N-(6-chloropyridin-3-yl)-6-methoxy-nicotinamide derivatives and analogues thereof as potentiators of kv7.2 and kv7.3 voltage-gated potassium channels for treatment of seizure, depression, pain or anhedonia

Abstract

Provided herein are compounds of formula (I) that can potentiate Kv7 potassium channels (e.g., Kv7.2 / Kv7.3). In some embodiments, the compounds provided herein are useful in the treatment and / or prevention of diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction, such as e.g. seizure, depression, pain or anhedonia. In some embodiments, the compounds provided herein target Kv7 voltage-sensing domains (VSDs). In some embodiments, the compounds provided herein are N-(6- chloropyridin-3-yl)-6-methoxy-nicotinamide derivatives and analogues thereof.

Description

Attorney Docket No: X0042.70031WO00 N-(6-CHLOROPYRIDIN-3-YL)-6-METHOXY-NICOTINAMIDE DERIVATIVES AND ANALOGUES THEREOF AS POTENTIATORS OF KV7.2 AND KV7.3 VOLTAGE-GATED POTASSIUM CHANNELS FOR TREATMENT OF SEIZURE, DEPRESSION, PAIN OR ANHEDONIARELATED APPLICATIONS

[0001] This application claims priority under 35 U. S. C. § 119(e) to U. S. Provisional Patent Applications, U. S. S. N. 63 / 736,794, filed December 20, 2024, and U. S. S. N. 63 / 832,705, filed June 30, 2025, the entire contents of each of which are incorporated herein by reference.BACKGROUND

[0002] Voltage-gated potassium channels, including the voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), are important in controlling neuronal excitability. Kv7.2 / Kv7.3 underlie the neuronal “M-current,” named according to its initial characterization as a neuronal current decreased in response to muscarinic / cholinergic agonists (see Brown, D. A. et al., Nature (1980), 283:673-676). The M-current is a non-inactivating, hyperpolarizing current known to act as a brake on neuronal hyperexcitability. Consequently, a decrease in the Kv7.2-mediated M-current, for example through genetic loss-of-function, can cause neuronal depolarization and an increase in membrane and neuronal excitability that can lead to action potential bursts that manifest as, e.g., epileptic seizures. In contrast, an increase in the Kv7.2-mediated M-current can hyperpolarize the cell membrane and thereby reduce neuronal excitability and prevent the initiation and propagation of action potential bursts and the resultant seizures. Enhancing the open state of Kv7.2 / Kv7.3 channels in neurons favors a hyperpolarized resting state, which reduces rapid action potential spiking (i.e., burst firing). Such enhancement can provide a stabilizing effect on excitable, particularly hyper-excitable, neurons and can therefore be useful in treating certain seizure disorders. This enhancement has been clinically proven to be effective for treatment of seizure disorders, such as partial onset seizures in adults with epilepsy, with retigabine (ezogabine), a known Kv7.2 / Kv7.3 potentiator.

[0003] Voltage-sensing domains (VSDs) are structural motifs found in voltage-gated ion channels, including in Kv7 ion channels (e.g., Kv7.2 / Kv7.3). The voltage-sensing domain of Kv7 channels functions by coupling changes in transmembrane electrical potential to conformational changes that regulate ion conductance. VSDs of Kv7 channels are a target for potentiating the Kv7 ion channel activity.

[0004] While significant advances have been made in this field, there remains a substantial need for improved compounds and methods for potentiating voltage-gated potassium channels, including the voltage-gated potassium channels Kv7.2 / Kv7.3. Such compounds and methods can be used to treat diseases, disorders, and conditions in which potassium channel dysfunction is implicated.SUMMARY

[0005] Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can potentiate Kv7 potassium channels (e.g., Kv7.2 / Kv7.3). In some embodiments, the compounds provided herein are useful in the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction). In some embodiments, theAttorney Docket No: X0042.70031WO00 compounds provided herein act as potentiators of Kv7 voltage -sensing domains (VSDs). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.

[0006] In one aspect, provided herein are compounds of Formula (I):and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein R1, R2, RN1, X1, X2, X3, Y1, Y2Y3, and Y4are as defined herein.

[0007] In certain embodiments, a compound of Formula (I) is of Formula (I-b):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Rx2, Rx3, X1, Ry2, Ry4, Y3, Z1, L1, and R3are as defined herein.

[0008] In certain embodiments, for example, a compound disclosed herein is selected from those recited in Table 1 (infra), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof.

[0009] In another aspect, provided herein are pharmaceutical compositions comprising a compound of disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0010] As described, compounds and pharmaceutical compositions provided herein can potentiate the Kv7 voltage -sensing domain and thus potentiate voltage-gated potassium channels (e.g., Kv7.2 / Kv7.3 potassium channels), and are therefore useful for treating and / or preventing diseases, disorders, and conditions in a subject.

[0011] In other aspects, provided herein are methods and uses of the compounds and pharmaceutical compositions provided herein, including, but not limited to, the following:Attorney Docket No: X0042.70031WO00 (a) Methods of potentiating a voltage-sensing domain (VSD) of a potassium channel (e.g., a Kv7 VSD) in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.(b) Methods of potentiating a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.(c) Methods of treating a disease, disorder, or condition associated with Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) dysfunction in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.(d) Method of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.(e) Methods of potentiating a voltage-sensing domain (VSD) of a potassium channel (e.g., a Kv7 VSD) in a cell in vitro comprising contacting the cell with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.(f) Methods of potentiating a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) in a cell in vitro comprising contacting the cell with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0012] In another aspect, provided herein are compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein. In another aspect, provided herein are compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use as medicaments and / or in the preparation of medicaments.

[0013] In another aspect, provided herein are kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof. The kits described herein are useful in any method or use provided herein, and optionally further comprise instructions for using the kit (e.g., instructions for using the compound or composition included in the kit).

[0014] Also provided herein are methods of preparing compounds disclosed herein, and pharmaceuticallyAttorney Docket No: X0042.70031WO00 acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. Synthetic intermediates useful in the preparation of the compounds and compositions are also provided herein.

[0015] The details of certain embodiments of the disclosure are set forth in the Detailed Description, as described below. Other embodiments of the disclosure will be apparent from the Definitions, Examples, Abstract, and Claims.DEFINITIONSChemical Definitions

[0016] 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, 75thEd., 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; Michael B. Smith, Marchs ’ Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0017] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric 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. 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, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0018] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C -enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the sameAttorney Docket No: X0042.70031WO00 number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0019] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1–4, C1–3, C1-2, C’2 C2-5, C2 4. C2-3, C3-6, C3-5, C3 4. C4 C4-5, and C5-6 alkyl.

[0020] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0021] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0022] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C, <> alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., w-propyl, isopropyl), butyl (C4) e.g., w-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., w-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertamyl), and hexyl (Ce) (e.g., w-hexyl). Additional examples of alkyl groups include w-heptyl (C7), w-octyl (C8), w-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-12 alkyl (such as substituted C1–6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0023] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atomsAttorney Docket No: X0042.70031WOOO (“Ci-io haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“Ci-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“Ci-s haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“Ci^ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“Ci-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“Ci_2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFC12, -CF2C1, and the like.

[0024] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-i2heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-s heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-6 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1-5 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“Ci^ heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1-3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1-2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“Ci heteroalkyl”). In some embodiments, a heteroalkylAttorney Docket No: X0042.70031WO00 group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.

[0025] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2-12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2-11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2 -6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (" C2 4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“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 C2–4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3or) may be in the (E)- or (^-configuration.

[0026] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-12 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-11 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-10Attorney Docket No: X0042.70031WO00 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (”€’2 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ('U 4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (" C'2,, heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.

[0027] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.

[0028] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfurAttorney Docket No: X0042.70031WO00 within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (" C2heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (”€’2 4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C1-6 heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.

[0029] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementionedAttorney Docket No: X0042.70031WO00 C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl 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. Exemplary C3–8 carbocyclyl groups include the aforementioned C3–10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (Cn), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0030] “Cycloalkyl” refers to a saturated carbocyclyl group. In some embodiments, a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C3-7 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0031] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“3-14 membered heterocyclyl”). In certain embodiments, the heterocyclyl group is a radical of a 3 - to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ringAttorney Docket No: X0042.70031WOOO carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits. For example, 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 polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0032] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5 -membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5 -membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms includeAttorney Docket No: X0042.70031WO00 triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1, 2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0034] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has 6-10 ring carbon atoms (“Ce-io aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.

[0035] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 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, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl group is a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p 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. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits. For example, 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 polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, theAttorney Docket No: X0042.70031WO00 number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g, either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0036] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.

[0037] Exemplary 5 -membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5 -membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 -membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 -membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. ExemplaryAttorney Docket No: X0042.70031WO00 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0038] The term “acyl” refers to a group having the general formula -C(=O)Raa, -C(=O)ORaa, -C(=O)-O-C(=O)Raa, -C(=O)SRaa, -C(=O)N(Rbb)2, -C(=S)Raa, -C(=S)N(Rbb)2, -C(=S)S(Raa), -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)SRaa, and -C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0039] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0040] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0041] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. 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 and includes any of the substituents described herein that results 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, oxygen, and sulfur may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The embodiments described herein are not limited in any manner by the exemplary substituents described herein.

[0042] Exemplary substituents (e.g., carbon atom substituents) include halogen, -CN, -NO2, -Ns, -SO2H, -SOsH, -OH, -ORaa, -0N(Rbb)2, -N(Rbb)2, -N(Rbb)3+X, -N(0Rcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -0C(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2,Attorney Docket No: X0042.70031WO00 -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, — Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2,-NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X, -P(ORCC)3+X, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X, -OP(ORCC)2, -OP(ORCC)3X, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein X is a counterion;or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbb, or =NORCC;wherein:each instance of Raais, independently, selected from Ci_2o alkyl, Ci_2o perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6–14aryl, and 5-14 membered heteroaryl, ortwo Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=0)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6–14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X, -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=0)N(Rff)2, -0C(=0)N(Rff)2, -NRffC(=0)Ree, -NRffC02Ree,Attorney Docket No: X0042.70031WO00 -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, — Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6–10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R88groups, or two geminal Rddsubstituents are joined to form =0 or =S, and wherein X is a counterion;each instance of Reeis, independently, selected from Ci-io alkyl, Cuo perhaloalkyl, C2-10 alkenyl, C2_io alkynyl, Ci-io heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, C6–10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;each instance of Rffis, independently, selected from hydrogen, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6–10aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi-6 alkyl, −ON(C1–6alkyl)2, −N(C1–6alkyl)2, −N(C1–6alkyl)3+X−, −NH(C1–6alkyl)2+X−, −NH2(C1–6alkyl)+X−, -NH3+X -, −N(OC1–6alkyl)(C1–6alkyl), −N(OH)(C1–6alkyl), −NH(OH), −SH, −SC1–6alkyl, −SS(C1–6alkyl), −C(=O)(C1–6alkyl), −CO2H, −CO2(C1–6alkyl), −OC(=O)(C1–6alkyl), −OCO2(C1–6alkyl), −C(=O)NH2, −C(=O)N(C1–6alkyl)2, −OC(=O)NH(C1–6alkyl), −NHC(=O)(C1–6alkyl), −N(C1–6alkyl)C(=O)(C1–6alkyl), −NHCO2(C1–6alkyl), −NHC(=O)N(C1–6alkyl)2, −NHC(=O)NH(C1–6alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6alkyl), −OC(=NH)(C1–6alkyl), −OC(=NH)OC1–6alkyl, −C(=NH)N(C1–6alkyl)2, −C(=NH)NH(C1–6alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6alkyl)2, −OC(NH)NH(C1–6alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6alkyl), −SO2N(C1–6alkyl)2, −SO2NH(C1–6alkyl), −SO2NH2, −SO2C1–6alkyl, −SO2OC1–6alkyl, −OSO2C1–6alkyl, −SOC1–6alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3, −C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6alkyl, SC(=S)SC1–6alkyl, −P(=O)(OC1–6alkyl)2, −P(=O)(C1–6alkyl)2, −OP(=O)(C1–6alkyl)2, −OP(=O)(OC1–6alkyl)2, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3–10carbocyclyl, C6–10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0043] In certain embodiments, the molecular weight of a substituent (e.g., carbon atom substituent) is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certainAttorney Docket No: X0042.70031WOOO embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0044] In certain embodiments, exemplary substituents (e.g., carbon atom substituents) include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -N(Rbb)2, -N(Rbb)3X, -SH, -SRaa, -C(=O)Raa, -CO2H, -CHO, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, — Si(Raa)3, -OSi(Raa)3, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2,-NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, wherein X is a counterion;or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=0)2Raa, =NRbb, or =NORCC;each instance of Raais, independently, selected from C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, ortwo Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring;each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CMO alkyl, CMO perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, CMO heteroalkyl, C2- 10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, ortwo Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; andeach instance of Rccis, independently, selected from hydrogen, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

[0045] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, −N(Rbb)2, −CN, −NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, −ORaa, -SRaa, -N(Rbb)2, -CN, -NO2, -C(=O)Raa, -CO2Raa, -C(=0)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -0C(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, or -NRbbC(=0)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–6alkyl, an oxygenAttorney Docket No: X0042.70031WOOO protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, / -Bn. 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, / -Bn. 3 -nitro-2 -pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0046] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CC R”, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0047] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, Ci-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-20 alkenyl, C2-20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.Attorney Docket No: X0042.70031WO00

[0048] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -pyridylcarboxamide, / V-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (A5-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0049] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fhioroenyhnethyl carbamate, 2.7-di- / -but l-|9-(IO. I0-dioxo-l0.10.10.10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-( I -adamantyl)- 1 -methylethyl carbamate (Adpoc), 1,1 -dimethyl -2 -haloethyl carbamate, 1, 1 -dimethyl -2,2-dibromoethyl carbamate (DB- / -BOC). 1,1 -dimethyl -2, 2, 2-trichloroethyl carbamate (TCBOC), 1 -methyl -I-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3.5-di- / -butylphcnyl)-l-mcthylcth l carbamate ( / -Bumcoc). 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (BOC or Boc), 1 -adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, A-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzy 1 carbamate, p-bromobenzy 1 carbamate, p-chlorobenzy 1 carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfmylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2 -methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4 -methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1 -dimethyl -2 -cyanoethyl carbamate, m-chloro- / ?-acyloxybenzyl carbamate. / ?-(dihydroxy bory I (benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophcnyl carbamate, 3,5 -dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, / -amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A. A-dimcthylcarboxamido)bcnzylAttorney Docket No: X0042.70031WOOO carbamate, l,l-dimethyl-3-(A, A-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p ’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1 -phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2.4.6-tri - / -bnty Iphcny 1 carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0050] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g, a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluene sulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),methane sulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0051] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, N ’-phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin- 2-one, A-phthalimide, A-dithiasuccinimide (Dts), A-2,3-diphenylmaleimide, A-2,5-dimethylpyrrole, N- 1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1, 3 -dibenzyl- 1,3, 5 -triazacyclohexan-2 -one, 1-substituted 3,5-dinitro-4-pyridone, A-mcthylaminc. A-allylaminc. A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-( l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4-methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), A-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phcnylfluorcnylaminc (PhF), N-2,7-dichloro-9-fIuorenylmethyleneamine, A-ferrocenyhnethylamino (Fem), N-2 -picolylamino A ’-oxide. N- 1,1 -dimethylthiomethyleneamine, A-benzylideneamine, A-p-methoxybenzylideneamine, A-diphenyhnethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’, A’-dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5-chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A-cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivatives, A-diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl]amine, A-copper chelate, A-zinc chelate, A-nitroamine,Attomey Docket No: X0042.70031WO00 N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzene sulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N, N" -isopropylidenediamine.

[0052] In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0053] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0054] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CC R”, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.

[0055] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3+X−, -P(ORcc)2, -P(ORCC)3+X, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0056] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), / -butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4 -methoxyphenoxy )methyl (p-AOM), guaiacolmethyl (GUM), / -butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-Attorney Docket No: X0042.70031WO00 (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3 -bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4 -methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxyethyl, 1 -methyl- 1 -benzyloxyethyl, 1 -methyl- 1-benzyloxy-2 -fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, / -butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3 -methyl -2 -picolyl / V-oxido, diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldi phenyl methyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4, 4', 4"-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3"'-[N-(imidazolylmethyl) Jtrityl Ether (IDTr-OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate,. S'-bcnzyl thiocarbonate, 4 -ethoxy- 1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1, 1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N, N, N’JM’-tetramethylphosphorodiamidate, alkyl / V-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).Attomey Docket No: X0042.70031WO00

[0057] In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1 -ethoxyethyl (EE), 2-methoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), / -butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0058] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0059] In certain embodiments, each sulfur atom substituent is independently substituted (e.g, substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a sulfur protecting group.

[0060] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of-Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X, -P(ORCC)2, -P(ORCC)3+X, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0061] In certain embodiments, a sulfur protecting group is acetamidomethyl, / -Bn. 3 -nitro-2 -pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0062] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g, including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F⁻, Cl⁻, Br⁻, I⁻), NO3⁻, ClO4⁻, OH⁻, H2PO4⁻, HCO3⁻, HSO4⁻, sulfonate ions (e.g., methansulfonate, trifluoromethane sulfonate, p-toluene sulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-Attorney Docket No: X0042.70031WOOO sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4, PF4, PF6, AsF6. SbF6⁻, B[3,5-(CF3)2C6H3]4⁻, B(C6F5)4⁻, BPh4⁻, Al(OC(CF3)3)4⁻, and carborane anions (e.g., CB11H12⁻ or (HCB11Me5Br6)⁻). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0063] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The embodiments provided herein are not limited in any manner by the above exemplary listing of substituents.Other Definitions

[0064] The following definitions are more general terms used throughout the present application.

[0065] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C’i4alkyl)4salts.Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0066] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in Pharmaceutical Sciences, 1977, 66, 1-19,Attorney Docket No: X0042.70031WO00 incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI.4 alkyl )4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0067] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0068] ‘ ‘Stereoisomers” that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and. S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.e., as (+)- or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

[0069] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0070] The term “solvate” refers to forms of a compound, including salts thereof, that are associated with aAttorney Docket No: X0042.70031WO00 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 described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. 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 isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0071] The term “hydrate” refers to a solvate wherein the compound 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 x is a number greater than 0.A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (Rx0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (Rx2 H2O) and hexahydrates (Rx6 H2O)).

[0072] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. See, e.g., Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985. Prodrugs include acid derivatives such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester-type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the subject.

[0073] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Isotopically labeled derivatives are also included.

[0074] The terms “composition” and “formulation” are used interchangeably.

[0075] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animalAttorney Docket No: X0042.70031WO00 may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease, disorder, or condition.

[0076] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0077] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0078] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0079] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0080] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for potentiating a Kv7 potassium channel (e.g., in a subject or in a cell in vitro).

[0081] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with Kv7 potassium channel dysfunction) in a subject. InAttorney Docket No: X0042.70031WO00 certain embodiments, a therapeutically effective amount is an amount sufficient for potentiating a Kv7 potassium channel in a subject.

[0082] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with Kv7 potassium channel dysfunction) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for potentiating a Kv7 potassium channel in a subject.

[0083] “Voltage-gated potassium channels” (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in a cell’s membrane potential. During action potentials, they play an important role in returning the depolarized cell to a resting state. In VGKCs, alpha subunits form the actual conductance pore. Based on sequence homology of the hydrophobic transmembrane cores, the alpha subunits of voltage-gated potassium channels are grouped into 12 families (Kvl-12), of which Kv7 is one family. The Kv7 family of voltage-gated potassium channels consists of five members (Kv7.1-7.5) which are encoded for by the KCNQ1-5 genes, respectively. Kv7 channels assemble as tetramers of identical (homotetramer) or compatible (heterotetramer) a subunits, with each a subunit consisting of six transmembrane segments (S1-S6) and cytoplasmic N- and C-termini. See, e.g., Gomis-Perez et al. “Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy” Epilepsia. 2019; 60: 139-148; Howard et al. “Structural Insight into KCNQ (Kv7) Channel Assembly and Channelopathy” Neuron 53, 663-675, March 1, 2007. Of the five, Kv7.2 / Kv7.3 is the active heterotetramer that is the main active Kv7 current in neurons (M-current). A Kv7 potassium channel can be a member selected from Kv7.1, Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5.

[0084] “Voltage-sensing domain,” also referred to herein as “VSD,” is a structural motif found in voltagegated ion channels, including in voltage-gated potassium channels. The voltage -sensing domain of Kv7 channels is formed by transmembrane segments (S 1 -S4) and function by coupling changes in transmembrane electrical potential to conformational changes that regulate ion conductance.

[0085] ‘ ‘Potassium channel potentiator” and “potassium channel opener” are used interchangeably and refer to an agent that restores, enhances, or increases the activity of a potassium channel (e.g., voltage-gated potassium channel, e.g., Kv7 potassium channel), for example, by facilitating ion transmission through the potassium channel. “Potentiating,” “potentiation,” and the like, for the purposes of this disclosure, refer to restoring, enhancing, or increasing the activity or effect of a potassium channel and / or of a voltagesensing domain of a potassium channel.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0086] Provided herein are compounds, including compounds of any of the formulae described herein (e.g.,Attorney Docket No: X0042.70031WOOO Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can act as potentiators of voltage-gated potassium channels (e.g., Kv7 potassium channels such as Kv7.2 / Kv7.3). Thus, the compounds provided herein can therefore be used in the treatment and / or prevention of diseases, disorders, and conditions (e.g, diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction). In some embodiments, the compounds provided herein act as modulators of Kv7 voltagesensing domains (VSDs). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.Compounds

[0087] Provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:X1is N or CRxl; X2is N or CRx2; and X3is N or CRx3;R1is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, -CN, -OR0, -N(RN)2, -SRS, or C1-6 acyl, wherein the alkyl, cycloalkyl, or acyl is optionally substituted;each instance of Rxl, Rx2, and Rx3is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted;Y1is N or CRyl; Y2is N or CRy2; Y3is N or CRy3; and Y4is N or CRy4, provided that at least one of Y1and Y3is N;each instance of R2, Ryl, Ry2, Ry3, and Ry4is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRs, C1-6 acyl, or -Z’-L’-R3, or any two instances of R2, Ryl, Ry2, Ry3, and Ry4on adjacent carbons are joined together to form C5-6 cycloalkyl or 5-6 membered heterocyclyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; provided that at least one of R2, Ry1, Ry2, Ry3, and Ry4is independently -Z1-L1-R3:each instance of Z1is independently absent, -O-, -N(RN)-, -S-, -S(=O)2-, -(C(RL)2)n-, -C(=O)-, -C = C-, -O-(C(RL)2)n-, -N(RN)-(C(RL)2)n-, -N(RN)-(C(RL)2)n-, -(C(RL)2)n-N(RN)-, -S-(C(RL)2)n-, -(C(RL)2)n-S-, -S(=O)2-(C(RL)2)n-, -(C(RL)2)n-S(=O)2-, -C(=O)-(C(RL)2)n-, -(C(RL)2)n-C(=O)-, -(C(RL)2)n- C = C-, or -Attorney Docket No: X0042.70031WO00 C = C-(C(RL)2)„-;each instance of L1is independently absent or -(C(RL)2)n-;each n is independently 1, 2, or 3;each instance of RLis independently H, halogen, Ci-6 alkyl, or Ci-6 haloalkyl, wherein each alkyl is independently optionally substituted, or wherein two RLattached to the same carbon are taken together to form =0;each instance of R3is independently C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6–10aryl, or 5-10 membered heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one or more instances of R3a;each instance of R3ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6–10aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, -S(=O)2RS1, -S(=O)RS1, -S(=O)2OR°, -S(=O)OR°, -S(=O)2N(RN)2, -S(=O)N(RN)2, -S(=O)(=NRN)RS1, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted;each instance of RN1and RNis independently H, Ci-6 alkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, -S(=O)2Rsl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted;each instance of R° is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted;each instance of Rsis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; andeach instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted.

[0088] In some embodiments, the compound is of Formula (I-a):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0089] In some embodiments, the compound is of Formula (I-b):Attorney Docket No: X0042.70031WOOO(I-b),or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0090] In some embodiments, the compound is of Formula (I-b-1):R3(I-b-1),or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0091] In some embodiments, the compound is of Formula (I-b-2):R3(I-b-2),or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0092] In some embodiments, the compound is of Formula (I-c):(I-c),

[0093] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeledAttorney Docket No: X0042.70031WOOO derivative, or prodrug thereof.

[0094] In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, as a free base.

[0095] In the various aspects and embodiments disclosed herein, express reference to a compound of Formula (I) is understood to alternatively refer to a compound of any disclosed subgenus or species thereof, for example, to a compound of Table 1.

