorney Docket No.: R2103-7054WO Synthesis of A363 To a stirred enyl)carbamate (A362, 1 g, 3.29 mmol) in THF (1 mL) was added LiHMDS (2 M, 2.47 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. To the above mixture was added CH3I (2.33 g, 16.44 mmol) at 0°C, and the reaction was stirred for additional 4 h at 0°C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford tert-butyl N-(2-bromo-6- fluoro-4-methyl-phenyl)-N-methyl-carbamate (A363, 0.93 g, 2.92 mmol, 89% yield) as a solid. LCMS (ES, m/z): 318 [M+H]+. Synthesis of A364 To a stirred solution of tert-butyl N-(2-bromo-6-fluoro-4-methyl-phenyl)-N-methyl- carbamate (A363, 600 mg, 1.89 mmol) in DCM (6 mL) were added 4 M HCl (gas) in dioxane (6 mL), and the reaction was stirred for 5 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-bromo-6-fluoro-N,4-dimethyl-aniline (A364, 300 mg, 1.38 mol, 73% yield) as a solid. LCMS (ES, m/z): 218 [M+H]+. Synthesis of A365 701 Attorney Docket No.: R2103-7054WO To a st 0 mg, 1.61 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.2 g, 4.73 mmol) in dioxane (3 mL) were added KOAc (472 mg, 4.81 mmol) and Pd(dppf)Cl2 (117 mg, 159.9 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 2-fluoro-N,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A365, 270 mg, 1.02 mmol, 63% yield) as a solid. LCMS (ES, m/z): 266 [M+H]+. Example 171: Synthesis of A371 Synthesis of A366 To a stirred mixture of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (20 g, 117.6 mmol) in DMF (200 mL) were added K2CO3 (32.5 g, 235.1 mmol) and iodomethane (25.0 g, 176.3 mmol, 10.98 mL), and the reaction was stirred for 16 h at room temperature. The reaction was quenched by the addition of ice water (200 mL). The resulting mixture was filtered, the precipitated solids were collected by filtration and washed with water (3 x 100 mL) to afford 3-fluoro-4,5-dimethoxy- benzaldehyde (A366, 16 g, 86.9 mmol, 74% yield) as a solid. LCMS (ES, m/z): 185 [M+H]+. Synthesis of A367 702 Attorney Docket No.: R2103-7054WO A mixture of 3 8 mmol) and conc. HNO3 (200 mL) was stirred for 2 h at room temperature. The resulting mixture was poured into ice water (100 mL) and the precipitated solids were collected by filtration and washed with water (100 mL). The resulting solids were purified by silica gel column chromatography (25% EtOAc in PE) to afford 3-fluoro-4,5-dimethoxy-2-nitro-benzaldehyde (A367, 8 g, 34.9 mmol, 40% yield) as a solid. LCMS (ES, m/z): 230 [M+H]+. Synthesis of A368 To a sti mmol, 1.9 mL) and HCOONa (5.87 g, 83.8 mmol) in HCOOH (80 mL) was added 3-fluoro-4,5-dimethoxy-2-nitro- benzaldehyde (8 g, 34.9 mmol), and the reaction was stirred for 3 h at 100 °C. The mixture was allowed to cool down to room temperature, and poured into ice water (100 mL). The precipitated solids were collected by filtration and washed with water (100 mL) to afford 3-fluoro-4,5- dimethoxy-2-nitro-benzonitrile (A368, 7 g, 30.95 mmol, 89% yield) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 7.76 (d, J = 1.8 Hz, 1H), 4.02 (s, 3H), 3.98 (d, J = 1.2 Hz, 3H). Synthesis of A369 Attorney Docket No.: R2103-7054WO To a stirred mixture of 3-fluoro-4,5-dimethoxy-2-nitro-benzonitrile (A368, 2.4 g, 10.6 mmol) and 1-[tert-butyl(dimethyl)silyl]oxybutan-2-amine (4.32 g, 21.2 mmol) in CH3CN (30 mL) was added K2CO3 (4.40 g, 31.8 mmol), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford 3-[1-[[tert-butyl(dimethyl)silyl]- oxymethyl]propylamino]-4,5-dimethoxy-2-nitro-benzonitrile (A369, 3 g, 7.33 mmol, 69% yield) as a solid. LCMS (ES, m/z): 410 [M+H]+. Synthesis of A370 To opylamino]-4,5- dimethoxy-2-nitro-benzonitrile (A369, 2.5 g, 6.10 mmol) in AcOH (50 mL) was added Fe (1.02 g, 18.31 mmol) at 90°C in batches, and the reaction was stirred for 0.5 h at 105 °C. The resulting mixture was filtered while still hot, the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure, diluted with water (30 mL), and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-amino-3- [1-[[tert-butyl(dimethyl)silyl]oxymethyl]propylamino]-4,5-dimethoxy-benzonitrile (A370, 1.8 g, 4.74 mmol, 78% yield) as a solid. LCMS (ES, m/z): 380 [M+H]+. Synthesis of A371 704 Attorney Docket No.: R2103-7054WO To a s yl]propylamino]- 4,5-dimethoxy-benzonitrile (A370, 1 g, 2.63 mmol) in DMSO (10 mL) were added K2CO3 (1.82 g, 13.17 mmol) and H2O2 (4 mL, 30%), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-amino-3-[1-[[tert- butyl(dimethyl)-silyl]oxymethyl]propylamino]-4,5-dimethoxy-benzamide (A371, 700 mg, 1.76 mmol, 67% yield) as a solid. LCMS (ES, m/z): 398 [M+H]+. Example 172: Synthesis of B2 Synthesis of B1 To a stirred solutio , , , . , 8.8 mmol) and TEA (2.68 g, 26.5 mmol) in DCM (20 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (SEMCl, 1.76 g, 10.6 mmol) at 0 oC, and the reaction was stirred for 2 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyl-trimethyl-silane (B1, 3.1 g, 8.68 mmol, 98% yield) as a solid. LCMS (ES, m/z): 356 [M+H]+. Synthesis of B2 705 Attorney Docket No.: R2103-7054WO To a stirred ]ethyl-trimethyl-silane (B1, 3.1 g, 8.7 mmol) and (3,5-difluorophenyl)boronic acid (1.64 g, 10.4 mmol) in dioxane (30 mL), H2O (3 mL) was added Pd(dppf)Cl2 (636 mg, 869.2 μmol) and K3PO4 (5.53 g, 26.0 mmol) under nitrogen atmosphere, and the reaction was stirred for 3 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 8, Gradient 35) to afford 2-[[5-bromo-3-(3,5-difluorophenyl)-1,2,4- triazol-1-yl]methoxy]-ethyl-trimethyl-silane (B2, 2.1 g, 5.4 mmol, 62% yield) as a solid. LCMS (ES, m/z): 390 [M+H]+. Example 173: Synthesis of B6 Synthesis of B5 To a so , y g, . ,5-difluorophenyl)- boronic acid (896 mg, 5.7 mmol) in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl2 (5.19 g, 7.1 mmol) and K3PO4 (1.51 g, 7.1 mmol), and the reaction was stirred for 8 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography 706 Attorney Docket No.: R2103-7054WO (Condition 5, Gradient 15) to afford 5-bromo-2-(3,5-difluorophenyl)-3-nitro-pyridine (B5, 1.4 g, 4.44 mmol, 63% yield) as a solid. LCMS (ES, m/z): 315 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 9.14 (d, J = 2.1 Hz, 1H), 8.90 (d, J = 2.1 Hz, 1H), 7.45 (tt, J = 9.4, 2.4 Hz, 1H), 7.31 (dt, J = 6.5, 2.1 Hz, 2H). Synthesis of B6 To a so 1.4 g, 4.44 mmol) in DCE (30 mL) was added DPPE (2.7 g, 6.78 mmol), and the reaction was stirred for 16 h at 160 °C under sealtube. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 3-bromo-6,8-difluoro-5H-pyrido[3,2-b]indole (B6, 650 mg, 2.3 mmol, 52% yield) as a solid. LCMS (ES, m/z): 283 [M+H]+. Example 174: Synthesis of B11 Synthesis of B8 To a solutio n o - romo- - m azo e ( g, . mmo ) n oxane (30 mL) and H2O (3 mL) was added (3,5-difluorophenyl)boronic acid (10 g, 63.3 mmol), K2CO3 (7 g, 50.7 mmol) and Pd(dppf)Cl2 (1.5 g, 2.05 mmol), and the reaction was stirred for 16 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (100 707 Attorney Docket No.: R2103-7054WO mL), and extracted with DCM/MeOH (3 x 300 mL). The combined organic layers were washed with water (2 x 50 mL), brine (1 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% THF in PE) to afford 2-(3,5-difluorophenyl)-1H-imidazole (B8, 2 g, 11.1 mmol, 54% yield) as an oil. LCMS (ES, m/z): 181 [M+H]+. Synthesis of B9 To a stirred mi 1.8 g, 9.99 mmol) in THF (20 mL) was added NIS (6.8 g, 30.2 mmol), and the reaction was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (18% EtOAc in PE) to afford 2-(3,5- difluorophenyl)-4,5-diiodo-1H-imidazole (B9, 1.6 g, 3.7 mmol, 37% yield) as a solid. LCMS (ES, m/z): 432 [M+H]+. Synthesis of B10 To a stirre , p y , azole (B9, 1.6 g, 3.7 mmol) in EtOH (6 mL) and H2O (14 mL) was added Na2SO3 (4.7 g, 37.3 mmol), and the reaction was stirred for 16 h at 80 °C. The mixture was allowed to cool down to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography 708 Attorney Docket No.: R2103-7054WO (18% EtOAc in PE) to afford 2-(3,5-difluorophenyl)-4-iodo-1H-imidazole (B10, 700 mg, 2.29 mmol, 62% yield) as a solid. LCMS (ES, m/z): 307 [M+H]+. Synthesis of B11 To a stirr (B10, 500 mg, 1.63 mmol) in THF (5 mL) was added NaH (47 mg, 1.96 mmol) in batches at 0°C, and the reaction was stirred for 1 h at room temperature. To the above mixture was added (2-(chloromethoxy)ethyl)- trimethylsilane (357 mg, 2.14 mmol) at 0°C, and the reaction was allowed to warm to room temperature and stirred another 2 h. The reaction was quenched by the addition of water (10 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The residue was purified by silica gel column chromatography (18% EtOAc in PE) to afford 2-[[2-(3,5-difluorophenyl)-4-iodo- imidazol-1-yl]methoxy]ethyl-trimethyl-silane (B11, 400 mg, 916.8 μmol, 56% yield) as a solid. LCMS (ES, m/z): 437 [M+H]+. Example 175: Synthesis of B23 Synthesis of B21 To a st , , . d methyl 4-chloro- 3-oxo-butanoate (12.3 g, 81.9 mmol, 9.44 mL) in EtOH (100 mL), and the reaction was stirred for 48 h at 70°C. