Compounds containing heteroaryl rings and compositions and methods thereof

Abstract

In particular, the present disclosure provides a compound of Formula I or a salt thereof. In some embodiments, the provided compounds are useful as TRPV3 inhibitors. In some embodiments, the present disclosure provides methods for preventing or treating TRPV3-related conditions, disorders, or diseases.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to PCT Application No. PCT / CN2022 / 141788, filed December 26, 2022, which is incorporated herein by reference in its entirety.

[0002] In some embodiments, the present disclosure provides compounds and compositions useful for, inter alia, regulating transient receptor potential vanilloid 3 (TRPV3) activity. In some embodiments, the provided compounds and compositions are useful for preventing or treating symptoms, disorders, or diseases associated with TRPV3, such as pain, pruritus, dermatitis, hair loss, etc. In some embodiments, the present disclosure provides techniques for preparing the provided compounds and compositions. [Background technology]

[0003] Compounds are useful for a variety of purposes, including modulation of biological function and activity. Transient receptor potential (TRP) channels have many biological functions and have been reported to be associated with various conditions, disorders, and diseases, including pain, pruritus, and hair loss. TRPV3 has been reported to be a member of the vanilloid TRP (TRPV) subfamily. Summary of the Invention

[0004] In some embodiments, the present disclosure provides various compounds, for example, compounds having the structure of Formula I or salts thereof, and compositions and methods thereof. The compound has the structure of Formula I:

[0005] [ka]

[0006] or a salt thereof, wherein Ring A is an optionally substituted 5- or 6-membered aromatic ring having 0 to 4 heteroatoms, or

[0007] [ka]

[0008] and; X 1 , X 2a , X 2b , and X 2c are independently -N=, -C(R 2 )=, or optionally substituted -CH=; X 1a is -O-, -S-, -N(R')-, -C(R')2-, or optionally substituted -CH2- or -NH-; X 3 is —O—, —S—, —Se—, —N(R′)—, or optionally substituted —NH—; X 4 , X 5 , X 6 , X 7 and X 8 are independently -N=, -C(R 6 )=, or optionally substituted -CH=; R 1 , R 2 , R s and R 6 are each independently halogen, —CN, —NO2, —L-R', —OR', —N(R')2, —N(R')C(O)OR', —C(O)R', —C(O)OR', —C(O)N(R')2, or —OC(O)N(R')2; L 1 is a covalent bond, -C(O)-, -C(S)-, -S(O)2-, -N(R')C(O)-, -N(R')S(O)2-, -N(R')C(S)-, or

[0009] [ka]

[0010] and; R 3 , R 4 and R 5 are each independently R'; L and L 2 are each independently an optionally substituted C alkylene, provided that one or more methylene units of the alkylene are optionally and independently selected from -O-, -S-, -C(R 4 )(R 5 )-, -N(R 4 )-, optionally substituted -CH=N-, optionally substituted -CH=CH- or -Cy-; Each -Cy- is independently

[0011] [ka]

[0012] wherein ring B is an optionally substituted saturated or partially saturated 3- to 10-membered ring having 0-4 heteroatoms; t is 0, 1, 2, 3, or 4; each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)R; Each R is independently hydrogen or C1-C 10 Aliphatic, C1-C with 1-3 heteroatoms 10 Heteroaliphatic, 3-10-membered cyclic aliphatic, 3-10-membered heterocyclyl having 1-4 heteroatoms, 6-10-membered aryl, 5-10-membered heteroaryl having 1-6 heteroatoms, 6-10-membered aryl-C-C 10 Aliphatic and 5-10 membered heteroaryl-C1-C having 1-6 heteroatoms 10 an optionally substituted group selected from aliphatic; or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3- to 10-membered ring having, in addition to the atom, 0-4 heteroatoms; or The present invention provides a compound characterized in that two R groups on two atoms optionally and independently combine with the intervening atoms to form an optionally substituted 3- to 10-membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.

[0013] In some embodiments, the present disclosure provides pharmaceutical compositions of provided compounds. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a provided compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides pharmaceutical compositions that deliver a provided compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] The provided technology is useful for many purposes. In some embodiments, the provided compounds are useful as TRPV3 modulators. In some embodiments, the provided technology (e.g., compounds, compositions, methods, etc.) is useful for the prevention or treatment of various conditions, disorders, or diseases. In some embodiments, the condition, disorder, or disease is a TRPV3-associated condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is or includes itch. In some embodiments, the condition, disorder, or disease is or includes pain. In some embodiments, the condition, disorder, or disease is or includes dermatitis. In some embodiments, the condition, disorder, or disease is or includes hair loss. In some embodiments, the condition, disorder, or disease is associated with the administration of another therapeutic agent.

[0015] In some embodiments, the present disclosure provides methods for preventing a condition, disorder, or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of a provided compound, e.g., a compound of Formula I or a salt thereof. In some embodiments, the present disclosure provides methods for treating a condition, disorder, or disease, comprising administering or delivering to a subject suffering therefrom an effective amount of a provided compound, e.g., a compound of Formula I or a salt thereof. In some embodiments, the condition, disorder, or disease is a TRPV3-associated condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is associated with TRPV3 activation. In some embodiments, the condition, disorder, or disease is or comprises itch. In some embodiments, the condition, disorder, or disease is or comprises pain. In some embodiments, the condition, disorder, or disease is or comprises hair loss.

[0016] In some embodiments, the present disclosure provides methods for preventing a condition, disorder, or disease, comprising administering or delivering to a subject susceptible to the condition, disorder, or disease an effective amount of a provided compound and other agent. In some embodiments, the present disclosure provides methods for treating a condition, disorder, or disease, comprising administering or delivering to a subject susceptible to the condition, disorder, or disease an effective amount of a provided compound and other agent.

[0017] In some embodiments, the disclosure provides techniques, eg, methods, reagents, etc., for preparing compounds of Formula I or pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0018] The techniques of the present disclosure may be more readily understood by reference to the following detailed description of specific embodiments. definition

[0019] As used herein, the following definitions apply unless otherwise specified. For purposes of this disclosure, chemical elements are identified according to the CAS Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th Edition. General principles of organic chemistry are also described in "Organic Chemistry" (Thomas Sorrell, University Science Books, Sausalito, 1999) and "March's Advanced Organic Chemistry" (5th Edition, Smith, M.B. and March, J., eds., John Wiley & Sons, New York, 2001).