[0096] In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1 (in free base form).Table 1Ex. Name and Structure Ex. Name and Structure\-(6-chloropyridin-3-yl)-2-((3-(2- hy droxypropan-2-y l)bicy clo [ 1.1.1 ]pentan- 1 - \-(6-chloropyridin-3-yl)-6-((3-(2- yl)methoxy)-4-methylpyrimidine-5- hy droxypropan-2-y l)bicy clo [1.1.1 ]pentan- 1 - carboxamide yl)methoxy)-2 -methylnicotinamide Cl / ^Cl1 2 °\_ _ A*NHHC / ^\-(6-chloropyridin-3-yl)-6-((3-(2- 7V-(6-chloropyridin-3-yl)-3-methyl-5-(thiazol-5- hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - ylmethoxy)pyrazine-2 -carboxamide yl)methoxy)-4-methylpyridazine-3-carboxamide / ^NyCI3MHNAJT 4o-Q / 0r.Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropyridin-3-yl)-5-((3.5- \-(6-chloropyridin-3-yl)-6-((3-(2- dimethylisoxazol-4-yl)methoxy)-3 - hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - methy lpyrazine-2-carboxamide yl)methoxy)-4-methylnicotinamide / ^NyCI5 6o-O^° 1A j N^A0N=^\-(6-chloropyridin-3-yl)-3-mcthyl-5-((3- methylisoxazol-5-yl)methoxy)pyrazine-2- \-(6-chlo ropy ridi n-3 -yl)-5-(l-(l- carboxamide (hydroxymethyl)cyclopropyl)ethoxy)-3- methylpyrazine-2-carboxamide / ^Nx^CI7 8 / ^NK^C|0O JNXpr\-(6-chloropyridin-3-yl)-3-mcthyl-5-((3- \-(6-chloropy ridin-3 -yl)-5-(isoxazol-3 - methylisoxazol-4-yl)methoxy)pyrazine-2- ylmethoxy)-3 -methy lpyrazine-2 -carboxamide carboxamide9MHN-'VJ' 10 HNAJX UO-N\-(6-chloropy ridi n-3 -yl)-5-((l- \-(6-chlo ropy ridi n-3 -y l)-5 -((3 -cy anooxetan-3 - (difluoromethyl)cyclopropyl)methoxy)-3- yl)methoxy)-3 -methy lpyrazine-2 -carboxamide methylpyrazine-2-carboxamide / ®NX^cl rsN)>'ci11 12NN o^! J of o-'O''*0F'$r / \-(6-chlo ropy ridi n-3 -y l)-3 -methy 1-5 -((1 -methy 1- \-(6-chlo ropy ridi n-3 -y l)-3 -methy 1-5 -(( 1 - l / / -pyrazol-5-yl)mcthoxy)pyrazinc-2- methyl- l / / -imidazol-5-y l)mcthoxy)py razinc-2- carboxamide carboxamide lst*1r'c> / ^NN^C|13 14, N1 / N^\Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure5-((3 -cyanobicyclo [1.1. l]pentan- 1 -yl)methoxy)- \-(6-chloropyridin-3-yl)-5-((3-(2- 3-mcthyl-\-(6-mcthylpyridin-3-yl)pyrazinc-2- hy droxypropan-2-y l)bicy clo [ 1.1.1 ]pentan- 1 - carboxamide yl)methoxy)-3-methylpyrazine-2 -c / =NK-X:115 HN-M 16 / a*rbNo^xa-mCidIe?-W °\-(6-chloropyridin-3-yl)-5-((4-fluoro-l-mcthyl- 1 / / -py razol-3 -yl)methoxy)-3 -methylpyrazine-2- \-(6-chloropyridin-3-yl)-5-((3- carboxamidehy droxyadamantan- 1 -yl)oxy)-3 -methylpyrazine- 2-carboxamide17 on / ^y-ci 18 HNA / 5NJ)r'4:iJ / ) r-NuN=\Z fV^,-VN-Nb5 -((3 -fluorobicyclo [1.1. l]pentan- 1 - \-(6-chloropy ridin-3 -y 1) -3 -fluoro-5-((3 -(2- yl)methoxy)-A-(5-methoxy-6-methylpyridin-3- hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - yl)pyrazine-2 -carboxamide yl)methoxy)picolinamide19 20o-QA)rN. zyjF\-(6-cyanopyridin-3-yl)-5-((4-fluoro-l-mcthyl- \-(6-cyanopy ridin-3 -yl)-5-(( 1 - 1 / / -py razol-3 -yl)methoxy)-3 -methylpyrazine-2- (difluoromethyl)cyclopropyl)methoxy)-3- carboxamide methylpyrazine-2-carboxamide21 22 / ^Ny^NZN-NAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropy ridi n-3 -yl)-5-(((3- \-(6-chloro-5-mctho\vpyridin-3-yl)-5-((4- (difluoromethyl)bicy clo [1.1.1 ]pentan- 1 - fluoro- 1 -methyl- 1 / / -py razol-3 -yl)methoxy)-3 - yl)methyl)amino)-3 -methylpyrazine- 2- methylpyrazine-2-carboxamidecarboxamide / ^NyCI 23 24’r& SzN-NF\-(6-chlo ropy ridi n-3 -y 1) -5 - ( (3 - ( 3 - \-(6-chloropy ridi n-3 -y l)-5 -(( 1 - hydroxy oxetan-3 -y l)bicy clo [1.1.1 ]pentan- 1 - (difluoromethyl)-5-methyl-l / 7-pyrazol-4- yl)methoxy)-3-methylpyrazine-2-carboxamide yl)methoxy)-3-methylpyrazine-2 -carboxamide / =N>-CI / ^N\^CI 25, N T'N-J' 26^7^5N=Z\-(6-chloropy ridi n-3 -yl)-5-(( 1 -(difluoromethyl)- \-(6-chloropyridin-3-yl)-3-mcthyl-5-((3-oxo- 3 -methyl- 1 H-py razol-4-y l)methoxy )-3- 2,3-dihydroisothiazol-5-yl)methoxy)pyrazine-2- methylpyrazine-2-carboxamide carboxamide / =Nx-ci / ^N / T 27 28CIN'N\ HN-s'\-(6-chloropy ridin-3 -yl)-5 -(( 1, 5 -dimethyl- 1H- \-(6-chlo ropy ridi n-3 -y l)-3 -methy 1-5 -(( 1 - pyrazol-4-yl)methoxy)-3-methylpicolinamide (oxetan-3 -ylmethyl)- l / 7-pyrazol-4-yl)methoxy) picolinamide / ^NX^C|29 HN-V# 30 HNAJ / N-4 \ oJ N= / Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3 -chloro-\-(6-chloropy ridin-3 -yl)-5-(( 1,5- \-(6-chlo ropy ridin-3 -y l)-5 -(( 1, 5 -dimethyl- 1H- dimethyl- 1 / / -py razol-4- pyrazol-4-yl)methoxy)-3 - yl)methoxy)picolinamide (trifluoromethyl)picolinamide / ^Vci / ^NyCI 31 32o-QA)O>Q^OClN-K O'7F F / \ / \\-(2-chloropyrimidin-5-yl)-5-((3-(2- \-(6-chloropy ridi n-3 -yl)-6-((( 1 -methyl- 1H- hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - pyrazol-4-yl)oxy)methyl)nicotinamide yl)methoxy)-3-methylpyrazine-2-carboxamide / ^Nyc|33NHN-VN 34N^VOA-(5-fluoro-6-methylpyridin-3-yl)-5-((3-(2- \-(6-chloropy ridin-3 -y l)-5 -(( 1 - hy droxypropan-2-y l)bicy clo [ 1.1.1 ]pentan- 1 - hydroxycyclobutyl)ethynyl) picolinamide yl)methoxy)picolinamide / ISN / >'CI35 360o-O^0\-(6-chloropy ridin-3 -yl)-5-(2-( 1 -methyl- 1H- \-(6-chlo ropy ridi n-3 -y l)-5 -(3 -( 1 -methyl- 1H- pyrazol-4-yl)ethoxy)picolinamide pyrazol-4-yl)propoxy)picolinamide / ®N)rcl / ^Nyc|37 38 HN-MN '. I rl-N k--kQ o-v / 0N^) — x 7 —N= / \-(6-chloropy ridi n-3 -yl)-5-(methyl(( 1 -methyl- 5-((2-acetyl-2-azabicyclo[2.1. l]hexan-4- l / / -pyrazol-4-yl)mcthvl)amino)picolinamidc yl)mcthoxy)-\-(6-chloropyridin-3-yl) picolinamider=Ny-ci39 40 HN-V40 O'C'0N-y / Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropyridin-3-yl)-6-((3-(2- 5-((3-(2-hydroxypropan-2- hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - yl)bicyclo [1.1. l]pentan- 1 -y Ijmcthoxy yl)methoxy)nicotinamide methy Ipy rimidin-5 -y l)picolinamide _^N. / -N^CI41 42NHN-VNHO7A / 5 -((3 -chloro- 1 -methyl- l / / -pyrazol-4- \-(6-chloro-5-mctho\vpyridin-3-yl)-5-((3- yl)methoxy)-3 -mcthy l-\-(6-mcthy Ipy ridi n-3 - (difluoromethyl) bicy clo [ 1.1.1 ]pentan- 1 - yl)pyrazine-2 -carboxamide yl)methoxy)pyrazine-2-carboxamide / ^NX^C|43N44 / T xvA oJOA / C!F. A / N\F\-(6-chlo ropy ridi n-3 -y l)-3 -ethy 1-5 -((3 -(2- / ra / / .s-\-(6-chloropy ridin-3 -y l)-5 -((3 -ethy 1-3 - hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - hydroxycyclopentyl)oxy)-3-methylpyrazine-2- yl)methoxy)pyrazine-2-carboxamide carboxamide / 5=Ny-c|45 HN-W 46#H0^ / ^ / T01\-(6-chloropy ridi n-3 -y l)-5 -((3 - \-(6-chloropyridin-3-yl)-5-(2-(3-(2- (cy clopropanecarboxamido)bicy clo [ 1.1.1 ]penta hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - n- 1 -yl)methoxy)-3-methy lpyrazine-2- yl)ethoxy)-3-methylpyrazine-2 -carboxamide carboxamide / ^Ny-CI Z^y-CI 47 48HO / klHN-V#34 r-*N IoN\H\-(6-chlo ropy ridi n-3 -y l)-3 -methy 1-5 -((3 - \-(6-chloropyridin-3-yl)-3-mcthvl-5-((3-(2- (methy lamino)bicy clo [1.1.1 ]pentan- 1 - oxooxazolidin-3 -yl)bicy clo [1.1.1 ]pentan- 1 - yl)methoxy)pyrazine-2 -carboxamide yl)methoxy)pyrazine-2-carboxamide / ^NN^C|49 r-NjT'V 500 P'VO’JI / V-7 XHAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureA-(6-chloropyridin-3-yl)-5-((3-(2- \-(6-chlo ropy ridi n-3 -y l)-5 -(( 1 -(3 - hydroxypropan-2-yl)oxetan-3-yl)methoxy)-3- hy droxypentan-3 -yl)-2 -oxabicyclo [2.1.1] hexan- methylpyrazine-2-carboxamide 4-yl)methoxy)-3 -methylpyrazine-2- carboxamide51 52 / ^NyCI HO / A JV3 -chloro-\-(6-chloropy ridi n-3 -yl)-5-((3 -(2- \-(6-chloropyridin-3-yl)-5-(( / ra / / .s-3-hydroxy- 3 -methylcyclohexyl)oxy)-3 -methylpyrazine-2- hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - carboxamide yl)methoxy)pyrazine-2-carboxamide / ^NyCI Z^NK^C|53 54#HNAJ N^\N\|5 -((5 -chloro- 1 -methyl- 1 / / -py razol-4- 5-((5-chloro-l-mcthvl-l / / -pyrazol-4- yl)mcthoxy)-\-(6-chloropyridin-3-vl)-3- yl)methoxy)-A-(6-chloropyridin-3-yl)-3- fluoropicolinamide methoxypicolinamide / ^Ny-CI / ^Nx^c|55 56 HN-MF NN- NVK -\ / '°' Cl / Cl\-(6-chloropyridin-3-yl)-5-((4- fluorophenyl)sulfonyl)picolinamide \-(6-chloropy ridi n-3 -yl)-5-(((3- fluorobicy clo [1.1.1 ]pentan- 1 - / ^NyCI yl)methyl)sulfonyl)picolinamide / *N)r 57cl" / Mb 58O=S-VN0o0FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropy ridi n-3 -yl)-5-( 1 -(3 -(2- hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - yl)ethoxy)picolinamide, Enantiomer 1 (59),Enantiomer 2 (60)*_N. / Cl \-(6-chloropyridin-3-yl)-6-((3-(2- hy droxypropan-2-y l)bicy clo [ 1.1.1 ]pentan- 1 - i I T yl)methoxy)-2 -methoxy nicotinamide 1h / ^NyCI 59, FJ06160* Hcr |. N. / ClI I T1HHCT |\-(6-chloropyridin-3-yl)-5-((3-(2.2-difluoro-l- \-(6-chloropy ridin-3 -yl)-5-((3- hy droxy ethy l)bicy clo [1.1.1 ]pentan- 1 - (cy clopropy l(hy droxy )methy l)bicy clo [1.1.1 ]pen yl)methoxy)-3-methylpyrazine-2 -carboxamide, tan-l-yl)methoxy)picolinamide, Enantiomer 1 Enantiomer 1 (62), Enantiomer 2 (63)* (64), Enantiomer 2 (65)*„ ^^ / Cl0r n j? / Al1H J H62, 64,63* F' y7'' 65*OH OH„ ^\ / CI0r H0flOH OH\-(6-chlo ropy ridin-3 -y l)-5 -((( 1, 5 -dimethyl- 1H- pyrazol-4-yl)methyl)amino)-3 - \-(6-chloropyridin-3-yl)-5-((2- methylpicolinamide (difluoromethy l)thiazol-5 -yl)methoxy )-3 - methylpyrazine-2-carboxamide / ^NK^C|66NHNAV 671 / rNHNA-Y0F^1 °f\\ Jr / N\Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropyridin-3-yl)-5-((3- methoxy isothiazol-5 -y l)methoxy )-3 - \-(6-chloropy ridin-3 -y l)-5 - ( (3 - methylpyrazine-2-carboxamide fluorobicyclo [1.1.1 ]pentan- 1 - yl)methoxy)pyrimidine-2-carboxamide Z^N\^CI68 69F^C / A-(5-chloropyrazin-2-yl)-5-((3-(2- \-(6-chloropy ridin-3 -vl)-5-(3 -(2- hy droxypropan-2-y l)bicy clo [ 1.1.1 ]pentan- 1 - hy droxypropan-2-y l)azetidin- 1 -y l)picolinamide yl)methoxy)picolinamide / =N'rC|N^V-CI 70 HN-M 71NHN-VJ o-Cr-o \__AN-O^°\-(6-chloropyridin-3-yl)-5-((3-(2- \-(6-chloropyridazin-3 -yl)-5-((3 -(2- hy droxypropan-2-y l)bicy clo [ 1.1.1 ]pentan- 1 - hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - yl)oxy)picolinamide yl)methoxy)picolinamideN-^CIHN-W „ HNA-? 72 73o-O^°3-(2-(5-chloro- 1 -methyl- l / / -pyrazol-4- yl)ethyl)-A-(6-chloropyridin-3-yl)-5- \-(6-chloropy ridin-3 -yl)-5 -(( 1, 5 -dimethyl- 1H- methoxypicolinamide pyrazol-4-yl)methoxy)-3-ethylpicolinamide / ^N / TCIHN^ Z^N / TCIHNAJ'74O>AO75XV ' JpNCI^N1Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropyridin-3-yl)-6-fluoro-5-((3-(2- \-(6-chlo ropy ridin-3 -y l)-3 -methy 1-5 -((3 - hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - (methy lsulfonamido)bicy clo [1.1.1 ]pentan- 1 - yl)methoxy)picolinamide yl)methoxy)pyrazine-2 -carboxamide 0 / ^Ny-CI " -O76 77N \ _ VAc. \-(6-chloropy ridin-3 -vl)-4-((3 -(2- \-(6-chloropy ridin-3 -y l)-5 -((3 - hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - yl)mcthoxy)-6.7-dihydro-5 / / - hydroxybicyclo [1.1.1 ]pentan- 1 - yl)methoxy)picolinamide cyclopenta[c]pyridine-l-carboxamide / ^N\^C|78 79O-QA)\-(6-chloropy ridin-3 -yl)-5-(( 1 -methyl- 1H- \-(6-chloropy ridin-3 -yl)-5-((3 -(2 -hydroxy-1 - pyrazol-4-yl)methoxy)-3 - methoxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - (methylamino)pyrazine-2-carboxamide yl)methoxy)picolinamide80N81#o-O^oNH• / / / \-(6-chloropyridin-3-yl)-3-mcthyl-5-(pyrimidin- A-(6-chloropyridin-3-yl)-5-((l-(2,2- 5-ylmethoxy)pyrazine-2 -carboxamide difluoroethyl)-5-methyl-l / 7-pyrazol-4- yl)methoxy)-3 -methy lpyrazine-2 -carboxamide / ^Nyc|82 83NXw p N= / \-(6-chloropyridin-3-yl)-5-((l-(2.2- \-(6-chloropyridin-3-yl)-6-((3-(2- difluoroethyl)-3 -methyl- 1 / / -py razol-4- hy droxypropan-2-y l)bicy clo [ 1.1.1 ]pentan- 1 - yl)methoxy)-3-methylpyrazine-2-carboxamide yl)methoxy)-4-methoxy nicotinamide84 HN-M 85 j? HN-CrF N=\Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chlo ropy ridi n-3 -y l)-5 -((3 -(A- methy lacetamido)bicyclo [1.1.1 ]pentan- 1 - \-(6-chloropv ridi n-3 -yl)-5-(((3- yl)oxy)picolinamidefluorobicy clo [1.1.1 ]pentan- 1 - yl)methyl)(methyl)amino)picolinamide / ®NS^CI 86 87NHN-Mo-O^° X. fl0A-(6-chloropyridin-3-yl)-5-((2-fluoro-5- \-(6-chloropv ridi n-3 -yl)-5-((3 -fluoro- 1 - ((methylsulfonyl)methyl)benzyl)oxy)-3- (methy I-J3)- 1 / / -pv razol-4-vl [methoxy )-3 - methylpyrazine-2-carboxamide methy lpyrazine-2-carboxamide Ck88 ii089 1 H XJI lHk IJ 0o" 'o O-V-N 1F D\-(6-chlo ropy ridi n-3 -y l)-5 -(( 1 -(2-(methoxy- z A ) c t hy 1 ) - 1 H-py razol-5 -yl)methoxy )-3 - 3-amino-\-(6-chloropyridin-3-vl)-5-((4-fluoro- methylpyrazine-2-carboxamide 1 -( methy 1 -c / 3)- 1 / / -py razo 1 -3 - yl)methoxy)pyrazine-2 -carboxamide 1 H \NH20 f^^CI90 91H_ II 1HN-N\ - < D o -f- N J0— (-D DV"" TD5 -((3 -chloro- 1 -(methy I-J3)- 1 / / -py razol -4-y 1 -5 - 3-amino-A-(6-chloropyridin-3-yl)-5-((4-fluoro- r / )mcthoxy)-\-(6-chloropyridin-3-vl)-3- 1 -(methy l-A,)- 1 H-py razol-3 -y 1-5 - methylpyrazine-2-carboxamide r / )methoxy)pyrazine-2 -carboxamideNH2o 1 H92 93 ci V a tlD N^O^ II N 1 H> / T[ 0N JID / N\-JkD N^'DDDJoAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureA-(6-chloropyridin-3-yl)-5-((5-((methoxy- \-(6-chlo ropy ridi n-3 -y l)-5 -(( 1 -(2-(methoxy- r / dmcthy l-r / 2)- 1 -(methyl-c / 3)- 1 / / -py razol-4- r / 3)ethy 1- 1, 1.2.2-r / i)- 1 / / -py razol-5-y l)mcthoxy- yl)methoxy-c / 2)-3 -methy lpyrazine-2- c / 2)-3 -methy lpyrazine-2 -carboxamide carboxamide / ^ / Cl1 H \94 A A / A ND N 95 oDAX AD N ZX XAANHii °N-X N-N DV DDZ>°TV°DOO < >D D D3 -ami no-\-(6-chloropy ridin-3 -y 1) -5 -((3 -fluoro- \-(6-chlo ropy ridi n-3 -y l)-5 -((5 -fluoro- 1 -(methy 1- 1 -methyl- 1 / / -py razol-4-y 1 Jmcthoxy )py razinc-2- r / 3)- 1 / / -py razol-4-y 1-3 -d) methoxy )-3 - carboxamidemethy lpyrazine-2-carboxamide / H^ / CI / Cl NH20 A Y 96 97 F NA^AN-A / ND kr^OA^'NOH— N \ N / I 0D N^D / 3 -ami no-\-(6-chloropy ridin-3 -yl)-5-(( 1 - 3 -amino-N-(6-chloropyridin-3 -yl)-5-(( 1 -methyl- methyl- l / / -pyrazol-4-yl)mcthoxy)pyrazinc-2- lH-pyrazol-5-yl)methoxy)pyrazine-2- carboxamide carboxamide / Cl / H\ / C NH2l o Y Y 98 NH2O fl 99V AUHN / I 0NO^° 'A / 3 -ami no-\-(6-chloropy ridin-3 -yl)-5-(( 1 - 3-amino-\-(6-chloropyridin-3-yl)-5-((4-fhioro- (difluoromethyl)- 1 / / -py razo 1-5 - 1 -methyl- 1 / / -py razol-3 -yl)methoxy)pyrazine-2- yl)methoxy)pyrazine-2 -carboxamide carboxamideNH2O A^CINH2o AACI100 F NAYANA- / N 101 N AVANAAAAUHHA / 0N-NN-N / kFFAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropyridin-3-yl)-5-((4-fluoro-l-(2- hvdroxypropyl)-l / / -pyrazol-5-yl)mcthoxy)-3- methylpyrazine-2 -carboxamide, Enantiomer 1 (103), Enantiomer 2 (104)* 3-amino-\-(6-chloropyridin-3-yl)-5-((5- (difluoromcthyl)-l-(mcthyl-t / 3)-l / / -pyrazol-4- 1 H \ yl)methoxy)pyrazine-2-carboxamide FNXN^NNH20 X JJH103,102 M-N\104* ^QHHN* / J0N-\1 N1FD D FHN-N^ _ ^OH\-(6-chloropy ridin-3 -y 1) -5 -( 1 -(4-fluoro- 1 - methyl- 1 / / -py razol-3 -yl)-2 -methoxy etho xy)-3 - methylpyrazine-2 -carboxamide, Enantiomer 1 (106), Enantiomer 2 (107)* \-(6-chloropyridin-3 -yl)-5-(( 1 -(cyanomethyl)-5- methyl- 1 H-py razol-4-y 1 )methoxy )-3 -11 H methylpyrazine-2-carboxamide106, NX XN1 5 —N y oH0107*Z~-N oHA 'N=^ % NXJAJOP — N N y J oHFA-(6-chloropyridin-3-yl)-5-((l-(2,2- difluoroethy l)-4-methy 1- 177-1,2,3 -triazol-5 - \-(6-chloropy ridi n-3 -yl)-5-(( 1 -(difluoromethyl)- yl)methoxy)-3 -methylpyrazine-2 -carboxamide 5-(hvdroxymcthyl)-l / / -pyrazol-4-yl)mcthoxy)- 3 -methylpyrazine-2 -carboxamide1 H XA 108 109C<0HNV N^NN; oHAN ^70N-NFhAFXAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropy ridin-3 -y 1) -3 -methyl-5-((6- \-(6-chloropyridin-3-vl)-5-((4- (methylsulfonyl)pyridin-3-yl)methoxy)pyrazine- (hydroxy methy l)thiazol-5 -y l)methoxy )-3 - 2-carboxamide methy lpyrazine-2-carboxamide 110 IllAJHr0HNV N^N1 / ^A 0AAO' JHO=S N\\-(6-chloropyridin-3-yl)-5-((c / .s-3- hydroxycyclohexyl)oxy)-3-methylpyrazine-2- \-(6-chloropy ridi n-3 -yl)-5-((3 -fluoro-2- carboxamide hydroxypyridin-4-yl)methoxy)-3 - methy lpyrazine-2-carboxamide A 1 A H A^N112 N A^ N 113 1 HJ 0 UHHOX A^X AJHHO*^^A-(6-chloropyridin-3-yl)-5-((6-(l,2- dihydroxy ethy l)-5 -fluoropy ridin-3 - yl)methoxy)-3-methylpyrazine-2-carboxamide, Enantiomer 1 (115), Enantiomer 2 (116)* 5-((5-chloropyrazin-2-yl)oxy)-A-(6- 115,chloropyridin-3-yl)-3-methylpyrazine-2- 116*carboxamide114 XX1 n HO''A / A" VA NX X OHAjH1 H NX'’SA^N'^: S^NF^^ X> NHOH\-(6-chloropy ridi n-3 -yl)-5-((4-fluoro- 1 -methy 1- \-(6-chloropyridin-3-yl)-5-((6-fluoro-4- 1 / / -py razol-3 -yl)methoxy )-3 - (hydroxymethyl)pyridin-3 -yl)methoxy)-3 - (methoxymethyl)pyrazine-2 -carboxamide methy lpyrazine-2-carboxamide d 9 f iT117 118 i if rv F N N r0HNA N^BA^x AUHA AJHN-N X J / F NAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure5-((2 -chloro- 1 -methyl- l / / -imidazol-5- y 1 Jmcthoxy )-\-(6-chloropy ridin-3 -yl)-3 -(oxetan- \-(6-chloropy ridi n-3 -yl)-6-((4-fluoro- 1 -methyl- 3 -yl)pyrazine-2 -carboxamide 1 H-py razol-3 -yl)methoxy)-2- O (methylamino)nicotinamide ^NH o AA 119 1 H AT 120CIN AA"NA^N A AF N N AS^N i AN AUHJHO AAo^"VN N-N / Clx\-(6-chloropyridin-3-yl)-5-((2-(l- \-(6-chloropyridin-3-yl)-5-((l-cyano-5- hydroxy ethyl)thiazol-5 -y l)methoxy )-3 - oxaspiro [2.3] hexan- 1 -y l)methoxy)-3 - methylpyrazine-2 -carboxamide, methylpyrazine-2 -carboxamide, Enantiomer 1 (123), Enantiomer 2 (124)* Enantiomer 1 (121), Enantiomer 2 (122)*1 H p A 1 n HAUH121, 12322*0,124* AsO-J HO- / 1 H \ i? rANNV N^NN AANA / N N 0 AUHHO" A<s\-(6-chloropy ridi n-3 -y 1) -5 -((3 -fluoro-1 -methyl- \-(6-chloropyridin-3-yl)-3-(difluoromcthyl)-5- l / / -pyrazol-4-yl)mcthoxy)-3-mcthvlpyrazinc-2- (( 1 -methyl- 1 H-py razol-4-y 1 )methoxy )py razine- carboxamide2-carboxamide125FYFO AA 1? fAN AANA^N 126F NAAA'A / NAAHA / - AUh--N ONx 70 / 5-((3 -chloro- 1 -methyl- 1 H-py razol-4- \-(6-chloropy ridi n-3 -yl)-5-((5- yl)mcthoxy)-\-(6-chloropyridin-3-yl)-3- (hydroxymethyl)- 1 -methyl- l / / -pyrazol-4- methylpyrazine-2-carboxamide yl)methoxy)-3 -methylpyrazine-2 -carboxamide 127 NA 1 SA HNA^N128H01 H p A > NMNAN Ajh— N 0 — N ZV 7^ A 0 MHN=\Cl iAAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureA-(6-chloropyridin-3-yl)-5-((5-(difluoromethyl)- 1 -methyl- 1 H-py razol-4-y l)methoxy )-3- 3 -ami no-\-(6-chloropy ridin-3 -y 1) -5 -((3 -fluoro- methylpyrazine-2-carboxamide 1 -(2 -fluoroethyl)- 1 / / -py razol-4- yl)methoxy)pyrazine-2 -carboxamide 1? AlT129 NAANA^NNH2o AACI130 NAA"NA^zAjlh NN i ONA N0 HV—' N=\ / AFFFA-(6-chloropyridin-3-yl)-5-((l-(2,2- 5-((3 -chloro- 1 -(methyl-X)- l / 7-pyrazol-4- dinuorocthvl)-4-fluoro-l / / -l.2.3-triazol-5- yl)mcthoxy)-\-(6-chloropyridin-3-yl)-3- yl)methoxy)-3 -methy lpyrazine-2 -carboxamide methylpyrazine-2-carboxamide131 A 1 A H A f " N 132 F-A NAA-NA / N D.HAJHDNN=\xA0Cl NA F\-(6-chloropy ridi n-3 -y 1) -5 -((3 -(difluoromethyl)- \-(6-chloropy ridi n-3 -yl)-5-((5- l-(methyl-c / 3)-177-pyrazol-4-yl)methoxy)-3- (methoxymethyl)-l -methyl- l / / -pyrazol-4- methylpyrazine-2-carboxamide yl)methoxy)-3 -methy lpyrazine-2 -carboxamide 133 134D. JI NHA ]0D N=\ c — N ^7 0HF iA\-(6-chloropy ridi n-3 -y l)-5 -((c / 5-3 - hydroxycyclopentyl)oxy)-3-methylpyrazine-2- carboxamide, Enantiomer 1 (136), Enantiomer! (137)*NA 1 SA H-NA l S / AN3-amino-\-(6-chloropyridin-3-yl)-5-((5- (methoxymethyl)- 1 -methy 1- 1 H-py razol-4- A 0 ANHyl)methoxy)pyrazine-2-carboxamide136,135 NH20 A|TCI / XNAANA / N 137*V- A«NHKA 1 H L A JANHHO~Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureA-(6-chloropyridin-3-yl)-5-((5-(difluoromethyl)- 3 -amino-5-((3 -chloro- 1 -methyl- 1 H-py razol-4- l-(mcthyl-z / 3)-l / / -pyrazol-4-yl)mcthoxy)-3- yl)mcthoxy)-\-(6-chloropyridin-3-yl)pyrazinc- methylpyrazine-2-carboxamide 2-carboxamide / ^ / Cl NH2O Y fl 138 139N AJN~ / \I OHAJ— N 7 ^ 0HN=\DA / fD D F Cl3 -ami no-\-(6-chloropy ridin-3 -y 1) -5 -((3 -fluoro- 5 -( 1 -hydroxy ethyl) - 1 -methyl- 1 / / - py razol-4- 3-ainino-\-(6-chloropyridin-3-yl)-5-((c / .s-3- yl)methoxy)pyrazine-2-carboxamide,Enantiomer 1 (141), Enantiomer 2 (142)* hydroxycyclopentyl)oxy)pyrazine-2- carboxamide NH2o AlTCI / ClNH20 f Y A NAANA / N 40#141, AANHH142* NA0 FNH2o AACIHOA N'\^N-^'N— N A 7^^ A 0 ANHNA FA-(6-chloropyridin-3-yl)-5-((l-(2,2- 3 -amino-\-(6-chloropyridin-3-yl)-5-(( 1 -(2,2- difluoroethy l)-4-(methy 1 -z / 3)- 1H- 1,2,3 -triazol-5- difluoroethyl)-4-methyl-1H-1,2,3-triazol-5- yl)methoxy)-3 -methylpyrazine-2 -carboxamide yl)methoxy)pyrazine-2-carboxamide / ClF NH20F\ 1 i143 144F^> NAA-NA^NAUAjH HNN' A. J °0N~\DA5 -((5 -( 1 -aminoethy l)-3 -fluoro- 1 -methyl- IH- pyrazol-4-vl)mcthoxy)-\-(6-chloropyridin-3-vl)- 3 -amino-\-(6-chloropy ridin-3 -yl)-5-((( IS,3R)- 3 -methylpyrazine-2 -carboxamide, Enantiomer 3 -hydroxy-3 -methy lcyclopentyl)oxy)pyrazine- 1 (141), Enantiomer! (142)* 2-carboxamide, Enantiomer 1 (147), Enantiomer 2 (148)* H2N^Zz1 1 A1 0(l 7 145, — N VA0JH147,46* NA 148* HO XJ JCV 'F / O''A'''AH2"o ^^ / Clrx / ^ / Cl1 UN0(l 7 H2N^." NAAAJ— N0 HNH0•zXi I": IA -'^O''A'''AJH2FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-N-(6-chloropyridin-3-yl)-6-(((lR,3S)- 3 -hydroxy-3 - methylcyclopentyl)oxy)nicotinamideEnantiomer 1 (149), Enantiomer 2 (150)*2-amino-\-(6-chloropvridin-3 -yl)-6-((( l.s.4.s)-4- u fv hydroxy-4-methylcyclohexyl)oxy)nicotinamide 49- \ II JH15150* uHO X^ ''O^N NH21 1 L II HNH2£ / vH0 X^ XT 'N^''''NH23 -amino-\-(6-chloropyridin-3 -yl)-5-((( 1 / ?.3, S’)- 3 -amino-\-(6-chloropyridin-3 -yl)-5-((( LS’.3 / ?)-3 - 3 -hydro xy -3- hydroxy-3-methylcyclohexyl)oxy)pyrazine-2- methylcyclopentyl)amino)pyrazine-2- carboxamide carboxamide Enantiomer 1 (152), Enantiomer 2 (153)* Enantiomer 1 (154), Enantiomer 2 (155)*0fl N0f 452- 154- •ZX / / / -•" 53* _□ / jAA " 155*H0 X^S*N' / KN' / VNH2V hi NH2H0(I N..,ja HO / N' / KN' / VNH2N NHH23 -amino-5-((3 -fluoro-1 -methyl- 1 H-py razol-4- yl)mcthoxy)-\-(2-mcthvlpvrimidin-5- 3 -amino-5-((3 -fluoro-1 -methyl- 1 H-py razol-4- yl)methoxy)-A-(2-methylpyrimidin-5- yl)pyrazine-2 -carboxamide yl)pyrazine-2 -carboxamide0rf N156 157v s x^clA V A' r_N / ;:Y^0 N NH2N^jj^O^N^NH2NAF3 -amino-\-(6-chloropyridin-3-yl)-5-(( 1 -(2,2- difluoroethy l)-4-(methy 1 -c / 3)- 1H- 1,2,3 -triazol-5- A-(6-chloropyridin-3-yl)-5-((l-(2,2- yl)methoxy)pyrazine-2-carboxamide difluoroethyl)- 1 / / - 1,2,4-triazol-5-yl)methoxy)- 3 -methylpyrazine-2 -carboxamide F 0 ^YCIF o ^Y 158 159CIAF, N^ ANAZN A JLHN;N^<^O^N^NH2' 1 H N' X^DVND^DAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-\-(6-chloropyridin-3-yl)-5-((4-(2.2- 3 -amino-\-(6-chloropyridin-3 -yl)-5-(( 1 -(2,2- difluorocthv l)-4 / / - 1,2,4-triazol-3 - difluoroethyl)-4-fluoro-177-l,2,3-triazol-5- yl)methoxy)pyrazine-2-carboxamide yl)methoxy)pyrazine-2 -carboxamide F O f -C' F 0 PA 160 161AlrNA’AN'1 AH FIT "N / NbA N H,N-N'p'O'^N^NH2\\ N' KN NAF3-amino-5-((4-chloro-l-(2,2-difluoroethyl)-l / 7- 3 -amino-\-(6-chloropyridin-3 -yl)-5-(( 1 -(2- l,2,3-triazol-5-yl)methoxy)-7V-(6-chloropyridin- methoxy ethyl)- l / / -pyrazol-5 - 3 -yl)pyrazine-2 -carboxamide yl)methoxy)pyrazine-2 -carboxamide F O fYC'0fl A 162 A A A 163JL YNH'NYAAANH2N N H2N'NX_NACI 0""5-(( 1 -(2-aminopropy l)-3 -fluoro- 177-pyrazol-4- yl)mcthoxy)-\-(6-chloropyridin-3-yl)-3- methylpyrazine-2-carboxamideEnantiomer 1 (164), Enantiomer 2 (165)*2-amino-\-(6-chloropyridin-3-yl)-6-((l-(2.2- ° (i y difluoroethy 1)- 1 / / - px razol-5 - yl)methoxy)nicotinamide64- 16665* k A I^CINH2N>OrFy XNN^J^O^N^NH2A NA NH2H\-(6-chloropy ridin-3 -y 1) -5 -((3 -fluoro-l-((> S'- methy Isulfonimidoy l)methy 1) - 1 / / - px razol-4- yl)methoxy)-3-methylpyrazine-2 -carboxamide 3-amino-5-((4-chloro-l-(2,2-difluoroethyl)-l / 7- Enantiomer 1 (168), Enantiomer 2 (169)* l,2,3-triazol-5-yl)methoxy)-7V-(6-chloropyridin- 3 -yl)pyrazine-2 -carboxamide ° ii Y F 0 <-YCI168- 167A AA V 169*JI J.HAonF O AVCINNy^O^N^NH2JNY^H 'NACIHN^NJT"0 / %N" FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methoxy)-3-(methoxymethyl)pyrazine-2-carboxamiderac-3-chloro-N-(6-chloropyridin-3-yl)-5-(((1R,3S)-3-hydroxy-3-methylcyclopentyl)oxy)pyrazine-2-carboxamide170 171#? INN / / 0X 1 JI 1 H / N-\ y- FF3-amino-N-(6-chloropyridin-3-yl)-5-((((1R,3S)-3- N-(6-chloropyridin-3-yl)-5-((3-(1-hydroxyethyl)isoxazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamide Enantiomer 1 (172), Enantiomer 2 (173)* Enantiomer 1 (174), Enantiomer 2 (175)* N. 0 |V o r n 72- HO* \ J. JI 2H174- 73* N NH2175*H02 — o JJ NHN'°% o rrcl0r n / Cl. N^ANX / N HO'X J JI HQ. JI'O N 2 NHH2\ 0 NH / N-03-amino-N-(6-chloropyridin-3-yl)-5-(((lR,3S)- 3 -hydroxy-3 - (hydroxymethyl)cyclopentyl)oxy)pyrazine-2- carboxamide 2-amino-A-(6-chloropyridin-3 -yl)-6-(( 1 -(2,2- Enantiomer 1 (176), Enantiomer 2 (177)* difluoroethyl)-4-fluoro-177-l,2,3-triazol-5- yl)methoxy)nicotinamideo r H76- 77* -XA ifNY^N^ 178 t s rvci0r iTN' Y0 N NH2N~\F2-amino-6-((4-chloro-1-(2,2-difluoroethyl)-1H-1,2,3-triazol-5-yl)methoxy)-N-(6-chloropyridin-3-yl)nicotinamide5-((4-chloro-1-(2,2-difluoroethyl)-1H-1,2,3-triazol-5-yl)methoxy)-N-(6-chloropyridin-3-yl)-3-methylpyrazine-2-carboxamide F 0 YYCI179 LFs rvrr^ci180ANNy^o^N-^NH2 n;n H'NACI N-\ClAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-N-(6-chloropyridin-3-yl)-6-((1-(2,2-difluoroethyl)-4-(methyl-d3)-1H-1,2,3-triazol-5-yl)methoxy)nicotinamideN-(6-chloropyridin-3-yl)-5-((3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-3-methylpyrazine-2-carboxamide F 9 p V0fl d 181 K. AAV 182riV -'"FN J Jl AHer N NH2" KDFD^DN-(6-chloropyridin-3-yl)-5-((5- 5 -((3 -chloro- 1 -methyl- IH-py razol-4- (difluoromethyl)- 1-methy 1- lH-pyrazol-4- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- yl)methoxy)-3 -methy Ipicolinamide methylpicolinamide183 u 184 N|f V N II HII J H / NyFFN-(6-chloropyridin-3-yl)-5-((3-(cyanomethyl)oxetan-3-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((3-(difluoromethyl)oxetan-3-yl)methoxy)-3-methylpyrazine-2-carboxamide185 186F FA JLHT A JLHO'"3I I NN-(6-chloropyridin-3-yl)-3-methyl-5-((1-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-((1-methyl-1H-imidazol-5-yl)methoxy)picolinamide187 u 188 urfx ix H II J HN / ^ 0N-NXN-(6-chloropyridin-3-yl)-5-((1,4-dimethyl-1H-pyrazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-(oxazol-5-ylmethoxy)pyrazine-2-carboxamidecarboxamide9 |f i189, N_A.. A^N 190 u, <N^rANA^Nif I " \ II JHN(V^°n A'Vo N-NXAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-(isothiazol-4-ylmethoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-(isothiazol-3-ylmethoxy)-3-methylpyrazine-2-carboxamide0Il Y191 192if y-XN^¥^°NO |5-((5-chloro-1-methyl-1H-pyrazol-4-yl)methoxy)-3-methyl-N-(6-methylpyridin-3-yl)pyrazine-2-carboxamide5-((3-fluoro-1-methyl-1H-pyrazol-4-yl)methoxy)-3-methyl-N-(6-methylpyridin-3-yl)pyrazine-2-carboxamide0193 Y -XX 194 A / N^N II JHN-r / Y^oNA NA / ClF5-((2-chloro-1-methyl-1H-imidazol-5-yl)methoxy)-N-(6-chloropyridin-3-yl)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((3-isopropyloxetan-3-yl)methoxy)-3-methylpyrazine-2-carboxamide0fi Y195 196 Ui JI JLHO'3ClN-(6-chloropyridin-3-yl)-5-((1-(difluoromethyl)cyclobutyl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-(thiazol-2-ylmethoxy)pyrazine-2-carboxamide / ^ / Cl197F F198. N A AxT JL JLHs 1 X "V-NN-(6-chloropyridin-3-yl)-3-methyl-5-(thiazol-4-ylmethoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-(((1s,4s)-4-hydroxycyclohexyl)oxy)-3-methylpyrazine-2-carboxamide199? IN 200M ANII H HCk. N. Ai i nN1 1 II JH^ / ^O^S'N^Ss'3-amino-N-(6-chloropyridin-3-yl)-5-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)oxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((1s,3s)-3-hydroxy-3-methylcyclobutoxy)-3-methylpyrazine-2-carboxamideo z^ / CI 201 202° liHO’Y1 IN / HNH0XV 1 X "X Y N N H2Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((1r,3r)-3-hydroxy-3-methylcyclobutoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-6-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)oxy)-2-methylnicotinamide203 ° (TV1204 0 (TV1\ Jl^NH0" TA 1 I “H0,YA f I HN-(6-chloropyridin-3-yl)-5-((1-cyanocyclopropyl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)methoxy)-3-methylpyrazine-2-carboxamide o < 2050II N 206NvCIN1 AH3-amino-N-(6-chloropyridin-3-yl)-5-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)oxy)pyrazine-2-carboxamiderac-3-amino-5-(((1R,3S)-3-amino-3-methylcyclopentyl)oxy)-N-(6-chloropyridin-3-yl)pyrazine-2-carboxamide 