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 52) to afford methyl 2-(6,7- dimethylimidazo[1,2-a]pyridin-2-yl)acetate (B21, 1.5 g, 6.87 mmol, 17% yield) as a solid. LCMS (ES, m/z): 233 [M+H]+. 709 Attorney Docket No.: R2103-7054WO Synthesis of B22 To a etate (B21, 500 mg, 2.15 mmol) in DMF (5 mL) were added t-BuOK (724 mg, 6.46 mmol) and 2-iodopropane (731 mg, 4.31 mmol), and the reaction was stirred for 4 h at room temperature. The residue was purified by reversed-phase flash chromatography (Condition 2, Gradient 53) to afford ethyl 2-(6,7- dimethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-butanoate (B22, 130 mg, 473.8 μmol, 22% yield) as an oil. LCMS (ES, m/z): 275 [M+H]+. Synthesis of B23 To din-2-yl)-3-methyl- butanoate (B22, 220 mg, 801.9 μmol) in MeOH (2 mL) and THF (2 mL) was added LiOH (96.0 mg, 4.01 mmol) in H2O (2 mL), and the reaction was stirred for 16 h at room temperature. The mixture was acidified to pH 5 with 2N HCl. The residue was purified by reversed-phase flash chromatography (Condition 5, Gradient 16) to afford 2-(6,7-dimethylimidazo[1,2-a]pyridin-2-yl)- 3-methyl-butanoic acid (B23, 110 mg, 446.6 μmol, 56% yield) as an oil. LCMS (ES, m/z): 247 [M+H]+. An analogous method was followed to obtain the following compounds. Compound Starting Characterization 710 Attorney Docket No.: R2103-7054WO Modification: Step 2 was ran using tert-butyl-(2- iodoethoxy)-dimethyl-silane at room temperature for 16 m rt- .6 - a p e : y es s o Synthesis of B26 To a stirred mixture of 3-chloro-4-methyl-pyridazine (8 g, 62.2 mmol) and 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (11.7 g, 93.3 mmol) in dioxane (180 mL) and H2O (20 mL) were added K3PO4 (39.6 g, 186.7 mmol) and Pd(dppf)Cl2 (4.6 g, 6.2 mmol), and the reaction was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (5% MeOH in DCM) to afford 3,4-dimethylpyridazine (B26, 2.5 g, 23.1 mmol, 37% yield) as a solid. LCMS (ES, m/z): 109 [M+H]+. Synthesis of B27 To a stirre m xture o , - met y pyr az ne ( , g, . mmo ) in DCM (4 mL) was added amino 2,4,6-trimethylbenzenesulfonate (8.96 g, 41.6 mmol), and the reaction was stirred for 711 Attorney Docket No.: R2103-7054WO 6 h at room temperature. The mixture was concentrated under reduced pressure and triturated with MTBE to give 1-amino-3,4-dimethylpyridazin-1-ium 2,4,6-trimethylbenzenesulfonate (B27, 3 g, 9.28 mmol, 33% yield) as a solid. LCMS (ES, m/z): 124 [M+H]+. Synthesis of B28 .2 mmol) and dimethyl 3-oxopentanedioate (6.31 g, 36.2 mmol, 5.3 mL) in 2,2,2-Trifluoroethanol (60 mL) was added Na2CO3 (7.68 g, 72.5 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 28) to afford methyl 6-(2-methoxy-2-oxo-ethyl)-2,3- dimethyl-pyrrolo[1,2-b]pyridazine-5-carboxylate (B28, 0.4 g, 1.45 mmol, 6% yield) as a solid. LCMS (ES, m/z): 278 [M+H]+. Synthesis of B29 To a st , ethyl-pyrazolo[1,5- b]pyridazine-3-carboxylate (B28, 0.4 g, 1.44 mmol) in THF (4 mL) and H2O (4 mL) was added NaOH (288 mg, 7.21 mmol), and the reaction was stirred for 16 h at room temperature. The mixture residue was acidified to pH 5 with 1 N HCl (aq.) The solid was collected by filtration and washed with water (20 mL). The solid was dried to afford 2-(carboxymethyl)-5,6-dimethyl- pyrazolo[1,5-b]pyridazine-3-carboxylic acid (B29, 0.23 g, 922.9 μmol, 64% yield) as a solid. LCMS (ES, m/z): 250 [M+H]+. 712 Attorney Docket No.: R2103-7054WO Synthesis of B30 To a solu dazine-3-carboxylic acid (B29, 0.23 g, 922.9 μmol) in H2O (5 mL) was added phosphoric acid (904 mg, 9.23 mmol), and the reaction was stirred for 16 h at 80 °C. The mixture was allowed to cool down to room temperature and purified by reversed-phase flash chromatography (Condition 5, Gradient 17) to afford 2-(5,6-dimethylpyrazolo[1,5-b]pyridazin-2-yl)acetic acid (B30, 0.13 g, 633.5 μmol, 69% yield) as a solid. LCMS (ES, m/z): 206 [M+H]+. Example 177: Synthesis of B34 Synthesis of B31 A stirred (11.5 g, 50.6 mmol) in DMF (220 mL) and H2O (30 mL) was stirred for 15 h at room temperature and then warm to 100°C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (300 mL), and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford methyl 5-(difluoromethoxy)-4-methoxy-2-nitro-benzoate (B31, 5 g, 18.0 mmol, 36% yield) as a solid. LCMS (ES, m/z): 278 [M+H]+. Synthesis of B32 713 Attorney Docket No.: R2103-7054WO To a stirre o-benzoate (B31, 400 mg, 1.44 mmol) and NH4Cl (772 mg, 14.4 mmol) in MeOH (8 mL) and H2O (2 mL) were added Fe (806 mg, 14.4 mmol), and the reaction was stirred for 16 h at 90°C under nitrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (67% EtOAc in PE) to afford methyl 2-amino-5-(difluoromethoxy)-4-methoxy-benzoate (B32, 350 mg, 1.42 mmol, 98% yield) as a solid. LCMS (ES, m/z): 248 [M+H]+. Synthesis of B33 To a stirred ethoxy-benzoate (B32, 320 mg, 1.29 mmol) in THF (3 mL) and MeOH (3 mL) and H2O (3 mL) was added LiOH (155 mg, 6.47 mmol), and the reaction was stirred for 16 h at room temperature. The resulting mixture was neutralized to pH 6 with 1 N of HCl (aq.). The solid was collected by filtration and washed with water (20 mL). The solid was dried to afford 2-amino-5-(difluoromethoxy)-4-methoxy- benzoic acid (B33, 300 mg, 1.29 mmol, 99% yield) as a solid. LCMS (ES, m/z): 234 [M+H]+. Synthesis of B34 Attorney Docket No.: R2103-7054WO To a stirred mixture of 2-amino-5-(difluoromethoxy)-4-methoxy-benzoic acid (B33, 290 mg, 1.24 mmol) and NH4Cl (333 mg, 6.22 mmol) in DMF (6 mL) was added DIEA (804 mg, 6.22 mmol, 1.08 mL) and HATU (1.42 g, 3.73 mmol), and the reaction was stirred for 24 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 51) to afford 2-amino-5- (difluoromethoxy)-4-methoxy-benzamide (B34, 260 mg, 1.12 mmol, 90% yield) as a solid. LCMS (ES, m/z): 233 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Characterization Material 2 sh 2- 2, S, Example 178: Synthesis of B38 Synthesis of B36 To a stirred - py - - . g, . ol) in pyridine (12 mL) was added TsCl (583 mg, 8.3 mmol), and the reaction was stirred for 16 h at 90°C. The mixture was allowed to cool down to room temperature and diluted with water (30 mL). The solid was collected by filtration and washed with water (30 mL). The solid was dried to afford N-(5- 715 Attorney Docket No.: R2103-7054WO bromopyrimidin-2-yl)-4-methyl-benzenesulfonamide (B36, 1 g, 3.05 mmol, 44% yield) as a solid. LCMS (ES, m/z): 328 [M+H]+. Synthesis of B37 To a stirred m zenesulfonamide (B36, 1 g, 3.05 mmol) and 3-bromobutan-2-one (B36, 690 mg, 4.57 mmol) in DMF (20 mL) was added DIEA (1.1 g, 9.14 mmol, 1.59 mL), and the reaction was stirred for 16 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc) to afford (NZ)-N-[5-bromo-1-(1-methyl-2-oxo- propyl)pyrimidin-2-ylidene]-4-methyl-benzenesulfonamide (B37, 700 mg, 1.76 mmol, 58% yield) as a solid. LCMS (ES, m/z): 398 [M+H]+. Synthesis of B38 To a solut y y pyrimidin-2-ylidene]-4- methyl-benzenesulfonamide (B37, 700 mg, 1.76 mmol) in THF (10 mL) was added TFAA (738 mg, 3.52 mmol), and the reaction was stirred for 16 h at 60°C. The resulting mixture was concentrated under reduced pressure and adjusted to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica 716 Attorney Docket No.: R2103-7054WO gel column chromatography (75% EtOAc in PE) to afford 6-bromo-2,3-dimethyl-imidazo[1,2- a]pyrimidine (B38, 300 mg, 1.33 mmol, 76% yield) as a solid. LCMS (ES, m/z): 226 [M+H]+. Example 179: Synthesis of B40 Synthesis of B39 To a solutio g, 18.9 mmol) in DMF (40 mL) was added NIS (4.6 g, 20.8 mmol), and the reaction was stirred for 6 h at room temperature. The resulting mixture was diluted with water (100 mL). The solid was collected by filtration and washed with water (50 mL). The solid was dried to afford 6-bromo-3-iodo-2-methyl- pyrazolo[1,5-a]pyrimidine (B39, 2.5 g, 7.40 mmol, 39% yield) as a solid. LCMS (ES, m/z): 338 [M+H]+. Synthesis of B40 To a st , dine (B39, 1.5 g, 4.44 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (835 mg, 6.7 mmol) in dioxane (10 mL) were added K3PO4 (2.8 g, 13.32 mmol), Pd(dppf)Cl2 (324 mg, 443.9 μmol) and H2O (1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (75% EtOAc in PE) to afford 6-bromo-2,3-dimethyl-pyrazolo[1,5-a]pyrimidine (B40, 250 mg, 1.11 mmol, 25% yield) as a solid. LCMS (ES, m/z): 226 [M+H]+. An analogous method was followed to obtain the following compound. 