[0020] As used in this disclosure, the terms "a" or "an" may be understood to mean "at least one." (ii) "or" may be understood to mean "and / or." (iii) The terms "comprise," "includes," "including," "including" (whether used in conjunction with "but not limited to"), and "comprising" (whether used in conjunction with "but not limited to") may be understood to encompass the itemized listed components or steps, whether presented by themselves or with one or more additional components or steps. (iv) The term "another" may be understood to mean at least one additional / second one or more. (v) The terms "about" and "approximately" may be understood to allow for standard variations understood by those of ordinary skill in the art. (vi) When ranges are provided, endpoints are included. Isomers of the compounds are included unless otherwise clear from the context. As will be understood by those of ordinary skill in the art, compounds may be provided, administered, or delivered in various forms, such as, for example, salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, esters, prodrugs, tautomers, etc.

[0021] Aliphatic: As used herein, "aliphatic" refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation (not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is fully saturated or contains one or more units of unsaturation (not aromatic), or combinations thereof. In some embodiments, an aliphatic group contains 1-50 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-20 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-9 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-7 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrid groups thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl groups).

[0022] Alkenyl: As used herein, the term "alkenyl" refers to an aliphatic group, as defined herein, having one or more double bonds.

[0023] Alkyl: As used herein, the term "alkyl" has its ordinary meaning in the art and can include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In some embodiments, an alkyl has 1 to 100 carbon atoms. In certain embodiments, a straight-chain or branched-chain alkyl has about 1 to 20 carbon atoms in its backbone (e.g., C1 to C6 for straight chain). 20 , C2 to C for branched chains 20), or about 1-10 carbon atoms. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure, and such rings are monocyclic, bicyclic, or polycyclic, or have about 5, 6, or 7 carbon atoms in the ring structure. In some embodiments, alkyl groups can be lower alkyl groups, which contain 1-4 carbon atoms (e.g., C1-C4 for a straight chain lower alkyl). 。

[0024] Alkynyl: As used herein, the term "alkynyl" refers to an aliphatic group, as defined herein, having one or more triple bonds.

[0025] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and / or worms. In some embodiments, the animal may be a transgenic animal, a genetically modified animal, and / or a cloned animal.

[0026] Aryl: As used herein, the term "aryl," whether used alone or as part of a larger moiety, such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 30 ring members, wherein at least one ring in the ring system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic, and wherein each ring in the ring system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, an aryl group is a biaryl group. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl.

[0027] Comparable: The term "comparable" is used herein to describe two (or more) sets of conditions or circumstances that are sufficiently similar so that the results obtained or the phenomena observed can be compared. In some embodiments, comparable sets of conditions or circumstances are characterized by multiple substantially identical characteristics and one or a few different characteristics. One skilled in the art will understand that sets of conditions are comparable to each other if they are characterized by a sufficient number and type of substantially identical characteristics to reasonably conclude that differences in the results obtained or the phenomena observed under different sets of conditions or circumstances are caused by or suggest changes in those different characteristics.

[0028] Alicyclic: The terms "alicyclic," "carbocycle," "carbocyclyl," "carbocyclic radical," and "carbocycle" are used interchangeably herein and, unless otherwise specified, refer to a saturated or partially unsaturated, but not aromatic, monocyclic, bicyclic, or polycyclic cycloaliphatic ring system, as described herein, having 3 to 30 ring members. Alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, an alicyclic group has 3 to 6 carbons. In some embodiments, an alicyclic group is saturated and is a cycloalkyl. The term "alicyclic" also includes an aliphatic ring fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl and tetrahydronaphthyl groups. In some embodiments, an alicyclic group is bicyclic. In some embodiments, an alicyclic group is tricyclic. In some embodiments, an alicyclic group is polycyclic. In some embodiments, "alicyclic" refers to a C3-C6 monocyclic hydrocarbon, or a C8-C 10 Bicyclic or polycyclic hydrocarbons (fully saturated or containing one or more units of unsaturation but not aromatic, with a single point of attachment to the rest of the molecule), or C9-C 16 Refers to polycyclic hydrocarbons (either fully saturated or containing one or more units of unsaturation but not aromatic, and having a single point of attachment to the rest of the molecule).

[0029] Heteroaliphatic: As used herein, the term "heteroaliphatic" has its usual meaning in the art and refers to an aliphatic group described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). In some embodiments, one or more units selected from C, CH, CH2, and CH3 are independently replaced with one or more heteroatoms (including oxidized and / or substituted forms thereof). In some embodiments, a heteroaliphatic group is a heteroalkyl. In some embodiments, a heteroaliphatic group is a heteroalkenyl.

[0030] Heteroalkyl: As used herein, the term "heteroalkyl" has its ordinary meaning in the art and refers to any alkyl group, as described herein, in which one or more carbon atoms are independently replaced by one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). Examples of heteroalkyl groups include, but are not limited to, alkoxy groups, poly(ethylene glycol) groups, alkyl-substituted amino groups, tetrahydrofuranyl groups, piperidinyl groups, morpholinyl groups, etc.

[0031] Heteroaryl: As used herein, the terms "heteroaryl" and "heteroaralkyl," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 30 ring members, in which at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, heteroaryl groups are groups having 5 to 10 ring atoms (i.e., monocyclic, bicyclic, or polycyclic), and in some embodiments, 5, 6, 9, or 10 ring atoms. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, heteroaryl groups have 6, 10, or 14 pi electrons shared in the cyclic arrangement, and have 1 to 5 heteroatoms, in addition to the carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, heteroaryl is a heterobiaryl group such as dipyridyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic, bicyclic, or polycyclic.The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl portions independently may be optionally substituted.