207 O fl 208#■ / iV -2X IH NX^S*O^N'^NH21N-(6-chloropyridin-3-yl)-5-((3-cyano-1-methyl-1H-pyrazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-3-methylpyrazine-2-carboxamide209 210II JHN'NXN-(6-chloropyridin-3-yl)-5-((5-cyano-1-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamide2-amino-N-(6-chloropyridin-3-yl)-6-((1-(difluoromethyl)-1H-pyrazol-5-yl)methoxy)nicotinamideu rv 211 212II J H L IIHN N HoNN-\ VyF1FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-N-(6-chloropyridin-3-yl)-6-((1-(2-methoxyethyl)-1H-pyrazol-5-yl)methoxy)nicotinamide3-amino-N-(6-chloropyridin-3-yl)-5-((4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl)methoxy)pyrazine-2-carboxamide ° NH2o213 214ftHHO^ 7 IT N N'M^Ob-NN-(6-chloropyridin-3-yl)-5-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-(((1,3-dimethyl-1H-pyrazol-4-yl)methyl)amino)picolinamide0ifV0b Y 215 216A II J H X / - NA^°NN, J HN-JN^ \ / N-(6-chloropyridin-3-yl)-5-((1-(2,2-difluoroethyl)-5-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpicolinamideN-(6-chloropyridin-3-yl)-5-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpicolinamide 217? AY 218\ II 1 H II JHN °FY AFY N*\F FN-(6-chloropyridin-3-yl)-5-((4-fluoro-1-methyl-1H-pyrazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamiderac-N-(6-chloropyridin-3-yl)-5-(((1R,3R)-3-hydroxy-3-(methoxymethyl)cyclopentyl)oxy)-3-methylpyrazine-2-carboxamide 2190h N220#0ii Y Ao^TkoTNThN'NX2-amino-N-(6-chloropyridin-3-yl)-6-((1-(methyl-d3)-1H-pyrazol-5-yl)methoxy)nicotinamiderac-3-amino-N-(6-chloropyridin-3-yl)-5-(((1R,3S)-3-hydroxy-3-(methoxymethyl)cyclopentyl)oxy)pyrazine-2-carboxamide222 u rv 221#L IIH0li N AyYi N N H2 / -. <NYN AT "q / oXA J, X,N NyKDHO ^"*0 N NHH2D^DAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)methoxy)-3-methylpicolinamiderac-N-(6-chloropyridin-3-yl)-5-(((1R,3S)-3-hydroxy-3-methylcyclopentyl)oxy)-3-(methoxymethyl)pyrazine-2-carboxamide.0. ~. N.. Cl24#223 HII J H HOA A, JANHH<y |N-(6-chloropyridin-3-yl)-5-((3-(3-hydroxyoxetan-3-yl)bicyclo[1.1.1]pentan-1-yl)methoxy)picolinamideN-(6-chloropyridin-3-yl)-5-((3-(3-hydroxyoxetan-3-yl)bicyclo[1.1.1]pentan-1-yl)methoxy)picolinamide0(Y226 225 «II HoAj0~A °N^'""F oAN-(6-chloropyridin-3-yl)-5-((5-fluoro-1-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpicolinamideN-(6-chloropyridin-3-yl)-5-(isoxazol-5-ylmethoxy)-3-methylpyrazine-2-carboxamidemethylpicolinamide° rV228 227 ° rY A -V\ ii JHN< JN-(6-chloropyridin-3-yl)-3-methyl-5-((4-methylisoxazol-5-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-((5-methylisoxazol-4-yl)methoxy)pyrazine-2-carboxamide2300ii V 2290A A JI JhAHZA°N0\N-(6-chloropyridin-3-yl)-3-methyl-5-((5-methylisoxazol-3-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((3-methoxyisoxazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamide. N.. Cl ° irV0rf A 232 231 / / A1 H A Al AH0Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-3-methyl-5-((3-(trifluoromethyl)isoxazol-5-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((3-cyclopropylisoxazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamide / N / CI0ifV 234 A L U 233 JI jh<rAX- <jA°NA3-chloro-N-(6-chloropyridin-3-yl)-5-((3-fluoro-1-methyl-1H-pyrazol-4-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-((3-(trifluoromethyl)isoxazol-4-yl)methoxy)pyrazine-2-carboxamide ~ / N. / Cl / bk / CI0if V236 2350f A xi°ANH N-J|0 N ClN-VF / F^ F3-chloro-N-(6-chloropyridin-3-yl)-5-((5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((3-fluoro-1-methyl-1H-pyrazol-4-yl)methoxy)-3-(methoxymethyl)pyrazine-2-carboxamide ~ / N.. Cl / O\ / N.. Cl C I O A V238 237, AA-XXHNY / 0N-J / FN-(6-chloropyridin-3-yl)-5-((1-(2,2-difluoroethyl)-3-fluoro-1H-pyrazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamide3-chloro-N-(6-chloropyridin-3-yl)-5-((4-fluoro-1-methyl-1H-pyrazol-3-yl)methoxy)pyrazine-2-carboxamide / N / / CI 1 H S ( Y 240Fr\ 111H 239LAi] 0N J in^c|hT N-N / FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure5-((5-chloropyrazin-2-yl)methoxy)-N-(6-chloropyridin-3-yl)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-(pyridazin-4-ylmethoxy)pyrazine-2-carboxamide0h V242 241I P A AHN PPt NCI^N^3-amino-N-(6-chloropyridin-3-yl)-5-((4-(2,2-difluoroethyl)-1,2,5-oxadiazol-3-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((2,3-difluoropyridin-4-yl)methoxy)-3-methylpyrazine-2-carboxamide <? rr244cl243? [TAFv Ji AHN H2A ANh^1 ^1 ONNKiCTNN-(6-chloropyridin-3-yl)-5-((1-(2,2-difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5-yl)methoxy)-3-(methoxymethyl)pyrazine-2-carboxamide5-((4-chloro-1-(2,2-difluoroethyl)-1H-1,2,3-triazol-5-yl)methoxy)-N-(6-chloropyridin-3-yl)-3-(methoxymethyl)pyrazine-2-carboxamide246 245 L? r^clA A A A A K N / Y°NNJ0 N'NACIN-(6-chloropyridin-3-yl)-3-methyl-5-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)methoxy)picolinamide2480(I N 247 / AX II J HN -N-(6-chloropyridin-3-yl)-3-methyl-5-((1-methyl-1H-pyrazol-4-yl)methoxy)pyrazine-2-carboxamide5-((5-chloro-1-methyl-1H-pyrazol-4-yl)methoxy)-N-(6-chloropyridin-3-yl)-3-methylpyrazine-2-carboxamide250 u 249II J H-NV"0hr NAY0 N / ClAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((3-fluorobicyclo[1.1.1]pentan-1-yl)methoxy)-3-methylpyrazine-2-carboxamide6-((5-chloro-1-methyl-1H-pyrazol-4-yl)methoxy)-N-(6-chloropyridin-3-yl)-2-methylnicotinamide2520|| J 251 ATA u AYN X 1H£A°AN> XF I ClN-(6-chloropyridin-3-yl)-5-((5-fluoro-1-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((2-methoxythiazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamide254 ° iV 2530f| 1 \ II J H s IN / ^N-NY '°NZ°Y jf'0N-(6-chloropyridin-3-yl)-5-((1-(2-methoxyethyl)-1H-imidazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-(cuban-1-ylmethoxy)-3-methylpyrazine-2-carboxamide° irNrcl° rV256 255 / Y\ I JLHII J HV-NO'"N-(6-chloropyridin-3-yl)-5-((1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((1-(2,2-difluoroethyl)-1H-imidazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamide0(i N258 257NA <xNjP° 'X'HN-(6-chloropyridin-3-yl)-5-((4-fluoro-1-(2-methoxyethyl)-1H-pyrazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamide. Cl0(I N uF260 \ II J H 259kN-N^ F-7A0 / Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropy ridi n-3 -yl)-5-(( 1 -(cyanomethyl)-4- \-(6-chloropyridin-3-yl)-5-((l-(cyanomcthvl)- fluoro- 1 / / -py razol-3 -yl)methoxy)-3 - 4-fluoro-l / / -pyrazol-5-yl)incthoxy)-3- methylpyrazine-2-carboxamide methylpyrazine-2-carboxamide ° fl 3 ^0h262 261H AYW\ )l JH / F ^^N-(6-chloropyridin-3-yl)-5-((1-(3,3-difluoropropyl)-4-fluoro-1H-1,2,3-triazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((3-fluoro-1-methyl-1H-pyrazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamide0X V / ^ / Cl264 A Xj 263N X I HFN'N1A \\V 1 AI N " AVFFN-(6-chloropyridin-3-yl)-5-((4-fluoro-1-methyl-1H-imidazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((2-(2,2-difluoroethyl)-5-methyl-2H-1,2,3-triazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamide266? 1TA 265F\ II J HNA N*\FN-(6-chloropyridin-3-yl)-3-methyl-5-((3-methyl-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)methoxy)pyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-5-((4-fluoro-1-(2-methoxyethyl)-1H-imidazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamide N Cl 268 267x A AHF <NAV"0 N1 A AHN=\ ^-Nx_O-^N-(6-chloropyridin-3-yl)-5-((1-(2-methoxyethyl)-1H-pyrazol-5-yl)methoxy)-3-methylpyrazine-2-carboxamideN-(6-chloropyridin-3-yl)-3-methyl-5-((5-methyl-1-(oxetan-2-ylmethyl)-1H-pyrazol-4-yl)methoxy)pyrazine-2-carboxamide 270? f T 2690II AT ff V Nn AHA fALINAHNN'N^ _N=^0^Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-N-(6-chloropyridin-3-yl)-5-((1-(methyl- N-(6-chloropyridin-3-yl)-5-((2-ethyl-2,4,6,7- d7,)-1H-pyrazol-5-yl)methoxy)pyrazine-2- tetrahydropyrano[4,3-c]pyrazol-3-yl)methoxy)- carboxamide 3 -methylpyrazine-2 -carboxamide o. C0^Y' l h Y272 271 O _. rf N Y - " / UN 1 HN H2N'NK ^DDD3-amino-N-(6-chloropyridin-3-yl)-5-((1-(2- N-(6-chloropyridin-3-yl)-5-((1-(2-fluoroethyl)- fluoroethyl)-4-methyl-1H-1,2,3-triazol-5- 4-methyl-1H-1,2,3-triazol-5-yl)methoxy)-3- yl)methoxy)pyrazine-2-carboxamide methylpyrazine-2-carboxamide «0 / ^YIl Y10|| 1 274 273Y N YH"2“.w YF F3-amino-N-(6-chloropyridin-3-yl)-5-((4-fluoro- N-(6-chloropyridin-3-yl)-5-((4-fluoro-1- 1 -(mcthy l-r / j)- 1 / / -py razol-5- ( mcthy 1-r / j )- 1 / / -py razol-5 -yl)methoxy )-3 - yl)methoxy)pyrazine-2-carboxamide methylpyrazine-2-carboxamide o0^Yifi YYu276 275F<N^N^NL Y - " \ ii JHNV N H2AYO^N^N NYDN NYDD^DDDN-(6-chloropyridin-3-yl)-5-((5-(difluoromethyl)- \-(6-chloropyridin-3-yl)-5-((4- 1 -methyl- 1 / / - 1,2,3-triazol-4-yl)methoxy)-3 - (difluoromethyl)- 1 -methyl- 1 / / - 1,2,3 -triazol-5- methylpyrazine-2-carboxamide yl)methoxy)-3 -methylpyrazine-2 -carboxamide278 _ 1 U 277 F 1 UV -MHV oAJH-N YNU N \3-amino-N-(6-chloropyridin-3-yl)-5-((1-(2- N-(6-chloropyridin-3-yl)-5-((5- hydroxy -2 -methylpropyl)- 1 / / -py razol-3 - (difluoromethyl)-2-methyl-2H-1,2,3-triazol-4- yl)methoxy)pyrazine-2-carboxamide yl)methoxy)-3 -methylpyrazine-2 -carboxamide u280 279 F 1 UA AH^~N' v°N NHzLYVHNYI^OHO ' V / Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((1-(2,2- N-(6-chloropyridin-3-yl)-5-((1-(2,2- difluoroethyl)-4-methyl-1H-1,2,3-triazol-5- difluoroethyl)-1H-1,2,4-triazol-3-yl)methoxy)- yl)methoxy-d2)-3-methylpyrazine-2- 3 -methylpyrazine-2 -carboxamide carboxamideu YA 282 F ° AYCI281II J HA A AFA FN"\N-(6-chloropyridin-3-yl)-5-((3- N-(6-chloropyridin-3-yl)-5-((3-hydroxyoxetan- (difluoromethoxy )bicy clo [1.1.1 ]pentan- 1 - 3 -y l)ethy ny l)picolinamide yl)methoxy)-3-methylpyrazine-2-carboxamideu fTY 284 AYCl283n NJU J H F A AHFAY°0>YHN-(6-chloropyridin-3-yl)-5-(3-hydroxy-3- N-(6-chloropyridin-3-yl)-5-(3-hydroxy-3- methylbut- 1-yn- 1 -yl)-3-methylpyrazine-2- methylbut- 1 -yn- 1 -y 1) -3 -methylpicolinamide carboxamidei? rv 286 285JjA^HOH OHN-(6-chloro-5-methoxypyridin-3-yl)-5-((1- N-(6-chloropyridin-3-yl)-5-((((1S,3R)-3- (difluoromethyl)cyclopropyl)methoxy)-3- hydroxy-3 -methylcyclopentyl)oxy)-3 - methylpicolinamide methylpyrazine-2-carboxamide / N.. Cl Enantiomer 1 (287), Enantiomer 2 (288)*? f Yu Or 290 Jl II J H 287- 288* X J II 1 HHO'HO^VXXM^YN-(6-chloropyridin-3-yl)-5-((3-(1- N-(6-chloropyridin-3-yl)-5- (difluoromethoxy )ethyl)bicy clo [1.1.1 ]pentan- 1 - phenoxypicolinamide yl)methoxy)-3 -methylpicolinamide / N.. Cl F.292 289 f YF ) C? X / T~ N, O r n if N'vo— / VA / \ L II II JNH'= / HN— < JJ—Cl\ \=NAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(2-chloropyrimidin-5-yl)-5-((1- 5-((3 -fluoro- 1 -methyl- 177-pyrazol-4- (difluoromethyl)cyclopropyl)methoxy)-3- yl)mctlioxy)-3-mctlivk\-(2-mctlivlpyrimidin-5- methylpyrazine-2-carboxamide yl)pyrazine-2 -carboxamide294 $ ACI291 i s rvF|fVl'NA^NX II X H F N— NN^F5-((5-chloroisoxazol-4-yl)methoxy)-N-(6- N-(6-chloro-5-methoxypyridin-3-yl)-5-((1- chloropyridin-3-yl)-3-methylpyrazine-2- (difluoromethyl)cyclopropyl)methoxy)-3- carboxamide methylpyrazine-2-carboxamide / bk / Cl / bk. Cl0if " V296 2930rf " Vc\br3-amino-N-(6-chloropyridin-3-yl)-5-((1s,3s)-3- N-(6-chloropyridin-3-yl)-5-((3-ethoxyisoxazol- hydroxy-3-methylcyclobutoxy)pyrazine-2- 5-yl)methoxy)-3-methylpyrazine-2- carboxamide carboxamide° rvcl0II V" 298 295HOTX 1 X ”Npp° XH / ^°3-amino-N-(6-chloropyridin-3-yl)-5-((1-(2,2- 5-((3-chloroisoxazol-4-yl)methoxy)-7V-(6- difluoroethyl)-1H-1,2,4-triazol-5- chloropyridin-3-yl)-3-methylpyrazine-2- yl)methoxy)pyrazine-2-carboxamide carboxamide / N. / Cl r 0 fycl 0k V 300 297No-^Y'o-^'N'Y-Ny^o-^N^NH2VNNCI3-amino-5-((1-(2,2-difluoroethyl)-4-fluoro-1H- N-(6-chloropyridin-3-yl)-5-((4-fluoro-1- 1,2,3 -triazol-5-yl)methoxy)-7V-(2- (methyl-d3)-1H-pyrazol-3-yl)methoxy)-3- methylpyrimidin-5-yl)pyrazine-2 -carboxamide methylpyrazine-2-carboxamide NH20302 299F\ _ NAX'Xk 1HD \==kNc I FN^FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-N-(6-chloropyridin-3-yl)-5-((4-fluoro- 5-((1-(2,2-difluoroethyl)-4-fluoro-1H-1,2,3- 1-(2-hydroxypropyl)-1H-pyrazol-5- triazol-5-yl)methoxy)-3-methyl-N-(2- yl)methoxy)pyrazine-2-carboxamide methylpyrimidin-5-yl)pyrazine-2 -carboxamide304 \ ° rV1301 F 1 1 rvN^ \J^0HO^ fNN^T^NH2^NAF, N-pA-NF N^F3-amino-N-(6-chloropyridin-3-yl)-5-((3-fluoro- 3-amino-N-(6-chloropyridin-3-yl)-5-((3-fluoro- 5-(2-hydroxypropyl)-1-methyl-1H-pyrazol-4- 1-(methyl-d3)-1H-pyrazol-4- yl)methoxy)pyrazine-2-carboxamide yl)methoxy)pyrazine-2 -carboxamide0[i Y 306 303 AX U NH2D NA NAF3-amino-5-((4-chloro-1-(2,2-difluoroethyl)-1H- 2-amino-N-(6-chloropyridin-3-yl)-6-((4-(2,2- 1,2,3 -triazol-5-yl)methoxy)-7V-(2- difluoroethyl)-4H-1,2,4-triazol-3- methylpyrimidin-5-yl)pyrazine-2 -carboxamide yl)methoxy)nicotinamidef; 0308 X j? jfA A A AN305clJL XHXF / AHN NH2 ZN^Y> AN^NH2N'NA5-((5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methoxy)-3-methyl-N-(2-methylpyrimidin-5- 3 -amino-\-(6-chloropy ridin-3 -yl)-5-(( 1 -(2,2- yl)pyrazine-2 -carboxamide difluoroethy 1)- 1H- 1,2, 3 -triazol-5 - yl)methoxy)pyrazine-2 -carboxamide0[T NF O PZ01310 307A ApN^Y^°NA 'AF5-((3 -chloro- 1 -methyl- 1 H-py razol-4- \-(2-chloropyrimidin-5-yl)-5-((5- yl)mcthoxy)-3-mcthyl-\-(2-mcthylpyrimidin-5- (difluoromethyl)- 1-methy 1- l / / -pyrazol-4- yl)pyrazine-2 -carboxamide yl)methoxy)-3 -methy lpyrazine-2 -carboxamide / N., CI0rf A 312 309k I 1 HNJ:":6pp0hr / FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(2-chloropyrimidin-5-yl)-5-((4-fluoro-1- 5-((3-chloro-1-methyl-1H-pyrazol-4- methyl- 1 / / -py razol-3 -yl)methoxy)-3 - yl)methoxy)-N-(2-chloropyrimidin-5-yl)-3- methylpyrazine-2-carboxamide methylpyrazine-2-carboxamide314 1 2 fV 311 2 fVF\ ^ A j* I^H) _. ^NNNAcz'°V hr / / 5-((3-(1-aminoethyl)isoxazol-5-yl)methoxy)-N- N-(2-chloropyrimidin-5-yl)-5-((4-fluoro-1- (6-chloropyridin-3 -y 1) -3 -methylpyrazine-2 - methyl- 1 / / -py razol-3 -yl)methoxy)-3 - carboxamide (methylamino)pyrazine-2-carboxamide -NH 0 fNYcl316 313FNH2N / v°V / N-(6-chloropyridin-3-yl)-5-((5-(2- N-(2-chloropyrimidin-5-yl)-5-((5-fluoro-1- hy droxypropan-2-yl)-3 -oxabicyclo [3.1.1] heptan- methyl-1H-pyrazol-4-yl)methoxy)-3- 1 -yl)methoxy)-3 -methylpyrazine-2 -carboxamide methylpyrazine-2-carboxamide318 1 2 ACIH HO | 315OJ I H HHN FN-(6-chloropyridin-3-yl)-5-((1-(difluoromethyl)- N-(6-chloropyridin-3-yl)-5-((1-(2- 1H-imidazol-5-yl)methoxy)-3-methylpyrazine- hydroxypropan-2-yl)-2-oxabicyclo[2.2.2]octan- 2-carboxamide 4-yl)methoxy)-3 -methylpyrazine-2-0carboxamidefl N320 317 / A A 0 0A HCT |FN-(6-chloropyridin-3-yl)-5-((3-fluoro-2- N-(6-chloropyridin-3-yl)-5-((1- (hydroxymethyl)pyridin-4-yl)methoxy)-3- (difluoromethyl)-1H-imidazol-4-yl)methoxy)- methylpyrazine-2-carboxamide 3 -methylpyrazine-2 -carboxamide / N.. Cl 322 u lOr 3190rf A F A / IAA JL JLHF z l / IH. N' < °NpAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-3-methyl-5-((3- 3-amino-N-(6-chloropyridin-3-yl)-5-((1-(2,2- nitroisoxazol-4-yl)methoxy)pyrazine-2- difluoroethyl)-3-fluoro-1H-pyrazol-4- carboxamide yl)methoxy)pyrazine-2 -carboxamide0fl N NH2o r 324 321F-i, / =<'OA-NO'' < °N'NN-°‘0N-(6-chloropyridin-3-yl)-5-((6-fluoro-4-(1- N-(6-chloropyridin-3-yl)-5-((1-(2,2- hydroxy ethyl)pyridin-3 -yl)methoxy)-3 - difluoroethyl)-5-methyl-1H-1,2,3-triazol-4- methylpyrazine-2 -carboxamide, Enantiomer 1 yl)methoxy)-3 -methylpyrazine-2 -carboxamide (326), Enantiomer 2 (327)*0fl N \ JN^HNII J HF\ F N=N26- J32327*OH0ii VA!OH5-((5-(1-aminoethyl)isothiazol-4-yl)methoxy)- 5-((3-aminoisoxazol-4-yl)methoxy)-A-(6- N-(6-chloropyridin-3 -y 1) -3 -methylpyrazine-2- chloropyridin-3-yl)-3-methylpyrazine-2- carboxamide, Enantiomer 1, (330), carboxamide Enantiomer! (331)*u, NH2AJ^ N H2N f 1 H 30- 32531*Sx J b'-JNT NH2S' N JAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-(((1S,3R)-3-hydroxy- N-(6-chloropyridin-3 -yl)-5-((5-( 1 - 3 -methylcyclopentyl)oxy)-3 - hydroxyethyl)isoxazol-4-yl)methoxy)-3- (methoxymethyl)pyrazine-2 -carboxamide, methylpyrazine-2 -carboxamide, Enantiomer 1 Enantiomer 1 (334), Enantiomer 2 (335)* (328), Enantiomer 2 (329)* / O- ~ / N.. Cl„ „N„J. ij 34- HO' ‘K A JI AH328-H0X I 1 H335* 329* O_ J / O- ~ / N. / Cl Nfl HO”\ J< -*0 JI AHHO-- / ''v A JLH°vJN^2-amino-N-(6-chloropyridin-3-yl)-6-((4-(2,2- N-(6-chloropyridin-3-yl)-5-((3-(1,2- difluoroethyl)-1,2,5-oxadiazol-3- dihydroxyethyl)-6-fluoropyridin-2- yl)methoxy)nicotinamide yl)methoxy)-3-methylpyrazine-2-carboxamide,Enantiomer 1 (332), Enantiomer 2 (333)* □ nrclN N H2N Kib"N0 N332- 337333*OH_ z^ / CIAh^^^^^OHOHN-(6-chloropyridin-3-yl)-5-((6-fluoro-2- N-(6-chloropyridin-3-yl)-5-((4-(2,2- (hydroxymethyl)pyridin-3 -yl)methoxy)-3 - difluoroethyl)- 1,2,5-oxadiazol-3 -yl)methoxy)- methylpyrazine-2-carboxamide 3 -methylpyrazine-2 -carboxamide 339 336 flr" / TW AHNCf°N- A J '0-NAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((1-(difluoromethyl)- N-(6-chloropyridin-3-yl)-5-((5-fluoro-2- 5-(2-hydroxypropan-2-yl)-1H-pyrazol-4- methylpyrimidin-4-yl)methoxy)-3 - yl)methoxy)-3-methylpyrazine-2-carboxamide methylpyrazine-2-carboxamide0II1 H341 N: / NZ"'N338 / J z"HAN^NFA J1OHF6-((4-chloro-1-(2,2-difluoroethyl)-1H-1,2,3- N-(6-chloropyridin-3-yl)-5-((6-fluoro-3- triazol-5-yl)methoxy)-N-(6-chloropyridin-3-yl)- (hydroxymethyl)pyridin-2-yl)methoxy)-3- 2-methylnicotinamide methylpyrazine-2-carboxamide 343 340r^Y^N^^ F / N.„ / z JL 1HNc|l Y Y0 NN^CIN-(6-chloropyridin-3-yl)-2-((1-(2,2- 3-amino-N-(6-chloropyridin-3-yl)-5-((5- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- (methoxymethyl)-l -methyl- lH-pyrazol-4- yl)methoxy)-4-methylpyrimidine-5-carboxamide yl)methoxy-d2)pyrazine-2 -carboxamide ^Cl NH20 p Y 345 k £ £vcl342 Y JX N^ N^NLD D N Y N_ _>7^1 oN X oNr / 3-amino-N-(2-chloropyrimidin-5-yl)-5-((1-(2,2- N-(6-chloropyridin-3 -yl)-6-(( 1 -(2,2- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- yl)methoxy)pyrazine-2-carboxamide yl)methoxy)-2 -methylnicotinamide r- - / bk / ClF ° < Y347 344A AV - ”NNy^o-^N^NH2F,"yvVNAFN> IIN^F3-amino-N-(6-chloropyridin-3-yl)-5-((1-(2,2- N-(2-chloropyrimidin-5-yl)-5-((1-(2,2- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- yl)methoxy)picolinamide yl)methoxy)-3-methylpyrazine-2 -carboxamide NH2o XYCIF 0 < V 349 346 AFrNpNJUNN.^ CANAN^F0NAFAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-3-methyl-5-(((1- 3-amino-5-((4-chloro-1-(2,2-difluoroethyl)-1H- methyl-1H-pyrazol-4-yl)oxy)methyl)pyrazine-2- 1,2,3 -triazol-5-yl)methoxy)-N-(6- carboxamide chlo ropy ridin-3 -y l)picolinamide NH2o XYCI352 348— N | N. T'i\rN-(6-chloropyridin-3-yl)-5-((3-(1- hydroxypropyl)bicyclo[1.1.1]pentan-1- yl)methoxy)-3-methylpyrazine-2-carboxamide, Enantiomer 1 (350), Enantiomer 2 (351)* / X ° h Y15-(bicyclo[1.1.1]pentan-1-yloxy)-N-(6- chloropyridin-3-yl)-3-methylpicolinamidervw350- 354 U 351*OH L II H0ii Y Y YOHN-(6-chloropyridin-3-yl)-5-((5-(difluoromethyl)- N-(6-chloropyridin-3-yl)-5-(((1-(2,2- 1-((methylsulfonyl)methyl)-1H-pyrazol-4- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- yl)methoxy)-3-methylpyrazine-2-carboxamide yl)methyl)amino)-3-methylpyrazine-2- carboxamide356 353, _ --x„A / NXd ON XFO°"s^ JNx' JkH / N^F3-amino-N-(6-chloropyridin-3-yl)-5-((5- N-(6-chloropyridin-3-yl)-5-((3-fluoro-1-(2- (difluoromethyl)- 1 -((methylsulfonyl)methyl)- (methylsulfonyl)ethyl)-lH-pyrazol-4- lH-pyrazol-4-yl)methoxy)pyrazine-2- yl)methoxy)-3 -methy lpyrazine-2 -carboxamide carboxamide1 HNH2O Xx*31F358 355r\ 111HoN JXn o NnN X FO°" M J / XAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-N-(6-chloropyridin-3-yl)-5-((((1S,3R)- 3-hydroxycyclopentyl)oxy)pyrazine-2- carboxamide, Enantiomer 1 (360), Enantiomer2 (361)NH20 f^^CIN-(6-chloropyridin-3-yl)-5-((2- A A A^N (difluoromethyl)- 1 -methyl- lH-imidazol-5 - yl)methoxy)-3-(methylamino)pyrazine-2- carboxamideAH\ / <\ / Cl NH 0 Y fl 360- 357 A A AY 361* Nr Yf NHNH20A A A^NFA AH6HO'N-(6-chloropyridin-3-yl)-5-((1-(difluoromethyl)- 3-amino-N-(6-chloropyridin-3-yl)-5-((4- 1H-pyrazol-3-yl)methoxy)-3-methylpyrazine-2- (difluoromethyl)- 1,2,5-oxadiazol-3 - carboxamide yl)methoxy)pyrazine-2 -carboxamide / Cl NH2O A |]^ 363 1 H 359pFA AS / N Y N ^L KI FH1\ 111H\ _ ^„ / A / N)— N JF b'NN-(6-chloropyridin-3-yl)-5-((1- N-(6-chloropyridin-3-yl)-5-((1-(2,2- (difluoromethyl)-3-methyl-1H-pyrazol-4- difluoroethyl)-1H-pyrazol-5-yl)methoxy)-3- yl)methoxy)-3-(methylamino)pyrazine-2- methylpyrazine-2-carboxamide carboxamideo / ^ / Cl365 F 1 u 362 ''■'NH o (<::ArclA A AS / N F \ _ JL y. HF _ _ k KIH\ / ===Y oM AN J FN-(6-chloropyridin-3-yl)-5-((3-fluoro-1- N-(6-chloropyridin-3-yl)-5-((1-(2,2- methyl-1H-pyrazol-4-yl)methoxy)-3- difluoroethyl)-3-fluoro-1H-pyrazol-4- methylpicolinamide yl)methoxy)-3 -methylpicolinamide367 364N J AF / Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((l- 5-(( 1,3,4-thiadiazol-2-yl)methoxy)-N-(6- (difluoromethyl)- lH-pyrazol-5-yl)methoxy)-3 - chloropyridin-3-yl)-3-methylpyrazine-2- methylpyrazine-2-carboxam carboxamide369 366AXXi II J HN'NyFVNF3 -amino-5 -((5 -(difluoro methy 1)- 1 -methyl- 1H- pyrazol-4-yl)methoxy)-N-(6-methylpyridin-3- 5-((l,2,4-thiadiazol-5-yl)methoxy)-N-(6- yl)pyrazine-2 -carboxamide chloropyridin-3-yl)-3-methylpyrazine-2- caiboxamide371 368 i? nr II J H NH2Q _ k N NHN^F N "F5-((3 -fluoro- 1 -methyl- lH-pyrazol-4- 3 -amino-5-((3 -fluoro- 1 -methyl- lH-pyrazol-4- yl)methoxy)-3-(methylamino)-N-(2- yl)methoxy)-N-(6-methylpyridin-3-yl)pyrazine- methylpyrimidin-5-yl)pyrazine-2 -carboxamide 2-carboxamide373 370II JH—N / ^^cr 'N NH2NAN-< FF3 -amino-N-(6-chloropyridin-3 -yl)-5-(( 1 - 5-((5-(difluoromethyl)- 1 -methyl- lH-pyrazol-4- (difluoromethyl)-2-methyl-lH-imidazol-5- yl)methoxy)-3 -methyl-N-(6-methylpyridin-3 - yl)methoxy)pyrazine-2-carboxamide yl)pyrazine-2 -carboxamide0IIu375 372II JHNNH2N^]^°N^NyF; N^FF FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure(S)-N-(6-chloropyridin-3-yl)-5-((3- (cyclopropyl(hydroxy)methyl)bicyclo [1.1. l]pentan- 1 -yl)methoxy)-3 -methylpyrazine-2- carboxamide, Enantiomer 1 (377), Enantiomer2 (378)*3 -amino-5-((3 -fluoro- 1 -(methyl-d3)-lH-0fl pyrazol-4-yl)methoxy)-N-(2-methylpyrimidin- 5-yl)pyrazine-2 -carboxamide 77- p^^pp^C) N "" X0[f N37478*OH D^N / ;Y^O^N^NH20Il Y Dp^^pp^X) N '"'X6HN-(6-chloropyridin-3 -yl)-5-(( 1 - N-(6-chloropyridin-3-yl)-5-((l-(2- (difluoromethyl)-2-methyl-lH-imidazol-5- hy droxypropan-2-y l)-2 -oxabicyclo [2.1.1] hexan- yl)methoxy)-3-methylpyrazine-2 -carboxamide 4-yl)methoxy)-3-methylpyrazine-2 -carboxamide0ii3800II 376jV "NHO Nzo-JFrac-3-amino-N-(6-chloropyridin-3-yl)-5- rac-N-(2-chloropyrimidin-5-yl)-5-(((lS,3R)-3- (((lR,3R)-3 -hydroxy-3 - hydroxy-3 -methylcyclohexyl)oxy)-3 - methylcyclopentyl)oxy)pyrazine-2- methylpyrazine-2-carboxamide carboxamide 82#379#T? ACI0ii V 1 1 II J HH0X'-'''\y^N^NH2rac -2 -amino -N-(6 -chloropy ridin-3 -y 1) -6 - N-(6-chloropyridin-3-yl)-5-((3-(2- (((lS,3R)-3-hydroxy-3- fluoropropan-2-y l)bicy clo [1.1.1 ]pentan- 1 - methylcyclohexyl)oxy)nicotinamide yl)methoxy)-3-methylpyrazine-2 -carboxamide OH 085#381 U [| l A II J H1 1 II J HNH2Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN -(2 -chloropy rimidin-5 -y l)-5 -((( 1 S, 3R)-3 - hydroxy-3 -methylcyclohexyl)oxy)-3 - methylpyrazine-2 -carboxamide, Enantiomer 1 rac -2 -amino -N-(6 -chloropy ridin-3 -y 1) -6 - (383), Enantiomer! (384)*((( IS, 3 S)-3 -hydroxy-3 - methylcyclohexyl)oxy)nicotinamide383- 86#A A Y "OH 0 [YA 384* 1 1 II J H A1 1 II J HX'^>\y 'N NH2YHj? jfNYclFT. / O J'^ON'X^AXrac -2 -amino -N-(6 -chloropy ridin-3 -y 1) -6 - rac-N-(6-chloropyridin-3-yl)-5-(((lR,3S)-3- (((lR,3S)-3-(difluoromethyl)-3- hydroxy-3 -methylcyclopentyl)amino)-3 - hydroxycyclopentyl)oxy)nicotinamide methylpyrazine-2-carboxamide 88#0flFA ° A f Y 387#N \, / A rf^YN'^^ / NNY 1HO RD 1 N A ''AX 1 Y "NHH2HO YXYNH2-amino-N-(6-chloropyridin-3-yl)-6-(((lS,3R)- 3 -(difluoromethyl)-3 - hydroxy cyclopentyl)oxy)nicotinamide, rac-N-(6-chloropyridin-3-yl)-5-(((lS,3R)-3- Enantiomer 1 (389), Enantiomer 2 (390)* hydroxy-3 -methylcyclopentyl)methyl)-3 - methylpyrazine-2-carboxamide? fY 389- 91#° ii V A / i n Yr390* FY\J.nJL AhHO 'O N NH2HO'9 li Y J / / Y fi yfnAA A ftHO RD N NHH2N-(6-chloropyridin-3-yl)-5-((3-(2- hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1 - yl)methoxy)-3-(methylamino)pyrazine-2- rac-N-(6-chloropyridin-3-yl)-5-(((lR,3R)-3- carboxamide hydroxy-3 -methylcyclopentyl)methyl)-3 - methylpyrazine-2-carboxamide 3940I 392#° ii VNA3 lftANH HO^JAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((l-(2,2- N -(6-chloropy ridin-3 -y l)-5 -(( 1 -methy 1- 1H- difluoroethyl)-4-methyl-lH-l,2,3-triazol-5- imidazol-5 -y l)methoxy )-3 - yl)methoxy)-3-(methoxymethyl)pyrazine-2- (methy lamino)pyrazine-2-carboxamide carboxamide0fl N F O YifCI396 393N / Y"'°H<NNAJAHN~\ °\N-(6-chloropyridin-3 -yl)-5-(( 1 -(difluoromethyl)- N -(6-chloropy ridin-3 -y l)-5 -(( 1 -methy 1- 1H- 5-methyl-lH-pyrazol-4-yl)methoxy)-3- py razol-5 -y l)methoxy )-3 - (methylamino)pyrazine-2-carboxamide (methy lamino)pyrazine-2-carboxamide 3980fl 3950fl.. SYN7'' Nz- Nzr °NH MF N N'N\HN-(6-chloropyridin-3 -y 1) -3 -(cyclopropylamino)- N-(6-chloropyridin-3 -yl)-5-((4-fluoro- 1 - 5 -(( 1 -methy 1- IH-py razol-4- methyl- lH-pyrazol-3 -yl)methoxy)-3 - yl)methoxy)pyrazine-2-carboxamide (methy lamino)pyrazine-2-carboxamide / Yz400 HN O f| XCI397 ° rr ^NYNYN clNA A HHN\ f HF5-((3-chloro-l-(2 -methoxy ethyl)-lH-pyrazol-4- 5-((5-chloro-l-methyl-lH-pyrazol-4- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- methylpyrazine-2-carboxamide (methylamino)picolinamide N^ / CI402 399 HNK o ff^ACI> °A J AY / NYH’ ciJMHA5 -((3 -chloro- 1 -(2-hy droxy ethyl)- lH-pyrazol-4- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- N-(6-chloropyridin-3-yl)-5-((5-methoxy-l,2,4- methylpyrazine-2-carboxamide thiadiazol-3-yl)methoxy)-3-methylpyrazine-2-, N^, CI carboxamide404 4010fl N HCY / V NH1 H^-N7^0A / XNAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((4-fluoro-l-(2- hy droxypropy 1)- 1H- 1,2, 3 -triazol-5 -y l)methoxy )- 5-((5-chloro-l-(2 -methoxy ethyl)-lH-pyrazol-4- 3 -methylpyrazine-2 -carboxamide yl)methoxy)-N-(6-chloropyridin-3-yl)-3- methylpyrazine-2-carboxamide O r^V 406 \0rrcl40301r0H(rNYt'N'Jx^N\ Cl N if N A. Al - A. / NhNAFN-(6-chloropyridin-3-yl)-3-methyl-5-((4-methyl- N-(6-chloropyridin-3-yl)-5-((5- 1 -((methylsulfonyl)methyl)- 1H- 1,2,3 -triazol-5- (hydroxymethyl)- 1-methyl- 1H- 1,2,3 -triazol-4- yl)methoxy)pyrazine-2-carboxamide yl)methoxy)-3 -methylpyrazine-2 -carboxamide / bk.ci 408 Q,z9 [| Y< ° x 405 i? f T z0HNM Ax « t / . AJHN'N- Y\^0 n■ N f °N-NN-(6-chloropyridin-3-yl)-5-((l-(2,2- N-(6-chloropyridin-3-yl)-5-((5-fluoro-2-(2- difluoroethyl)-5-fluoro- 1H- 1,2,3 -triazol-4- hydroxypropyl)-2H-l,2,3-triazol-4- yl)methoxy-d2)-3-methylpyrazine-2- yl)methoxy)-3 -methylpyrazine-2 -carboxamide carboxamide410 ° rrcl4071 V f 1 HF~~ ( N=NNAF OHhN-(6-chloropyridin-3-yl)-5-((5-fluoro-l-methyl- 3 -amino-N-(6-chloropyridin-3 -yl)-5-((4- lH-l,2,3-triazol-4-yl)methoxy)-3- methyl- 1 -((methy lsulfonyl)methyl)- 1H- 1,2,3- methylpyrazine-2-carboxamide triazol-5-yl)methoxy)pyrazine-2 -carboxamide 90fl A 412 X A A 409F < N\ II J H k Ac1- N^Y^0 N"NH*N^N N'Yk w ON-(6-chloropyridin-3-yl)-5-((4-fluoro-l-methyl- N-(6-chloropyridin-3-yl)-5-((l-(2,2- 1H- 1,2, 3 -triazol-5 -y l)methoxy )-3 - difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- methylpyrazine-2-carboxamide yl)methoxy-d2)-3-methylpyrazine-2- carboxamide0fl A413 411F o rvcl' HF^N X 1 1 H NAFNNNXFAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3 -yl)-5-((3 -fluoro- 1 - methyl-5-((S-methylsulfonimidoyl)methyl)-lH- pyrazol-4-yl)methoxy)-3-methylpyrazine-2- carboxamide, Enantiomer 1 (414), Enantiomer! (415)N-(6-chloropyridin-3-yl)-5-((4-fluoro-l-(2,2,2-0h N trifluoroethyl)-lH-l,2,3-triazol-5-yl)methoxy)- 3 -methylpyrazine-2 -carboxamide414- 416 NVO0 N^415* / NH. W. I - NAF0h YNN-\.