717 Attorney Docket No.: R2103-7054WO Compound Starting Characterization Material h. n o- % y Synthesis of B55 To a s 0 mL) was added amino 2,4,6-trimethylbenzenesulfonate (3.52 g, 16.4 mmol) at 0 oC, and the reaction was stirred for 2 h at 0 oC. The resulting mixture was concentrated under reduced pressure and purified by trituration with diethyl ether (50 mL) to afford 1,2-diamino-4,5-dimethylpyridin-1-ium 2,4,6- trimethylbenzenesulfonate (B55, 2.4 g, 7.11 mmol, 44% yield) as a solid. LCMS (ES, m/z): 138 [M+H]+. Synthesis of B56 o a sou on o ,- amno-,- me ypyr n--um ,, -rme y enzenesulfonate (B55, 8.1 g, 24.0 mmol) and diethyl 3-oxopentanedioate (2.4 g, 11.9 mmol) in EtOH (18 mL) was added NaOH (480 mg, 12.0 mmol) under nitrogen atmosphere, and the reaction was stirred for 5 718 Attorney Docket No.: R2103-7054WO h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with Et2O (3 x 100 mL). The combined organic layers were washed with water (1 x 100 mL) and brine (1 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford ethyl 2-(6,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetate (B56, 800 mg, 3.43 mmol, 29% yield) as a solid. LCMS (ES, m/z): 234 [M+H]+. Synthesis of B57 To a idin-2-yl)acetate (B56, 500 mg, 2.28 mmol) in MeOH (4 mL), THF (4 mL) and H2O (2 mL) was added LiOH (274 mg, 11.44 mmol), and the reaction was stirred for 5 h at room temperature. The resulting mixture was concentrated under reduced pressure and adjusted to pH6 with saturated 10% citric acid. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1 x 20 mL) and brine (1 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2- (6,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetic acid (B57, 100 mg, 487.3 μmol, 21% yield) as a solid. LCMS (ES, m/z): 206 [M+H]+. Example 181: Synthesis of B58 To a mixture o tert- uty ( , )- , - met y - -oxo-p per ne-1-carboxylate (300 mg, 1.32 mmol) in MeOH (1 mL) was NaBH4 (160 mg, 4.23 mmol), and the reaction was stirred for 4 h at room temperature. The reaction was quenched with water (10 mL) and extracted with 719 Attorney Docket No.: R2103-7054WO EtOAc (3 x 20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl (2R,6S)-4- hydroxy-2,6-dimethyl-piperidine-1-carboxylate (B58, 200 mg, 872.2 μmol) as an oil. Example 182: Synthesis of B64 Synthesis of B63 A soluti .8 g, 22.5 mmol) and phenylmethanamine (3.14 g, 29.3 mmol) in MeOH (48 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. To the mixture was added NaBH(AcO)3 (9.54 g, 45.0 mmol), and the reaction was stirred at room temperature for 2 h. The mixture was purified by Prep- HPLC (Condition 18, Gradient 1) to afford tert-butyl N-[(1R,3R)-3-(benzylamino)-1-methyl- cyclopentyl]carbamate (B63, 2.1 g, 6.9 mmol, 31% yield) as a solid. LCMS (ES, m/z): 305 [M+H]+. Synthesis of B64 To a sol y , y y yclopentyl]carbamate (B63, 0.5 g, 1.64 mmol) in MeOH (10 mL) was added Pd/C (0.5 g, 4.70 mmol) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The filter cake was washed with CH3OH (2 x 20 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl N-[(1R,3R)-3-amino-1-methyl-cyclopentyl]carbamate (B64, 0.35 g, 1.63 mmol, 99% yield) as an oil. LCMS (ES, m/z): 215 [M+H]+. 720 Attorney Docket No.: R2103-7054WO An analogous method was followed to obtain the following compound. Compound Starting Characterization Material ). re l- % m n 1- g, Example 183: Synthesis of B71 To a solution of 2-methylsulfonylethanol (7.0 g, 56.7 mmol) in DMF (73.5 mL) was added NaH (60% dispersion in oil) (3.8 g, 94.4 mmol), and the reaction was stirred for 30 min at room temperature. Methyl 4-bromo-5-fluoro-2-nitro-benzoate (10.5 g, 37.8 mmol) was added to the reaction and the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched by NH4Cl (aq.) and extracted with EtOAc (3 x 100 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (80% EtOAc in PE) to afford methyl 4-bromo-5-hydroxy-2-nitro-benzoate (B71, 7.3 g, 26.5 mmol, 70% yield) as a solid. LCMS (ES, m/z): 276 [M+H]+. Example 184: Synthesis of B76 Synthesis of B75 721 Attorney Docket No.: R2103-7054WO To a stirred mmol) in THF (17 mL) was added 6-bromo-3-methyl-1H-pyrrolo[3,2-b]pyridine (1.7 g, 8.1 mmol) in THF (5 mL) dropwise at 0°C, and the reaction was stirred for 0.5 h at 0°C.2,4,6-trimethylbenzenesulfonyl chloride (2.3 g, 10.5 mmol) in THF (5 mL) was added to the reaction at 0°C, and the reaction was stirred for 0.5 h at 25 °C. The mixture was quenched with NH4Cl (aq.) (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (33% EtOAc in PE) to afford 6- bromo-3-methyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2-b]pyridine (B75, 2.4 g, 6.10 mmol, 76% yield) as a solid. LCMS (ES, m/z): 395 [M+H]+. Synthesis of B76 To a s , , fonyl- pyrrolo[3,2-b]pyridine (B75, 2.4 g, 6.1 mmol) in THF (24 mL) was added LDA (2 M, 3.1 mL) dropwise at -80~-60°C, and the reaction was stirred for 0.5 h at -80 ~ -60℃ under a nitrogen atmosphere. The compound of iodomethane (866 mg, 6.1 mmol) was added at -80~-60℃. The resulting mixture was allowed to return to room temperature and stirred for 0.5 h at room temperature. The mixture was quenched with saturated NH4Cl(aq.) (30 mL) and extracted with 722 Attorney Docket No.: R2103-7054WO EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford 6-bromo-2,3-dimethyl-1-(2,4,6- trimethylphenyl)-sulfonyl-pyrrolo[3,2-b]pyridine (B76, 1.1 g, 2.70 mmol, 44% yield) as a solid. LCMS (ES, m/z): 409 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Characterization Material .0 re er n 1- a Example 185: Synthesis of B80 Synthesis of B78 A mixture py y y g, . butan-2-one (1.53 g, 21.3 mmol, 1.91 mL) in EtOH (40 mL) was stirred for 2 h at 80°C. The reaction was allowed to cool down to room temperature, and the resulting mixture was used directly in the next step. Synthesis of B79 723 Attorney Docket No.: R2103-7054WO A mixture o -amine (4.9 g, 20.2 mmol) and PPA (40 g) in EtOH (40 mL) was stirred for 2 h at 160°C. The reaction was allowed to cool down to room temperature and concentrated under reduced pressure. The reaction was quenched by the addition of water (80 mL) at room temperature, and the resulting mixture was cooled to 0°C. The mixture was neutralized to pH 7 with 2 M NaOH (aq). The precipitated solids were collected by filtration and washed with ice water (3 x 20 mL) and (18% MeOH in H2O) (3 x 20 mL). The residue was purified by silica gel column chromatography (5% EtOAc in PE) to afford 5-bromo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (B79, 3 g, 13.3 mmol, 66% yield) as a solid. LCMS (ES, m/z): 266 [M+CH3CN]+. Synthesis of B80 To a stirre , , idine (500 mg, 2.22 mmol) in DMF (5 mL) were added NaH (60% dispersion in oil) (53 mg, 2.22 mmol) and MeI (364 mg, 2.22 mmol) dropwise at 0°C under nitrogen atmosphere, and the reaction was stirred at room temperature for 2 h. The reaction was quenched by the addition of water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (2 x 3 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in PE) to afford 5- bromo-1,2,3-trimethyl-pyrrolo[2,3-b]pyridine (B80, 400 mg, 1.67 mmol, 75% yield) as a solid. LCMS (ES, m/z): 239 [M+H]+. Example 186: Synthesis of B92 Synthesis of B85 724 Attorney Docket No.: R2103-7054WO To a stirred m , 106.9 mmol) in DMF (400 mL) were added NIS (24.06 g, 106.9 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (800 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (3 x 400 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 6-bromo-2-iodo-5-methyl-pyridin-3-amine (B85, 30 g, 95.9 mmol, 90% yield) as a solid. LCMS (ES, m/z): 313 [M+H]+. Synthesis of B86 To a st , 30 g, 95.9 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (19 g, 95.9 mmol) in THF (260 mL) were added NaOH (11.5 g, 287.6 mmol) and Pd(PPh3)4 (2.22 g, 1.92 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 600 mL). The combined organic layers were washed with brine (1 x 600 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (67% EtOAc in PE) to afford 6-bromo-2-[(E)-2- ethoxyvinyl]-5-methyl-pyridin-3-amine (B86, 15.2 g, 59.1 mmol, 62% yield) as a solid. LCMS (ES, m/z): 257 [M+H]+. 