[0032] Heteroatom: As used herein, the term "heteroatom" refers to an atom other than carbon or hydrogen. In some embodiments, the heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon, charged forms of nitrogen (e.g., quaternized forms, forms such as iminium groups, etc.), phosphorus, sulfur, oxygen, etc.). In some embodiments, the heteroatom is silicon, phosphorus, oxygen, sulfur, or nitrogen. In some embodiments, the heteroatom is silicon, oxygen, sulfur, or nitrogen. In some embodiments, the heteroatom is oxygen, sulfur, or nitrogen.

[0033] Heterocycle: As used herein, the terms "heterocycle," "heterocyclic," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a monocyclic, bicyclic, or polycyclic ring moiety (e.g., a 3- to 30-membered ring) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, a heterocyclic group is a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used with respect to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or . +It can be NR (in the case of N-substituted pyrrolidinyl). The heterocycle can be attached to the pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclic," "heterocyclic ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocycle is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclic groups may be monocyclic, bicyclic, or polycyclic. The term "heterocyclealkyl" refers to an alkyl group substituted with a heterocycle, wherein the alkyl group and the heterocycle moiety may each independently be optionally substituted.

[0034] Optionally substituted: As described herein, compounds of the present disclosure may be optionally substituted and / or contain substituted moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in a given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. In some embodiments, an optionally substituted group is unsubstituted. Combinations of substituents envisioned by the present disclosure preferably result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" means that the compound remains substantially unchanged when exposed to conditions that allow for its preparation, detection, and, in certain embodiments, recovery, purification, and use for one or more purposes disclosed herein. Specific substituents are described below.

[0035] Suitable monovalent substituents include halogen; -(CH2) 0‐4 R°;-(CH2) 0‐4 OR°;-O(CH2) 0‐4 R°;-O-(CH2) 0‐4 C(O)OR°;-(CH2) 0‐4 CH(OR°)2;-(CH2) 0‐4 Ph (optionally substituted with R°); -(CH2) 0‐4 O(CH2) 0‐1 Ph (optionally substituted with R°); -CH=CHPh (optionally substituted with R°); -(CH2) 0‐4 O(CH2) 0‐1 -pyridyl (optionally substituted by R°); -NO2; -CN; -N3; ​​-(CH2) 0‐4 N(R°)2;-(CH2) 0‐4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0‐4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0‐4 C(O)R°;-C(S)R°;-(CH2) 0‐4 C(O)OR°;-(CH2) 0‐4 C(O)SR°;-(CH2) 0‐4 C(O)OSiR°3;-(CH2) 0‐4 OC(O)R°;-OC(O)(CH2) 0‐4 SR, -SC(S)SR°;-(CH2)0-4SC(O)R°;-(CH2) 0‐4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0‐4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0‐4 SSR°;-(CH2) 0‐4 S(O)2R°;-(CH2) 0‐4 S(O)2OR°;-(CH2) 0‐4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0‐4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-OSiR°3;-(C 1‐4 Linear or branched alkylene)ON(R°)2; or -(C 1‐4 linear or branched alkylene)C(O)ON(R°)2, where each R may be optionally substituted as defined below and independently represents hydrogen, C 1‐10 (For example, C 1‐9 , C 1‐6 , C 1‐5 , C 1‐4 etc.) C having 1 to 5 heteroatoms independently selected from aliphatic, nitrogen, oxygen, sulfur, silicon and phosphorus 1‐10 (For example, C 1‐9 , C 1‐6 , C 1-5 , C 1‐4etc.) heteroaliphatic, -CH2-(C 6‐14 (For example, C 6‐10 , C6 etc.) aryl), -O(CH2) 0‐1 (C 6‐14 (For example, C 6‐10 , C6, etc.) aryl), -CH2- (5-14 (e.g., 5-10, 5-6, 5, 6, 9, 10, 14, etc.) membered heteroaryl ring) having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-10 (e.g., 3-9, 3-7, 3-6, 5-10, 5-6, etc.) membered monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated, having 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus. or an aryl ring, or, notwithstanding the above definitions, two independent occurrences of R°, together with their intervening atoms, may form a 3-10 (e.g., 3-9, 3-7, 3-6, 5-10, 5-6, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated, or aryl ring (which may be substituted as defined below) having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus.

[0036] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with their intervening atoms) are independently halogen, —(CH2), 0‐2 R ● ,-(Halo R ● ), -(CH2) 0‐2 OH, -(CH2) 0‐2 OR ● , -(CH2) 0‐2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0‐2 C(O)R ● , -(CH2) 0‐2 C(O)OH, -(CH2) 0‐2 C(O)OR ● , -(CH2) 0‐2 SR ● , -(CH2) 0‐2 SH, -(CH2) 0‐2 NH2, -(CH2) 0‐2 NHR● , -(CH2) 0‐2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1‐4 Linear or branched alkylene)C(O)OR ● , or -SSR ● (However, each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1‐4 Aliphatic, -CH2Ph, -O(CH2) 0‐1 Ph, or a 3-6 (e.g., 4-6, 5-6, etc.) membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (each independently selected). Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0037] Suitable divalent substituents include: =O, =S, =NNR * 2, =NNHC(O)R*, =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2‐3 O-, or -S(C(R * 2)) 2‐3 S-(where R * Each independent occurrence of is selected from hydrogen, an optionally substituted C1-6 aliphatic, or an unsubstituted 3-6 (e.g., 4-6, 5-6, etc.) membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2‐3O— (where each independent occurrence of R* is selected from hydrogen, a C1-6 aliphatic ring which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 4-6, 5-6, etc.) membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0038] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, provided that each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens and is independently C1-4 aliphatic, -CH2Ph, -O(CH2) 0‐1 Ph, or a 3-6 (eg, 4-6, 5-6, etc.) membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0039] In some embodiments, suitable substituents on a substitutable nitrogen include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R †are independently hydrogen, C aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-6 (e.g., 4-6, 5-6, etc.) membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, regardless of the definition above, R † two independent occurrences of, taken together with their intervening atoms, form an unsubstituted 3-12 (e.g., 3-10, 3-7, 3-6, 5-10, 5-7, 5-6, etc.) membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0040] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1‐4 Aliphatic, -CH2Ph, -O(CH2) 0‐1 Ph, or a 3-6 (e.g., 4-6, 5-6, etc.) membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0041] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, and does not include aryl or heteroaryl moieties, as defined herein.