„syNHN-(6-chloropyridin-3-yl)-5-((3- N-(6-chloropyridin-3-yl)-5-((l- (difluoromethy l)isothiazol-5 -y l)methoxy )-3 - (difluoromethyl)-4-fluoro-lH-pyrazol-3- methylpyrazine-2-carboxamide yl)methoxy)-3 -methylpyrazine-2 -carboxamide ~ / N.. Cl / N. / Cl 418 o f XX 10Y V 4 7Y / y o x- N / YF F \==\FN-(6-chloropyridin-3-yl)-5-(((l-(2,2- difluoroethyl)-5 -methyl- IH-py razol-4- N-(6-chloropyridin-3-yl)-5-((5-cyanoisothiazol- yl)methyl)amino)-3-methylpyrazine-2- 3 -yl)methoxy)-3 -methylpyrazine-2- carboxamide carboxamide / N.. Cl4200f V 4190I 3 r IN: / HNN ' 'cNFH YNS'NF5 -((3 -carbamoy Ibicy clo [ 1.1.1 ]pentan- 1 - N-(6-chloropyridin-3-yl)-5-((l-(2,2- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- difluoroethyl)-5-fluoro-lH-pyrazol-4- methylpyrazine-2-carboxamide yl)methoxy)-3-methylpyrazine-2-carboxamide / Cl ~ / N. / Cl i x X T 422 421II1HY / 0F NH2Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3 -yl)-5 -( 1 -(4-fluoro- 1 - N-(6-chloropyridin-3-yl)-5-((3-cyanoisothiazol- methyl- lH-pyrazol-3 -yl)ethoxy)-3 - 5-yl)methoxy)-3-methylpyrazine-2- methylpyrazine-2-carboxamide carboxamide. N.. Cl0f424 4230[i N 1 / IV'H -NV" °ANAXF N'sN-(6-chloropyridin-3-yl)-5-(l-(4-fluoro-l- methyl- lH-pyrazol-3 -yl)ethoxy)-3 - methylpyrazine-2 -carboxamide, Enantiomer 1 (425), Enantiomer 2 (426)* N-(6-chloropyridin-3-yl)-5-((3-(2-. N^. Cl hydroxypropan-2-yl)- 1 -methyl- lH-pyrazol-4- yl)methoxy)-3-methylpyrazine-2-carboxamide. N. A A. / „. N.. Cl0f V 425- 427426* ~N0S F °N'J". N.. Cl0f V roH! / XFN-(6-chloropyridin-3-yl)-5-((4-fluoro-l-methyl- N-(6-chloropyridin-3 -yl)-5-(( 1 - lH-pyrazol-3-yl)methoxy)-3- (difluoromethyl)-3 -(hydroxymethyl)- 1H- (hydroxymethyl)pyrazine-2 -carboxamide pyrazol-4-yl)methoxy)-3-methylpyrazine-2-.bk. Cl carboxamideo f430 4280fl N A A,,. r A ' \=Y OHFN " X^OHFN-(6-chloropyridin-3 -yl)-5-(( 1 -(difluoromethyl)- N-(6-chloropyridin-3 -yl)-5-(( 1 - 5-methyl-lH-pyrazol-4-yl)methoxy)-3- (difluoromethyl)-4-(hydroxymethyl)-lH- (hydroxymethyl)pyrazine-2 -carboxamide pyrazol-3-yl)methoxy)-3-methylpyrazine-2-. N.. Cl carboxamide4320f Y 429XX ° A y, A "F OHF X— A-OHAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3 -yl)-5-(( 1 - N-(6-chloropyridin-3-yl)-5-((l-(2- (difluoromethyl)-5-(methoxymethyl)-lH- methoxy ethyl)- lH-imidazol-5-yl)methoxy)-3 - pyrazol-4-yl)methoxy)-3-methylpyrazine-2- (methylamino)pyrazine-2-carboxamide carboxamide_N. / Cl Oz-NH O <NY ° 434CIX431> AA XJY xJhAY7<v J0 NF-\FN-(6-chloropyridin-3 -yl)-5 -((3 -fluoro-5 -( 1 - hydroxyethyl)-! -methyl- lH-pyrazol-4- yl)methoxy)-3-methylpyrazine-2 -carboxamide,Enantiomer 1 (436), Enantiomer 2 (437)*_ AA / CI0[| 1N-(6-chloropyridin-3 -yl)-5-(( 1 - (difluoromethyl)-5-methyl-lH-pyrazol-4- i IY HNyl)methoxy)-3 -methylpicolinamide 36- ° rNrcl43337* / ;HOF \ JI J H r. AA. / CI0h A^FNN^A / [HO3-amino-N-(6-chloropyridin-3-yl)-5-((5-(l- hydroxyethyl)-! -methyl- lH-pyrazol-4- yl)methoxy)pyrazine-2 -carboxamide,Enantiomer 1 (440), Enantiomer 2 (441)*~ / A / Cl0[| 7 5-((2 -chloro- 1 -methyl- lH-imidazol-5- yl)methoxy)-N-(6-chloropyridin-3-yl)-3 -( 1 - A - " hydroxyethyl)pyrazine-2 -carboxamideN^y^O^N^NH2HO. / . Cl 40- 41* N^A ^ 435 / :HO \N. / .. / ? A AA~ / 'A,01 NH- / 0fl NCIA\ TAN N- "H2N^A ^- / 4HOAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3 -yl)-5-(( 1 - (difluoromethyl)-5-(l-hydroxyethyl)-lH- pyrazol-4-yl)methoxy)-3-methylpyrazine-2- carboxamide, Enantiomer 1 (438), Enantiomer! (439)*zx / -^ / Cl N-(6-chloropyridin-3-yl)-5-((l-(2,2-0h N difluoroethyl)- 1H- 1,2,3 -triazol-5-yl)methoxy)-3 - methylpyrazine-2-carboxamide438- NPP°443 V 1 JO^CI N439* NA^N L ANAHFPz HON-70fl NNP NAP,°NFpz HON-(6-chloropyridin-3 -yl)-5-((3 -fluoro-1 - 2-amino-N-(6-chloropyridin-3 -yl)-6-((3 -fluoro- methyl-5-( 1 -(methylamino)ethyl)- IH-pyrazol- l-(methyl-d3)-lH-pyrazol-4- 4-yl)methoxy)-3 -methylpyrazine-2- yl)methoxy)nicotinamide carboxamide„ / N.. Cl 445 u 4420f VD xx CT 1 N 1 NHH2DN=>N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro-1 -methyl- 2-amino-N-(6-chloropyridin-3-yl)-6-((4-fluoro- 5-(methylsulfonamidomethyl)-lH-pyrazol-4- 1 -(methy 1 -d3 )- IH-py razol-3 - yl)methoxy)-3-methylpyrazine-2-carboxamide yl)methoxy)nicotinamiden / Cl NH2447 ° i ° f V OrAVcl444V— N ANNAFFAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((5-(l,2- dihydroxyethyl)-3 -fluoro-1 -methyl- IH-pyrazol- 4-yl)methoxy)-3 -methylpyrazine-2- carboxamide, Enantiomer 1 (449), Enantiomer2 (450)*0fl 5-((5-(acetamidomethyl)-3-fluoro-l-methyl- lH-pyrazol-4-yl)methoxy)-N-(6-chloropyridin-F3 -y 1) -3 -methylpyrazine-2-carboxamide \ 1 AH. N.. Cl 49-N44650*N / OH A. AWHO— NNAF. A UI 1 I HNN / k OHHO3 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro- 1-((methylsulfonyl)methyl)-1H-pyrazol-4- N-(6-chloropyridin-3-yl)-5-((3-fluoro-5-(2- yl)methoxy)pyrazine-2-carboxamide hydroxypropyl)-! -methyl- lH-pyrazol-4- / bk / ClNH20 A yl)methoxy)-3-methylpyrazine-2 -carboxamide / N.. Cl 452 448H° I jf £ YNY< S=OFn \Otert-butyl (5-(((5-((6-chloropyridin-3- N-(6-chloropyridin-3-yl)-5-((3-fluoro-5-(2- yl)carbamoyl)-6-methylpyrazin-2- hydroxypropan-2-yl)-l-methyl-lH-pyrazol-4- yl)oxy)methyl)- 1 -methyl- 1H-1,2,3 -triazol-4- yl)methoxy)-3-methylpyrazine-2 -carboxamide yl)carbamate° ii454 0'^ 451A rNvk rVciN^AN-N^ N^\M / / A OH3 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro- 3 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro- l-methyl-5-(2-(methylamino)-2-oxoethyl)-lH- 1 -methyl-5-((methylsulfonyl)methyl)- 1H- pyrazol-4-yl)methoxy)pyrazine-2 -carboxamide pyrazol-4-yl)methoxy)pyrazine-2-carboxamide HI\K° rNr 456 453cloF\ II J HN NH2F NH27'6Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((6-fluoro-4- 3-amino-N-(6-chloropyridin-3-yl)-5-((l-(2,2- ((methylsulfonyl)methyl)pyridin-3-yl)methoxy)- difluoroethyl)-4-(methyl-d3)- 1H- 1,2,3 -triazol- 3 -methylpyrazine-2 -carboxamide 5-yl)methoxy-d2)pyrazine-2 -carboxamide ~ / N. / Cl458 XA Zi 455FX NH2O (XCIN X^ O ^^ N^1*£A A YA Uh□A xo^o DuN-(6-chloropyridin-3-yl)-5-((5-(2- rac-N-(6-chloropyridin-3-yl)-5-(((lR,3S)-3- hy droxy-3 -(methy 1 -d3 )cy clopenty 1- 1 -d)oxy )-3 - (dimethylamino)-2-oxoethyl)-3-fluoro- 1 - methyl-1H-pyrazol-4-yl)methoxy)-3- methylpyrazine-2-carboxamidemethy lpyrazine-2-carboxamide / X1461#° Il X^ 457_D0 _ Ndrx<DJLXu ykX O NhX DHO ° NXvH rF3 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro- 5-(l-hydroxy-2-methoxyethyl)-l-methyl-lH- pyrazol-4-yl)methoxy)pyrazine-2 -carboxamide, Enantiomer 1 (459), Enantiomer 2 (460) r. / X / CI0II 1 N-(6-chloropyridin-3 -yl)-5-(( 1 -(difluoromethyl)- 5-((methylsulfonyl)methyl)-lH-pyrazol-4- yl)methoxy)-3-methylpyrazine-2-carboxamide L X 'NXX^O^N^NH2459- 460*460* N'X^-x / .•F \ L 1HHOF0II 4L XG / 1 ^0"HO3 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro- 5-(( 1 -(2-aminoethyl)-3 -fluoro- lH-pyrazol-4- 5 -methy 1- 1 -((methy lsulfonyl)methy 1)- 1H- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- pyrazol-4-yl)methoxy)pyrazine-2 -carboxamide methylpyrazine-2-carboxamide / N. / Cl 465 4620f Vxx JOs rNA °N NH2H2NX ' XS / '0NF FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3 -amino-N-(6-chloropyridin-3 -yl)-5-((5-( 1,2- dihydroxyethyl)-3 -fluoro-1 -methyl- IH-pyrazol- 4-yl)methoxy)pyrazine-2 -carboxamide,Enantiomer 1 (467), Enantiomer 2 (468)3 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro-0fl l-methyl-5-((S-methylsulfonimidoyl)methyl)- lH-pyrazol-4-yl)methoxy)pyrazine-2- carboxamideN^Fky^O^N^NH2~ / N. / Cl 467- 4640f V 468*N / k OHHO" O°N NH20fl / ''NH1. A VN^y^O'^N'xKNH2N / ; OHHON-(6-chloropyridin-3 -yl)-5-((3 -fluoro-1 - 5-(( 1 -(2-(azetidin- 1 -yl)ethyl)-3 -fluoro- 1H- methyl-5-((N-methylsulfamoyl)methyl)-lH- pyrazol-4-yl)methoxy)-N-(6-chloropyridin-3- pyrazol-4-yl)methoxy)-3-methylpyrazine-2- yl)-3-methylpyrazine-2 -carboxamide carboxamide„ / N.. Cl / N. / Cl 470 466MN-S° |i'NYU'Nx^J NAF“ — NYJAHNA TF5-((5-(aminomethyl)-3 -chloro- 1 -methyl- 1H- pyrazol-4-yl)methoxy)-N-(6-chloropyridin-3- 3 -amino-N-(6-chloropyridin-3 -yl)-5-(( 1 - yl)-3-methylpyrazine-2 -carboxamide (difluoromethyl)-5-((methylsulfonyl)methyl)- / N.. Cl lH-pyrazol-4-yl)methoxy)pyrazine-2-0f V carboxamide472 469 ^^ / Cl ( fTN' T °NH^ 'N NN ' V^NH2F\-(6-chloropyridin-3-yl)-6-((l-(2.2- 5-((4-chloro- 1 -(2,2-difluoroethyl)- 1H- 1,2,3- di fluorocthy l)-4-fluoro- 1 / / - 1,2,3 -triazol-5- triazol-5-yl)methoxy)-3-methyl-N-(2- yl)methoxy-c / 2)-2 -methylnicotinamide methylpyrimidin-5-yl)pyrazine-2 -carboxamide474 471if 7NHNxifuNCI'NAFAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure4-amino-N-(6-chloropyridin-3-yl)-6-((l-(2,2- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- 5-((4-chloro- 1 -(2,2-difluoroethyl)- 1H- 1,2,3- yl)methoxy)pyridazine-3 -carboxamide triazol-5-yl)methoxy)-N-(6-chloropyridin-3-yl)- 3 -cyanopyrazine-2 -carboxamide L A fAcl476 473F\? Y Y JL 1HN'Ny^O'-'^^NH2;’. C",7 «NAFN'NjY°N" AJNAI3-amino-N-(6-chloropyridin-3-yl)-5-(((lR,3S)- 3 -hy droxy-3 -(1 -methyl- IH-py razol-5 - yl)cyclopentyl)oxy)pyrazine-2-carboxamide, N-(6-chloropy ridin-3 -yl)-5-(((3 -fluoro- 1 - Enantiomer 1 (479), Enantiomer 2 (480)* methyl-lH-pyrazol-4-yl)methyl)thio)-3- methylpyrazine-2-carboxamide « ^s^CI, CI __ H fY79- 47580* i? £TNJL JL JLHF N " ' «| HO ^^*0 N NH2___ U AY \ / T^sN. if Y B / N^ \ JZJi JL| HO / O N NHH23-amino-N-(6-chloropyridin-3-yl)-5-(((lR,3S)- 3 -hydroxy -3 -methylcyclopentyl)thio)pyrazine- N-(6-chloropyridin-3-yl)-3-methyl-5-((3-(2- 2-carboxamide, Enantiomer 1 (477), oxopy rrolidin- 1 -y l)bicy clo [1.1.1 ]pentan- 1 - Enantiomer 2 (478) yl)methoxy)pyrazine-2-carboxamide0ii Y477- 482rA1478*H0XXVA^A*S,'^r" Ni' / K°NH2"0hH0'S^N^NHzN-(6-chloropyridin-3-yl)-5-((l- 5-((3 -acetamidobicyclo [1.1. l]pentan- 1 - (hydroxymethyl)cyclopropyl)methoxy)-3- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- methylpyrazine-2-carboxamide methylpyrazine-2-carboxamide ° ii Y 4840II 4 481(TY NAN II JHO HO / ^'O'AN / XHAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure5-((l-(2,2-difluoroethyl)-5-methyl-lH-pyrazol- N -(6-chloropy ridin-3 -y l)-3 -methy 1-5 -((3 -(N- 4-yl)methoxy)-3 -methyl-N-(6-methylpyridin-3 - methy lacetamido)bicyclo [1.1.1 ]pentan- 1 - yl)pyrazine-2 -carboxamide yl)methoxy)pyrazine-2 -carboxamide0iSY. Cl 486 483 N A H A 11 A^ k JY OI XO ryA)HFYF1N-(6-chloropyridin-3 -y 1) -5 -((3 -cyano- 1 -methy 1- 5-((l-(2,2-difluoroethyl)-3-methyl-lH-pyrazol- lH-pyrazol-4-yl)methoxy)-3-methylpyrazine-2- 4-yl)methoxy)-3 -methyl-N-(6-methylpyridin-3 - carboxamide yl)pyrazine-2 -carboxamide0YY U fO 487 4854 / 0 II J HF-NV"Y F NY0 N%N-(6-chloropyridin-3-yl)-5-((l-(2,2- N-(6-chloropyridin-3-yl)-5-((3-(3-fluorooxetan- difluoroethyl)-3 -fluoro- lH-pyrazol-5- 3 -y l)bicy clo [1.1.1 ]pentan- 1 - yl)methoxy)-3 -methy Ipicolinamide yl)methoxy)picolinamidez^ / CI489 488II J H JY " OsFN-(6-chloropyridin-3-yl)-5-(2,2-difluoro-l-(3- (hydroxy methy l)bicy clo [1.1.1 ]pentan- 1 - N-(6-chloropyridin-3-yl)-5-((2-cyanothiazol-5- yl)ethoxy)-3 -methy lpyrazine-2 -carboxamide yl)methoxy)-3-methylpyrazine-2-carboxamide / N. / Cl0(i Y? f ¥491 490 ANA / JII 1HN -<SONX HFN-(6-chloropyridin-3-yl)-5-((3-(2- N-(6-chloropyridin-3 -yl)-5-((2 -cyano- 1 -methy 1- methoxyethoxy)isothiazol-5-yl)methoxy)-3- lH-imidazol-5-yl)methoxy)-3-methylpyrazine- methylpyrazine-2-carboxamide 2-carboxamide. Cl493 AA u S f T 4920N N _ ji JHN4 S AH / - — O / N"sAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-N-(6-chloropy ridin-3 -yl)-6-((l -(2,2- N-(6-chloropy ridin-3 -y l)-3 -methy 1-5 -(( 1 - difluoroethyl)-1H-1,2,4-triazol-5- (methy Icarbamoy l)-2 -oxabicyclo [2.1.1] hexan- yl)methoxy)nicotinamide 4-yl)methoxy)pyrazine-2 -carboxamide / N^ / CI 495 494 1?Z LT i / -V r^rNci(Fr YN1 [J HJL AH— NH _ >^ / N / ^O^N^NH2V / yf0VN5-((2 -chloro-l-(2 -hydro xyethyl)-lH-imidazol-5- yl)methoxy)-N-(6-chloropyridin-3-yl)-3- N-(6-chloropyridin-3-yl)-5-((4-fluoro-l-(2- methylpyrazine-2-carboxamide hydroxypropyl)-lH-pyrazol-3-yl)methoxy)-3- methylpyrazine-2-carboxamide_ / ^ / Cl 497 u 496AYW II J HNf^ / .y AX " VN. °OHCl OHFN-(6-chloropy ridin-3 -yl)-5 -(( 1 -(3 -cyanopropyl) - N-(6-chloropyridin-3-yl)-5-((3-fluoro-l-(2- lH-pyrazol-3 -yl)methoxy)-3 -methy lpyrazine-2- methoxy ethyl)- lH-pyrazol-4-yl)methoxy)-3 - carboxamide methy lpyrazine-2-carboxamide O <zNycl499 ° rNrcl498n / —N 'N4F0N-(6-chloropyridin-3-yl)-5-((4-fluoro-l-(3- N-(6-chloropyridin-3-yl)-5-((4-fluoro-l-(2-(2- hydroxypropyl)- lH-pyrazol-3 -yl)methoxy)-3 - fluoroethoxy)ethyl)- lH-pyrazol-3 -yl)methoxy)- methy lpyrazine-2-carboxamide 3 -methy lpyrazine-2 -carboxamide / N. / Cl0f Y O Yv 501 500CI / —HZ FF7ON-(6-chlo ropy ridin-3 -y l)-5 -(( 1 -(( 1 - cy anocy clopropy l)methy 1)- IH-py razol-5 - N-(6-chloropyridin-3-yl)-5-((5-cyano-3- yl)methoxy)-3-methylpyrazine-2-carboxamide oxabicy clo [3.1.0] hexan- 1 -yl)methoxy )-3 - methy lpyrazine-2-carboxamide0ii Y / N. / Cl u f Y 503 Y " 502o-v / -. A AHN'NN illAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((2- N-(6-chloropyridin-3-yl)-5-((5- (difluoromethyl)- 1 -(2 -methoxy ethyl)- 1H- (hydroxymethyl)thiazol-4-yl)methoxy)-3- imidazol-5-yl)methoxy)-3-methylpyrazine-2- methylpyrazine-2-carboxamide carboxamideo <NvCI505 504N; OV-NS' X^-OH F-AFN-(6-chloropyridin-3 -yl)-5-(( 1 -(difluoromethyl)- 1H- 1,2, 3 -triazol-5 -y l)methoxy )-3 - N-(6-chloropyridin-3 -yl)-5-(( 1 - methylpyrazine-2-carboxamide (difluoromethyl)- 1H- 1,2,3-triazol-4- yl)methoxy)-3 -methy lpyrazine-2 -carboxamide0fl N507 5060fi A N'Y ° / A*A i" AN-yF / -■N:NF 'NO=NF3 -amino-N-(6-chloropy ridin-3 -yl)-5-(( 1 - N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro-1 -methy l- (difluoromethy 1)- 1H- 1,2, 3 -triazol-5 - 5-(2-(methylamino)-2-oxoethyl)-lH-pyrazol-4- yl)methoxy)pyrazine-2 -carboxamide yl)methoxy)-3-methylpyrazine-2-carboxamiderx AX / CIHNX0 ANYCI0fl A^ 509 508^N. A Ax JIAGA A AH— N 0 N' \N==\ N'NyFF FN -(6-chloropy ridin-3 -y l)-5 -((3 -fluoro-1 - 5-((5-(2-amino-2-oxoethyl)-3 -fluoro- 1 -methy 1- ((methylsulfonyl)methyl)-lH-pyrazol-4- lH-pyrazol-4-yl)methoxy)-N-(6-chloropyridin- yl)methoxy)-3-methylpyrazine-2-carboxamide 3 -y 1) -3 -methy lpyrazine-2-carboxamide\ ~ ^Sx / Cl0fl N H2N O [AY01511 510\ II JH0. 7-N-X^0 NAon'F N< FN-(6-chloropyridin-3 -yl)-5-((3 -fluoro-1 - N -(6-chloropy ridin-3 -y l)-5 -((3 -fluoro-1 -(methy 1- methyl-5-((methylsulfonyl)methyl)-lH- d3)-lH-pyrazol-4-yl)methoxy-d2)-3- pyrazol-4-yl)methoxy)-3-methylpyrazine-2- methylpyrazine-2-carboxamide carboxamide 5130f Y 512F□ A AC" \ II JH0N^ NATAO N^DN=AN'AJsr'7'6Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((l-(2- hydroxypropyl)- lH-pyrazol-5-yl)methoxy)-3 - methylpyrazine-2 -carboxamide, Enantiomer 1(515), Enantiomer 2 (516)*QN-(6-chloropyridin-3-yl)-5-((l-(2- hydroxypropyl)-lH-pyrazol-5-yl)methoxy)-3- methylpyrazine-2-carboxamide A W15- 51416* Aon M A0V JAhvj0 NA" A W3-amino-N-(6-chloropyridin-3-yl)-5-((l-(2- hydroxypropyl)-lH-pyrazol-5- yl)methoxy)pyrazine-2 -carboxamide,Enantiomer 1 (518), Enantiomer 2 (519)*3 -amino-N-(6-chloropyridin-3 -yl)-5-(( 1 -(2- hydroxypropyl)-lH-pyrazol-5- \ o f| YY yl)methoxy)pyrazine-2 -carboxamide 18- 51719* 'N0H-fy~-< W'W'NH2\ 0 fl YTN0Y°N NH2\0HJTY^HN^JP°N NH23 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro- N-(6-chloropyridin-3-yl)-5-((3-fluoro-l-(2- 5-((methoxy-d3)methyl-d2)-l-(methyl-d3)-lH- fluoroethyl)- lH-pyrazol-4-yl)methoxy)-3 - pyrazol-4-yl)methoxy)pyrazine-2-carboxamide methylpyrazine-2-carboxamide° rNrcl0II Y521 520JLHNZII o N^NH2 / -N'W"'''NAF0DA D D DYDDXZDDAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure(4-(((5-((6-chloropyridin-3-yl)carbamoyl)-6- methylpyrazin-2-yl)oxy)methyl)-3 -fluoro- 1 - methyl- IH-py razol-5 -y l)methy 1 N-(6-chloropyridin-3-yl)-5-((l-(2- methylcarbamate hydroxyethyl)-lH-pyrazol-5-yl)methoxy)-3- methylpyrazine-2-carboxamide N^CI5230NXN 522 u< VNII 1 H( KHF\ J"N"01 0 N OH^ 11' 03 -amino-N-(6-chloropyridin-3 -y 1) -5 -((3 -fluoro- l-methyl-5-((S-methylsulfonimidoyl)methyl)- lH-pyrazol-4-yl)methoxy)pyrazine-2- carboxamide, Enantiomer 1 (525), Enantiomer2 (526)*N-(6-chloropyridin-3 -yl)-5-((3 -fluoro- 1-(2- (methylamino)ethyl)- lH-pyrazol-4-F<N^N^Nyl)methoxy)-3-methylpyrazine-2 -carboxamide \ II J H25-N NH252426* ',NM-AA < " SNH A AHHN- / XFuF\ II J H'M-A o°o>xN NH2N^ \,. S / "NH3-amino-N-(6-chloropyridin-3-yl)-5-((5- N-(6-chloropyridin-3-yl)-5-((5- (methoxymethyl)- 1 -methyl- 1H- 1,2,3 -triazol-4- (methoxymethyl)- 1 -methyl-lH- 1,2,3 -triazol-4- yl)methoxy)pyrazine-2-carboxamide yl)methoxy)-3-methylpyrazine-2 -carboxamide528 u 527II 1 H HN--N'ZXOZXNH2 / N'X-°xAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-5-((5-((N, S- dimethylsulfonimidoyl)methyl)-3 -fluoro- 1 - methyl-1H-pyrazol-4-yl)methoxy)-3- N-(6-chloropyridin-3-yl)-5-((l-(2,2- methylpyrazine-2-carboxamide difluoroethyl)- lH-tetrazol-5-yl)methoxy)-3 - Ci methylpyrazine-2-carboxamideF 0 frCIo C JN 530 529A A / A' 1 H f AN-N' zN3-amino-N-(6-chloropyridin-3-yl)-5-(((lr,4r)-4- hydroxy-4- (hydroxymethyl)cyclohexyl)oxy)pyrazine-2- carboxamide (532) / N., CI 3-amino-N-(6-chloropyridin-3-yl)-5-((l-(2,2- O <HOHOMII 1 1 difluoroethyl)-lH-tetrazol-5- yl)methoxy)pyrazine-2 -carboxamide 32-X," D I / ” F 0 fY ''O^N NHzCI5315333 -amino-N-(6-chloropyridin-3 -yl)-5-((( 1 s,4r)-4- A A / A "hydroxy-4- JL Ah(hydroxymethyl)cyclohexyl)oxy)pyrazine-2-NNy^O^N^NH2carboxamide (533) N'N. ClHOep.N-(6-chloropyridin-3-yl)-5-(((lr,4r)-4-hydroxy- 4-(hydroxymethyl)cyclohexyl)oxy)-3- methylpyrazine-2-carboxamide (534) N-(6-chloropyridin-3-yl)-5-((5- ((cyclopropylsulfonyl)methyl)-3 -fluoro- 1 - / N. / Cl 0 Y methyl-1H-pyrazol-4-yl)methoxy)-3- - HOHCDMII L 1 methylpyrazine-2-carboxamideX" D. 1 1 H536 °so < AT 534- A / N. A A^N 535N-(6-chloropyridin-3-yl)-5-(((lr,4r)-4-hydroxy- (0If Y H 4-(hydroxymethyl)cyclohexyl)oxy)-3- methylpyrazine-2-carboxamide (535) -A '0N " / N. / Cl 0" A Y- HOHQ,KIII L 1Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-N-(6-chloropyridin-3-yl)-5-((((1S,3R)- 3 -((difluoromethoxy )methy 1) -3 - hydroxy cyclopentyl)oxy)pyrazine-2- rac-N-(6-chloropyridin-3-yl)-5-(((lR,3S)-3- carboxamide, Enantiomer 1 (537), hydroxy-3 -(methoxymethyl)cyclopentyl)oxy)-3 - Enantiomer 2 (538)* methylpyrazine-2-carboxamide537- 539#538*F ° hANH2X HcO / A A N Ah0 r^N\ / CII ° NANH2HN-(6-chloropyridin-3-yl)-5-(((lR,3S)-3- N-(6-chloropyridin-3-yl)-5-(((lR,3S)-3- hydroxy-3-(methoxymethyl)cyclopentyl)oxy)- hydroxy-3 -(hydroxymethyl)cyclopentyl)oxy)-3 - 3 -methylpyrazine-2 -carboxamide, Enantiomer methylpyrazine-2 -carboxamide, Enantiomer 1 1 (540), Enantiomer 2 (541)* (542), Enantiomer 2 (543)*0fl N42- 540- u43* / - / AHc zo NH541* A / NXN ho vk A AX HoOXA A N AH0fl N0fl NH3ACA,0ANAH^CC>O<,OANXH3 -amino-N-(6-chloropyridin-3 -yl)-5-(( 1 - (difluoromethyl)- lH-pyrazol-5 - N-(6-chloropyridin-3-yl)-5-((l-(2,2- yl)methoxy)picolinamide difluoroethyl)-lH-pyrazol-5-yl)methoxy-d2)-3- methylpyrazine-2-carboxamide u iTX545 544II J H N H2pzA V Jf T HNXF0Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-N-(6-chloropyridin-3-yl)-5-(((lR,3S)- 3 -hydroxy-3 - (hydroxymethyl)cyclohexyl)oxy)pyrazine-2- carboxamide, Enantiomer 1 (547), Enantiomer 2 (548)* 3-amino-N-(6-chloropyridin-3-yl)-5-((3-fluoro-1-methyl-1H-pyrazol-4-yl)methoxy)picolinamide0rYcl47- 546 u48*. A X " II J H, CI —N / A^O^^NH20fl An (AHOW ^"°N NH*3-amino-N-(6-chloropyridin-3-yl)-5-(((ls,4s)-4- rac-3 -amino-5-((( 1R,3 S)-3 -carbamoyl-3 - hydroxy-4-(2-hydroxypropan-2- hydroxycyclohexyl)oxy)-N-(6-chloropyridin-3- yl)cyclohexyl)oxy)pyrazine-2 -carboxamide yl)pyrazine-2 -carboxamide 550h° h°,?H / O XYC' 549YX 11 AJ#i H H2N rx r Nx^ N HH2NAA 'ct l\L NH2n OHoN-(6-chloropyridin-3-yl)-5-(((lR,3S)-3- ((dimethylamino)methy l)-3 - hydroxycyclopentyl)oxy)-3-methylpyrazine-2- carboxamide, Enantiomer 1 (552), Enantiomer2 (553)*rac-3-amino-N-(6-chloropyridin-3-yl)-5- ((( 1 S,3R)-3 -hydroxy-3 -(2 -hydroxypropan-2- / " Y A1yl)cyclopentyl)oxy)pyrazine-2 -carboxamide 52- u fA 551 53*#° || > OXAO1NAHHYH0OA,'QAN'ANH2N0h Y. XAHAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-N-(6-chloropyridin-3-yl)-5-(((1S,4s)-4-hydroxy-4-((R)-1-hydroxyethyl)cyclohexyl)oxy)pyrazine-2-carboxamide, Stereoisomer 1 (555), N-(6-chloropyridin-3-yl)-5-((l-(2-cyanoethyl)- Stereoisomer 2 (556)* 3-fluoro-lH-pyrazol-4-yl)methoxy)-3- methylpyrazine-2-carboxamide OH 0. N _ -Cl 55- 55456*■"fl X" / AJL XH / Cl / -N TNS- / 'NAF1 1 L II H■ / XX N NH23-amino-N-(6-chloropyridin-3-yl)-5-(((1s,4s)-4-hydroxy-4-isopropylcyclohexyl)oxy)pyrazine-2-carboxamide | rac-3-amino-N-(6-chloropyridin-3-yl)-5-(((1S,3S)-3-hydroxy-3-(hydroxymethyl)cyclopentyl)oxy)pyrazine-2-carboxamide558 557#0ii V — JU. — 'ZO^N NH2A JLHO 'O N NHH25-(( 1 -(2,2-difluoroethyl)-3-fluoro-1H-pyrazol-4- 3 -amino-5-(( 1 -(2,2-difluoroethyl)-3 -fluoro- 1H- yl)methoxy)-3-methyl-N-(2-methylpyrimidin-5- pyrazol-4-yl)methoxy)-N-(2-methylpyrimidin- yl)pyrazine-2 -carboxamide 5-yl)pyrazine-2 -carboxamide 560 559 u fII J HN NH2F< " AF< A3-amino-N-(6-chloropyridin-3-yl)-5-(((l-(2,2- N-(6-chloropyridin-3-yl)-5-((l-(2,2- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- difluoroethyl)-3 -fluoro-lH- 1,2,4-triazol-5- yl)methyl)thio)pyrazine-2 -carboxamide yl)methoxy)-3-methylpyrazine-2 -carboxamide NH20562 561 L 1 jP^clk KIHN; ^0k'N, kN^F F5-(((4-chloro-l-(2,2-difluoroethyl)-lH-l,2,3- N-(6-chloropy ridin-3 -y l)-3 -methy 1-5 -(( 1 - triazol-5-yl)methyl)amino)-N-(6-chloropyridin- methyl-3-(mefliylcarbamoyl)-lH-pyrazol-4- 3-yl)-3-methylpyrazine-2 -carboxamide yl)methoxy)pyrazine-2 -carboxamide564 1? [kf 563hI? IAA \ fl / ' k K 1 II JNIH HNC kHN-kN" Xl / Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-N-(6-chloropyridin-3-yl)-6-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)oxy)nicotinamide, Enantiomer 1 (567), Enantiomer 2 (568)* | 2-amino-N-(6-chloropyridin-3-yl)-6-(((1S,3R)-3-hydroxy-3-(trifluoromethyl)cyclopentyl)oxy)nicotinamide, Enantiomer 1 (565), Enantiomer 2 (566)*9 fV OH 9 f JJ 67- 565- 68* 1 1 L 1) H 566*< L JI J.HHO ^ ''0 nNH2NH29 fYn i i1 1 1 II HHC\ J JI JL P^O^N^NH2H(R)-3-amino-N-(6-chloropyridin-3-yl)-5-((l- (S)-3-amino-N-(6-chloropyridin-3-yl)-5-((l- (difluoromethyl)-5-(l,2-dihydroxyethyl)-lH- (difluoromethyl)-5-( 1, 2-dihydroxy ethyl)- 1H- pyrazol-4-yl)methoxy)pyrazine-2 -carboxamide pyrazol-4-yl)methoxy)pyrazine-2-carboxamide0ii V0fl N 570 569I" / " " xAN NH2N^yAD^N^NH2NF— ( -- OHXFFAXFI OH HO HO3-amino-N-(6-chloropyridin-3-yl)-5-((4-methyl- 5-((5-(aminomethyl)isoxazol-3-yl)methoxy)-N- l-(2,2,2-trifluoroethyl)-lH-l,2,3-triazol-5- (6-chloropyridin-3 -y 1) -3 -methylpyrazine-2- yl)methoxy)pyrazine-2-carboxamidecarboxamideE F o rrcl572 5710ii V JL JLHN;Ny^o-^N^NH2N—\ H2N crN5-((4-chloro- 1 -(2,2,2-trifluoroethyl)- 1H- 1,2,3- N-(6-chloropyridin-3-yl)-5-((2-(3,3- triazol-5-yl)methoxy)-N-(6-chloropyridin-3-yl)- difluoropropyl)-5-methyl-2H- 1,2,3 -triazol-4- 3 -methylpyrazine-2 -carboxamide yl)methoxy)-3-methylpyrazine-2-carboxamideF o (TYCI574 F 573FA^.|?NN0 z,. ° A.N\0N=\ "N^VJ^CI / P ANCIAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3 -amino-N-(6-chloropy ridin-3 -y l)-5 -(( 1 -(3,3 - 3-amino-5-((5-chloro-2-(2,2-difluoroethyl)-2H- difluoropropyl)-4-methyl- 1H- 1,2,3 -triazol-5- 1,2,3 -triazol-4-yl)methoxy)-N-(2- yl)methoxy)pyrazine-2-carboxamide methylpyrimidin-5-yl)pyrazine-2 -carboxamide N-A576 K 57NIx.. / z- \ \ / z^N 0 5 / A / / f. / Xt N O-^ p — \ z=NN=( HN— Cl\ NH2F-<A FCl2-amino-6-((4-chloro-l-(2,2-difluoroethyl)-lH- 3 -amino-5-((3 -chloro- 1 -methyl- lH-pyrazol-4- 1,2,3 -triazol-5-yl)methoxy)-N-(2- yl)methoxy)-N-(2-methylpyrimidin-5- methy Ipy rimidin-5 -y l)nicotinamide yl)pyrazine-2 -carboxamide° |f 1 578 577AfrrAJ:":: sNNy^O^N^NH2_N / ::y^O^N^NH2'NACI 'N\3-amino-N-(6-chloropyridin-3-yl)-5-(((ls,4s)-4- hydroxy-4- rac-3 -amino-N-(6-chloropyridin-3 -yl)-5- (methoxymethyl)cyclohexyl)oxy)pyrazine-2- ((( 1R, 3 S)-3 -hydroxy-3 - carboxamide phenylcyclohexyl)oxy)pyrazine-2-carboxamide080#H2N N 579HOVA Z=N k / A-H Z^N HN— d / )— Cl A ocrN=( 0NH23-amino-N-(6-chloropyridin-3-yl)-5-(((lR,3S)- 3 -hydroxy -3 -(2-hydroxypropan-2- 4-amino-N-(6-chloropyridin-3-yl)-2-((1-(2,2- yl)cyclopentyl)oxy)pyrazine-2 -carboxamide, difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- Enantiomer 1 (581), Enantiomer 2 (582)* yl)methoxy)pyrimidine-5-carboxamideo fl 592 L 3 JACI581- A A AN582*H0 X^S*O'X^N' / KNH2A ANH^Ny^O^N^NH2O r^V'CINAF”< O X " " HOX^ 'O^N / KNH2Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-N-(6-chloropy ridin-3 -yl)-6-((l -(2,2- 2-amino-N-(6-chloropy ridin-3 -yl)-6-((l -(2,2- difluoroethyl)-lH-l,2,4-triazol-5-yl)methoxy)-4- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- fluoronicotinamide yl)methoxy)-4-fluoronicotinamide F NH F NH20 YP 82O5 4 ff^YCI583AFNPPN''PNYFNPP' II H ' H NP^H / V-O^PF j / Pt-N NAF3-chloro-N-(6-chloropyridin-3-yl)-5-((l-(2,2- rac-3 -amino-N-(6-chloropyridin-3 -yl)-5- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- ((( 1R, 3 S)-3 -hydroxy-3 -( 1 -methyl- lH-pyrazol-3 - yl)methoxy)pyrazine-2 -carboxamide yl)cyclopentyl)oxy)pyrazine-2 -carboxamide F o ^YCI86#° rvcl585XrfNXUN-X^N^NP> CL X P”NAFrac-3 -amino-N-(6-chloropyridin-3 -yl)-5- rac-3-amino-N-(6-chloropyridin-3-yl)-5- ((( 1R,3 S)-3-hydroxy-3 -(pyridin-3 - ((( 1R, 3 S)-3 -hydroxy-3 -(pyridin-4- yl)cyclopentyl)oxy)pyrazine-2 -carboxamide yl)cyclopentyl)oxy)pyrazine-2 -carboxamide 88# / ^Cl 587#0II J CY iPH0 X^S'O'X^N'^NH2N-(6-chloropyridin-3-yl)-6-(((lR,3S)-3- hydroxy-3-methylcyclopentyl)oxy)-2- methylnicotinamide Enantiomer 1 (590),Enantiomer! (591)*rac-3-amino-N-(6-chloropyridin-3-yl)-5- ((( 1R, 3 S)-3 -hydroxy-3 -(pyridin-2- yl)cyclopentyl)oxy)pyrazine-2 -carboxamide 90- u fP589 91*#X LH k LH0li T O OY p PHOu fP< X^O^hANH2Y \ 1 1 HHO'rac -4 -amino -N-(6 -chloropy ridin-3 -y 1) -2 - N-(6-chloropyridin-3-yl)-2-(((ls,4s)-4-hydroxy- ((( 1R, 3 S)-3 -hydroxy-3 - 4-methylcyclohexyl)oxy)-4-methylpyrimidine- methylcyclopentyl)oxy)pyrimidine-5- 5 -carboxamidecarboxamide94#593u fP u fp HOX 1 L*xHOJ 1H1 J NI 1 N1 HNH2Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure3-amino-N-(6-chloropyridin-3-yl)-5-(((l-(2,2- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- 4-amino-N-(6-chloropyridin-3-yl)-2-(((ls,4s)-4- yl)methyl)amino)pyrazine-2-carboxamide hydroxy-4-methylcyclohexyl)oxy)pyrimidine- 5 -carboxamideF 0 fyCI596 595 A^A1A A A " u fv A -AHHO-A A N AANAN NH21 1 jl JHN-AFN N H24-amino-N-(6-chloropyridin-3-yl)-2-((1-(2,2- 4-amino-N-(6-chloropyridin-3-yl)-2-(((l-(2,2- difluoroethyl)-lH-pyrazol-5- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- yl)methoxy)pyrimidine-5-carboxamide yl)methyl)amino)pyrimidine-5-carboxamide598 597 L i r^k 1 XCI cA NA AiA A ANN^JX0^ AN^NHH2A AHN' AHN"AFNH2N-(6-chloropyridin-3 -y 1) -5 -(((3 -fluoro - 1 -methyl- 3 -amino-N-(6-chloropyridin-3 -yl)-5-((( 1 -(2,2- lH-pyrazol-4-yl)methyl)amino)-3 - difluoroethyl)-lH-pyrazol-5- methylpyrazine-2-carboxamide yl)methyl)amino)pyrazine-2-carboxamide 600. N. X u A 599if VNL x JO^CIII JHA -NAAN NH:AN-(2-chloropyrimidin-5-yl)-5-((l-(2,2- 3-amino-N-(6-chloropyridin-3-yl)-5-(((ls,4s)-4- difluoroethyl)-lH-l,2,4-triazol-5-yl)methoxy)-3- hydroxy-4-methylcyclohexyl)amino)pyrazine- methylpyrazine-2 -carboxamide 2-carboxamide / -AX 602 F O A 'N601A, N A. JVN ° fl 1 \ 1 H “-n r A -“NN / oA ^^ / S*N' / KN' / KNH2AN HN-(6-chloropyridin-3-yl)-5-(((l-(2,2- 3 -amino-N-(6-chloropyridin-3 -yl)-5-(( 1 -(2- difluoroethyl)-lH-pyrazol-5-yl)methyl)amino)- methoxyethyl)-lH-l,2,4-triazol-5- 3 -methylpyrazine-2 -carboxamide yl)methoxy)pyrazine-2 -carboxamide 604 603rLA JT A0jr rA N OA 7 — \ / =NXNAHNA Z>—C1NjANH2Attorney Docket No: X0042.70031WOOO Ex. Name and Structure Ex. Name and StructureN-(6-chloropyridin-3-yl)-6-((l-(2,2- N-(6-chloropyridin-3 -yl)-6-(( 1 -(2,2- difluoroethyl)-4-fluoro-1H-1,2,3-triazol-5- difluoroethyl)-1H-1,2,4-triazol-5-yl)methoxy)- yl)methoxy)-2-(methyl-d3)nicotinamide 2-methylnicotinamide 606 L £ £vc' 605 L. j?('c'N / A JL H X 1HxJ iDNA. D N'NAN* Compounds isolated as individual stereoisomers with unassigned absolute stereochemistry#Compound isolated as a mixture of enantiomers