725 Attorney Docket No.: R2103-7054WO Synthesis of B87 To a stirr din-3-amine (B86, 15 g, 58.3 mmol) in MeOH (70 mL) was added conc. HCl (18 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 85°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The mixture was basified to pH 7 with NaOH (aq, 2M) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 5-bromo-6-methyl- 1H-pyrrolo[3,2-b]pyridine (B87, 10 g, 47.4 mmol, 81% yield) as a solid. LCMS (ES, m/z): 211 [M+H]+. Synthesis of B88 To a stirred mix y y , yridine (B87, 10 g, 47.4 mmol) and DMAP (1.74 g, 14.21 mmol) in DCM (200 mL) were added DIEA (18.37 g, 142.14 mmol, 24.8 mL) at 0°C under nitrogen atmosphere, and the resulting mixture was stirred for 5 h at room temperature under nitrogen atmosphere. The mixture was diluted with water (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (80% EtOAc in PE) to 726 Attorney Docket No.: R2103-7054WO afford 5-bromo-6-methyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2-b]pyridine (B88, 11 g, 27.97 mmol, 59% yield) as a solid. LCMS (ES, m/z): 393 [M+H]+. Synthesis of B89 To a stirr l)sulfonyl-pyrrolo[3,2- b]pyridine (B88, 11 g, 27.97 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (14.04 g, 111.9 mmol) in H2O (20 mL) and dioxane (220 mL) were added K3PO4 (17.8 g, 83.9 mmol) and Pd(dppf)Cl2.CH2Cl2 (2.28 g, 2.80 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (75% EtOAc in PE) to afford 5,6-dimethyl-1- (2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2-b]pyridine (B89, 7 g, 21.3 mmol, 76% yield) as a solid. LCMS (ES, m/z): 329 [M+H]+. Synthesis of B90 To a stirred mix ture o , - met y - -( , , -trmet y p eny )sulfonyl-pyrrolo[3,2- b]pyridine (B89, 3 g, 9.13 mmol) in THF (20 mL) was added LDA (1.0 M in THF) (13.7 mL, 13.7 mmol) and stirred for 30 min at -78 °C under nitrogen atmosphere. To the resulting 727 Attorney Docket No.: R2103-7054WO mixture was added I2 (2.55 g, 10.05 mmol) at -78 ℃, and the reaction was stirred for 2 h at - 78°C under nitrogen atmosphere. The resulting mixture was diluted with sat. NH4Cl (aq.) (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford 2-iodo-5,6-dimethyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2-b]pyridine (B90, 1.8 g, 3.96 mmol, 43% yield) as a solid. LCMS (ES, m/z): 455 [M+H]+. Synthesis of B91 To a st 1.94 mL) and 2,2’- bipyridine (206 mg, 1.32 mmol) in DMAc (20 mL) were added NiCl2 (570 mg, 4.4 mmol) under nitrogen atmosphere, and the reaction was stirred for 4 h at 60°C under nitrogen atmosphere.2- iodo-5,6-dimethyl-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrolo[3,2-b]pyridine (B90, 2 g, 4.4 mmol) and Zn (858 mg, 13.2 mmol) were then added and the resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (50% EtOAc in PE) to afford tert-butyl 2-[5,6-dimethyl-1-(2,4,6- trimethylphenyl)sulfonyl-pyrrolo[3,2-b]pyridin-2-yl]acetate (B91, 900 mg, 2.03 mmol, 46% yield) as a solid. LCMS (ES, m/z): 443 [M+H]+. Synthesis of B92 728 Attorney Docket No.: R2103-7054WO To a st yl)sulfonyl- pyrrolo[3,2-b]pyridin-2-yl]acetate (B91, 900 mg, 2.03 mmol) in DCM (20 mL) was added 4 M HCl (gas) in 1,4-dioxane (10 mL), and the reaction was stirred for 2 h at room temperature. The mixture residue was concentrated under reduced pressure and purified by reversed-phase flash chromatography (Condition 1, Gradient 7) to afford 2-[5,6-dimethyl-1-(2,4,6-trimethylphenyl)- sulfonyl-pyrrolo[3,2-b]pyridin-2-yl]acetic acid (B92, 470 mg, 1.22 mmol, 60% yield) as a solid. LCMS (ES, m/z): 387 [M+H]+. Example 187: Synthesis of C1 To a stirred mixture of 3-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-6,7-dimethoxy-2H- isoquinolin-1-one (Compound 456, 500 mg, 1.22 mmol) in DMF (10 mL) was added NIS (360 mg, 1.60 mmol). The reaction was stirred for 5 h at 25 °C. The resulting mixture was diluted with water (10 mL). The solid was collected by filtration and washed with water (10 mL) to afford 3-[[6-(3,5-difluorophenyl)-3-pyridyl]methyl]-4-iodo-6,7-dimethoxy-2H-isoquinolin-1- one (C1, 350 mg, 655.1 μmol, 53.51% yield) as a solid. LCMS (ES, m/z): 535 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Material Characterization 729 Attorney Docket No.: R2103-7054WO Modifications: The reaction was run in HOAc solvent for 16 h. n o- g, S, c n yl % ed to as c S Example 188: Synthesis of C4 A mix ue o e y - -oopy o --y aceae g, . ol), triphenylbismuthane (968 mg, 2.20 mmol), TEA (222 mg, 2.20 mmol,) and copper diacetate hydrate (439 mg, 2.20 mmol) in DCM (2.3 mL) was stirred for 16 h at room temperature. The filtrate was concentrated under reduced pressure and purified by silica gel column 730 Attorney Docket No.: R2103-7054WO chromatography (PE/EA, 1:1) to afford methyl 2-(5-oxo-1-phenyl-pyrrolidin-3-yl)acetate (C4, 0.25 g, 1.07 mmol, 73%) as a solid. LCMS (ES, m/z):234 [M+H]+. Example 189: Synthesis of C8 Synthesis of C7 To O (20 mL) were added diethyl malonate (3.5 g, 21.7 mmol) and K2CO3 (3 g, 21.7 mmol) at room temperature. The resulting mixture was stirred for 16 h at 80 °C. The mixture was cooled to room temperature and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 10:1) to afford diethyl 2-(5-iodopyrazin-2-yl)malonate (C7, 2.3 g, 6.31 mmol, 90% yield) as a solid. LCMS (ES, m/z): 365 [M+H]+. Synthesis of C8 To y - - py - -y , . g, . mol) in DMSO (45 mL) were added LiCl ( 1.2 g, 15.77 mmol) and H2O (0.11 g, 6.31 mmol) at room temperature. The resulting mixture was stirred for 16 h at 100 °C. The reaction mixture was quenched by NaHCO3 (aq.) (30 mL) and extracted with EA (3 x 60 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and 731 Attorney Docket No.: R2103-7054WO concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 5:1) to afford ethyl 2-(5-iodopyrazin-2-yl)acetate (C8, 1.5 g, 5.3 mmol, 82% yield) as a solid. LCMS (ES, m/z): 293 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Characterization Material O yl n 2- % Example 190: Synthesis of C91 , n- 4-one (200 mg, 523.2 μmol) and methyl 6-aminopyridine-2-carboxylate (159 mg, 1.05 mmol) in dioxane (2 mL) were added tBuBrettPhos Pd G3 (44 mg, 52.3 μmol) and Cs2CO3 (511 mg, 1.57 mmol) in portions at room temperature. The resulting mixture was stirred at 100 °C for additional 16 h under nitrogen atmosphere and then diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 0:1) to afford methyl 6-[[4-[(6,7-dimethoxy-4-oxo-3H- quinazolin-2-yl) methyl] thiazol-2-yl] amino] pyridine-2-carboxylate (C91, 150 mg, 330.8 μmol, 63%) as a solid. LCMS (ES, m/z): 454 [M+H]+. Example 191: Synthesis of C11 732 Attorney Docket No.: R2103-7054WO To the so -carboxylate (1 g, 4.40 mmol) and NH4OAc (1.02 g, 13.20 mmol) in MeOH (10 mL) was added NaBH3CN (553 mg, 8.80 mmol) at 0 °C. The solution was stirred at room temperature for 16 h. The solution was purified by reversed-phase flash chromatography (Condition 2, Gradient 2) to afford tert-butyl (2R,6S)-4-amino-2,6-dimethyl-piperidine-1-carboxylate (C11, 0.15 g, 656.9 μmol, 15% yield) as a solid. LCMS (ES, m/z): 129 [M-Boc]+. Example 192: Synthesis of C13 -4- one (C13, 200 mg, 469.2 μmol) and tributyl(1-ethoxyvinyl)stannane (170 mg, 470.7 μmol) in dioxane (2 mL) was added Pd(PPh3)2Cl2 (33 mg, 47.0 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere and then quenched at room temperature with addition of HCl in water (2 M, 1 mL) and stirring for 3 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / DCM, 10:1) to afford 2-[(6-acetyl-3- quinolyl)methyl]-6,7-dimethoxy-3H-quinazolin-4-one (C14, 120 mg, 308.2 μmol, 66% yield) as a solid. LCMS (ES, m/z): 390 [M+H]+. Example 193: Synthesis of C15 733 Attorney Docket No.: R2103-7054WO To a stirred solution of tert-butyl 2-(8-bromo-4-methoxy-3-quinolyl)acetate (A291, 300 mg, 851.7 μmol) in DCM (3 mL) was added 4M HCl in dioxane (3 mL). The resulting mixture was stirred for 6 h at room temperature and then concentrated under reduced pressure to afford 2- (8-bromo-4-methoxy-3-quinolyl)acetic acid (C15, 170 mg, 574.1 μmol, 67% yield) as a solid. LCMS (ES, m/z): 296 [M-H]+. An analogous method was followed to obtain the following compound. Compound Starting Material Characterization The reaction solution was concentrated under 5- 0 - Example 194: Synthesis of C21 To a stirred solution o - e y p pe a e- -su o y c oride (300 mg, 1.51 mmol) in dioxane (2 mL) were added 0.5 M NH3 in dioxane (6 mL) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 3 h. The reaction solution was concentrated under reduced pressure. The solid was purified by reverse-phase flash 734 Attorney Docket No.: R2103-7054WO chromatography (Condition 2, Gradient 56) to afford 4-methylpiperazine-1-sulfonamide (C21, 90 mg, 502.1 μmol, 33% yield) as a solid. LCMS (ES, m/z): 180 [M+H]+. Example 195: Synthesis of C23 Synthesis of C22 O H N r To a stirred mixture of CaO (4.96 g, 88.49 mmol, 1.50 mL) in H2O (20 mL) was added 7- bromoindoline-2,3-dione (10 g, 44.24 mmol) at room temperature. The resulting mixture was stirred for 45 min at 80 °C. The mixture was allowed to cool down to room temperature. To the above mixture was added N-acetonylacetamide (5.60 g, 48.67 mmol) at room temperature. The resulting mixture was stirred for additional 16 h at 80 °C and then cooled down to room temperature. The resulting mixture was diluted with 2 M HCl (1000 mL), stirred for 16 h at 100 °C, and cooled down to room temperature. The mixture was basified to pH 8 with 2 M NaOH and extracted with EA (2 x 1000 mL), washed with brine (1 x 1000 mL), and dried over anhydrous Na2SO4. The combined organic extracts were filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA, 2:1) to afford 8-bromo-2- methyl-quinolin-3-amine (C22, 7 g, 29.52 mmol, 67% yield) as a solid. LCMS (ES, m/z): 237 [M+H]+. Synthesis of C23 Attorney Docket No.: R2103-7054WO To a stirred mixture of 8-bromo-2-methyl-quinolin-3-amine (C22, 5.5 g, 23.20 mmol) and CuI (6.63 g, 34.80 mmol) in CH3CN (79 mL) were added t-BuONO (3.6 g, 34.91 mmol, 4.15 