[0042] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition may be specially formulated for administration in solid or liquid form. This includes those adapted for the following forms: orally, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and systemically absorbed tablets, boluses, powders, granules, and pastes for application to the tongue; parenterally, e.g., as a sterile solution or suspension, or as a sustained-release formulation, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection; topically (e.g., as a cream, ointment, or sustained-release patch or spray applied to the skin, lungs, or mouth), vaginally or rectally (e.g., as a pessary, cream, or foam), sublingually, ophthalmically, transdermally, or to the nasal, pulmonary, and other mucosal surfaces.

[0043] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0044] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; and excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter, and suppository wax. Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, etc.; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, polyethylene glycol, etc.; esters such as ethyl oleate, ethyl laurate, etc.; buffers such as agar, magnesium hydroxide, aluminum hydroxide, etc.; alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, pH buffers, polyesters, polycarbonates, and / or polyanhydrides, and other non-toxic, compatible substances used in pharmaceutical formulations.

[0045] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of compounds that are suitable for pharmaceutical use, i.e., salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, or the like, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, or by other methods used in the art, such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, and the like. Examples of salts include phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, provided compounds contain one or more acidic groups, and pharmaceutically acceptable salts are alkali metal, alkaline earth metal, or ammonium (e.g., ammonium salts of N(R)3 (each R is independently defined and described herein)). Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, a pharmaceutically acceptable salt is a sodium salt. In some embodiments, a pharmaceutically acceptable salt is a potassium salt. In some embodiments, a pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C6 alkylsulfonates, and arylsulfonates, as appropriate. In some embodiments, provided compounds contain two or more acidic groups. In some embodiments, pharmaceutically acceptable salts, or salts in general, of such compounds contain two or more cations, which may be the same or different. In some embodiments, in a pharmaceutically acceptable salt (or salt in general), all ionizable hydrogens in an acidic group (e.g., a pKa in aqueous solution of about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 or less; in some embodiments, about 7 or less; in some embodiments, about 6 or less; in some embodiments, about 5 or less; in some embodiments, about 4 or less; in some embodiments, about 3 or less) are replaced with a cation.

[0046] Protecting Group: As used herein, the term "protecting group" is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis by T.W. Greene and P.G.M. Wuts (3rd ed., John Wiley & Sons, 1999), the entire contents of which are incorporated herein by reference. It also includes protecting groups particularly suitable for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al. (June 2012), the entire contents of Chapter 2 of which are incorporated herein by reference. Suitable amino protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- Phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-Dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitro Dibenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophene Phenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl Carbamates, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivatives, N'-p-toluenesulfonylaminocarbonyl derivatives, N'-phenylaminothiocarbonyl derivatives, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-Dimethoxycarbonylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoboryl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methyl 1-methyl-1-cyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamates, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenoxy)acetamide Nyl)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, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-Tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, Quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamine (Fcm), N-2-picolylamine N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methylamine N-nitrobenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylamine Nylborinic acid derivatives, N-[phenyl(pentacarbonylchromium or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitramine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-Dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridine sulfenamide (Npys), p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4 -methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0047] Suitable protected carboxylic acids further include, but are not limited to, carboxylic acids protected with silyl, alkyl, alkenyl, aryl, and arylalkyl groups. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and triisopropylsilyl groups. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and tetrahydropyran-2-yl groups. Examples of suitable alkenyl groups include allyl groups. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl groups. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), and 2- and 4-picolyl.

[0048] Suitable hydroxyl protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl ( MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]phenyl ]-4-Methoxypiperidin-4-yl (CTMP), 1,4-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, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trimethyl- methylethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, 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 Thiyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropyl Silyl (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, phenoxy Acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonic acid, 4-methoxycrotonic acid, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl Tyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoic acid, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonic acid, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosacinoate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl Examples of protecting groups for 1,2- or 1,3-diols include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-Dimethoxybenzylidene acetal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidine orthoester, ester, 1,2-dimethoxyethylidene orthoester, α-methoxybenzylidene orthoester, 1-(N,N-dimethylamine) These include N-(N,N'-dimethylamino)ethylidene derivatives, α-(N,N'-dimethylamino)benzylidene derivatives, 2-oxacyclopentylidene orthoesters, di-t-butylsilylene groups (DTBS), 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivatives (TIPDS), tetra-t-butoxydisiloxane-1,3-diylidene derivatives (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0049] In some embodiments, the hydroxyl protecting group is acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl(trityl), 4,4′-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloacetyl, or benzoylmethylsilyl. yl, 9-fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr) and 4,4',4''-trimethoxytrityl (TMTr), 2-cyanoethyl (CE or Cne), 2-(trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl, 2-(4-nitrophenyl)ethyl (NPE), 2-(4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4,6-trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4' ,4"-tris(benzoyloxy)trityl, diphenylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenylxanthin-9-yl (piXyl), or 9-(p-methoxyphenyl)xanthin-9-yl (MOX). In some embodiments, each hydroxyl protecting group is independently selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and 4,4'-dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl, and 4,4'-dimethoxytrityl groups.In some embodiments, the protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxamido)-1-propyl, 4-oxopentyl, 4-methylthio-1-butyl, 2-cyano-1,1-dimethylethyl, 4-N-methylaminobutyl, 3-(2-pyridyl)-1-propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, 2-(N-formyl,N-methyl)aminoethyl, or 4-[N-methyl-N-(2,2,2-trifluoroacetyl)amino]butyl.

[0050] Subject: As used herein, the term "subject" or "test subject" refers to any organism to which a compound or composition according to the present disclosure is administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, humans, insects, worms, etc.) and plants. In some embodiments, the subject is a human. In some embodiments, the subject may be suffering from and / or susceptible to a disease, disorder, and / or condition.

[0051] Substantially: As used herein, the term "substantially" refers to the qualitative state in which a property or characteristic of interest is exhibited to a complete or nearly complete degree. Those of ordinary skill in the art of biology and / or chemistry will understand that biological and chemical phenomena rarely proceed to completion and / or perfection, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and / or chemical phenomena.