[0097] In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 3, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 3, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 3, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 3 (in free base form).Table 3Ex. Name and Structure Ex. Name and Structure3-ainino-\-(6-chloropyridin-3-yl)-5-(((I. S.3 / ?)- 3-ainino-\-(6-chloropyridin-3-yl)-5-(((l / ?.3. S)- 3 -hydroxy-3 - 3 -hydro xy -3- methylcyclohexyl)amino)pyrazine-2- methylcyclohexyl)amino)pyrazine-2- carboxamide carboxamide XX. / CI6070li Y 6080r ¥XANAN n A - 1 I H HO ^ " JjN"NH2 "N NH2\-(6-chloropyridin-3-yl)-5-(((I. S.3 / ?)-3- \-(6-chloropyridin-3-yl)-5-((( l / ?.3. S)-3- hydroxy-3-methylcyclohexyl)amino)-3- hydroxy-3 -methylcyclo hexyl)amino)-3 - methylpyrazine-2 -carboxamide methylpyrazine-2-carboxamide, X\ / CI6090fl X 610x xJA -D.HOHHO H3 -amino-5 -((3,5 -difluoro- 1 -methyl- 1 / / - px razol- 5-((3,5-difluoro- 1 -methyl- 1 / / -py razol-4- 4-yl)mcthoxy)-\-(2-mcthvlpvrimidin-5- yl)mcthoxy)-3-mcthvl-\-(2-mcthvlpvrimidin-5- yl)pyrazine-2 -carboxamide yl)pyrazine-2 -carboxamide611 612 j?\ II J H__N / A^O^N^NH2'A 'AAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-\-(6-chloropyridin-3-yl)-6-((3.5- 2-amino-6-((5-chloro-3-fluoro- 1 -methyl- 1H- difluoro- 1 -methyl- 1 / / -py razol-4- pyrazol-4-yl)mcthoxy)-\-(6-chloropyridin-3- yl)methoxy)nicotinamide yl)nicotinamide613 u fV 614 u XFci£ \ X\ XH1 |l N H-VNH2NXFNXFN NHz2-amino-6-((3 -chloro-5-fluoro- 1 -methyl- 1H- 3 -ami no-\-(6-chloropy ridin-3 -yl)-5-((( 15,37?)- pyrazol-4-yl)mcthoxy)-\-(6-chloropyridin-3- 3 -(difluoromethyl)-3 - yl)nicotinamide hydroxycyclopentyl)oxy)pyrazine-2- carboxamide615 616Fuh° rY \ 1 1clNH2V i <NXXNFlP^ 'PPNH2'Npl3 -amino-\-(6-chloropyridin-3 -yl)-5-((( 17?,3S)- 3 -(difluoromethyl)-3 - A-(6-chloropyridin-3-yl)-5-(((15,37?)-3- hydroxycyclopentyl)oxy)pyrazine-2- (difluoromethyl)-3-hydroxycyclopentyl)oxy)-3- carboxamide (methoxymethyl)pyrazine-2 -carboxamide 617 618° PYCI° ii VI / AJ, / -x AYX NH0\'^O^N''XH2FHXV> X0ANX^XA-(6-chloropyridin-3-yl)-5-(((15,37?)-3- \-(6-chloropy ridi n-3 -yl)-5-((( 17?, 35) -3 - hy droxy-3 -methylcyclopentyl- l-<7)oxy)-3- (difluoromethyl)-3-hydroxycyclopentyl)oxy)-3- methylpyrazine-2-carboxamide (methoxymethyl)pyrazine-2-carboxamide619 ° PYCI6200fl Y irNXXN< X D J x / A XFHOZO>OXNX. P.HXj 'v NHO\-(6-chloropy ridi n-3 -yl)-5-((( 17?, 35) -3 - A-(6-chloropyridin-3-yl)-5-(((15,37?)-3- hydroxy-3 -methylcyclopentyl- 1 -<7)oxy )-3 - hy droxy-3 -methylcyclopentyl- l-<7)oxy)-3- methylpyrazine-2 -carboxamide (methoxymethyl)pyrazine-2 -carboxamide 621 622? fT^n< V nDl| 1 HPxDJ „ X K„.i • - HO HO\-(6-chloropy ridi n-3 -yl)-5-((( 17?, 35) -3 - A-(6-chloropyridin-3-yl)-5-(((15,37?)-3- hydroxy-3 -methylcyclopentyl- 1 -<7)oxy )-3 - hy droxy-3 -methylcyclopentyl)oxy)-3 -(methyl- (methoxymethyl)pyrazine-2-carboxamide <73)pyrazine-2 -carboxamide 623? XX 624 ° fl Yn rv nA if-yPp X) N x x \ HO-X-J -O''N:HOAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropy ridi n-3 -yl)-5-((( 17?, 3S) -3 - A-(6-chloropyridin-3-yl)-5-(((lS',37?)-3- hydroxy-3 -methylcyclopentyl)oxy)-3 -(methyl- hydroxy-3 -methylcyclopentyl)oxy)-3 - c / 3)pyrazinc-2 -carboxamide (methoxymethyl-<72)pyrazine-2 -carboxamide 6250fl 6260fl <NANAN Hcf V-J O N* / 0D D\-(6-chloropy ridi n-3 -yl)-5-((( 17?, 3S) -3 - hydroxy-3-methylcyclopentyl)oxy)-3- A-(6-chloropyridin-3-yl)-5-(((lS',37?)-3- (difluoromethyl)-3-hydroxycyclopentyl)oxy)-3- (methoxymethyl-<72)pyrazine-2 -carboxamidemethylpyrazine-2-carboxamide 627 ° fl N 628 ° iTYclV ilfNA'N^ND D\-(6-chloropy ridi n-3 -yl)-5-((( 17?, 3S) -3 - 3-(aminomcthvl)-\-(6-chloropyridin-3-vl)-5- (difluoromethyl)-3-hydroxycyclopentyl)oxy)-3- ((5 -(difluoro methy 1)- 1 -methyl- l / / -pyrazol-4- methylpyrazine-2 -carboxamide yl)methoxy)pyrazine-2 -carboxamide 629 ° fi 630 / N'yF°xF>o>nFH2N\-(6-chloropyridin-3-yl)-5-((5- 3 -( 1 -aminocthv l)-\-(6-chloropy ridin-3 -yl)-5- (difluoromethyl)- 1-methy 1- l / / -pyrazol-4- ((5-(difluoromethyl)- 1 -methyl- 1 / / -py razol-4- yl)methoxy)-3- yl)methoxy)pyrazine-2 -carboxamide ((dimethylamino)methyl)pyrazine-2- carboxamideu rv631 6320fi NII 1 HII JHN1NAFNH2 / / F / N\F / / F\-(6-chloropyridin-3-yl)-5-((5- (difluoromethyl)- 1 -methyl- 1 / / -py razol-4- 3 -(azetidin- 1 -y Imcthy 1 )-\-(6-chloropy ridin-3 - yl)methoxy)-3-((methylamino)methyl)pyrazine- yl)-5-((5-(difluoromethyl)- 1 -methyl- 1H- 2-carboxamide pyrazol-4-yl)methoxy)pyrazine-2-carboxamide NH r- N / 9 _ _ 633 634 / \ N — X. H \=N N=\ H Av<\ / =” / r JTo AFF^FAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure\-(6-chloropyridin-3-yl)-6-((5- 3-(aminomcthvl)-\-(6-chloropyridin-3-yl)-5- (difluoromethyl)- 1-methy 1- 177-pyrazol-4- ((4-fluoro- 1 -methyl- 1 / / -py razol-3 - yl)methoxy)-2-(methoxymethyl)nicotinamide yl)methoxy)pyrazine-2 -carboxamideFxo635 A 9 636HYN _ z=N ZN'N B \=Nci-AA / / T H2N o F A F \-(6-chloropyridin-3-yl)-6-((l-(2.2- 6-((4-chloro-l-(2,2-difluoroethyl)-177-l,2,3- difluoroethy l)-4-fluoro- 1H- 1,2, 3 -triazol-5 - triazol-5-yl)mcthoxy)-\-(6-chloropyridin-3-yl)- yl)methoxy)-2-(methoxymethyl)nicotinamide 2-(methoxymethyl)nicotinamide \) / F. / Cl 637 638H_ Y-N,N=VN r Y A(,r" U lr Y. N cAY y0 FCIYY? Y F F\-(6-chloropyridin-3-yl)-5-((( I. S.3 / ?)-3- A-(6-chloropyridin-3-yl)-5-(((17?,3>$)-3- (difluoromethyl)-3-hydroxycyclopentyl)oxy)-3- (difluoromethyl)-3-hydroxycyclopentyl)oxy)-3- (methoxymethyl)pyrazine-2-carboxamide (methoxymethyl)pyrazine-2 -carboxamide 6390ITYCI6400ITYCIV i A. / A rNYN'JYNFHYJYNYK\-(6-chlo ropy ridi n-3 -y 1) -6 -(( 1 - 2-amino-A-(6-chloropyridin-3 -yl)-6-(( 1 -(2,2- (difluoromethyl)-5-methyl-177-pyrazol-4- difluoroethyl)- 177- 1,2,4-triazol-5-yl)methoxy)- yl)methoxy)-2-(methoxymethyl)nicotinamide 4-fluoronicotinamide HH2N^NnN-^ 641xo 642HVNN / =Nn T 10FO1F F 2-amino-A-(6-chloropyridin-3-yl)-6-((l-(2,2- 2-amino-\-(6-chloropy ridi n-3 -yl)-6-((( l,s.4.s)-4- difluoroethyl)-4-fluoro- 177- 1,2, 3 -triazol-5 - (difluoromethy 1) -4- yl)methoxy)-4-methylnicotinamide hydroxycyclohexyl)oxy)nicotinamide E643 N=Y Y N 644 V vo HN\ Y\ / / -NCI" YY? Vv n2NH0H NF, ' CAFNJ OF?F2-amino-\-(6-chloropy ridi n-3 -yl)-6-((( l.s.4.s)-4- 2-amino-N-(6-chloropyridin-3-yl)-6-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)oxy)nicotinamidedimethylcyclohexyl)oxy)nicotinamide HOY \ xr. N NH2HOY^A. NH2645H. 0 646 o'1\ / ''' / 1xHNYYHN\YYAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-A-(6-chloropy ridin-3 -yl)-6-(((lr, 4r)-4- hydroxy-1,4- 2 -ami no-\-(6-chloropy ridin-3 -yl)-6-((( IS',47?)- dimethylcyclohexyl)oxy)nicotinamide 2,2-difluoro-4-hydroxy-4- methylcyclopentyl)oxy)nicotinamideHOJA°VN^NH2647 6480flHN\ „ / -XFFU JU KI Y X X X IHT 1HO V' XX 'N NH22-amino-\-(6-chloropy ridin-3 -yl)-6-((( 1 / ?.3, S’)- 2-amino-\-(6-chloropy ridin-3 -yl)-6-((( I / / .4. S')- 2,2-difluoro-4-hydroxy-4- 2,2-difluoro-3 -hydroxy -3 - methylcyclopentyl)oxy)nicotinamide methylcyclopentyl)oxy)nicotinamide 6490ii Y 650 u px / Y rN*x J L XHX X X IHH0NH2HO4%O' / ^N NH2FF2-ainino-\-(6-chloropyridin-3-yl)-6-(((I. S'.3 / ?)- 2-amino-\-(6-chloropy ridin-3 -yl)-6-((( 1 / ?.3, S’)- 2, 2-difluoro-3 -hydroxy-3 - 3-ethyl-3- methylcyclopentyl)oxy)nicotinamide hydroxycyclopentyl)oxy)nicotinamide 651 652P uP PN^ u P^ J X XHX X XPN HA^NHO4 uNZXNH2 / x XH0NHF2FN-(6-chloropyridin-3 -yl)-6-((( 1 R, 3S) -3 - 2-amino-\-(6-chloropy ridin-3 -yl)-6-((( 1S,3R)- hydroxy-3-methylcyclopentyl)oxy)-2- 3-ethyl-3- (methylamino)nicotinamide hydroxycyclopentyl)oxy)nicotinamide653 654 s n ”? P^YX J X XHHOHO\y 'N NH2HA-(6-chloropyridin-3-yl)-6-(((lS',3^)-3- 2-amino-\-(6-chloropy ridin-3 -yl)-6-((( 1 / ?.3, S’)- hydroxy-3 -methylcyclopentyl)oxy)-2- 3-(2,2-difluoroethyl)-3- (methylamino)nicotinamidehydroxycyclopentyl)oxy)nicotinamide 655 656 U P^ u P^ J X XHFY X X X XHI. HOV-"'S»CT hYNH;, HO' lYH2-amino-\-(6-chloropy ridin-3 -yl)-6-((( IS,3R)- 2-amino-\-(6-chloropy ridin-3 -yl)-6-((( 1 / ?.3, S’)- 3 -(2,2-difluoroethyl)-3 - 3 -hydro xy -3- hydroxy cyclopentyl)oxy)nicotinamide (methoxymethyl)cyclopentyl)oxy)nicotinamide 657 658? P^ u P^FXPNA^NJ X JIHX X X XHI. HO' 'ct i\t NH2V^^O N NH2Attorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and Structure2-amino-\-(6-chloropyridin-3 -yl)-6-((( I. S.3 / ?)- 2-amino-A-(6-chloropyridin-3 -yl)-6-((( 17?,3S)- 3 -hydroxy-3 - 3 -((difluoromethoxy )methy 1) -3 - (methoxymethyl)cyclopentyl)oxy)nicotinamide hydroxycyclopentyl)oxy)nicotinamide 659 670 O r^NV'CI' 'O^ iM N H2F ° N^NH23 -amino-5-(( 1 -(difluoromethyl)-3 -fluoro-177- 2-amino-\-(6-chloropyridin-3 -yl)-6-((( IS,3R)- pyrazol-4-yl)mcthoxy)-\-(2-mcthvlpyrimidin- 3 -((difluoromethoxy)methyl)-3 - 5-yl)pyrazine-2 -carboxamide hydroxy cyclopentyl)oxy)nicotinamideF671 0 r<jNV'CI672 - (zNH N^x | J4O,, X JN= / ^N^F 1 z JI H ° MUF0N^NHZH2NFA-(6-chloropyridin-3-yl)-5-((l-(2,2- difluoroethyl)-3 -methoxy- 1H- 1,2, 4-triazol-5- yl)methoxy)-3-methylpyrazine-2 -carboxamide 4-amino-\-(6-chloropyridin-3-yl)-6-(((l-(2.2- „. CI difluoroethyl)-4-fluoro-177-l,2,3-triazol-5- yl)methyl)amino)pyridazine-3-carboxamide0(f 1N'673N674°A-NF MF5-((3 -amino- 1 -(2, 2-difluoroethyl)- 1H-1,2,4- 2-amino-\-(6-chloropyridin-3 -yl)-6-(( 1 -(2,2- triazol-5-yl)mcthoxy)-\-(6-chloropyridin-3-yl)- difluoroethyl)-3 -fluoro-177- 1,2,4-triazol-5- 3 -methylpyrazine-2 -carboxamide yl)methoxy)nicotinamide NH2H2N..M / F675 H „ N- / 676N^VN r Nc-v n / y ciM / ?° F^ J °Rj F F\-(6-chloropyridin-3-vl)-6-((l-(2.2- 6-((4-chloro-l -(2, 2-difluoroethyl)- 177- 1,2,3 - difluoroethyl)-3 -fluoro- 177-1,2, 4-triazol-5- triazol-5-yl)mcthoxy-t / 2)-\-(6- yl)methoxy)-2 -methylnicotinamide chloropyridin-3-yl)-2 -methylnicotinamide F N'-N\-CI677 H \^N „ N- / 678ciM / "0Mfo^o^y_5NA^clF N=Z 0A-(2-chloropyrimidin-5-yl)-6-(( 1 -(2,2- 2-amino-\-(2-chloropyrimidin-5-yl)-6-((l-(2.2- difluoroethy l)-4-fluoro- 177- 1,2, 3 -triazol-5 - difluoroethyl)-4-fluoro-177-l,2,3-triazol-5- yl)methoxy-<72)-2 -methylnicotinamide yl)methoxy)nicotinamideH2N..F\, 679 N" VF680 N^\ H n / \ _ r ox / Z / 7~No ^~ / NVD / =NVci-A J yv N 6ZFxJ N=Z OFAttorney Docket No: X0042.70031WO00 Ex. Name and Structure Ex. Name and StructureA-(2-chloropyrimidin-5-yl)-6-(( 1 -(2,2- 2-amino-6-((4-chloro-l-(2,2-difluoroethyl)-177- difluoroethy l)-4-fluoro- 177- 1,2, 3 -triazol-5 - 1,2,3 -triazol-5-y l)mcthoxy )-\-(2- yl)methoxy)-2 -methylnicotinamide chloropy rimidin-5 -yl)nicotinamideF H2N..CL\.. 681 ^x H VN^\ H M V / Nx r\ 682Nx rxJx / / A / / , " N sUT ITN" Y, N ClA J N a-A J N O Fx JN°FvF F2-ami no-\-(6-chloropy ridin-3 -y 1) -6 -(( 1 - 2-amino-\-(6-chloropy ridin-3 -yl)-6-(( 1 - (mcthy l-r / p- 1 / / -py razol-3 - methyl- 177-py razol-3 - yl)methoxy)nicotinamide yl)methoxy)nicotinamide683 _ O 684 _ O' » — V-fY* / AV- ci V y TPVCIDXN-N °A=( AZN-N° -NYD D NH2NH22-ami no-\-(6-chloropy ridin-3 -yl)-6-((3 - \-(6-chloropyridin-3-yl)-6-((3- (difluoromethyl)isoxazol-4- (difluoromethyl)isoxazol-4-yl)methoxy)-2- yl)methoxy)nicotinamide methylnicotinamideH2N685 686NAH / / AN\AX\ / / AY ci-Ax / / FA> | ci^AJ / II A ]° oF Ax F F A F \-(6-chloropy ridin-3 -yl)-6-((3 -(2,2- 2-amino-7V-(6-chloropy ridin-3 -yl)-6-((3 -(2,2- difluoroethyl)isoxazol-4-yl)methoxy)-2- difluoroethyl)isoxazol-4- methylnicotinamide yl)methoxy)nicotinamideH2N687NAH 688 N^\ H > A7 3 V-4 / / —Cl" A j / II A Y / / TCI-'-'A AN\A / FA2 / Y0Fx J0 F\AF F2-amino-\-(6-chloropyridin-3-yl)-6-(isoxazol- \-(6-chloropyridin-3-yl)-6-(isoxazol-5- 5 -y Imethoxy )nicotinamide ylmethoxy)-2 -methylnicotinamide H2N.. _689 690 NA H VNA0 O / YN\AX / / A „N CIA^J / 0o 0