mL) at 0 °C. The resulting mixture was stirred for 16 h at 60 °C and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 5:1) to afford 8-bromo-3-iodo-2-methyl-quinoline (3 g, 8.62 mmol, 37% yield) as a solid. LCMS (ES, m/z): 348 [M+H]+. Example 196: Synthesis of C57 To a sti Cl4 (160 mL) were added Br2 (9.90 g, 61.95 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature, and then pyridine (2.03 g, 25.62 mmol) was added dropwise. The resulting mixture was stirred for 24 h at room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA, 3:1) to afford 3-bromoquinoline-6- carbonitrile (C57, 4.3 g, 18.45 mmol, 47% yield) as a solid. LCMS (ES, m/z): 233 [M+H]+. Example 197: Synthesis of C61 Synthesis of C60 To a sti y y y g, . mol) and DIEA (3.5 g, 27.24 mmol) in DMF (40 mL) was added tert-butyl(2-iodoethoxy)dimethylsilane (3.9 g, 13.62 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h, quenched by the addition of water (200 mL), and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / 736 Attorney Docket No.: R2103-7054WO EA, 2:1) to afford benzyl N-[(3R)-1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrrolidin-3- yl]carbamate (C60, 1.8 g, 52% yield) as a solid. LCMS (ES, m/z): 379 [M+H]+. Synthesis of C61 To a yrrolidin-3- yl]carbamate (C60, 1.8 g, 4.755 mmol) in MeOH (40 mL) was added Pd/C (10% in water, 0.6 g) under nitrogen atmosphere in a 100 mL round-bottom flask. The mixture was hydrogenated at room temperature for 6 h under hydrogen (~1 atm), filtered through a Celite pad, and concentrated under reduced pressure to afford (R)-1-(2-((tert- butyldimethylsilyl)oxy)ethyl)pyrrolidin-3-amine (C61, 900 mg, 77% yield) as a solid, which was used in the next step directly without further purification. An analogous method was followed to obtain the following compound. Compound Starting Characterization Material ad )- ), er Example 198: Synthesis of C63 A mixtu re o - romo- -( uoromet y )- -met oxy- enzene ( g, .09 mmol), tert- butyl carbamate (2.97 g, 25.31 mmol), XantPhos Pd G4 (2.03 g, 2.11 mmol) and Cs2CO3 (20.62 g, 63.28 mmol) in 1,4-dioxane (50 mL) were stirred for 4 h at 100 °C under nitrogen 737 Attorney Docket No.: R2103-7054WO atmosphere. The reaction was cooled to room temperature, diluted with water (30 mL), and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA, 1:1) to afford tert-butyl N- [4-(difluoromethyl)-3-methoxy-phenyl]carbamate (C63, 3.10 g, 11.34 mmol, 54% yield) as a solid. LCMS (ES, m/z): 272 [M-H]-. Example 199: Synthesis of C72 Synthesis of C71 A stirr fonyl- pyrrolo[3,2-b]pyridine (B76, 0.5 g, 1.23 mmol) and NaOH (147 mg, 3.68 mmol) in water (0.5 mL) and MeOH (5 mL) was stirred for 16 h at 70 °C . The mixture was concentrated under reduced pressure. The residue was dissolved with DCM (100 mL), dried over anhydrous Na2SO4, filtered, and re-concentrated under reduce pressure to afford 6-bromo-2,3-dimethyl-1H- pyrrolo[3,2-b]pyridine (C71, 250 mg, 1.11 mmol, 90% yield) as a solid. LCMS (ES, m/z): 225 [M+H]+. Synthesis of C72 To a stirred m xture o a ( mg, . mmo , purty) n F (1 mL) was added a solution of 6-bromo-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (C71, 250 mg, 1.11 mmol) in 1 mL THF at 0°C. After stirring for 0.5 h, a solution of iodomethane (205 mg, 1.44 mmol, 89.89 μL) in 738 Attorney Docket No.: R2103-7054WO THF (0.5 mL) was added. The resulting mixture was stirred for 1 h at 25 °C and then quenched with NH4Cl (aq.) (20 mL) and extracted with EA (2 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and purified by silica gel column chromatography (PE/EA, 2:1) to afford 6-bromo-1,2,3-trimethyl-pyrrolo[3,2- b]pyridine (C72, 220 mg, 920.1 μmol, 83% yield) as a solid. LCMS (ES, m/z): 239 [M+H]+. Example 200: Synthesis of C77 To a solutio mol),4-iodo-2-methyl- 1H-imidazole (3 g, 14.42 mmol) in DCE (40 mL) was added Cu(OAc)2 (8.64 g, 43.27 mmol, 4.59 mL) and pyridine (3.42 g, 43.27 mmol, 3.49 mL) in a pressure tank. The mixture was stirred at 60 °C under 10 atm of O2 atmosphere for 16 h and then cooled to room temperature and stirred for another 16 h. The resulting mixture was extracted with EAm washed with water and brine, dried over anhydrous Na2SO4., filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE, 0-50% EA gradient) to afford 1-(3,5-difluorophenyl)-4-iodo-2-methyl-imidazole (C77, 2.5 g, 7.81 mmol, 54% yield) as a solid. LCMS (ES, m/z): 321 [M+H]+. Example 201: Synthesis of C84 T a stirred solution of 3-methylpentane-2,4-dione (5.5 g, 48.19 mmol, 5.61 mL) in EtOH (50 mL) was added guanidine (5.69 g, 96.37 mmol). The resulting mixture was stirred for 24 h 739 Attorney Docket No.: R2103-7054WO at 80 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 4,5,6-trimethylpyrimidin-2- amine (C84, 5.1 g, 37.18 mmol, 77% yield) as a solid. LCMS (ES, m/z): 138 [M+H]+. Example 202: Synthesis of D12 0.6 μL) in DCM (2 mL) was added t-BuOH (17 mg, 236.5 μmol) at 0 °C. The resulting mixture was stirred for 1.5 h at 0 °C.6-Chloro-2-[(6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl]-8- piperazin-1-yl-3H-quinazolin-4-one (C90, 100 mg, 236.5 μmol) and TEA (71 mg, 709.4 μmol, 98.9 μL) were added to the mixture at 0 °C and stirred for 1 h at 0 °C before stirring for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH, 20:1) to afford tert-butyl N-[4-[6-chloro-2- [(6,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-3H-quinazolin-8-yl]piperazin-1- yl]sulfonylcarbamate (D12, 50 mg, 83.0 μmol, 35% yield) as a solid. LCMS (ES, m/z): 602 [M+H]+. Example 203: Synthesis of D20 740 Attorney Docket No.: R2103-7054WO To a solution of 5-bromopyridine-2,3-diamine (9 g, 47.87 mmol) in PEG-400 (6.04 mL) was added butane-2,3-dione (4.12 g, 47.87 mmol, 4.19 mL) at room temperature. The reaction mixture was irradiated with microwave radiation at 120 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 5:1) to afford 7-bromo-2,3-dimethyl-pyrido[2,3-b]pyrazine (D20, 9 g, 37.8 mmol, 79% yield) as a solid. LCMS (ES, m/z): 238 [M+H]+. Example 204: Synthesis of D41 To a s g, 14.15 mmol) in THF (60 mL) was added NaH (60% dispersion in oil) (567 mg, 14.15 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0°C under nitrogen atmosphere. Then SEMCl (2.36 g, 14.15 mmol) was added at 0°C under nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred another 16 h. The reaction was quenched by the addition of water (100 mL) and extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA eluent) to afford 2-[(6-bromo-2-methyl-imidazo[4,5-b]pyridin-3- yl)methoxy]ethyl-trimethyl-silane (D41, 3.5 g, 10.22 mmol, 72% yield) as solid. LCMS (ES, m/z): 342 [M+H]+. An analogous method was followed to obtain the following compound. 741 Attorney Docket No.: R2103-7054WO Compound Starting Characterization Material n 2- - l, +. p y To (10 g, 41.32 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (6.22 g, 49.59 mmol) in dioxane (100 mL) and H2O (20 mL) were added K3PO4 (26.31 g, 123.97 mmol) and Pd(dppf)Cl2 (6.75 g, 8.26 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 80 °C and then allowed to cool down to room temperature. The reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc in PE) to afford 5-methyl-4-(trifluoromethyl)pyrimidin-2-amine (D66, 2.8 g, 15.81 mmol, 38% yield) as a soild. LCMS (ES, m/z): 178 [M+H]+. An analogous method was followed to obtain the following compound. Compound Starting Characterization 742 Attorney Docket No.: R2103-7054WO Modification: The reaction was run with 1.5 equiv. of trioxatriborinane and 0.1 equiv of Pd(dppf)Cl2 at 70 ºC n 4- .5 ): Example 206: Synthesis of D71 To a stirred 0 mg, 2.97 mmol) in THF (5 mL) was added LiAlH4 (2.4 M in THF, 1.86 mL, 4.45 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h and then quenched with Na2SO4•10H2O at 0 °C. The reaction mixture was filtered, concentrated under reduced pressure, purified by reverse-phase column chromatography (Condition 2, Gradient 73) to afford (3,4-dimethyl-1H-pyrazol-5-yl)methanol (D71, 100 mg, 792.7 μmol, 27% yield) as a solid. LCMS (ES, m/z): 127 [M+H]+. Example 207: Synthesis of D97 A mi x ure o -am no- -[ -me y- -p per y oxy]-5-(tr uoromet y) enzonitrile (D96, 450 mg, 1.50 mmol) and Ghaffar-Parkins catalyst (65 mg, 150.4 μmol) in EtOH (6 mL) and H2O (2 mL) was stirred 3 h at 80 °C. The resulting mixture was purified by reversed-phase flash chromatography (Condition 743 Attorney Docket No.: R2103-7054WO 2, Gradient 74) to afford 2-amino-4-[(1-methyl-4-piperidyl)oxy]-5-(trifluoromethyl)benzamide (D97, 300 mg, 945.5 μmol, 63% yield) as a solid. LCMS (ES, m/z): 318 [M+H]+. Example 208: Synthesis of E3 mol) and 1-ethylpiperidin-4-amine (660.4 mg, 5.15 mmol, 448.49 μL) in DMSO (10 mL) were added K2CO3 (1.55 g, 11.20 mmol) at room temperature. The resulting mixture was stirred for 6 h at 80 °C. The resulting mixture was