[0052] Susceptible: An individual who is "susceptible" to a disease, disorder, and / or condition is an individual who is at higher risk than the general population of developing that disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition is predisposed to contracting that disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not have been diagnosed with that disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition develops the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition does not develop the disease, disorder, and / or condition.

[0053] Therapeutic Agent: As used herein, the term "therapeutic agent" generally refers to any agent that induces a desired effect (e.g., a desired biological, clinical, or pharmacological effect) when administered to a subject. In some embodiments, an agent is considered a therapeutic agent if it demonstrates a statistically significant effect in a relevant population. In some embodiments, a relevant population is a population of subjects suffering from and / or susceptible to a disease, disorder, or condition. In some embodiments, a relevant population is a population of model organisms. In some embodiments, a relevant population may be defined by one or more criteria, such as age group, sex, genetic background, pre-existing clinical conditions, exposure to previous treatments, etc. In some embodiments, a therapeutic agent is a substance that, when administered to a subject in an effective amount, alleviates, ameliorates, reduces, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition in the subject. In some embodiments, a "therapeutic agent" is a drug that has been approved, or is seeking approval from, a government agency before being sold for administration to humans. In some embodiments, a "therapeutic agent" is a drug that requires a physician's prescription for administration to humans. In some embodiments, the therapeutic agent is a provided compound.

[0054] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of skill in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, and the target cell or tissue. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, ameliorates, relieves, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose. In some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0055] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, reduce, inhibit, prevent, delay onset, reduce severity, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not show signs of the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who shows only early signs of the disease, disorder, and / or condition, for example, to reduce the risk of developing pathology associated with the disease, disorder, and / or condition.

[0056] Unsaturated: As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0057] As will be appreciated by one of skill in the art, the methods and compositions described herein relating to compounds also generally apply to pharmaceutically acceptable salts of such compounds. Specific Embodiments of the Compound

[0058] Among other things, the present disclosure provides compounds useful for a variety of purposes. In some embodiments, the compounds provided are compounds having the structure of Formula I:

[0059] [ka]

[0060] or a salt thereof, wherein Ring A is an optionally substituted 5- or 6-membered aromatic ring having 0 to 4 heteroatoms, or

[0061] [ka]

[0062] and X 1 , X 2a , X 2b , and X 2c are independently -N=, -C(R 2 )= or optionally substituted —CH=; X 1a is —O—, —S—, —N(R′)—, —C(R′)—, or optionally substituted —CH— or —NH—; X 3 is —O—, —S—, —Se—, —N(R′)—, or optionally substituted —NH—; X 4 , X 5 , X 6 , X 7 and X 8 are independently -N=, -C(R 6 )= or optionally substituted —CH=; R 1 , R 2 , R s and R 6are each independently halogen, —CN, —NO2, —L-R', —OR', —N(R')2, —N(R')C(O)OR', —C(O)R', —C(O)OR', —C(O)N(R')2, or —OC(O)N(R')2; L 1 is a covalent bond, -C(O)-, -C(S)-, -S(O)2-, -N(R')C(O)-, -N(R')S(O)2-, -N(R')C(S)-, or

[0063] [ka]

[0064] and R 3 , R 4 and R 5 are each independently R', L and L 2 each independently represents an optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are optionally and independently selected from —O—, —S—, —C(R 4 )(R 5 )-, -N(R 4 )-, optionally substituted -CH=N-, optionally substituted -CH=CH- or -Cy-; Each -Cy- is independently

[0065] [ka]

[0066] and Ring B is an optionally substituted saturated or partially saturated 3- to 10-membered ring having 0 to 4 heteroatoms. t is 0, 1, 2, 3, or 4. Each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)R. Each R is independently hydrogen or C1-C 10Aliphatic, C1-C with 1-3 heteroatoms 10 Heteroaliphatic, 3-10-membered cyclic aliphatic, 3-10-membered heterocyclyl having 1-4 heteroatoms, 6-10-membered aryl, 5-10-membered heteroaryl having 1-6 heteroatoms, 6-10-membered aryl-C-C 10 Aliphatic and 5-10 membered heteroaryl-C1-C having 1-6 heteroatoms 10 an optionally substituted group selected from aliphatic, or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3- to 10-membered ring having, in addition to the atom, 0-4 heteroatoms; or The two R groups on the two atoms may optionally and independently be joined together with the intervening atoms to form an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms.

[0067] Specific embodiments are described herein as examples for various variables in various formulas (e.g., Formula I). ​​After reading this disclosure, one of ordinary skill in the art can select and combine embodiments for each variable. Such combinations are within the scope of this disclosure. In addition, one of ordinary skill in the art can easily understand that an embodiment described for a variable (e.g., R) can be combined with other variables (e.g., R 1 , R', R 2 , R 3 , R 4 , R 5 , R s Understand that it can also be used for other things (such as R). Ring A

[0068] In some embodiments, ring A is an optionally substituted phenyl ring. In some embodiments, ring A is phenyl.

[0069] In some embodiments, ring A is an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 1 to 4 heteroatoms. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 1 to 3 heteroatoms. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 1 to 2 heteroatoms. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 1 to 2 heteroatoms. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 2 heteroatoms. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having a heteroatom selected from O, N, and S. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having a nitrogen atom. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having two heteroatoms independently selected from O, N, and S. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having two heteroatoms, each N. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having three heteroatoms. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having three heteroatoms independently selected from O, N, and S. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having three heteroatoms, one of which is N.

[0070] In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1 to 3 heteroatoms. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 2 heteroatoms. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1 heteroatom. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having an oxygen atom. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having a nitrogen atom. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having a sulfur atom. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from O, N, and S. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having two heteroatoms, one of which is N. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from N and S. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from N and O. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from O and S. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having three heteroatoms.In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from O, N, and S. In some embodiments, the ring has one heteroatom. In some embodiments, the ring has two or more heteroatoms, at least one of which is nitrogen. In some embodiments, all heteroatoms are nitrogen. In some embodiments, all heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatoms.