[0098] The following definitions and embodiments apply to all generic formulae comprising the relevant groups (e.g., Formula (I) or any subgeneric formula thereof) provided herein. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0099] As defined herein, X1is N or CRxl; X2is N or CRx2; and X3is N or CRx3.

[0100] In some embodiments, X1is N or CRxl. In some embodiments, X1is N. In some embodiments, X1is CRxl. In some embodiments, X1is CH.

[0101] In some embodiments, X2is N or CRx2. In some embodiments, X2is N. In some embodiments, X2is CRx2. In some embodiments, X2is CH.

[0102] In some embodiments, and X3is N or CRx3. In some embodiments, X3is N. In some embodiments, X3is CRx3. In some embodiments, X3is CH.Attorney Docket No: X0042.70031WO00

[0103] In some embodiments, no more than two of X1, X2, and X3is N. In some embodiments, no more than one of X1, X2, and X3is N. In some embodiments, none of X1, X2, and X3is N. In some embodiments, X1is N, X2is CRx2, and X3is CRx3. In certain embodiments, X1is CRxl, X2is CRx2, and X3is CRx3. In certain embodiments, X1is CH; X2is CH; and X3is CH. In certain embodiments, X1is CH; X2is CH; and X3is N. In certain embodiments, X1is CH; X2is N; and X3is CH. In certain embodiments, X1is N; X2is CH; and X3is CH.

[0104] As defined herein, each instance of Rxl, Rx2, and Rx3is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6–10aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or Ci-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted.

[0105] In some embodiments, each instance of Rxl, Rx2, and Rx3is independently H, halogen, Ci-6 alkyl, Ci.6 haloalkyl, -CN, -ORO, or -N(RN)2. In some embodiments, each instance of Rxl, Rx2, and Rx3is independently H, halogen, Ci-6 alkyl, -CN, or -OR0. In some embodiments, each instance of Rxl, Rx2, and Rx3is independently H, fluoro, chloro, methyl, -CN, -OH, or -OCH3. In some embodiments, each instance of Rxl, Rx2, and Rx3is independently H, fluoro, chloro, methyl, -OH, or -OCH3. In some embodiments, each instance of Rx2and Rx3is H, and Rxlis H, fluoro, chloro, methyl, -CN, -OH, or -OCH3. In some embodiments, each instance of Rx2and Rx3is H, and Rxlis H, fluoro, or -OCH3.

[0106] In some embodiments, Rxlis H. In some embodiments, Rx2is H. In some embodiments, Rx3is H. In some embodiments, Rxl, Rx2, and Rx3are each H.

[0107] As defined herein, R1is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, -CN, -OR0, -N(RN)2, -SRs, or Ci-6 acyl, wherein the alkyl, cycloalkyl, or acyl is optionally substituted. In some embodiments, R1is H, halogen, C1-6 alkyl, C1-6 haloalkyl, -CN, -OR0, or -N(RN)2. In some embodiments, R1is H, halogen, Ci-6 alkyl, -CN, or -OR0. In some embodiments, R1is H, fluoro, chloro, methyl, -CN, -OH, or -OCH3. In certain embodiments, R1is chloro or methyl. In certain embodiments, R1is chloro.

[0108] As defined herein, Y1is N or CRyl; Y2is N or CRy2; Y3is N or CRy3; and Y4is N or CRy4, provided that at least one of Y1and Y3is N.

[0109] In some embodiments, Y1is N or CRyl. In some embodiments, Y1is N. In some embodiments, Y1is CRyl. In some embodiments, Y1is CH.

[0110] In some embodiments, Y2is N or CRy2. In some embodiments, Y2is N. In some embodiments, Y2is CRy2. In some embodiments, Y2is CH.

[0111] In some embodiments, Y3is N or CRy3. In some embodiments, Y3is N. In some embodiments, Y3is CRy3. In some embodiments, Y3is CH.

[0112] In some embodiments, Y4is N or CRy4. In some embodiments, Y4is N. In some embodiments, Y4is CRy4. In some embodiments, Y4is CH.

[0113] In some embodiments, no more than three of Y1, Y2, Y3, and Y4is N. In certain embodiments, no more than two of Y1, Y2, Y3, and Y4is N. In some embodiments, Y1is N, Y2is CRy2, Y3is N, and Y4is CRy4. In some embodiments, Y1is N, Y2is CH, Y3is N, and Y4is CH. In certain embodiments, Y1is N, Y2is CH, Y3is CH, and Y4is CH.Attorney Docket No: X0042.70031WOOO

[0114] As provided herein, each instance of R2, Ryl, Ry2, Ry3, and Ry4is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6–10aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, CI-6 acyl, or -Z -L -R wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; provided that at least one of R2, Ryl, Ry2, Ry3, and Ry4is independently -Z’-L’-R3.

[0115] In certain embodiments, R2is -Z1-L1-R3. In some embodiments, R2is -Z1-L1-R3and Ryl, Ry2, Ry3, and Ry4are independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6–10aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or Ci-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted. In some embodiments, R2is -Z’-L’-R3and Ryl, Ry2, Ry3, and Ry4are independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, -CN, -OR0, or -N(RN)2. In some embodiments, R2is -Z’-L’-R3and Ryl, Ry2, Ry3, and Ry4are independently H, fluoro, chloro, methyl, ethyl, -CF3, -OH, -OCH3, -NH2, -NHCH3, or N(CH3)2.

[0116] In some embodiments, Ry4is -Z’-L’-R3and Ryl, Ry2, Ry3, and R2are independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or Ci-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted.

[0117] In some embodiments, Ry4is optionally substituted C1-6 alkyl, C1-6 haloalkyl, halogen, -OR0, -N(RN)2, or optionally substituted 3 to 6 membered heterocyclyl. In some embodiments, Ry4is methyl, ethyl, F, Cl, -CF3, -CF2H, -OMe, -CH2OMe, -NH2, -NHMe, or 3-oxetanyl. In some embodiments, Ry4is methyl or -NH2.

[0118] In some embodiments, R2is -Z’-L’-R3; Y3is N; Ry2is H; and Ry4is optionally substituted C1-6 alkyl, C1-6 haloalkyl, halogen, -OR0, -N(RN)2, or optionally substituted 3 to 6 membered heterocyclyl. In some embodiments, R2is -Z’-L’-R3; Y3is N; Ry2is H; and Ry4is methyl, ethyl, F, Cl, -CF3, -CF2H, -OMe, -CH2OMe, -NH2, -NHMe, or 3-oxetanyl. In some embodiments, R2is -Z’-L’-R3; Y3is N; Ry2is H; and Ry4is methyl or -NH2.

[0119] As provided herein, Z1is absent, -O-, -N(RN)-, -S-, -S(=O)2-, -(C(RL)2)n-, -C(=O)-, -C^=C-, -O-(C(RL)2)n-, -(C(RL)2)n-O-, -N(RN)-(C(RL)2)n-, -(C(RL)2)n-N(RN)-, -S-(C(RL)2)n-, -(C(RL)2)n-S-, -S(=O)2-(C(RL)2)n-, -(C(RL)2)n-S(=O)2-, -C(=O)-(C(RL)2)n-, -(C(RL)2)n-C(=O)-, -(C(RL)2)n-C = C-, or -C=C-(C(RL)2)n-.

[0120] In some embodiments, Z1is -O-, -N(RN), -C^=C-, -S(=O)2-, -(C(RL)2)n-O-, or absent. In some embodiments, Z1is -O-, -N(RN), or absent. In some embodiments, Z1is -O-, -NH-, -N(CH3)-, or absent. In some embodiments, Z1is -O-. In certain embodiments, Z1is -N(RN)-. In some embodiments, Z1is -NH-. In certain embodiments, Z1is -N(CH3)-. In some embodiments, Z1is absent.

[0121] As provided herein, L1is absent or -(C(RL)2)n-. In some embodiments, L1is absent or— (CH2)n-. In certain embodiments, L1is absent, -CH2-, -C(CH3)H-, -(CH2)2-, or-(CH2)3-. In someembodiments, L1is -CH2-. In some embodiments, L1is -C(D)2-. In some embodiments, L1is. InAttorney Docket No: X0042.70031WO00some embodiments,L1is

[0122] In some embodiments, -Z’-L1- is: absent,. In some embodiments, -Z’-L1- is:

[0123] As defined herein, each n is independently 1, 2, or 3. In some embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is 3.

[0124] As defined herein, each instance of RLis independently H, halogen, Ci-6 alkyl, or Ci-6 haloalkyl, wherein the alkyl is optionally substituted, or wherein two RLattached to the same carbon are taken together to form =0.

[0125] In some embodiments, each instance of RLis H. In some embodiments, one instance of RLis Ci-6 alkyl and the remaining instances of RLare H.

[0126] As defined herein, R3is C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6–10aryl, or 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more instances of R3a.

[0127] In some embodiments, R3is C3-10 cycloalkyl optionally substituted with one or more instances of R3a. In some embodiments, R3is C3-6 cycloalkyl optionally substituted with one or more instances of R3a. In certain embodiments, R3is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, Ce cycloalkyl, or C10 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more instances of R3a. In some embodiments, R3is C5 cycloalkyl optionally substituted with one or more instances of R3a. In some embodiments, R3is C„ cycloalkyl optionally substituted with one or more instances of R3a. In certain embodiments, R3is bicyclofl.1. l]pentanyl optionally substituted with one or more instances of R3a.

[0128] In some embodiments, R3is 3-10 membered heterocyclyl optionally substituted with one or moreAttorney Docket No: X0042.70031WO00 instances of R3a. In some embodiments, R3is 3-10 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O and N, and wherein the heterocyclyl is optionally substituted with one or more instances of R3a. In some embodiments, R3is 3-6 membered heterocyclyl optionally substituted with one or more instances of R3a. In some embodiments, R3is 3-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O and N, and wherein the heterocyclyl is optionally substituted with one or more instances of R3a. In certain embodiments, R3is 3 membered heterocyclyl, 4 membered heterocyclyl, or 5 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more instances of R3a. In certain embodiments, R3is 3 membered heterocyclyl, 4 membered heterocyclyl, or 5 membered heterocyclyl, wherein the heterocyclyl has 1 or 2 ring heteroatoms independently selected from O and N, and wherein the heterocyclyl is optionally substituted with one or more instances of R3a.

[0129] In some embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo [l.l.l]pentanyl, cyclohexyl, adamantanyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxabicyclo[2.1.1]hexanyl, or azabicyclo[2.1. l]hexanyl, wherein each is optionally substituted with one or more instances of R3a. In some embodiments, R3is bicyclo [l.l.l]pentanyl optionally substituted with one or more instances of R3a.

[0130] In some embodiments, R3is C6–10aryl, wherein the aryl is optionally substituted with one or more instances of R3a. In certain embodiments, R3is phenyl optionally substituted with one or more instances of R3a.

[0131] In some embodiments, R3is 5-10 membered heteroaryl, wherein heteroaryl is optionally substituted with one or more instances of R3a. In some embodiments, R3is 5-10 membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein heteroaryl is optionally substituted with one or more instances of R3a. In certain embodiments, R3is 5 or 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more instances of R3a. In certain embodiments, R3is 5 or 6 membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of R3a. In certain embodiments, R3is 5-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of R3a. In certain embodiments, R3is 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of R3a.

[0132] In some embodiments, R3is furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein each is optionally substituted with one or more instances of R3a. In some embodiments, R3is pyrazolyl optionally substituted with one or more instances of R3a.

[0133] In some embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo [l.l.l]pentanyl, cyclohexyl, adamantanyl, oxetanyl, azetidinyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, oxabicyclo [2. l.l]hexanyl, azabicyclo [2. l.l]hexanyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein each is optionally substituted with one or more instances of R3a.

[0134] In some embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo [l.l.l]pentanyl,Attorney Docket No: X0042.70031WOOO cyclohexyl, adamantanyl, oxetanyl, azetidinyl, oxabicyclo [2. l.l]hexanyl, azabicyclo [2. l.l]hexanyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, or pyrimidinyl, wherein each is optionally substituted with one or more instances of R3a.

[0135] In some embodiments, R3is triazolyl optionally substituted with one or more instances of R3a.

[0136] In some embodiments, R3is bicyclo [l.l.l]pentanyl optionally substituted with one or more instances of R3a, or pyrazolyl optionally substituted with one or more instances of R3a. In some embodiments, R3is bicyclofl.1. l]pentanyl optionally substituted with one or more instances of R3a. In some embodiments, R3is pyrazolyl optionally substituted with one or more instances of R3a. In some embodiments, R3is 3-pyrazolyl optionally substituted with one or more instances of R3a. In some embodiments, R3is 4-pyrazolyl optionally substituted with one or more instances of R3a. In some embodiments, R3is 5-pyrazolyl optionally substituted with one or more instances of R3a.Attorney Docket No: X0042.70031WO00 F FAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00OHAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00FAttorney Docket No: X0042.70031WOOO

[0151] In some embodiments, R3is:

[0153] In some embodiments, R3is:Attorney Docket No: X0042.70031WOOO

[0155] In some embodiments, each instance of R3ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, -S(=O)2RS1, -S(=O)RS1, -S(=O)2ORO, -S(=O)OR°, -S(=O)2N(RN)2, -S(=O)N(RN)2, -S(=O)(=NRN)RS1, or Ci-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted.

[0156] In some embodiments, each instance of R3ais independently halogen, C1.6 alkyl, -OR0,Attorney Docket No: X0042.70031WOOO -CN, -N(RN)2, C3-7 cycloalkyl, 3-7 membered heterocyclyl, or Ci-6 acyl, wherein each instance of alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.

[0157] In some embodiments, each instance of R3ais independently halogen, C1-6 alkyl, -OR0, -CN, -N(RN)2, -S(=O)2RS1, C3-7 cycloalkyl, 3-7 membered heterocyclyl, or Ci-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted

[0158] In certain embodiments, each instance of R3ais optionally substituted with one or more of halogen, Ci-6 alkyl, -OR0, -S(=O)2Rsl, C3-7 cycloalkyl, and / or 3-7 membered heterocyclyl. In certain embodiments, each instance of R3ais optionally substituted with one or more of halogen, Ci-6 alkyl,-OR0, -N(RN)2, -CN, -S(=O)2RS1, C3-7 cycloalkyl, and / or 3-7 membered heterocyclyl. In certain embodiments, each instance of R3ais optionally substituted with one or more of -F, methyl, -OCH3, -OH, -S(=O)2Me, cyclopropyl, and / or oxetanyl. In certain embodiments, each instance of R3ais optionally substituted with one or more of -F, methyl, -OCH3, -OH, -NH2-CN, -S(=O)2Me, cyclopropyl, and / or oxetanyl.

[0159] In certain embodiments, each instance of R3ais independently Ci-6 alkyl, -OH, -F, -CN, -N(CH3)H, -NHC(=O)CH3, -N(CH3)C(=O)CH3, 2-oxazolidonyl, oxetanyl, -NHC(=O)(cyclopropyl), or -C(=O)CH3, wherein each instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted. In certain embodiments, each instance of R3ais independently Ci-6 alkyl, -OH, -F, -CN, -N(CH3)H, -NHC(=0)CH3, -N(CH3)C(=O)CH3, 2-oxazolidonyl, oxetanyl, -NHC(=O)(cyclopropyl), or

[0160] -C(=O)CH3, wherein each instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted with one or more instances of halogen, Ci-6 alkyl, -OR0, -S(=O)2Rsl, C3-7 cycloalkyl, and / or 3-7 membered heterocyclyl. In certain embodiments, each instance of R3ais independently Ci-6 alkyl, -OH, -F, -CN, -N(CH3)H, -NHC(=O)CH3, 2-oxazolidonyl, oxetanyl, -N(CH3)C(=O)CH3, -NHC(=O)(cyclopropyl), or -C(=O)CH3, wherein each instance of alkyl, 2-oxazolidonyl, and oxetanyl are independently optionally substituted with one or more instances of -F, methyl, -OCH3, -S(=O)2Me, -OH, cyclopropyl, and / or oxetanyl.

[0161] In some embodiments, each instance of R3ais independently Ci-6 alkyl, -OH, -F, -Cl, -CN, -N(CH3)H, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)(cyclopropyl), -S(=O)2Me, 2-oxazolidonyl, oxetanyl, or -C(=O)CH3, wherein each instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted with one or more instances of halogen, Ci-6 alkyl, -OR0, -N(RN)2, -CN, -S(=O)2Rsl, C3-7 cycloalkyl, and / or 3-7 membered heterocyclyl. In some embodiments, each instance of R3ais independently Ci6alkyl, -OH, -Cl, -F, -CN, -N(CH3)H, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)(cyclopropyl), -S(=O)2Me, 2-oxazolidonyl, oxetanyl, or -C(=O)CH3, wherein each of instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted with one or more instances of -F, methyl, -OCH3, -OH, -NH2, -CN, -S(=O)2Me, cyclopropyl, and / or oxetanyl.

[0162] In some embodiments, at least one instance of R3ais methyl, ethyl, Cl, F, -OH, -NH2, -NO2, -OMe, -OEt, -CH2OH, -CH2NH2, -CH2OCH3, -CH2S(=O)2Me, -C(=O)Me, -CN, -CH2CN, -CH2CH2CN, -Attorney Docket No: X0042.70031WO00 CH2CH2CH2CN, -N(H)Me, OH HO

[0163] In some embodiments, at least one instance of R3ais -CF2H, -CH2CF2H, -CH2CH2F -CH2CN, -CH2OMe, -S(=O)2Me

[0164] In some embodiments, at least one instance of R3ais D, -CD3, D DorDAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00

[0168] In some embodiments, -Z1-L1-R3is:Attorney Docket No: X0042.70031WO00

[0170] In some embodiments, -Z’-L’-R3is:Attorney Docket No: X0042.70031WOOO

[0171] In some embodiments, -Z1-L1-R3is:OH

[0172] In some embodiments, -Z1-L1-R3is:Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Atorney Docket No: X0042.70031 WOOOAttorney Docket No: X0042.70031WOOO

[0178] In some embodiments, -Z1-L1-R3is:Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOO

[0182] In some embodiments, -Z1-L1-R3is: O N O N, or O N

[0183] In some embodiments, -Z1-L1-R3is:

[0184] In some embodiments, -Z1-L1-R3is:

[0185] In some embodiments, -Z1-L1-R3is: HN S

[0187] In some embodiments, -Z'-L'-R3is:Attorney Docket No: X0042.70031WOOO

[0189] In some embodiments, -Z1-L1-R3is:

[0190] In some embodiments, -Z1-L1-R3is:o N

[0191] In some embodiments, -Z1-L1-R3is:

[0192] In some embodiments, -Z1-L1-R3is:Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00

[0195] In some embodiments, -Z1-L1-R3is:

[0196] In some embodiments, -Z1-L1-R3is:Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00

[0200] In some embodiments, -Z1-L1-R3is:Attorney Docket No: X0042.70031WOOO

[0201] In some embodiments, -Z1-L1-R3is:Attorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00

[0204] As defined herein, RN1is H, Ci-6 alkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, -S(=O)2RS1, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted.

[0205] In some embodiments, RN1is H. In certain embodiments, RN1is optionally substituted Ci-6 alkyl. In certain embodiments, RN1is optionally substituted C3-7 cycloalkyl. In certain embodiments, RN1is optionally substituted C1-6 acyl. In certain embodiments, RN1is -S(=O)2RS1. In certain embodiments, RN1is a nitrogen protecting group.

[0206] As defined herein, each RNis independently H, C1.6 alkyl, C3-7 cycloalkyl, Ci-6 acyl, -S(=O)2RS1, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted.

[0207] In certain embodiments, at least one instance of RNis H. In certain embodiments, each instance of RNis H. In certain embodiments, at least one instance of RNis optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of RNis optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of RNis optionally substituted Ci-6 acyl. In certain embodiments, at least one instance of RNis -S(=O)2RS1. In certain embodiments, at least one instance of RNis a nitrogen protecting group. In certain embodiments, two RNattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, two RNattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 4-6 membered heterocyclyl.

[0208] As defined herein, each instance of R° is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-gacyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.

[0209] In certain embodiments, at least one instance of R° is H. In certain embodiments, each instance of R° is H. In certain embodiments, at least one instance of R° is optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of R° is Ci-6 haloalkyl. In certain embodiments, at least one instance of R° is optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of R° is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of R° is optionally substituted Ci-gacyl. In certain embodiments, at least one instance of R° is an oxygen protecting group.

[0210] As defined herein, each instance of Rsis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.Attorney Docket No: X0042.70031WO00

[0211] In certain embodiments, at least one instance of Rsis H. In certain embodiments, at least one instance of Rsis optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of Rsis unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of Rsis optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of Rsis unsubstituted C1.3 alkyl. In certain embodiments, at least one instance of Rsis methyl. In certain embodiments, at least one instance of Rsis Ci-6 haloalkyl. In certain embodiments, at least one instance of Rsis optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of Rsis optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of Rsis optionally substituted Ci-6 acyl. In certain embodiments, at least one instance of Rsis a sulfur protecting group.

[0212] As defined herein, each instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6–10aryl, or 5-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted.

[0213] In certain embodiments, at least one instance of RS1is optionally substituted Ci-6 alkyl. In certain embodiments, at least one instance of RS1is Ci-6 haloalkyl. In certain embodiments, at least one instance of RS1is optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of RS1is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of RS1is optionally substituted C6–10aryl. In certain embodiments, at least one instance of RS1is optionally substituted 5-10 membered heteroaryl.Pharmaceutical Compositions, Kits, and Administration

[0214] The present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof) and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a compound described herein 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.

[0215] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi -dose unit.

[0216] 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 one-half or one-third of such a dosage. Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or anyAttorney Docket No: X0042.70031WO00 additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0217] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0218] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g, systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0219] 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.

[0220] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0221] 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, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g, multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue orAttorney Docket No: X0042.70031WO00 cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.

[0222] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophy tactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. 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.

[0223] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0224] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U. S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.Methods of Treatment and Uses

[0225] As described in some aspects, compounds provided herein can act as voltage-gated potassium channel potentiators (e.g., Kv7.2 / Kv7.3 potentiators) by potentiating a voltage-sensing domain (VSD) of the potassium channel and are therefore useful, e.g., for the treatment of diseases, disorders, and conditions.

[0226] In one aspect, provided herein are methods of potentiating a Kv7 potassium channel in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the method potentiates a voltage -sensingAttorney Docket No: X0042.70031WO00 domain (VSD) of a Kv7 potassium channel.

[0227] In certain embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In certain embodiments, the Kv7 potassium channel is Kv7.2. In certain embodiments, the Kv7 potassium channel is Kv7.3. In certain embodiments, the Kv7 potassium channel is Kv7.2 / Kc7.3. In certain embodiments, the compound or composition is selective for one or more of Kv7.2-Kv7.5 over Kv7.1. In certain embodiments, the compound or composition is selective for one or more of Kv7.2 / Kv7.3 over Kv7.1.

[0228] Also provided herein are compounds, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in potentiating a Kv7 potassium channel in a subject. In certain embodiments, the compound potentiates a voltage-sensing domain (VSD) of a Kv7 potassium channel.

[0229] In another aspect, provided herein are methods of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is associated with Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5 dysfunction. In certain embodiments, the disease, disorder, or condition is associated with Kv7.2 dysfunction. In certain embodiments, the disease, disorder, or condition is associated with Kv7.3 dysfunction. In certain embodiments, the disease, disorder, or condition is associated with Kv7.2 / Kc7.3 dysfunction. In certain embodiments, disease, disorder, or condition is associated with dysfunction of a voltage -sensing domain (VSD) of a Kv7 potassium channel.

[0230] Also provided herein are compounds, and a pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject. In certain embodiments, disease, disorder, or condition is associated with dysfunction of a voltage -sensing domain (VSD) of a Kv7 potassium channel.

[0231] In another aspect, provided herein are methods of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0232] Also provided herein are compounds, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof.