extracted with EA (2 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA, 3:1) to afford methyl 2-amino-5-cyano-4-[(1-ethyl-4-piperidyl)amino]benzoate (E3, 400 mg, 1.32 mmol, 51% yield) as a solid. LCMS (ES, m/z): 302 [M+H]+. Example 209: Synthesis of E14 , quinazolin-4-one (E13, 200 mg, 510.4 μmol) and K2OsO4 (27.26 mg, 102.08 μmol) in THF (1 mL) and H2O (1 mL) was added NaIO4 (327.5 mg, 1.53 mmol), and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water (50 mL), extracted with EA (3 x 50 mL), washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 6-chloro-2-[[6-(3,4-dimethylpyrazol-1-yl)-3-pyridyl]methyl]-4-oxo-3H-quinazoline-7- carbaldehyde (E14, 110 mg, 279.3 μmol, 55% yield) as an oil. LCMS (ES, m/z):394[M+H]+. Example 210: Synthesis of E25 744 Attorney Docket No.: R2103-7054WO Synthesis of E24 A mixture of 3-iodo-6,7-dimethoxy-quinolin-4-ol (E23, 6.00 g, 18.12 mmol) in POCl3 (30.0 mL) was stirred at 110 ℃ for 3 h and then cooled to room temperature and concentrated. The mixture was quenched with saturated aqueous NaHCO3 (300 mL), extracted with DCM (3 x 200 mL), washed with brine (1x100 mL), and dried over anhydrous Na2SO4. The mixture was filtered, concentrated under reduced pressure, and purified by flash chromatography (0-20% EA in hexane) to give 4-chloro-3-iodo-6,7-dimethoxy-quinoline (E24, 4.50 g, 12.87 mmol, 71% yield) as a solid. LCMS (ES, m/z): 349.9 [M+H]+. Synthesis of E25 A solution of 4-chloro-3-iodo-6,7-dimethoxy-quinoline (E24, 2 g, 5.72 mmol) and CsF (1.74 g, 11.44 mmol) in DMF (30 mL) was stirred for 16 h at 120 °C. The mixture was quenched with H2O (100 mL), extracted with DCM (3 x 100 mL), washed with brine (1 x 100 mL), and dried over anhydrous Na2SO4. The mixture was filtered, concentrated under reduced pressure and purified by flash chromatography (0-20% EA in hexane) to afford 4-fluoro-3-iodo-6,7-dimethoxy- quinoline (E25, 0.90 g, 2.70 mmol, 47% yield) as a solid. LCMS (ES, m/z): 334.0 [M+H]+. 745 Attorney Docket No.: R2103-7054WO Example 211: Exemplary assay for measuring effects of compounds on Cyclin K protein abundance Compounds described herein were used to screen for reduction of Cyclin K protein levels. Quantitative protein abundance was determined by measuring the protein levels of HiBiT-tagged protein targets expressed in cell culture via luminescence using the Nano-Glo HiBiT Lytic Detection System (Promega), which uses a split complementation assay format to reconstitute NanoBiT enzyme to generate a luminescent signal. A protein abundance assay was developed such that endogenous protein targets could be modified with the HiBiT peptide tag and their abundance could be assessed after compound treatment. Briefly, A549 cell lines containing a HiBiT- modification were treated with various compounds described herein (e.g., compounds of Formula (I)). After treatment for 24 hours, the protein abundance of a specific target was determined by measuring luminescence. The Promega Nano-Glo HiBiT Lytic Detection System (cat#N3030) was used in conjunction with Corning 384-well TC-treated microplates (cat#3570), Promega Engineered Cells Knock-In Clone, and the A549 HiBiT CCNK off-the-shelf cell line. Cells were maintained in F12/K with 10% FBS. Before the assay, cells were diluted with phenolphthalein-free growth media (F12/K + 10% FBS media) to an appropriate density for plating in a 384-well plate (5000 cells/well). Compound serial dilutions and DMSO controls were prepared on an Echo 550 Liquid Handler (Labcyte) by direct addition to assay plates. Each compound was prepared as a 10-point 3-fold serial dilution in DMSO with the top dose at a final concentration of 10uM in the well. Flanking columns were DMSO only for positive and negative control (PC and NC, respectively). Final DMSO concentration was kept at or below 0.25%. Compounds were added to assay plates followed by addition of cells at the specified density to columns 1-11 and 13-23. To columns 12 and 24, unmodified A549 cells at the previously specified density or phenol-free growth media (F12/K with 10% FBS) were added to serve as an assay baseline and PC. Treated cell plates were placed in an incubator at 37°C with 5% CO2 for 6 hours. After 6 hours, 25uL of Complete HiBiT Lytic reagent was added to each well at room temperature (e.g. one plate requiring 10mL Lytic Buffer, 100uL LgBiT Protein, 200uL Lytic Substrate), shaken 746 Attorney Docket No.: R2103-7054WO for 5 minutes at 600 RPM, then left to sit for 10 minutes for signal to stabilize before reading on a Spark Cyto plate reader (Tecan) with a 500ms measurement time. To determine compound effects on protein abundance of each target in Table 2, the percent response for each respective cell line was calculated at each compound concentration as follows: % response = 100 * (S – PC) / (NC – PC) For the normalized response at each concentration, a four-parameter logistical regression was fit to the data and the response was interpolated at the 50% value to determine a concentration for protein abundance at 50% (DC50) the untreated control. Dmax is defined as the maximal decrease in HiBiT-Cyclin K protein achieved by the compound and is measured for each compound. A summary of these results are illustrated in Table 2, wherein “A” refers to a DC50 of less than 500 nM; “B” refers to a DC50 of between 500 nM and 2 µM; and “C” refers to a DC50 greater than 2 µM Table 2. Modulation of Cyclin K Abundance by Exemplary Compounds Cmpd CCNK1 CCNK1 CCNK1 DC50 Cmpd DC50 Cmpd DC50 747 Attorney Docket No.: R2103-7054WO Cmpd CCNK1 C CCNK1 CCNK1 DC5 mpd Cmpd No 0 No DC50 No DC50 748 Attorney Docket No.: R2103-7054WO Cmpd CCNK1 C CCNK1 CCNK1 DC5 mpd Cmpd No 0 No DC50 No DC50 749 Attorney Docket No.: R2103-7054WO Cmpd CCNK1 C CCNK1 CCNK1 DC5 mpd Cmpd No 0 No DC50 No DC50 750 Attorney Docket No.: R2103-7054WO Cmpd CCNK1 C CCNK1 CCNK1 DC5 mpd Cmpd No 0 No DC50 No DC50 751 Attorney Docket No.: R2103-7054WO Cmpd CCNK1 C CCNK1 CCNK1 DC5 mpd Cmpd No 0 No DC50 No DC50 752 Attorney Docket No.: R2103-7054WO Cmpd CCNK1 C CCNK1 CCNK1 DC50 mpd D Cmpd No No C50 No DC50 Example 212: Exemplary cytotoxicity assay for measuring effects of compounds on cell viability Compounds described herein were used to assess for viability effects across a panel of cell lines. Quantitative cell viability was determined by measuring the free concentration of adenosine triphosphate (ATP) in cell culture solution via luminescence using the CellTiter-Glo assay kit (Promega), which corresponds to the number of living cells at the endpoint of the assay. A viability assay was developed such that the cytotoxicity of compounds could be assessed for both cytocidal (cell-killing, LD50) and cytostatic (inhibition of cellular proliferation, GI50) simultaneously in a single-assay format. Briefly, VCaP cells (ATCC) were treated with various compounds described herein (e.g., compounds of Formula (I)). After treatment for 144 hours, the viability of each sample was determined by measuring luminescence. The Promega CellTiter-Glo 2.0 Cell Viability Assay (cat#G9243) was used in conjunction with Corning 384-well TC-treated microplates (cat#3570). Cells were cultured in DMEM with 10% FBS. Cells were plated in a 384-well plate (2.6k cells/well for VCaP in 50uL media per well) with a media-only column for background control (no cells, positive control, PC). Compound serial dilutions were prepared on an Echo 550 Liquid Handler (Labcyte) by direct addition to assay plates. For adherent cell lines (VCaP), cells were plated at the specified density and incubated at 37°C with 5% CO2 for 24 hours, followed by addition of compound. Each compound was prepared as a 11-point 3-fold serial dilution in DMSO with the top dose at a final concentration of 10uM in the well and the bottom dose as DMSO only negative control (NC). Final DMSO concentration was kept at or below 0.25%. Treated cell plates 753 Attorney Docket No.: R2103-705402 were placed in an incubator at 37°C with 5% CO2 for 144 hours. After 144 hours, 25uL of CellTiter-Glo reagent was added to each well at room temperature, shaken for 5 minutes at 600 RPM, then left to sit for 10 minutes for signal to stabilize before reading on a Spark Cyto plate reader (Tecan) with a 500ms measurement time. In parallel, “time zero” assay plates were made up by plating 6 columns of cells 2.6k cells/well for VCaP in 50uL media per well) in complete media + 0.1% DMSO and 6 columns of 50uL complete media alone + 0.1% DMSO as background controls. For adherent cell lines, “time zero” assay plates were incubated for 24 hours at 37°C with 5% CO2 then luminescence values were determined by adding 25uL of CellTiter-Glo reagent to each well and measuring as previously described. To determine compound effects on cell viability of VCaP cells, the percent