[0071] In some embodiments, ring A is

[0072] [ka]

[0073] wherein each variable is independently as described herein. In some embodiments, ring A is

[0074] [ka]

[0075] wherein each variable is independently as described herein. In some embodiments, ring A is

[0076] [ka]

[0077] wherein each variable is independently as described herein. In some embodiments, ring A is

[0078] [ka]

[0079] wherein each variable is independently as described herein. In some embodiments, ring A is

[0080] [ka]

[0081] wherein each variable is independently as described herein. In some embodiments, ring A is

[0082] [ka]

[0083] wherein each variable is independently as described herein. In some embodiments, ring A is

[0084] [ka]

[0085] wherein each variable is independently as described herein. In some embodiments, R 1 is -OR', where R' is as described herein. In some embodiments, R 2 is -OR', where R' is as described herein. In some embodiments, R 1 and R 2 is independently -OR', where R' is as described herein. In some embodiments, R 1 and R 2 and are the same. In some embodiments, R 1 and R 2 In some embodiments, R' is an optionally substituted C aliphatic. In some embodiments, R' is an optionally substituted C 1-6In some embodiments, R' is an optionally substituted methyl. In some embodiments, R' is methyl. In some embodiments, ring A is

[0086] [ka]

[0087] and each variable is independently as described herein. In some embodiments, ring A is

[0088] [ka]

[0089] and each variable is independently as described herein. In some embodiments, ring A is

[0090] [ka]

[0091] and each variable is independently as described herein. In some embodiments, ring A is

[0092] [ka]

[0093] and each variable is independently as described herein. In some embodiments, ring A is

[0094] [ka]

[0095] In some embodiments, ring A is an optionally substituted pyrimidinyl. In some embodiments, ring A is an optionally substituted 2'-pyrimidinyl. In some embodiments, ring A is an optionally substituted 4'-pyrimidinyl. In some embodiments, ring A is an optionally substituted

[0096] [ka]

[0097] is.

[0098] In some embodiments, ring A is

[0099] [ka]

[0100] and each variable is independently as described herein. In some embodiments, ring A is

[0101] [ka]

[0102] and each variable is independently as described herein. In some embodiments, ring A is

[0103] [ka]

[0104] and each variable is independently as described herein. In some embodiments, ring A is

[0105] [ka]

[0106] and each variable is independently as described herein. In some embodiments, ring A is

[0107] [ka]

[0108] and each variable is independently as described herein. In some embodiments, ring A is

[0109] [ka]

[0110] and each variable is independently as described herein. In some embodiments, ring A is

[0111] [ka]

[0112] and each variable is independently as described herein. In some embodiments, ring A is

[0113] [ka]

[0114] In some embodiments, ring A is

[0115] [ka]

[0116] In some embodiments, ring A is an optionally substituted pyridazinyl. In some embodiments, ring A is an optionally substituted 3'-pyridazinyl. In some embodiments, ring A is an optionally substituted

[0117] [ka]

[0118] is.

[0119] In some embodiments, ring A is

[0120] [ka]

[0121] wherein each variable is independently as described herein. In some embodiments, ring A is

[0122] [ka]

[0123] wherein each variable is independently as described herein. In some embodiments, ring A is

[0124] [ka]

[0125] wherein each variable is independently as described herein. In some embodiments, ring A is

[0126] [ka]

[0127] In some embodiments, ring A is optionally substituted.

[0128] [ka]

[0129] is.

[0130] In some embodiments, ring A is

[0131] [ka]

[0132] and each variable is independently as described herein. In some embodiments, ring A is

[0133] [ka]

[0134] and each variable is independently as described herein. In some embodiments, ring A is

[0135] [ka]

[0136] and each variable is independently as described herein. In some embodiments, ring A is

[0137] [ka]

[0138] In some embodiments, ring A is an optionally substituted pyridinyl. In some embodiments, ring A is an optionally substituted 2'-pyridinyl. In some embodiments, ring A is an optionally substituted 3'-pyridinyl. In some embodiments, ring A is an optionally substituted 4'-pyridinyl.

[0139] In some embodiments, ring A is

[0140] [ka]

[0141] wherein each variable is independently as described herein. In some embodiments, ring A is

[0142] [ka]

[0143] and each variable is independently as described herein. In some embodiments, ring A is

[0144] [ka]

[0145] and each variable is independently as described herein. In some embodiments, ring A is

[0146] [ka]

[0147] and each variable is independently as described herein. In some embodiments, ring A is

[0148] [ka]

[0149] and each variable is independently as described herein. In some embodiments, ring A is

[0150] [ka]

[0151] and each variable is independently as described herein. In some embodiments, ring A is

[0152] [ka]

[0153] where R 2 is as described herein. In some embodiments, ring A is

[0154] [ka]

[0155] In some embodiments, ring A is

[0156] [ka]

[0157] where R 1 and R 2 is independently an optionally substituted C1-C6 alkyl, and R is as described herein. In some embodiments, ring A is

[0158] [ka]

[0159] where R 1 and R 2 In some embodiments, ring A is

[0160] [ka]

[0161] In some embodiments, ring A is optionally substituted.

[0162] [ka]

[0163] is.

[0164] X 1

[0165] In some embodiments, X 1 is -N=, -C(R 2 )=, or optionally substituted -CH=, where each variable is independently as described herein. In some embodiments, X 1 In some embodiments, X 1 -C(R 2 )=, where R 2 is as described herein. In some embodiments, R 2 is R as described herein 1 In some embodiments, R 2 is R as described herein. In some embodiments, X 1 is optionally substituted -CH=. In some embodiments, X 1 is -CH=.

[0166] X 2a

[0167] In some embodiments, X 2a is -N=, -C(R 2 )=, or optionally substituted -CH=, where each variable is independently as described herein. In some embodiments, X 2a In some embodiments, X 2a -C(R 2 )=, where R 2 is as described herein. In some embodiments, R 2 is as described herein. In some embodiments, R 2 is as described herein. In some embodiments, X 2ais optionally substituted -C(H)=. In some embodiments, X 2a is -C(H)=. In some embodiments, X 2a is -C(OR')=, where R' is as described herein. In some embodiments, X 2a is -C(OH)=. In some embodiments, X 2a -C(OR ' )=, where R ' is optionally substituted C1-C6 alkyl. In some embodiments, X 2a is -C(OMe)=. In some embodiments, X 2a is -C(N(R')2)=. In some embodiments, X 2a is -C(NH)=. In some embodiments, X 2a is —C(N(R′)═), and each R′ is independently an optionally substituted C1-C6 alkyl. In some embodiments, X 2a -C(R 2 )= and R 2 is optionally substituted C1-C6 alkyl. In some embodiments, X 2a is -C(Me)=. In some embodiments, X 2b is -C(halogen)=. In some embodiments, X 2b is -C(F)=. In some embodiments, X 2b is -C(Cl)=. In some embodiments, X 2b is -C(Br)=. In some embodiments, X 2b is -C(I)=.