[0233] In certain embodiments, the disease, disorder, or condition is a seizure disorder. In certain embodiments, the seizure disorder are seizures associated with a disease, disorder, or condition (e.g., wherein seizures / epileptic episodes are symptoms of a disease, disorder, or condition). In certain embodiments, the seizure disorder refers to focal onset epilepsy, also known as partial onset epilepsy. InAttorney Docket No: X0042.70031WO00 some embodiments, the seizure disorder is photosensitive epilepsy. In some embodiments, the seizure disorder are seizures associated with self-induced syncope. In some embodiments, the seizure disorder is intractable epilepsy. In some embodiments, the seizure disorder are seizures associated with Angelman syndrome. In some embodiments, the seizure disorder is benign rolandic epilepsy. In some embodiments, the seizure disorder is CDKL5 disorder. In some embodiments, the seizure disorder is childhood and juvenile absence epilepsy. In some embodiments, the seizure disorder is Dravet syndrome. In some embodiments, the seizure disorder is frontal lobe epilepsy. In some embodiments, the seizure disorder is Glutl deficiency syndrome. In some embodiments, the seizure disorder are seizures associated with hypothalamic hamartoma. In some embodiments, the seizure disorder is infantile spasms / West’s syndrome. In some embodiments, the seizure disorder is juvenile myoclonic epilepsy. In some embodiments, the seizure disorder is Landau-Kleffner syndrome. In some embodiments, the seizure disorder is Lennox-Gastaut syndrome (LGS). In some embodiments, the seizure disorder is epilepsy with myoclonic-absences. In some embodiments, the seizure disorder is Ohtahara syndrome. In some embodiments, the seizure disorder is Panayiotopoulos syndrome. In some embodiments, the seizure disorder is PCDH19 epilepsy. In some embodiments, the seizure disorder is progressive myoclonic epilepsies. In some embodiments, the seizure disorder are seizures associated with Rasmussen’s syndrome. In some embodiments, the seizure disorder is ring chromosome 20 syndrome. In some embodiments, the seizure disorder is reflex epilepsies. In some embodiments, the seizure disorder is temporal lobe epilepsy. In some embodiments, the seizure disorder is Lafora progressive myoclonus epilepsy. In some embodiments, the seizure disorder are seizures associated with neurocutaneous syndromes. In some embodiments, the seizure disorder are seizures associated with tuberous sclerosis complex. In some embodiments, the seizure disorder is early infantile epileptic encephalopathy. In some embodiments, the seizure disorder is early onset epileptic encephalopathy. In some embodiments, the seizure disorder is generalized epilepsy. In some embodiments, the seizure disorder is generalized epilepsy with febrile seizures. In some embodiments, the seizure disorder are seizures associated with Rett syndrome. In some embodiments, the seizure disorder are seizures associated with multiple sclerosis. In some embodiments, the seizure disorder are seizures associated with Alzheimer’s disease. In some embodiments, the seizure disorder are seizures associated with autism. In some embodiments, the seizure disorder are seizures associated with ataxia. In some embodiments, the seizure disorder are seizures associated with hypotonia. In some embodiments, the seizure disorder is paroxysmal dyskinesia. In some embodiments, the seizure disorder is generalized onset seizures. In some embodiments, the seizure disorder is focal onset seizures (also known as partial onset seizures). In some embodiments, the generalized onset seizures are primary generalized tonic-clonic seizures. In some embodiments, the seizure disorder is primary generalized tonic-clonic seizures.

[0234] In certain embodiments, the disease, disorder, or condition is a depressive disorder. “Depressive disorders” are mood disorders characterized by depressed mood. In certain embodiments, the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar depression, postpartum depression, premenstrual dysphoric disorder (PMDD),Attorney Docket No: X0042.70031WO00 seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof.

[0235] In some embodiments, the depressive disorder is major depressive disorder (MDD). In some embodiments, the depressive disorder is disruptive mood dysregulation disorder. In some embodiments, the depressive disorder is persistent depressive disorder. In some embodiments, the depressive disorder is bipolar depression. In some embodiments, the depressive disorder is postpartum depression. In some embodiments, the depressive disorder is premenstrual dysphoric disorder (PMDD). In some embodiments, the depressive disorder is seasonal affective disorder (SAD). In some embodiments, the depressive disorder is atypical depression. In some embodiments, the depressive disorder is treatment-resistant depression (TRD). In some embodiments, the depressive disorder is depression associated with agitation or anxiety. In some embodiments, the depressive disorder is adjustment disorder with depressed mood. In some embodiments, the depressive disorder is prolonged depressive reaction.

[0236] In some embodiments, the depressive disorder is bipolar depression (i.e., the depressive disorder is depression associated with bipolar disorder). In some embodiments, the bipolar disorder is treatmentresistant bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, or bipolar disorder not otherwise specified. In some embodiments, the bipolar disorder is bipolar I disorder, bipolar II disorder, or cyclothymic disorder. In certain embodiments, the depressive disorder is depression associated with bipolar I disorder and / or bipolar II disorder.

[0237] Also contemplated by the disclosure is treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, social phobia, agoraphobia, agoraphobia with panic disorder, hypochondriasis, post-traumatic stress disorder (PTSD), treatment-resistant bipolar disorder, generalized anxiety disorder, attention-deficit / hyperactivity disorder (ADHD), bipolar I disorder, bipolar II disorder, manic disorder, cyclothymic disorder and bipolar disorder not otherwise specified, dysthymic disorder, depressive disorder not otherwise specified, minor depression, recurrent brief depressive disorder, depressive-type psychosis, impulse -control disorders, schizophrenia, schizophreniform disorder, schizoaffective disorder, Parkinson's disease, dementia, Alzheimer's disease, Huntington's disease, Tourette's syndrome, aggression, and substance use and / or abuse, or a combination thereof.

[0238] In certain embodiments, the disease, disorder, or condition is pain. “Pain” as used herein refers to all categories of pain and includes, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, nociplastic pain, idiopathic pain, neuralgic pain, orofacial pain, bum pain, burning mouth syndrome, somatic pain, visceral pain, myofacial pain, dental pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal and post-operative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache (e.g., with or without aura), hemiplegic migraine (e.g., familial hemiplegic migraine), conditions associated with cephalic pain, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, pain following stroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain, non-cardiacAttorney Docket No: X0042.70031WO00 chest pain, irritable bowel syndrome, pain associated with bowel disorders and dyspepsia, osteoarthritis (OA) pain, chronic back pain, bone pain, soft tissue pain, and combinations thereof.

[0239] In certain embodiments, the disease, disorder, or condition is anhedonia. “Anhedonia” as used herein refers to markedly diminished interest or pleasure in all, or almost all activities. Anhedonia of mild degree is sometimes referred to as hypohedonia. Social anhedonia is a type of anhedonia. “Social anhedonia” as used herein refers to a disinterest in social contact and a lack of pleasure in social situations. Social anhedonia is characterized by social withdrawal and typically manifests as an indifference to social interactions with other people. This trait is considered to be a central characteristic, as well as a predictor, of schizophrenia spectrum disorders. In another aspect, provided herein are compounds, and a pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use as medicaments. In certain embodiments, the medicament is for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject (e.g., Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5 dysfunction, e.g., Kv7.2 / Kc7.3 dysfunction). In certain embodiments, disease, disorder, or condition is associated with dysfunction of a voltage -sensing domain (VSD) of a Kv7 potassium channel. In certain embodiments, the medicament is for treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject.

[0240] Also provided herein are methods of potentiating a Kv7 potassium channel and / or voltage-sensing domain (VSD) of a Kv7 potassium channel in a cell in vitro comprising contacting the cell with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In certain embodiments, the Kv7 potassium channel is Kv7.2. In certain embodiments, the Kv7 potassium channel is Kv7.3. In certain embodiments, the Kv7 potassium channel is Kv7.2 / Kc7.3. In certain embodiments, the compound or composition is selective for one or more of Kv7.2-Kv7.5 over Kv7.1. In certain embodiments, the compound or composition is selective for one or more of Kv7.2 / Kv7.3 over Kv7.1.

[0241] Provided herein are methods of potentiating a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) in a subject or in a cell in vitro. In certain embodiments, the activity of the Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100%, relative to control. In certain embodiments, the activity of the Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) is increased by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, or at least 1000-fold, relative to control. In certain embodiments, activity of the Kv7 channel is potentiated by targeting a voltage -sensing domain (VSD) of the Kv7 channel.Additional Embodiments

[0242] Additional embodiments are provided according to the following numbered Embodiments:Attorney Docket No: X0042.70031WO00 Embodiment 1. A compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:X1is N or CRxl; X2is N or CRx2; and X3is N or CRx3;R1is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, -CN, -OR0, -N(RN)2, -SRS, or C1-6 acyl, wherein the alkyl, cycloalkyl, or acyl is optionally substituted;each instance of Rxl, Rx2, and Rx3is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted;Y1is N or CRyl; Y2is N or CRy2; Y3is N or CRy3; and Y4is N or CRy4, provided that at least one of Y1and Y3is N;each instance of R2, Ryl, Ry2, Ry3, and Ry4is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRs, C1-6 acyl, or -Z’-L’-R3, or any two instances of R2, Ryl, Ry2, Ry3, and Ry4on adjacent carbons are joined together to form C5-6 cycloalkyl or 5-6 membered heterocyclyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; provided that at least one of R2, Ryl, Ry2, Ry3, and Ry4is independently -Z1-L1-R3each instance of Z1is independently absent, -O-, -N(RN)-, -S-, -S(=O)2-, -(C(RL)2)n-, -C(=O)-, -C≡C-, -O-(C(RL)2)n-, -(C(RL)2)n-O-, -N(RN)-(C(RL)2)n-, -(C(RL)2)n-N(RN)-, -S-(C(RL)2)n-, -(C(RL)2)n-S-, -S(=O)2-(C(RL)2)n-, -(C(RL)2)n-S(=O)2-, -C(=O)-(C(RL)2)n-, -(C(RL)2)n-C(=O)-, -(C(RL)2)n-C = C-, or -C = C-(C(RL)2)n-;each instance of L1is independently absent or -(C(RL)2)n-;each n is independently 1, 2, or 3;each instance of RLis independently H, halogen, C1-6 alkyl, or C1-6 haloalkyl, wherein each alkyl is independently optionally substituted, or wherein two RLattached to the same carbon are taken together to form =0;each instance of R3is independently C3-10 cycloalkyl, 3-10 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one or more instances of R3a;each instance of R3ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, -S(=O)2RS1,Attorney Docket No: X0042.70031WOOO -S(=O)RS1, -S(=O)2OR°, -S(=O)OR°, -S(=O)2N(RN)2, -S(=O)N(RN)2, -S(=O)(=NRN)RS1, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted;each instance of RN1and RNis independently H, Ci-6 alkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, -S(=O)2Rsl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted;each instance of R° is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted;each instance of Rsis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; andeach instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6–10aryl, or 5-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted.Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein no more than two of X1, X2, and X3is N.Embodiment 3. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein no more than one of X1, X2, is X3are N.Embodiment 4. The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein no more than three of Y1, Y2, Y3, and Y4is N.Embodiment 5. The compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein no more than two of Y1, Y2, Y3, and Y4is N.Embodiment 6. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X1is CRxl, X2is CRx2, and X3is CRx3.Embodiment 7. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X1is N, X2is CRx2, and X3is CRx3.Embodiment 8. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y1is N, Y2is CRy2, Y3is N, and Y4is CRy4.Embodiment 9. The compound of any one of the preceding Embodiments, or a pharmaceuticallyAttorney Docket No: X0042.70031WOOO acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y1is N, Y2is CRy2, Y3is CRy3, and Y4is CRy4.Embodiment 10. The compound of Embodiment 1, wherein the compound is of Formula (I-a):RX\^N<^ / R1NRy2. FL A. y Rx2R^ XYX^RsV4(I-A),or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Embodiment 11. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X1is CRxl.Embodiment 12. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is halogen.Embodiment 13. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is Cl.Embodiment 13a. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RN1is H.Embodiment 14. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y3is N.Embodiment 15. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y3is CRy3.Embodiment 16. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is -Z’-L’-R3.Embodiment 17. The compound of Embodiment 1, wherein the compound is of formula (I-b):Attorney Docket No: X0042.70031WOOO(I-b),or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Embodiment 18. The compound of Embodiment 1, wherein the compound is of formula (I-b-1):R3(I-b-1), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Embodiment 19. The compound of Embodiment 1, wherein the compound is of formula (I-b-2):R3(I-b-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Embodiment 20. The compound of Embodiment 1, wherein the compound is of formula (I-c):(I-c),Attorney Docket No: X0042.70031WOOO or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Embodiment 21. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is -O-.Embodiment 22. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is -N(RN)-.Embodiment 23. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is -NH- or -N(CH3)-.Embodiment 24. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is absent.Embodiment 25. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L1is -(CH2)n-.Embodiment 26. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L1is -CH2-.Embodiment 27. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L1is -C(CH3)H-.Embodiment 28. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L1is absent.Embodiment 29. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, orprodrug thereof, wherein -Z’-L1- is: absent,Embodiment 30. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C3-10 cycloalkyl optionally substituted with one or more instances of R3a.Embodiment 31. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, orAttorney Docket No: X0042.70031WOOO prodrug thereof, wherein R3is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, Ce cycloalkyl, or C10 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more instances of R3a.Embodiment 32. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C5 cycloalkyl optionally substituted with one or more instances of R3a.Embodiment 33. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is bicyclo [l.l.l]pentanyl optionally substituted with one or more instances of R3a.Embodiment 34. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is 3-10 membered heterocyclyl optionally substituted with one or more instances of R3a.Embodiment 35. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is 3 membered heterocyclyl, 4 membered heterocyclyl, or 5 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more instances of R3a.Embodiment 36. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is phenyl optionally substituted with one or more instances of R3a.Embodiment 37. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is 5 or 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more instances of R3a.Embodiment 38. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein each is optionally substituted with one or more instances of R3a.Embodiment 39. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is bicyclo [l.l.l]pentanyl optionally substituted with one or more instances of R3a, or pyrazolyl optionally substituted with one or more instances of R3a.Embodiment 40. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein the one or more instances of R3aare each independently halogen, C1-6 alkyl, -OR0, -CN, -N(RN)2, C3-7 cycloalkyl, 3-7 membered heterocyclyl, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.Attorney Docket No: X0042.70031WOOO Embodiment 41. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein the one or more instances of R3aare each independently Ci-6 alkyl, -OH, -F, -CN, -N(CH3)H, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)(cyclopropyl), 2-oxazolidonyl, oxetanyl, or -C(=O)CH3, wherein each instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted with one or more instances of halogen, Ci-6 alkyl, -OR0, -S(=O)2RS1, C3.7cycloalkyl, or 3-7 membered heterocyclyl.Embodiment 42. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein the one or more instances of R3aare each independently Ci-6 alkyl, -OH, -F, -CN, -N(CH3)H, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)(cyclopropyl), 2-oxazolidonyl, oxetanyl, or -C(=O)CH3, wherein each of instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted with one or more instances of -F, methyl, -OCH3, -OH, -S(=O)2Me, cyclopropyl, or oxetanyl.Embodiment 43. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, orOHAttorney Docket No: X0042.70031WO00Embodiment 44. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, orAttorney Docket No: X0042.70031WOOOEmbodiment 45. The compound of Embodiment 1, wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Embodiment 46. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof.Embodiment 47. A pharmaceutical composition comprising a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Embodiment 48. A method of potentiating a Kv7 potassium channel in a subject comprising administering to the subject a compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.Embodiment 49. The method of Embodiment 48, comprising potentiating a voltage -sensing domain (VSD) of the Kv7 potassium channel.Attorney Docket No: X0042.70031WOOO Embodiment 50. A method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject in need thereof comprising administering to the subject a compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.Embodiment 51. The method of Embodiment 49 or 50, wherein the method potentiates a voltage-sensing domain (VSD) of a Kv7 potassium channel.Embodiment 52. The method of any one of Embodiments 48-51, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.Embodiment 53. The method of any one of Embodiments 48-52, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.Embodiment 54. A method of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.Embodiment 55. The method of any one of Embodiments 48-54, wherein the subject is a human.Embodiment 56. A compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in potentiating a Kv7 potassium channel in a subject.Embodiment 57. A compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject.Embodiment 58. The compound for use of Embodiment 56 or 57, wherein the compound potentiates a voltage-sensing domain (VSD) of a Kv7 potassium channel.Embodiment 59. The compound for use of any one of Embodiments 56-58, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.Embodiment 60. The compound for use of any one of Embodiments 56-59, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.Embodiment 61. A compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject.Embodiment 62. The compound for use of any one of Embodiments 56-61, wherein the subject is a human.Embodiment 63. A compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament.Attorney Docket No: X0042.70031WO00 Embodiment 64. Use of a compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for: (a) potentiating a Kv7 potassium channel; (b) treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction; and / or (c) treating a seizure disorder, a depressive disorder, pain, or anhedonia.Embodiment 65. A kit comprising a compound of any one of Embodiments 1-46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.EXAMPLES

[0243] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological 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 in their scope.

[0244] The examples provided below include procedures, intermediates, and characterization data useful, e.g., for the preparation of compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc. are included herein as aspects of the present disclosure.Synthesis of CompoundsEXAMPLE 1: Synthesis of A-(6-chloropyridin-3-yl)-6-((3-(2-hydroxypropan-2-yl)bicyclo[l.l.l]pentan-l-yl)methoxy)-2-methylnicotinamideStep 1. Preparation of 2-(3-(hydroxymethyl)bicyclo[l.1. l]pentan-l-yl)propan-2-ol

[0245] To a solution of methyl 3-(hydroxymethyl)bicyclo[l.l.l]pentane-l-carboxylate (1.00 g, 6.40 mmol) in anhydrous tetrahydrofuran (50 mL) was added a 3.0 M solution of methyl magnesium bromide in diethyl ether (8.54 mL, 25.6 mmol) at 0 °C. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was then quenched by slow addition of brine (20 mL) at 0 °C and diluted with saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.00 g, 100% yield): 'HNMR (400 MHz, DMSO-6) 84.40 (t, J= 5.6 Hz, 1H), 4.02 (s, 1H), 3.36 (d, J= 5.8 Hz, 2H), 1.41 (s, 6H), 1.01 (s, 6H).Step 2. Preparation ofN-(6-chloropyridin-3-yl)-6fluoro-2-methylnicotinamide

[0246] To a solution of 6-fluoro-2 -methylnicotinic acid (1.00 g, 6.45 mmol) in tetrahydrofuran (13 mL) was added N, A-diisopropylethylamine (3.6 mL, 25.8 mmol) and 2-chloro-l -methylpyridinium iodide (1.98 g, 7.74 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h, and then 5-amino-2-chloropyridine (0.99 g, 7.74 mmol) was added. The reaction mixture was heated to 70 °C for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with a 0.5 M aqueous solution of hydrochloric acid (50 mL) and ethyl acetate (10 mL). Brown precipitate was formed. Solid was filtered,Attorney Docket No: X0042.70031WO00 rinsed with water (3 x 5 mL) and ethyl acetate (5 mL), and dried to afford the title compound as a light brown solid (1.05 g, 61% yield): 'HNMR (400 MHz, DMSO-t / 6) 8 10.82 (s, 1H), 8.72 (d, J= 2.6 Hz, 1H), 8.21-8.15 (m, 2H), 7.54 (d, J= 8.6 Hz, 1H), 7.19-7.16 (m, 1H), 2.54 (s, 3H); MS (ES+) m / z 266.4 (M + 1), 268.4 (M + 1).Step 3. Preparation ofN-(6-chloropyridin-3-yl)-6-((3-(2-hydroxypropan-2-yl)bicyclo[l.l.l]pentan-l-yl)methoxy)-2-methylnicotinamide

[0247] To a solution of 2-(3-(hydroxymethyl)bicyclo[l.l.l]pentan-l-yl)propan-2-ol (0.079 g, 0.506 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.51 mmol), and A-(6-chloropyridin-3-yl)-6-fluoro-2 -methylnicotinamide (0.100 g, 0.377 mmol). The reaction mixture was stirred at 60 °C for two days. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous ammonium chloride (30 mL) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography, eluting with a gradient of 0 to 80% of ethyl acetate in heptane, to afford the title compound as a colorless solid (0.080 g, 53% yield): ’H NMR (400 MHz, DMSO-t / e) 8 10.62 (s, 1H), 8.73 (d, J= 2.7 Hz, 1H), 8.20 (dd, J= 8.7, 2.7 Hz, 1H), 7.89 (d, J= 8.5 Hz, 1H), 7.53 (d, J= 8.7 Hz, 1H), 6.76 (d, J= 8.4 Hz, 1H), 4.35 (s, 2H), 4.10 (s, 1H), 1.55 (s, 6H), 1.02 (s, 6H); MS (ES+) m / z 402.0 (M + 1), 404.0 (M + 1).EXAMPLES 2-5, 182-222, 317-318, 370-374