growth compared to the “time zero” average (T0) for each respective cell line was calculated at each compound concentration. If luminescence signal was greater than that of the T0 average, signal (S) is normalized as follows: % response = 100 * (S – PC – T0) / (NC – PC – T0) If luminescence signal was less than that of the T0 average, signal is normalized as follows: % response = 100 * (S – PC – T0) / T0 For the normalized response at each concentration, a four-parameter logistical regression was fit to the data and the response was interpolated at the +50% and -50% value to determine a concentration for Growth Inhibition at 50% (GI50) and Lethal Dose for 50% cell death (LD50). A summary of these results is illustrated in Table 3, wherein “A” refers to a GI50 of less than1 µM ; “B” refers to a GI50 of between 1 µM and 3 µM; and “C” refers to a GI50 greater than 3 µM. Table 3: Exemplary cell viability data over a panel of cell lines 754 Attorney Docket No.: R2103-705402 Cmpd THP1 K562 SHSY5Y VCAP LNCAP No GI50 GI50 GI50 GI50 GI50 Attorney Docket No.: R2103-705402 176 C C C C C 177 C C C C C Attorney Docket No.: R2103-705402 275 C C B B C 278 B B B B B Attorney Docket No.: R2103-705402 367 B B B B B 370 A A A A A Attorney Docket No.: R2103-705402 430 C C A A A 432 B B B B B Attorney Docket No.: R2103-705402 497 C C A A B 499 C C A A A Attorney Docket No.: R2103-705402 547 C C B A B 548 A A A A A Attorney Docket No.: R2103-705402 594 C B A A A 595 C C A A B Attorney Docket No.: R2103-705402 642 A A - A A 643 C B - A A Attorney Docket No.: R2103-705402 683 A A A A A 684 A A A A A Attorney Docket No.: R2103-705402 724 C B - A A 725 C B - A A Attorney Docket No.: R2103-705402 766 A A A A A 767 A A A A A Attorney Docket No.: R2103-705402 810 A A A A A 811 C B C B C Attorney Docket No.: R2103-705402 852 C C C B C 853 C C B B B Attorney Docket No.: R2103-705402 894 A A A A A 895 A A A A A Example 213: Exemplary kinase activity assay for measuring CDK12 kinase activity with partner protein, Cyclin K The ability of compounds described herein to inhibit CDK12 kinase activity was assessed using an enzymatic assay, monitoring the phosphorylation of a peptide substrate by the CDK12/Cyclin K complex in a luminescence based readout. Materials: ▪ Corning 384-well, white, low volume, non-binding surface (Cat #3824) ▪ ADP-Glo kinase assay kit (Promega catalog #V9102) Assay Buffer ^ 50mM HEPES-NaOH, pH 7.5 ^ 50mM NaCl ^ 10mM MgCl2 ^ 0.1mg/mL BSA ^ 1mM TCEP Peptide Substrate Sequence ^ N-YSPTSPSPYSPTSPSPYSPTSPSPYSKKKK-C 769 Attorney Docket No.: R2103-705402 Where SP denotes a phospho-Serine Assay ready plates were generated by adding compound to plates using an Echo acoustic dispenser.2.5 uL of CDK12/CCNK was added directly to the assay ready plate using a combi liquid handler. After incubating CDK12/CCNK with compound for 20 minutes, 2.5 uL of ATP and peptide substrates diluted in assay buffer were added to each well using a combi liquid handler to initiate the reaction. The final concentrations of CDK12/CCNK, ATP and peptide were 25 nM, 20 uM and 100 uM, respectively. Plates were sealed and incubated at room temperature for 4 hrs. To quench the reaction, 5 uL of ADP-Glo reagent was added to each well using a combi liquid handler and incubated for 1 hr at room temperature. Next, 10 uL of kinase detection reaction was added to each well using a combi liquid handler and incubated for 1 hr at room temperature. Luminescence signal was then read on an EnVision plate reader. ATP/Substrate CDK12/CCNK Master Mix Master Mix Percent inhibition was calculated using the equation below, where negative control (NC) wells contain all components of the reaction plus DMSO and positive control (PC) wells contain no CDK12/Cyclin K complex, with all other assay components present. % response = 100* (S - PC)/(NC - PC) EQUIVALENTS AND SCOPE This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because 770 Attorney Docket No.: R2103-705402 such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, Figures, or Examples but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims. ***************************************** 771

Claims

Attorney Docket No.: R2103-705402 CLAIMS 1. A compound of Formula (I): a pharmaceutically acceptable salt, solvate, hydrate, rein: W1, W2, W3, and W4 are each independently N or CR4a; X is N or CR4b; Ring A is a 6-membered aryl, 5-membered heteroaryl, or 6-membered heteroaryl, each of which is optionally substituted with one or more R5; Ring B is aryl, heteroaryl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R5; L is absent, a bond, -O-, -NR8-, -C(O)-, –NRBC(O)-, –C(O)NRB-, C1-C6-alkylene, or C1- C6-heteroalkylene, wherein when L is absent, Ring A and Ring B are fused together (e.g., to form a bicyclic or tricyclic ring) and the fused ring is optionally substituted with one or more R5; each of R3a and R3b is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, oxo, –ORA, –NRBRC, –C(O)RD, – C(O)ORD, -P(O)RDRE, or –S(O)xRD; each R4a is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, - P(O)yRD, -S(O)(=NH)RD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R4a adjacent groups, together with the atoms to which they are attached, form a 3-7- membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; 772 Attorney Docket No.: R2103-705402 each R4b is independently hydrogen, C1-C6-alkyl, cycloalkyl, heterocyclyl, or halo, wherein each alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R6; each R5 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, –NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, - P(O)yRD, or –S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; or two R5 groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6; each R6 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –ORA, –NRBRC, – NRBC(O)RD, –NO2, –C(O)NRBRC, –C(O)RD, –C(O)ORD, -P(O)RDRE, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7; each RA is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6- heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1- C6 alkylene-heteroaryl, –C(O)RD, -P(O)yRD, or –S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; each of RB and RC is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, -P(O)yRD, -S(O)xRD, or –ORA; wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7; each RD and RE is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene- aryl, C1-C6 alkylene-heteroaryl, or -N(RB1)(RC1), wherein each alkyl, alkenyl, alkynyl, 773 Attorney Docket No.: R2103-705402 heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; each R7 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NRB1RC1, oxo, –ORA1, –C(O)NRB1RC1, or – C(O)RD1, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9; R8 is hydrogen or C1-C6-alkyl; each R9 is independently C1-C6-alkyl, cycloalkyl, heterocyclyl, oxo, -ORA1, or - N(RB1)(RC1); each RA1 is independently hydrogen or C1-C6-alkyl; each of RB1, RC1, and RD1 is independently hydrogen or C1-C6-alkyl; n is 0, 1, 2, or 3; and each of x and y is independently 0, 1, or 2. 2. The compound of claim 1, wherein Ring A is 6-membered aryl (e.g., phenyl) optionally substituted with one or more R5. 3. The compound of claim 1, wherein Ring A is 5-membered or 6-membered heteroaryl, each of which is optionally substituted with one or more R5. 4. The compound of claim 1, wherein Ring A is a nitrogen-containing 5-membered or 6- membered heteroaryl, each of which is optionally substituted with one or more R5. 5. The compound of claim 1, wherein Ring A is selected from , , Attorney Docket No.: R2103-705402 , 6. The compound of claim 1, wherein Ring A is selected from , wherein R5 is as described in claim 1. 7. The compound of claim 1, wherein Rin , wherein R5 is as described in claim 1. 775 Attorney Docket No.: R2103-705402 , , , , 9. The compound of claim 1, wherein Ring A is selected from 76 Attorney Docket No.: R2103-705402 10. The compound of claim 1, wherein Ring A . 11. The compound of claim 1, wherein L is absent, a bond, -O-, -NR8-, -C(O)-, or -S(O)x-. 12. The compound of claim 1, wherein L is a bond. 13. The compound of claim 1, wherein Ring B is aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more R5. 14. The compound of claim 1, wherein Ring B is a nitrogen-containing heteroaryl or heterocyclyl, each of which is optionally substituted with one or more R5. 15. The compound of claim 1, wherein Ring B is a 5-membered or 6-membered nitrogen- containing heteroaryl or heterocyclyl, each of which is optionally substituted with one or more R5. 16. The compound of claim 1, wherein Ring B is selected from (R5)0-4 , , Attorney Docket No.: R2103-705402 nd , wherein R5 is as described in claim 1. 17. The compound of claim 1, wherein Ring B is selected from (R5)0-4 N , wherein R5 is as described in claim 1. 