[0168] X 2b

[0169] In some embodiments, X 2b is -N=, -C(R 2 )=, or optionally substituted -CH=, where each variable is independently as described herein. In some embodiments, X 2bIn some embodiments, X 2b -C(R 2 )=, where R 2 is as described herein. In some embodiments, R 2 is as described herein. In some embodiments, R 2 is as described herein. In some embodiments, X 2b is optionally substituted -C(H)=. In some embodiments, X 2b is -C(H)=. In some embodiments, X 2b is -C(OR')=, where R' is as described herein. In some embodiments, X 2b is -C(OH)=. In some embodiments, X 2b -C(OR ' )=, where R ' is optionally substituted C1-C6 alkyl. In some embodiments, X 2b is -C(OMe)=. In some embodiments, X 2b is -C(N(R')2)=. In some embodiments, X 2b is -C(NH)=. In some embodiments, X 2b is —C(N(R′)═), and each R′ is independently an optionally substituted C1-C6 alkyl. In some embodiments, X 2b -C(R 2 )= and R 2 is optionally substituted C1-C6 alkyl. In some embodiments, X 2b is -C(Me)=. In some embodiments, X 2b is -C(halogen)=. In some embodiments, X 2b is -C(F)=. In some embodiments, X 2b is -C(Cl)=. In some embodiments, X 2b is -C(Br)=. In some embodiments, X 2b is -C(I)=.

[0170] X 2c

[0171] In some embodiments, X 2c is -N=, -C(R 2 )=, or optionally substituted -CH=, where each variable is independently as described herein. In some embodiments, X 2c In some embodiments, X 2c -C(R 2 )=, where R 2 is as described herein. In some embodiments, R 2 is R as described herein. In some embodiments, R 2 is R as described herein. In some embodiments, X 2c is optionally substituted -C(H)=. In some embodiments, X 2c is -C(H)=. In some embodiments, X 2c is -C(OR')=, where R' is as described herein. In some embodiments, X 2c is -C(OH)=. In some embodiments, X 2c is -C(OR')=, where R' is an optionally substituted C1-C6 aliphatic. In some embodiments, X 2c is -C(OR')=, and R' is C1-C6 aliphatic. In some embodiments, X 2c is -C(OR')=, where R' is an optionally substituted C1-C6 alkyl. In some embodiments, X 2b is -C(OMe)=. In some embodiments, X 2c teeth

[0172] [ka]

[0173] In some embodiments, X 2c In some embodiments, X 2c teeth

[0174] [ka]

[0175] In some embodiments, X 2c teeth

[0176] [ka]

[0177] In some embodiments, X 2c teeth

[0178] [ka]

[0179] In some embodiments, X 2c teeth

[0180] [ka]

[0181] In some embodiments, X 2c teeth

[0182] [ka]

[0183] is.

[0184] In some embodiments, X 2c is -C(N(R')2)=. In some embodiments, X 2c is —C(N(R′)═), and each R′ is independently an optionally substituted C1-C6 alkyl. In some embodiments, X 2c teeth

[0185] [ka]

[0186] In some embodiments, X 2c is —C(N(R′)2), optionally substituted, where one R′ is not a substituted R group (e.g., R when R 3 ) together to form an optionally substituted ring as described herein. In some embodiments, X 2c teeth

[0187] [ka]

[0188] where R′ and another R group on another atom (e.g., R which may be R 3 ) together with their intervening atoms form an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms described herein. In some embodiments, the present disclosure provides

[0189] [ka]

[0190] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the present disclosure provides a compound having the structure:

[0191] [ka]

[0192] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, X 2c is -C(NH2)=

[0193] In some embodiments, X 2c -C(R 2 )= and R 2 is an optionally substituted C1-C6 aliphatic group. In some embodiments, X 2c -C(R 2 )= and R 2 is a C1-C6 aliphatic group. In some embodiments, X 2c -C(R 2 )= and R 2 is an optionally substituted C1-C6 alkyl group. In some embodiments, X 2c is -C(Me)=. In some embodiments, X 2c teeth

[0194] [ka]

[0195] In some embodiments, X 2c teeth

[0196] [ka]

[0197] is.

[0198] In some embodiments, X 2c is -C(halogen)=. In some embodiments, X 2c is -C(F)=. In some embodiments, X 2c is -C(Cl)=. In some embodiments, X 2c is -C(Br)=. In some embodiments, X 2c is -C(I)=.

[0199] X 1a

[0200] In some embodiments, X 1ais -O-, -S-, -N(R')-, -C(R')2-, or optionally substituted -CH2- or -NH-, where R' is as described herein. In some embodiments, X 1a is —O—. In some embodiments, X 1a is -S-. In some embodiments, X 1a is -N(R')-, where R' is as described herein. In some embodiments, X 1a is —N(H)—. In some embodiments, X 1a is -N(R')-, where R' is an optionally substituted C1-C6 aliphatic 。 In some embodiments, X 1a -N(R ' )-, where R' is an optionally substituted C1-C6 alkyl. In some embodiments, X 1a is -N(Me)-. In some embodiments, X 1a is —C(R′)2—, where each R′ is independently as described herein. In some embodiments, X 1a is optionally substituted -CH-. In some embodiments, X 1a is -CH-. In some embodiments, X 1a is optionally substituted -NH-. In some embodiments, X 1a is -NH-.