[0248] In a similar manner as described in EXAMPLE 1, utilizing the appropriately substituted starting materials and intermediates, the following compounds were prepared:Example MS (ES+)Name NMRNo. m / z1H NMR (400 MHz, DMSO- A-(6-chloropyridin-3-yl)-2-((3-(2- d6) δ 10.79 (s, 1H), 8.77 (s, 1H), 8.72403.0 (M +hydroxypropan-2-yl)bicyclo [1.1. l]pentan- (d, J = 2.6 Hz, 1H), 8.20 (dd, J = 8.8, 2 1), 405.0 (Ml-yl)methoxy)-4-methylpyrimidine-5- 2.7 Hz, 1H), 7.55 (d, J= 8.7 Hz, 1H), carboxamide + 1). 4.42 (s, 2H), 4.11 (s, 1H), 2.56 (s, 3H),1.57 (s, 6H), 1.02 (s, 6H). A-(6-chloropyridin-3-yl)-6-((3-(2-1H NMR (400 MHz, DMSO-Aj 8403.0 (M + 11.19 (s, 1H), 8.90 (d, J = 2.6 Hz, 1H), hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 3 1), 405.0 (M1 -yl)methoxy)-4-methylpyridazine-3 - 8.35-8.32 (m, 1H), 7.55-7.53 (m, 1H),7.30 (s, 1H), 4.57 (s, 2H), 4.13 (s, 1H), carboxamide + 1).2.55 (s, 3H), 1.60 (s, 6H), 1.03 (s, 6H).1H NMR (400 MHz, DMSO-Aj 8 \-(6-chloro-3-pyridyl)-3-mcthvl-5- 362.0 (M +4 10.86 (s, 1H), 9.14 (s, 1H), 8.88 (d, J =(thiazol-5-ylmethoxy)pyrazine-2- 1), 364.0 (M 2.5 Hz, 1H), 8.34-8.30 (m, 2H), 8.11 carboxamide + 1). (s, 1H), 7.52 (d, J= 8.7 Hz, 1H), 5.76(s, 2H), 2.84 (s, 3H).1H NMR (400 MHz, DMSO- d6) δ 10.67 (s, 1H), 8.73 (d, J = 2.6 Hz, A-(6-chloropyridin-3-yl)-6-((3-(2- 402.0 (M +1H), 8.35 (s, 1H), 8.20 (dd, J= 8.7, 2.7 5 hydroxypropan-2-yl)bicyclo [1.1. l]pentan- 1), 404.0 (MHz, 1H), 7.52 (d, J= 8.7 Hz, 1H), 6.79 1 -yl)methoxy)-4-methylnicotinamide + 1) (s, 1H), 4.35 (s, 2H), 4.10 (s, 1H), 2.39(s, 3H), 1.55 (s, 6H), 1.01 (s, 6H).Attorney Docket No: X0042.70031WO00 Example MS (ES+)Name NMRNo. m / z1H NMR (400 MHz, CDC13) £9.89 (s, A-(6-chloropyridin-3-yl)-5-((3- 1H), 8.55 (d, J= 2.6 Hz, 1H), 8.36 (dd,395.2 (M +182 (difluoromethy l)bicy clo [1.1.1 ]pentan- 1 - J= 8.6, 2.6 Hz, 1H), 8.02 (s, 1H), 7.341), 397.2 (Myl)methoxy)-3 -methy lpyrazine-2- (d, J= 8.6 Hz, 1H), 5.71 (t, J = 56.4 carboxamide + 1). Hz, 1H), 4.48 (s, 2H), 2.91 (s, 3H),1.92 (s, 7H).1H NMR (400 MHz, DMSO- 5-((3 -chloro- 1 -methyl- 1 / / -py razol-4- 392.0 (M + d6) δ 10.81 (s, 1H), 8.88 (s, 1H), 8.35- 183y 1 )methoxy )-\-(6-chloropy ridin-3 -y 1) -3 - 1), 394.0 (M 8.25 (m, 2H), 8.00 (s, 1H), 7.56-7.53 methylpicolinamide + 1). (m, 2H), 5.07 (s, 2H), 3.82 (s, 3H),2.64 (s, 3H).1H NMR (400 MHz, DMSO- \-(6-chloropyridin-3-vl)-5-((5- 408.0 (M +184 d6) δ 10.82 (s, 1H), 8.88 (s, 1H), 8.35- (difluoromethyl)- 1 -methyl- 1 / / -py razol-4- 1), 410.0 (M 8.32 (m, 1H), 8.26-8.25 (m, 1H), 7.70 yl)methoxy)-3-methylpicolinamide + 1). (d, J= 0.5 Hz, 1H), 7.56-7.29 (m, 3H),5.24 (s, 2H), 3.95 (s, 3H), 2.64 (s, 3H).1H NMR (400 MHz, DMSO- d6) δ 10.90 (s, 1H), 8.89 (s, 1H), 8.34 185 \-(6-chloropv ridin-3 -yl)-5-((3 - 374.0 (M +(cyanomethyl)oxetan-3 -yl)methoxy)-3 - 1), 376.0 (M (d, J= 9.1 Hz, 1H), 8.29 (s, 1H), 7.53(d, J= 8.7 Hz, 1H), 4.66 (s, 2H), 4.60 methylpyrazine-2 -carboxamide + 1). (d, J= 6.6 Hz, 2H), 4.50 (d, J= 6.7Hz, 2H), 3.11 (s, 2H), 2.80 (s, 3H).1H NMR (400 MHz, DMSO-t / e) 8 10.90 (s, 1H), 8.89 (d, J= 2.6 Hz, 1H), \-(6-chloropv ridin-3 -yl)-5-((3 - 385.0 (M +186 8.34 (dd, J = 8.6, 2.7 Hz, 1H), 8.31 (s, (difluoromethyl)oxetan-3 -y l)methoxy )-3 - 1), 387.0 (M1H), 7.53 (d, J= 8.7 Hz, 1H), 6.46 (t, J methylpyrazine-2 -carboxamide + 1). = 55.6 Hz, 1H), 4.76 (s, 2H), 4.65-4.61(m, 4H), 2.80 (s, 3H).1H NMR (400 MHz, DMSO- 187 \-(6-chlo ropy ridin-3 -y 1) -3 -methy 1-5 -(( 1 - 360.0 (M + d6) δ 10.87 (s, 1H), 8.87 (d, J = 2.6 Hz, methyl- 1H- 1,2,3 -triazol-5- 1), 362.0 (M 1H), 8.33-8.31 (m, 2H), 7.88 (s, 1H), yl)methoxy)pyrazine-2 -carboxamide + 1). 7.52 (d, J= 8.7 Hz, 1H), 5.64 (s, 2H),4.12 (s, 3H), 2.81 (s, 3H).1H NMR (400 MHz, CD3OD) 8 8.81 \-(6-chlo ropy ridin-3 -y 1) -3 -methy 1-5 -(( 1 - 358.0 (M + (d, J = 2.1 Hz, 1H), 8.31 (dd, J = 7.9, 188methyl- 1 / / -i midazo 1-5 - 1), 360.0 (M 2.4 Hz, 2H), 7.72 (s, 1H), 7.47 (d, J = yl)methoxy)picolinamide + 1). 9.0 Hz, 2H), 7.17 (s, 1H), 5.32 (s, 2H),3.79 (s, 3H), 2.75 (s, 3H).1H NMR (400 MHz, CDCI3) 8 9.90 (s, \-(6-chloropy ridin-3 -y 1) -3 -methy 1-5- 346.0 (M + 1H), 8.57 (d, J= 2.6 Hz, 1H), 8.38 (d, 189(oxazol-5-ylmethoxy)pyrazine-2- 1), 348.0 (M J= 8.7 Hz, 1H), 8.07 (s, 1H), 7.95 (s,1H), 7.36 (d, J= 8.7 Hz, 1H), 7.28 (d, carboxamide + 1). J= 5.4 Hz, 1H), 5.55 (s, 2H), 2.99 (s,3H).1H NMR (400 MHz, DMSO-t / ,) 8 \-(6-chloropyridin-3-yl)-5-((l.4-dimcthyl- 373.0 (M +190 10.86 (s, 1H), 8.87 (d, J= 2.6 Hz, 1H),1 / / -py razol-5 -y l)methoxy)-3 - 1), 375.0 (M 8.33-8.29 (m, 2H), 7.51 (d, J= 8.7 Hz, methylpyrazine-2 -carboxamide + 1). 1H), 7.24 (s, 1H), 5.50 (s, 2H), 3.86 (s,3H), 2.81 (s, 3H), 2.09 (s, 3H).1H NMR (400 MHz, DMSO-t / ,) 8 \-(6-chloropyridin-3-yl)-5-(isothiazol-4- 362.0 (M + 10.88 (s, 1H), 9.20 (s, 1H), 8.88 (dt, J 191ylmethoxy)-3 -methy lpyrazine-2- 1), 364.0 (M = 1.6, 0.6 Hz, 1H), 8.74 (s, 1H), 8.34- carboxamide + 1). 8.30 (m, 2H), 7.53-7.50 (m, 1H), 5.60(s, 2H), 2.82 (s, 3H).1H NMR (400 MHz, DMSO-t / ,) 8 192 \-(6-chloropy ridin-3 -yl)-5-(isothiazol-3 - 362.0 (M + 10.90 (s, 1H), 9.14 (d, J = 4.7 Hz, 1H), ylmethoxy)-3 -methy lpyrazine-2- 1), 364.0 (M 8.89 (d, J= 2.6 Hz, 1H), 8.37-8.33 (m, carboxamide + 1). 2H), 7.55-7.53 (m, 2H), 5.64 (s, 2H),2.79 (s, 3H).Attorney Docket No: X0042.70031WO00 Example MS (ES+)Name NMRNo. m / z1H NMR (400 MHz, DMSO-rfc) δ 10.58 (s, 1H), 8.83 (d, J= 2.4 Hz, 1H),193 5-((5-chloro-1-methyl-1H-pyrazol-4- 373.0 (M +yl)mcthoxy)-3-mcthvl-\-(6-mcthvlpvridin- 8.22 (s, 1H), 8.11 (dd, J = 8.4, 2.5 Hz,1), 375.0 (M1H), 7.73 (s, 1H), 7.22 (d, J= 8.5 Hz, 3 -yl)pyrazine-2 -carboxamide + 1). 1H), 5.29 (s, 2H), 3.81 (s, 3H), 2.80 (s,3H), 2.43 (s, 3H).1H NMR (400 MHz, DMSO-rfc) δ 10.57 (s, 1H), 8.84-8.83 (m, 1H), 8.22194 5-((3-fluoro-1-methyl-1H-pyrazol-4- 357.0 (M +yl)mcthoxy)-3-mcthvl-\-(6-mcthvlpvridin- (s, 1H), 8.12-8.10 (m, 1H), 7.82 (d, J =1.8 Hz, 1H), 7.23 (d, J= 8.3 Hz, 1H), 3 -yl)pyrazine-2 -carboxamide 1).5.27 (s, 2H), 3.72 (s, 3H), 2.80 (s, 3H),2.43 (s, 3H).1H NMR (400 MHz, DMSO-rfc) 8 195 5 -((2-chloro- 1 -methyl- 1 H-i midazo 1-5 - 393.0 (M + 10.86 (s, 1H), 8.88 (d, J= 2.1 Hz, 1H), yl)methoxy)-N-(6-chloropyridin-3 -yl)-3 - 1), 395.0 (M 8.34-8.28 (m, 2H), 7.52 (d, J= 8.7 Hz, methylpyrazine-2 -carboxamide + 1). 1H), 7.12 (s, 1H), 5.49 (s, 2H), 3.64 (s,3H), 2.82 (s, 3H).1H NMR (400 MHz, DMSO-r / e) δ 10.86 (s, 1H), 8.87 (d, J= 2.8 Hz, 1H), \-(6-chloropy ridin-3 -yl)-5-((3 - 377.2 (M + 8.33 (dd, J= 2.8, 8.8 Hz, 1H), 8.28 (s, 196isopropy loxetan-3 -y l)methoxy )-3 - 1), 379.2 (M 1H), 7.51 (d, J= 8.8 Hz, 1H), 4.58 (s, methylpyrazine-2 -carboxamide + 1). 2H), 4.49-4.45 (m, 2H), 4.45-4.39 (m,2H), 2.79 (s, 3H), 2.16 (td, J= 1.2, 13.6 Hz, 1H), 0.96 (d, J= 1.2 Hz, 6H).1H NMR (400 MHz, DMSO-r / e) δ 10.88 (s, 1H), 8.88 (d, J= 2.1 Hz, 1H), \-(6-chlo ropy ridi n-3 -y l)-5 -(( 1 - 383.4 (M + 8.34 (dd, J= 8.7, 2.7 Hz, 1H), 8.28 (s, 197(difluoromethy l)cy clobuty l)methoxy) -3 - 1), 385.4 (M 1H), 7.52 (d, J= 8.7 Hz, 1H), 6.21 (t, J methylpyrazine-2 -carboxamide + 1). = 56.6 Hz, 1H), 4.55 (s, 2H), 2.79 (s,3H), 2.23-2.16 (m, 2H), 2.08-1.88 (m,4H).1H NMR (400 MHz, DMSO-r / e) δ 10.91 (s, 1H), 8.88 (t, J= 2.1 Hz, \-(6-chloropy ridin-3 -y 1) -3 -methyl-5- 362.0 (M +198 1H), 8.39 (s, 1H), 8.35-8.32 (m, 1H),(thiazol-2-ylmethoxy)pyrazine-2- 1), 364.0 (M7.86 (dd, J= 18.1, 3.2 Hz, 2H), 7.53 carboxamide + 1). (d, J= 8.7 Hz, 1H), 5.80 (s, 2H), 2.81(s, 3H).1H NMR (400 MHz, DMSO-r / e) δ 10.89 (s, 1H), 9.16 (d, J= 1.8 Hz, \-(6-chloropy ridin-3 -y 1) -3 -methyl-5- 362.0 (M +199 1H), 8.88 (d, J= 2.1 Hz, 1H), 8.35- (thiazol-4-ylmethoxy)pyrazine-2- 1), 364.0 (M8.33 (m, 2H), 7.90-7.90 (m, 1H), 7.53 carboxamide + 1). (d, J= 8.7 Hz, 1H), 5.60 (s, 2H), 2.81(s, 3H).1H NMR (400 MHz, DMSO-r / e) δ 10.82 (s, 1H), 8.87 (d, J = 2.6 Hz, 1H), 8.32 (dd, J= 8.7, 2.8 Hz, 1H),N-(6-chloropyridin-3-yl)-5-(((1s,4s)-4- 363.2 (M +200 8.20 (s, 1H), 7.51 (d, J= 8.7 Hz, 1H), hy droxy cyclo hexy l)oxy)-3 - 1), 365.2 (M5.20-5.15 (m, 1H), 4.56 (d, J= 3.7 Hz, methylpyrazine-2 -carboxamide + 1). 1H), 3.67-3.64 (m, 1H), 2.75 (s, 3H),1.96-1.88 (m, 2H), 1.76-1.69 (m, 2H), 1.62 (q, J = 6.0 Hz, 4H).1H NMR (400 MHz, DMSO-r / 6) 3 -amino-\-(6-chloropy ridi n-3 -yl)-5- 8 10.58 (s, 1H), 8.87 (dd, J= 2.7, 0.3362.0 (M + Hz, 1H), 8.30 (dd, J= 8.8, 2.8 Hz, 1H), 201 (((lr,4r)-4-hydroxy-4- 1), 364.0 (M 7.49 (d, J= 8.0 Hz, 2H), 5.19-5.15 (m, methylcyclohexyl)oxy)pyrazine-2- 1H), 4.23 (s, 1H), 1.99-1.92 (m, 2H), carboxamide + 1).1.72-1.56 (m, 4H), 1.47-1.42 (m, 2H),1.17 (s, 3H), NH2not observed.Attorney Docket No: X0042.70031WO00 Example MS (ES+)Name NMRNo. m / z1H NMR (400 MHz, DMSO-t / e) δ 10.83 (s, 1H), 8.86 (d, J= 2.8 Hz, 1H),349.1 (M + 8.32 (dd, J= 2.8, 8.8 Hz, 1H), 8.22 (s,202 N-(6-chloropyridin-3-yl)-5-((1s,3s)-3- hydroxy-3 -methylcyclobutoxy)-3 - 1), 351.1 (M 1H), 7.51 (d, J= 8.8 Hz, 1H), 5.20 (s, methylpyrazine-2 -carboxamide + 1). 1H), 4.95-4.86 (m, 1H), 2.75 (s, 3H),2.56 (ddd, J= 2.8, 6.8 Hz, 9.6, 2H), 2.22-2.14 (m, 2H), 1.29 (s, 3H).1H NMR (400 MHz, DMSO-t / e) <510.8 (s, 1H), 8.86 (d, J= 2.4 Hz, 1H), 8.31 \-(6-chloropyridin-3-yl)-5-(( lr3r)-3- 349.1 (M + (dd, J= 2.8 Hz, 8.4 Hz, 1H), 8.21 (s, 203hydroxy-3 -methylcyclobutoxy)-3 - 1), 351.1 (M 1H), 7.50 (d, J= 8.8 Hz, 1H), 5.39- methylpyrazine-2 -carboxamide + 1). 5.32 (m, 1H), 5.03 (s, 1H), 2.74 (s,3H), 2.53-2.50 (m, 2H), 2.13-2.08 (m, 2H), 1.34 (s, 3 H).1H NMR (400 MHz, DMSO-J6) <5 10.59 (s, 1H), 8.72 (d, J= 2.6 Hz, 1H), 8.19 (dd, J= 8.7, 2.8 Hz, 1H), 7.86 (d, A-(6-chloropyridin-3-yl)-6-(((15,45)-4- 376.2 (M + J= 8.5 Hz, 1H), 7.51 (d, J = 8.7 Hz, 204hydroxy-4-methylcyclohexyl)oxy)-2- 1), 378.2 (M 1H), 6.70 (d, J= 8.5 Hz, 1H), 5.05- methylnicotinamide + 1). 4.98 (m, 1H), 4.17 (s, 1H), 2.51 (s,3H), 1.78 (td, J= 8.5, 4.1 Hz, 4H), 1.63-1.60 (m, 2H), 1.47-1.40 (m, 2H),1.14 (s, 3H).1H NMR (400 MHz, DMSO-rfc) 8 \-(6-chlo ropy ridi n-3 -y l)-5 -(( 1 - 10.88 (s, 1H), 8.88 (d, J= 2.6 Hz, 1H),344.0 (M +205 8.37 (s, 1H), 8.33 (dd, J= 8.6, 2.6 Hz, cyanocyclopropyl)methoxy)-3 - 1), 346.0 (M1H), 7.51 (d, J= 8.7 Hz, 1H), 4.45 (s, methylpyrazine-2 -carboxamide + 1). 2H), 2.77 (s, 3H), 1.40 (t, J= 3.4 Hz,2H), 1.29-1.26 (m, 2H).1H NMR (400 MHz, DMSO-rfc) 8 \-(6-chloropyridin-3-yl)-5-((5.6-dihvdro- 401.0 (M + 10.84 (s, 1H), 8.87 (dt, J= 1.6, 0.4 Hz, 206 8 / / -i midazo [2, 1 -c] [ 1,4] oxazin-3 - 1), 403.0 (Myl)methoxy)-3 -methylpyrazine-2- 1H), 8.34-8.27 (m, 2H), 7.52-7.50 (m,1H), 7.08 (s, 1H), 5.48 (s, 2H), 4.73 (s, carboxamide + 1).2H), 4.04 (s, 4H), 2.81 (s, 3H).1H NMR (400 MHz, DMSO-rfc) 8 3 -amino-\-(6-chloropy ridi n-3 -yl)-5- 10.58 (s, 1H), 8.87 (d, J= 2.1 Hz, 1H),377.2 (M +207 (((15,45)-4-hydroxy-4- 8.32-8.29 (m, 1H), 7.49 (t, J= 4.4 Hz,1), 379.2 (Mmethylcyclohexyl)oxy)pyrazine-2- 2H), 5.01-4.94 (m, 1H), 4.21 (s, 1H),1.84-1.78 (m, 4H), 1.66-1.61 (m, 2H), carboxamide + 1).1.44-1.37 (m, 2H), 1.14 (s, 3H), NH2not observed.1H NMR (400 MHz, DMSO-rfc) 8 10.59 (s, 1H), 8.87-8.87 (m, 1H), 8.30 rac-3 -amino-5-((( 17?, 3S) -3 -amino-3 - 363.2 (M + (dd, J = 8.7, 2.8 Hz, 1H), 7.51 (s, 1H), 208methylcyclopentyl)oxy)-A-(6- 1), 365.2 (M 7.49 (d, J = 8.8 Hz, 1H), 5.37-5.31 (m, chloropyridin-3-yl)pyrazine-2 -carboxamide + 1). 1H), 2.24-2.17 (m, 2H), 1.98-1.80 (m,3H), 1.68-1.61 (m, 1H), 1.25 (s, 3H), two NH2not observed.1H NMR (400 MHz, DMSO- \-(6-chlo ropy ridi n-3 -yl)-5-((l- d6) 810.88 (s, 1H), 8.88 (d, J = 2.6 Hz,411.4 (M +209 (difluoromethyl)-2- 1H), 8.34 (dt, J= 8.2, 3.8 Hz, 1H),1), 413.4 (Moxabicyclo[2.1. l]hexan-4-yl)methoxy)-3- 8.30 (s, 1H), 7.52 (d, J= 8.7 Hz, 1H),6.31 (t, J = 54.7 Hz, 1H), 4.75 (s, 2H), methylpyrazine-2 -carboxamide + 1).3.80 (s, 2H), 2.78 (s, 3H), 2.01 (d, J = 4.7 Hz, 2H), 1.69-1.68 (m, 2H).1H NMR (400 MHz, DMSO- \-(6-chloropyridin-3 -yl)-5-((3 -cyano- 1 - 384.0 (M + d6) 810.87 (s, 1H), 8.88 (d, J = 2.6 Hz, 210methyl- 177-py razol-5 -y l)methoxy )-3 - 1), 386.0 (M 1H), 8.34-8.31 (m, 2H), 7.52 (d, J = methylpyrazine-2 -carboxamide + 1). 8.8 Hz, 1H), 7.17 (s, 1H), 5.60 (s, 2H),4.03 (s, 3H), 2.82 (s, 3H).Attorney Docket No: X0042.70031WO00 Example MS (ES+)Name NMRNo. m / z1H NMR (400 MHz, DMSO- d6) δ 10.85 (s, 1H), 8.88-8.86 (m, 1H), A-(6-chloropyridin-3 -yl)-5-((5-cyano- 1 - 384.0 (M +211methyl- 1 H-py razol-4-y l)methoxy )-3 - 1), 386.0 (M 8.32 (dd, J= 8.7, 2.7 Hz, 1H), 8.28 (s,1H), 7.87 (s, 1H), 7.52 (d, J= 8.7 Hz, methylpyrazine-2 -carboxamide + 1). 1H), 5.50 (s, 2H), 4.02 (s, 3H), 2.82 (s,3H).1H NMR (400 MHz, DMSO- d6) δ 10.15 (s, 1H), 8.70 (d, J= 2.4 Hz, 2-ami no-\-(6-chloropy ridin-3 -yl)-6-((l- 395.0 (M +212 1H), 8.15-8.11 (m, 2H), 7.93 (t, J =(difluoromethyl)- 1 / / -py razo 1 -5 - 1), 397.0 (M 57.6 Hz, 1H), 7.76 (d, J= 1.5 Hz, 1H), yl)methoxy)nicotinamide + 1). 7.49-7.45 (m, 3H), 6.70 (d, J= 1.6 Hz,1H), 6.11 (d, J= 8.5 Hz, 1H), 5.51 (s,2H).1H NMR (400 MHz, DMSO- d6) δ 10.95 (s, 1H), 9.51 (d, J = 2.7 Hz, 2-amino-A-(6-chloropyridin-3-yl)-6-((l-(2- 403.0 (M +213 1H), 8.97-8.92 (m, 2H), 8.31-8.23 (m, methoxy ethyl)- 1 / / -py razo 1 -5 - 1), 405.0 (M 4H), 7.21 (s, 1H), 6.92 (dd, J= 8.6, 0.3 yl)methoxy)nicotinamide + 1). Hz, 1H), 6.19 (s, 2H), 5.12 (t, J= 5.4Hz, 2H), 4.49-4.46 (m, 2H), 4.01 (d, J = 0.5 Hz, 3H).1H NMR (400 MHz, DMSO- d6) δ 10.65 (s, 1H), 8.88 (d, J = 2.4 Hz, 3 -ami no-\-(6-chloropy ridin-3 -yl)-5-((4- 378.0 (M +214 1H), 8.30 (dd, 5= 8.8, 2.8 Hz, 1H),(hydroxymethyl)-l,2,5-oxadiazol-3- 1), 380.0 (M 7.65 (s, 1H), 7.50 (d, J= 8.5 Hz, 1H), yl)methoxy)pyrazine-2 -carboxamide + 1). 5.81 (t, J= 5.8 Hz, 1H), 5.66 (s, 2H),4.81 (d, J= 5.8 Hz, 2H), NH2not observed.1H NMR (400 MHz, DMSO- \-(6-chloropy ridin-3 -yl)-5-((3 - 409.0 (M + d6) δ 10.86 (s, 1H), 8.88 (d, J= 2.5 Hz, (difluoromethyl)- 1 -methyl- 1 H-py razo 1-4- 215 1), 411.0 (M 1H), 8.35-8.34 (m, 1H), 8.24 (s, 1H), yl )methoxy )-3 -methylpyrazine-2- 8.01 (d, J = 0.2 Hz, 1H), 7.52 (d, J = carboxamide + 1). 8.7 Hz, 1H), 7.23-6.96 (m, 1H), 5.43(s, 2H), 3.89 (s, 3H), 2.82 (s, 3H).1H NMR (400 MHz, DMSO-5.) 5 10.62 (s, 1H), 8.90 (d, J= 2.4 Hz, 1H), 8.35 (dd, J= 2.8, 8.8 Hz, 1H), 8.08 (d, \-(6-chloropyridin-3-yl)-5-(((l.3-dimcthyl- 357.2 (M +216 l / / -pyrazol-4- J= 2.8 Hz, 1H), 7.89 (d, J= 8.8 Hz,1), 359.2 (M1H), 7.56 (s, 1H), 7.47 (d, J= 8.8 Hz, yl)methyl)amino)picolinamide + 1). 1H), 7.09 (dd, 5= 2.8, 8.8 Hz, 1H),6.94 (t, 5= 5.2 Hz, 1H), 4.12 (d, J = 5.2 Hz, 2H), 3.71 (s, 3H), 2.14 (s, 3H).1H NMR (400 MHz, DMSO-5.) 5 = 10.80 (s, 1H), 8.88 (d, J= 2.4 Hz, 1H), \-(6-chloropyridin-3-yl)-5-((l-(2.2- 8.33 (dd, J= 2.4, 8.8 Hz, 1H), 8.26 (d,422.2 (M +217 diriuorocthyl)-5-mcthyl-l / / -pyrazol-4- J= 2.4Hz, 1H), 7.61 (s, 1H), 7.58-7.471), 424.2 (M(m, 2H), 6.53-6.20 (m, 1H), 5.10 (s, yl)methoxy)-3-methylpicolinamide + 1). 2H), 4.58 (dt, J= 3.6, 15.1 Hz, 2H),2.64 (s, 3H), 2.31 (s, 3H). 1H NMR (400 MHz, DMSO-r / 6) 5 10.80 (s, 1H), 8.87 (d, J= 2.8 Hz, 1H), \-(6-chloropyridin-3-yl)-5-((l-(2.2- 422.1 (M + 8.33 (dd, J= 2.8, 8.8 Hz, 1H), 8.26 (d, 218 J= 2.8 Hz, 1H), 7.85 (s, 1H), 7.56- difluoroethyl)-3 -methyl- 1 / / -py razol-4- 1), 424.1 (M7.47 (m, 2H), 6.52-6.10 (m, 1H), 5.11 yl)methoxy)-3-methylpicolinamide + 1). (s, 2H), 4.53 (dt, 5= 3.6, 15.2 Hz, 2H),2.64 (s, 3H), 2.19 (s, 3H).Attorney Docket No: X0042.70031WO00 Example MS (ES+)Name NMRNo. m / z1H NMR (400 MHz, DMSO-t / e) 8 A-(6-chloropyridin-3-yl)-5-((4-fluoro-l- 377.1 (M + 10.84 (s, 1 H), 8.86 (d, J= 2.4 Hz, 1 219methy 1- 1 / / - py razol-5 -y l)methoxy )-3 - 1), 379.1 (M H), 8.28-8.35 (m, 2 H), 7.45-7.55 (m, methylpyrazine-2 -carboxamide + 1). 2 H), 5.54 (s, 2 H), 3.88 (s, 3 H), 2.80(s, 3 H).1H-NMR (400 MHz; DMSO-rfc) 8 10.82 (s, 1H), 8.87 (d, J= 2.6 Hz, 1H), 8.33 (dd, J= 8.7, 2.7 Hz, 1H), 8.18 (s, rac-\-(6-chloropyridin-3-yl)-5-(((l / ?.3 / ?)- 393.1 (M + 1H), 7.51 (d, J= 8.7 Hz, 1H), 5.56 (dd, 220 3 -hydroxy-3 - 1), 395.1 (M J= 5.9, 4.1 Hz, 1H), 4.62 (s, 1H), 3.30 (methoxymethyl)cyclopentyl)oxy)-3 - (d, J= 1.7 Hz, 5H), 2.77 (s, 3H), 2.34- methylpyrazine-2 -carboxamide + 1).2.29 (m, 1H), 2.16 (dd, J= 14.0, 6.9 Hz, 1H), 1.94-1.73 (m, 3H), 1.57 (ddd, J= 12.4, 8.2, 4.0 Hz, 1H).1H NMR (400 MHz, DMSO-t / p δ 10.6rac-3-amino-N-(6-chloropyridin-3-yl)-5- (s, 1H), 8.86 (d, J= 2.4 Hz, 1H), 8.29 221 394.1 (M + (dd, J = 8.8 Hz, 2.8 Hz, 1H), 8.06-7.31((( 17?, 3S)-3 -hydroxy-3 - 1), 396.1 (M (m, 4H), 5.31-5.20 (m, 1H), 4.60 (s, (methoxymethyl)cyclopentyl)oxy)pyrazine- 1H), 3.30 (s, 3H), 3.26-3.19 (m, 2H), 2-carboxamide + 1).2.31-2.23 (m, 1H), 2.17-2.06 (m, 1H), 1.99-1.88 (m, 1H), 1.72-1.63 (m, 3H).1H NMR (400 MHz, DMSO-t / p 8 2-ami no-\-(6-chloropv ridin-3 -yl)-6-((l- 362.0 (M + 10.14 (s, 1H), 8.70 (d, J = 2.7 Hz, 1H), 222( mcthy 1 -<7;)- 1 / / -pv razo 1 -5 - 1), 364.0 (M 8.16-8.11 (m, 2H), 7.50-7.37 (m, 4H), yl)methoxy)nicotinamide + 1). 6.42 (d, J= 1.6 Hz, 1H), 6.12 (d, J =8.5 Hz, 1H), 5.39 (s, 2H).1H NMR (400 MHz, DMSO- \-(6-chloropyridin-3-yl)-5-((l-(2- d6) 810.86 (s, 1H), 8.88 (d, J = 2.7 Hz,447.4 (M + 1H), 8.34 (s, 1H), 8.25 (s, 1H), 7.52 (d, 317 hydroxypropan-2-yl)-2- 1), 449.4 (M J= 8.7 Hz, 1H), 4.12 (s, 2H), 3.97 (s, oxabicyclo[2.2.2]octan-4-yl)methoxy)-3- 1H), 3.74 (s, 2H), 2.76 (s, 3H), 1.88- methylpyrazine-2 -carboxamide + 1).1.85 (m, 2H), 1.69-1.58 (m, 6H), 1.04(s, 6H).1H NMR (400 MHz, DMSO- \-(6-chloropyridin-3-yl)-5-((5-(2- d6) 810.87 (s, 1H), 8.88 (d, J = 2.6 Hz,433.0 (M +318 hydroxypropan-2-yl)-3 - 1H), 8.34-8.32 (m, 1H), 8.25 (s, 1H),1), 435.0 (Moxabicyclo [3.1.1] heptan- 1 -y l)methoxy )-3 - 7.52 (d, J= 8.6 Hz, 1H), 4.28 (s, 1H),4.26 (s, 2H), 3.73 (d, J= 6.5 Hz, 4H), methylpyrazine-2 -carboxamide + 1).2.77 (s, 3H), 2.00-1.98 (m, 2H), 1.45- 1.43 (m, 2H), 0.96 (s, 6H).1H NMR (400 MHz, DMSO- d6) δ 10.32 (s, 1H), 8.83 (d, J= 2.5 Hz, 3 -amino-5-((3 -fluoro- 1 -methyl- 177- pyrazol-4-vl)mcthoxy)-\-(6- 1H), 8.07 (dd, J= 8.4, 2.6 Hz, 1H),358.0 (M +370 7.89 (d, J= 2.3 Hz, 1H), 7.49 (s, 1H), methylpy ridin-3 -yl)pyrazine-2- 1). 7.20 (d, J= 8.4 Hz, 1H), 5.16 (s, 2H), carboxamide3.71 (s, 3H), 2.42 (s, 3H), NH2not oberved.1H NMR (400 MHz, DMSO- 3 -amino-5 -((5 -(difluoro methyl)- 1 -methy 1- d6) δ 10.32 (s, 1H), 8.83 (d, J = 2.4 Hz, 371 l / / -pvrazol-4-vl)mcthoxy)-\-(6- 390.2 (M + 1H), 8.07 (dd, J= 8.4, 2.6 Hz, 1H), methylpy ridin-3 -yl)pyrazine-2- 7.75 (s, 1H), 7.61-7.35 (m, 2H), 7.201). (d, J= 8.4 Hz, 1H), 5.34 (s, 2H), 3.93 carboxamide(s, 3H), 2.42 (s, 3H), NH2not observed.1H NMR (400 MHz, DMSO- 5 -((5 -(difluoro methy 1)- 1 -methyl- 177- d6) δ 10.56 (s, 1H), 8.84-8.83 (m, 1H), 372 pyrazol-4-yl)mcthoxy)-3-incthyl-\-(6- 389.2 (M + 8.22 (s, 1H), 8.12-8.09 (m, 1H), 7.69 methylpy ridin-3 -yl)pyrazine-2- 1). (s, 1H), 7.50 (t, J= 52.1 Hz, 1H), 7.23 carboxamide (d, J= 8.6 Hz, 1H), 5.45 (s, 2H), 3.94(s, 3H), 2.79 (s, 3H), 2.43 (s, 3H).Attorney Docket No: X0042.70031WO00 Example MS (ES+)Name NMRNo. m / z1H NMR (400 MHz, DMSO-J6) 5 -((3 -fluoro- 1 -methyl- 1 / / -py razo 1-4- <510.58 (s, 1H), 9.10 (s, 2H), 8.63 (q, 373 yl ) methoxy )-3 -(methy lamino)-7V-(2- 373.2 (M + J= 4.3 Hz, 1H), 7.81 (d, J= 2.3 Hz, methylpyrimidin-5-yl)pyrazine-2- 1). 1H), 7.46 (s, 1H), 5.28 (s, 2H), 3.73 (s, carboxamide 3H), 3.05 (d, J= 4.8 Hz, 3H), 2.58 (s,3H).3 -amino-5-((3 -fluoro- 1 -(mcthy l-c / j)- 1H-1H NMR (400 MHz, DMSO- 374 pyrazol-4-vl)mcthoxy)-\-(2- 362.2 (M + d6) δ 10.55 (d, J = 0.8 Hz, 1H), 9.08 (s, methylpyrimidin-5-yl)pyrazine-2- 1). 2H), 7.90 (s, 1H), 7.52 (s, 1H), 5.17 (s,carboxamide 2H), 2.57 (s, 3H), NH2not observed.EXAMPLE 6: Synthesis of 2V-(6-chloropyridin-3-yl)-5-((3,5-dimethylisoxazol-4-yl)methoxy)-3-methylpyrazine-2-carboxamideStep 1. Preparation of 5-chloro-3-methylpyrazine-2-carboxylic acid

[0249] To a solution of methyl 5 -chloro-3 -methyl -pyrazine-2 -carboxylate (3.00 g, 16.1 mmol) in tetrahydrofuran (80 mL) was added a solution of lithium hydroxide monohydrate (3.37 g, 80.4 mmol) in water (80 mL). The reaction mixture was stirred at ambient temperature for 1 h, acidified with a 1 M aqueous hydrochloric acid to pH 2-3, and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford the title compound as a colorless solid (2.56 g, 92% yield): ’H NMR (400 MHz, DMSO-6) δ 13.77 (br s, 1H), 8.72 (s, 1H), 2.70 (s, 3H); MS (ES+) m / z 173.0 (M + 1), 175.0 (M + 1).Step 2. Preparation of 5-chloro-N-(6-chloropyridin-3-yl)-3-methylpyrazine-2-carboxamide

[0250] Using a similar procedure as described in EXAMPLE 1, Step 2, 5 -chloro-3 -methylpyrazine-2-carboxylic acid (2.60 g, 15.1 mmol) was converted to the title compound as a pale purple solid (3.07 g, 72% yield): ’HNM...

Claims

Attorney Docket No: X0042.70031WO00CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:X1is N or CRxl; X2is N or CRx2; and X3is N or CRx3;R1is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, -CN, -OR0, -N(RN)2, -SRS, or C1-6 acyl, wherein the alkyl, cycloalkyl, or acyl is optionally substituted;each instance of Rxl, Rx2, and Rx3is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted;Y1is N or CRyl; Y2is N or CRy2; Y3is N or CRy3; and Y4is N or CRy4, provided that at least one of Y1and Y3is N;each instance of R2, Ryl, Ry2, Ry3, and Ry4is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRs, C1-6 acyl, or -Z’-L’-R3, or any two instances of R2, Ryl, Ry2, Ry3, and Ry4on adjacent carbons are joined together to form C5-6 cycloalkyl or 5-6 membered heterocyclyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; provided that at least one of R2, Ryl, Ry2, Ry3, and Ry4is independently -Z1-L1-R3each instance of Z1is independently absent, -O-, -N(RN)-, -S-, -S(=O)2-, -(C(RL)2)n-, -C(=O)-, -C≡C-, -O-(C(RL)2)n-, -(C(RL)2)n-O-, -N(RN)-(C(RL)2)n-, -(C(RL)2)n-N(RN)-, -S-(C(RL)2)n-, -(C(RL)2)n-S-, -S(=O)2-(C(RL)2)n-, -(C(RL)2)n-S(=O)2-, -C(=O)-(C(RL)2)n-, -(C(RL)2)n-C(=O)-, -(C(RL)2)n-C≡C-, or -C≡C-(C(RL)2)n-;each instance of L1is independently absent or -(C(RL)2)n-;each n is independently 1, 2, or 3;each instance of RLis independently H, halogen, C1-6 alkyl, or C1-6 haloalkyl, wherein each alkyl is independently optionally substituted, or wherein two RLattached to the same carbon are taken together to form =0;each instance of R3is independently C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6–10aryl, or 5-10 membered heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is independentlyAttorney Docket No: X0042.70031WOOO optionally substituted with one or more instances of R3a;each instance of R3ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl, -CN, -OR0, -N(RN)2, -SRS, -S(=O)2RS1, -S(=O)RS1, -S(=O)2OR°, -S(=O)OR°, -S(=O)2N(RN)2, -S(=O)N(RN)2, -S(=O)(=NRN)RS1, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted;each instance of RN1and RNis independently H, Ci-6 alkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, -S(=O)2RS1, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted;each instance of R° is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted;each instance of Rsis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ci-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; andeach instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, Ce-io aryl, or 5-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) no more than two of X1, X2, and X3is N; or(b) no more than one of X1, X2, is X3are N; or(c) X1is CRX1, X2is CRx2, and X3is CRx3; or(d) X1is N, X2is CRx2, and X3is CRx3;3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) no more than three of Y1, Y2, Y3, and Y4is N; or(b) no more than two of Y1, Y2, Y3, and Y4is N; or(c) Y1is N, Y2is CRy2, Y3is N, and Y4is CRy4; or(d) Y1is N, Y2is CRy2, Y3is CRy3, and Y4is CRy4.Attorney Docket No: X0042.70031WOOO 4. The compound of claim 1, wherein the compound is of Formula (I -a):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) X1is CRxl; or(b) X1is CH.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) R1is halogen;(b) R1is Cl;(c) R1is Ci alkyl; or(d) R1is -CH3.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RN1is H.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) Y3is N; or(b)Y3is CRy3.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is -Z’-L1-R3.Attorney Docket No: X0042.70031WOOO 10. The compound of claim 1, wherein the compound is of formula (I-b):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

11. The compound of claim 1, wherein the compound is of formula (I-b- 1 ):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

12. The compound of claim 1, wherein the compound is of formula (I-b-2):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.Attorney Docket No: X0042.70031WOOO 13. The compound of claim 1, wherein the compound is of formula (I-c):(I-c),or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) Z1is -O-; or(b) Z1is -N(RN)-; or(c) Z1is -NH- or -N(CH3)-; or(d) Z1is -S- or -SCH2-; or(e) Z1is -S(O)2- or -S(O)2CH2-; or(f) Z1is absent.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) L1is -(CH2)n-; or(b) L1is -CH2-; or(c) L1is -C(CH3)H-; or(d) L1is -C(D)2-; or(e) L1is absent.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein -Z’-L1- is:Attorney Docket No: X0042.70031WOOO17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) R3is C3-10 cycloalkyl optionally substituted with one or more instances of R3a; or(b) R3is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C„ cycloalkyl, or C10 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more instances of R3a; or(c) R3is C5 cycloalkyl optionally substituted with one or more instances of R3a; or(d) R3is Ce cycloalkyl optionally substituted with one or more instances of R3a; or(e) R3is bicyclo [l.l.l]pentanyl optionally substituted with one or more instances of R3a; or (f) R3is 3-10 membered heterocyclyl optionally substituted with one or more instances of R3a; or (g) R3is 3 membered heterocyclyl, 4 membered heterocyclyl, or 5 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more instances of R3a; or(h) R3is phenyl optionally substituted with one or more instances of R3a; or(i) R3is 5 or 6 membered heteroaryl optionally substituted with one or more instances of R3a; or (j) R3is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein each is optionally substituted with one or more instances of R3a; or(k) R3is triazolyl optionally substituted with one or more instances of R3a; or(l) R3is tetrazolyl optionally substituted with one or more instances of R3a(m) R3is bicyclo [l.l.l]pentanyl optionally substituted with one or more instances of R3a; or (n) R3is pyrazolyl optionally substituted with one or more instances of R3a.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) at least one instance of R3ais independently halogen, C1-6 alkyl, -OR0, -CN, -N(RN)2, -S(=O)2RS1, C3-7 cycloalkyl, 3-7 membered heterocyclyl, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; or(b) at least one instance of R3ais independently C1-6 alkyl, -OH, -F, -Cl, -CN, -N(CH3)H, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)(cyclopropyl), -S(=O)2Me, 2-oxazolidonyl, oxetanyl, or -C(=O)CH3, wherein each instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted with one or more instances of halogen, C1-6 alkyl, -OR0, -N(RN)2, -CN, -S(=O)2RS1, C3-7 cycloalkyl, and / or 3-7 membered heterocyclyl; or(c) at least one instance of R3ais independently C1-6 alkyl, -OH, -Cl, -F, -CN, -N(CH3)H, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)(cyclopropyl), -S(=O)2Me, 2-oxazolidonyl, oxetanyl, or -C(=O)CH3, wherein each of instance of alkyl, 2-oxazolidonyl, and oxetanyl is independently optionally substituted with one or more instances of -F, methyl, -OCH3, -OH, -NH2, -CN, -S(=O)2Me, cyclopropyl,Attorney Docket No: X0042.70031WOOO and / or oxetanyl; or(d) at least one instance of R3is independently -CD3, -CH2CH2OCD3, -CD2OCD3, or -CD2CD2OCD3.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is:Attorney Docket No: X0042.70031WO00 F FAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00 F 5 F 5Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00 FF20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein -Z’-L’-R3is:Attorney Docket No: X0042.70031WO00o-AAttorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WOOOAttorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WO00Attorney Docket No: X0042.70031WOOO21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) Rxlis H; and / or(b) Rx2is H; and / or(c) Rx3is H; and / or(d) Ry2is H.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein:(a) Ry4is optionally substituted C1-6 alkyl, C1-6 haloalkyl, halogen, -OR0, -N(RN)2, or optionally substituted 3 to 6 membered heterocyclyl; or(a) Ry4is methyl, ethyl, F, Cl, -CF3, -CF2H, -OMe, -CH2OMe, -NH2, -NHMe, or 3-oxetanyl; or (b) Ry4is methyl or -NH2.Attorney Docket No: X0042.70031WOOO 23. The compound of claim 1, wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

26. A method of:(a) potentiating a Kv7 potassium channel in a subject;(b) treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject in need thereof; and / or(c) treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof,the method comprising administering to the subject a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

27. The method of claim 26, comprising potentiating a voltage-sensing domain (VSD) of the Kv7 potassium channel, optionally potentiating a voltage-sensing domain (VSD) of a Kv7 potassium channel; optionally wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5; and optionally wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

28. The method of claim 26 or 27, wherein the subject is a human.

29. A compound of any one of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in:(a) potentiating a Kv7 potassium channel in a subject;(b) treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject; and / or(c) treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject.

30. The compound for use of claim 30, wherein the compound potentiates a voltage-sensing domain (VSD) of a Kv7 potassium channel, optionally wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5, and optionally wherein the Kv7 potassium channel isAttorney Docket No: X0042.70031WOOO Kv7.2 / Kv7.3.

31. The compound for use of claim 29 or 30, wherein the subject is a human.

32. A compound of any one of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament.

33. Use of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for: (a) potentiating a Kv7 potassium channel; (b) treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction; and / or (c) treating a seizure disorder, a depressive disorder, pain, or anhedonia.

34. A kit comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

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