18. The compound of claim 1, wherein Ring B is selected fro , , , Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , . 20. The compound of claim 1, wherein A-L-B is selecte , , Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 1. Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , . 22. The compound of claim 1, wherein L is absent. 23. The compound of claim 22, wherein L is absent and A and B are fused together to form a fused cycloalkyl, fused heterocyclyl, fused aryl, or fused heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5. 24. The compound of claim 22, wherein L is absent and A and B are fused together to form a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R5. 25. The compound of claim 22, wherein when A and B are fused together, A and B are , , Attorney Docket No.: R2103-705402 , , , , . 26. The compound of claim 22, wherein when A and B are fused together, A and B are Attorney Docket No.: R2103-705402 , , Attorney Docket No.: R2103-705402 , , Attorney Docket No.: R2103-705402 , , 27. The compound of claim 1, wherein W1 is N or CR4a. 28. The compound of claim 1, wherein W2 is N or CR4a. 29. The compound of claim 1, wherein W3 is N or CR4a. 792 Attorney Docket No.: R2103-705402 30. The compound of claim 1, wherein W4 is N or CR4a. 31. The compound of claim 1, wherein one of W1, W2, W3 and W4 is independently N. 32. The compound of claim 1, wherein two of W1, W2, W3 and W4 is independently N. 33. The compound of claim 1, wherein W1 is N and each of W2, W3, and W4 is independently CR4a. 34. The compound of claim 1, wherein W2 is N and each of W1, W3, and W4 is independently CR4a. 35. The compound of claim 1, wherein W3 is N and each of W1, W2, and W4 is independently CR4a. 36. The compound of claim 1, wherein W4 is N and each of W1, W2, and W3 is independently CR4a. 37. The compound of claim 1, wherein W4 is N and each of W1, W2, and W3 is independently CR4a. 38. The compound of claim 1, wherein each of W1, W2, W3 and W4 is independently CR4a. 39. The compound of claim 1, wherein each R4a is hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, –ORA, or cycloalkyl. 40. The compound of claim 1, wherein each R4a is hydrogen, C1-C6-alkyl, halo, or –ORA. 793 Attorney Docket No.: R2103-705402 41. The compound of claim 1, wherein R4a is hydrogen. 42. The compound of claim 1, wherein X is N. 43. The compound of claim 1, wherein X is CR4b. 44. The compound of claim 1, wherein R4b is hydrogen. 45. The compound of claim 1, wherein n is 1. 46. The compound of claim 1, wherein RA is C1-C6-alkyl (e.g., -CH3). 47. The compound of claim 1, wherein the compound comprises 1 or 2 R5. 48. The compound of claim 1, wherei is selected from: and 794 Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , Attorney Docket No.: R2103-705402 , . 50. The compound of claim 1, wherein the compound is a compound of Formula (I-b): a pharmaceutically acceptable salt, solvate, hydrate, each of W1 4a , X, A, B, L, and R are as defined in claim 1. 51. The compound of claim 1, wherein the compound is a compound of Formula (I-c): a pharmaceutically acceptable salt, solvate, hydrate, rein each of W1, A, B, L, and are as defined in claim 1. 52. The compound of claim 1, wherein the compound is a compound of Formula (I-d): 797 Attorney Docket No.: R2103-705402 a pharmaceutically acceptable salt, solvate, hydrate, each of W1, A, B, L, R4a, and R4b, are as defined in claim 1. 53. The compound of claim 1, wherein the compound is a compound of Formula (I-e): a pharmaceutically acceptable salt, solvate, hydrate, each of X, A, B, L, R4a, and R4b, are as defined in claim 1. 54. The compound of claim 1, wherein the compound is a compound of Formula (I-f): a pharmaceutically acceptable salt, solvate, hydrate, n eac 4a h of X, A, B, L, and R , are as defined in claim 1. 55. The compound of claim 1, wherein the compound is a compound of Formula (I-g): a pharmaceutically acceptable salt, solvate, hydrate, , , each of W1, X, B, and R4a, are as defined in claim 1, and each of Z1, Z2, Z3, and Z4 is independently N or CR5b. 798 Attorney Docket No.: R2103-705402 56. The compound of claim 1, wherein the compound is a compound of Formula (I-h): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, B, R4a, and R5, are as defined in claim 1. 57. The compound of claim 1, wherein the compound is a compound of Formula (I-i): a pharmaceutically acceptable salt, solvate, erein each of W1, X, A, B, L, and R4a, are as defined in claim 1. 58. The compound of claim 1, wherein the compound is a compound of Formula (I-j): a pharmaceutically acceptable salt, solvate, erein each of W1 4a A , X, A, B, L, R , and R , are as defined in claim 1. 59. The compound of claim 1, wherein the compound is a compound of Formula (I-j’): 799 Attorney Docket No.: R2103-705402 a pharmaceutically acceptable salt, solvate, hydrate, V1 is halogen, and each of W1, X, A, B, L, R4a, and RA, are as defined in claim 1. 60. The compound of claim 1, wherein the compound is a compound of Formula (I-j”): a pharmaceutically acceptable salt, solvate, hydrate, V2 is C1-C6-haloalkyl, and each of W1, X, A, B, L, , , . 61. The compound of claim 1, wherein the compound is a compound of Formula (I-k): a pharmaceutically acceptable salt, solvate, hydrate, in each of W1, 4a X, A, B, and R are as defined in claim 1. 62. The compound of claim 1, wherein the compound is a compound of Formula (I-k’): a pharmaceutically acceptable salt, solvate, hydrate, , , each of W1, X, A, B, and R4a are as defined in claim 1. 800 Attorney Docket No.: R2103-705402 63. The compound of claim 1, wherein the compound is a compound of Formula (I-l): a pharmaceutically acceptable salt, solvate, hydrate, herein each of W1, X, A, B, and R4a are as defined in claim 1. 64. The compound of claim 1, wherein the compound is a compound of Formula (I-l’): a pharmaceutically acceptable salt, solvate, hydrate, each of W1, X, A, B, and R4a are as defined in claim 1. 65. The compound of claim 1, wherein the compound is a compound of Formula (I-m): a pharmaceutically acceptable salt, solvate, hydrate, ein each of W1, X, A, B, and R4a are as defined in claim 1. 66. The compound of claim 1, wherein one of R3a and R3b is H, and the other is selected from H, C1-C6-alkyl, and C1-C6-heteroalkyl. 67. The compound of claim 1, wherein the compound is 801 Attorney Docket No.: R2103-705402 selected from a compound listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. 68. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient. 69. A method of modulating the rate of degradation of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) as described in claim 1. 70. The method of claim 69, wherein the compound increases the rate of degradation of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 71. A method of modulating the level of a cyclin (e.g., cyclin K) in a sample or subject, comprising contacting the cyclin (e.g., cyclin K) with a compound of Formula (I) as described in claim 1. 72. The method of claim 71, wherein the compound reduces the level of a cyclin (e.g., cyclin K) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 73. A method of modulating the activity of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) as described in claim 1. 74. The method of claim 73, wherein the compound inhibits the activity of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 802 Attorney Docket No.: R2103-705402 75. A method of modulating the rate of degradation of a cyclin dependent kinase (CDK), e.g., CDK12 or CDK13, in a sample or subject, comprising contacting the CDK with a compound of Formula (I) as described in claim 1. 76. The method of claim 75, wherein the compound increases the rate of degradation of the CDK, e.g., CDK12 or CDK13, by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. 77. A method for treating a disease or disorder in a subject comprising administering to the subject a compound of Formula (I) according to claim 1 or the pharmaceutical composition of claim 68. 78. The method of claim 77, wherein the disease or disorder comprises a proliferative disease (e.g., cancer, a benign neoplasm, or angiogenesis). 79. The method of claim 77, wherein the disease or disorder comprises cancer. 80. The method of claim 79, wherein the cancer is selected from breast cancer, prostate cancer, lung cancer, skin cancer, blood cancer, or ovarian cancer. 81. The method of claim 77, wherein the disease or disorder comprises a neurological disease or disorder, autoimmune disease or disorder, immunodeficiency disease or disorder, lysosomal storage disease or disorder, cardiovascular disease or disorder, metabolic disease or disorder, respiratory disease or disorder, renal disease or disorder, or infectious disease. 803
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