[0201] X 3

[0202] In some embodiments, X 3 is -O-, -S-, -Se-, -N(R')-, or optionally substituted -NH-, where R' is as described herein. In some embodiments, X3 is -O-. In some embodiments, X 3 is -S-. In some embodiments, X 3 is -Se-. In some embodiments, X 3 -N(R ' )-, where R' is as described herein. In some embodiments, X 3 -N(R ' )-, where R ' is an optionally substituted C1-C6 aliphatic. In some embodiments, X 3 is -N(R')-, where R' is an optionally substituted C1-C6 alkyl. In some embodiments, X3 is - N In some embodiments, X is (Me)-. 3 is optionally substituted -NH-. In some embodiments, X 3 is -NH-.

[0203] X 4

[0204] In some embodiments, X 4 is -N=, -C(R 6 )=, or optionally substituted —CH=, where R6 is as described herein. In some embodiments, X 4 In some embodiments, X 4 -C(R 6 )=, where R 6 is as described herein. In some embodiments, R 6 R is as described herein 1 In some embodiments, R 6 is R, as described herein. In some embodiments, X 4 is optionally substituted -CH=. In some embodiments, X 4 is -CH=.

[0205] X 5

[0206] In some embodiments, X 5 is -N=, -C(R 6 )=, or optionally substituted -CH=, where R 6is as described herein. In some embodiments, X 5 In some embodiments, X 5 -C(R 6 )=, where R 6 is as described herein. In some embodiments, R 6 R is as described herein 1 In some embodiments, R 6 is as described herein. In some embodiments, X 5 is optionally substituted -CH=. In some embodiments, X 5 is -CH=. In some embodiments, X 5 -C(R 6 )=, where R 6 is an optionally substituted C1-C6 aliphatic. In some embodiments, X 5 -C(R 6 )=, where R 6 is a C1-C6 aliphatic. In some embodiments, X 5 is -C(CF3)=.

[0207] X 6

[0208] In some embodiments, X 6 is -N=, -C(R 6 )=, or optionally substituted —CH=, where R 6 is as described herein. In some embodiments, X 6 In some embodiments, X 6 -C(R 6 )=, where R 6 is as described herein. In some embodiments, R 6 R is as described herein 1 In some embodiments, R 6 is as described herein. In some embodiments, X 6is optionally substituted -CH=. In some embodiments, X 6 is -CH=. In some embodiments, X 6 is -C(OH)=. In some embodiments, X 6 is -C(OR')=, where R' is an optionally substituted C1-C6 aliphatic. In some embodiments, X 6 is -C(OR')=, where R' is C1-C6 aliphatic. In some embodiments, X 6 is -C(OR')=, where R' is an optionally substituted C1-C6 alkyl. In some embodiments, X 6 is -C(OR')=, and R' is halogen-substituted C1-C6 alkyl. In some embodiments, X 6 is -C(OR')=, R' is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, X 6 is -C(OMe)=. In some embodiments, X 6 is -C(OCF3)=. In some embodiments, X 6 is -C(OCHF2)=. In some embodiments, X 6 is -C(OCHF). In some embodiments, X 6 is -C(OCF2Cl)=. In some embodiments, X 6 is -C(OR')=, where R' is an optionally substituted C1-C6 alkyl, and R', together with other R' groups on other atoms and their intervening atoms, form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. In some embodiments, X 6 and X 7 are both -C(OR')-, and the two R's together with their intervening atoms form an optionally substituted 4-10 (e.g., 5-10, 5-9, 5-6, etc.) membered ring having 0-3 heteroatoms in addition to the intervening atoms. In some embodiments, X 6 and X 7 are both -C(R 6 )- and two R6 together with the intervening atoms form an optionally substituted 4-10 (e.g., 5-10, 5-9, 5-6, etc.) membered ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms in addition to the intervening atoms. In some embodiments, the present disclosure provides

[0209] [ka]

[0210] The present invention provides a compound having the structure:

[0211] In some embodiments, X 6 is -C(OR')=, R' is -C(O)R, and R is as described herein. In some embodiments, X 6 is -C(OR')=, R' is -C(O)R, and R is an optionally substituted C1-C6 aliphatic. In some embodiments, X 6 teeth

[0212] [ka]

[0213] In some embodiments, X 6 -C(R 6 )= and R 6 is —C(O)OR′, where R′ is as described herein. In some embodiments, X 6 -C(R 6 )= and R 6 is —C(O)OR′, where R′ is an optionally substituted C1-C6 aliphatic. In some embodiments, X 6 -C(R 6 )= and R 6 is —C(O)OCH. In some embodiments, X 6 -C(R 6 )= and R 6 is -C(O)OCH2CH3.

[0214] In some embodiments, X 6 -C(R 6 )=, where R 6 is —C(O)R, where R is as described herein. In some embodiments, X 6 -C(R 6 )=, where R 6 is —C(O)R, where R is an optionally substituted C1-C6 aliphatic. In some embodiments, X 6 -C(R 6 )=, where R 6 is -C(O)CH3.

[0215] In some embodiments, X 6 -C(R 6 )= and R 6 is -CN. In some embodiments, X 6 -C(R 6 )= and R 6 is —NO. In some embodiments, X 6 -C(R 6 )= and R 6 is —N(R′) 2 , where R′ is as described herein. In some embodiments, X 6 is -C(R6)=, and R 6 is -N(R')2, and each R' is independently an optionally substituted C1-C6 aliphatic. In some embodiments, X6 is -C(R 6 )= and R 6 is —N(R′) 2 , and each R′ is independently an optionally substituted C 1 -C 6 alkyl. In some embodiments, X 6 -C(R 6 )= and R 6 is —N(R′)2, where each of the two R′ is independently as described herein and, together with the intervening nitrogen atom, forms an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the nitrogen atom. In some embodiments, X 6 -C(R 6 )= and R6 is —N(R′)2, where each of the two R′ is independently as described herein and, together with the intervening nitrogen atom, forms an optionally substituted 3- to 6-membered ring having zero heteroatoms in addition to the nitrogen atom. In some embodiments, X 6 -C(R 6 )= and R 6 is —N(R′)2, where each of the two R′ is independently as described herein and, together with the intervening nitrogen atom, forms an optionally substituted 3- to 6-membered ring having one heteroatom in addition to the nitrogen atom. In some embodiments, X 6 -C(R 6 )= and R 6 is —N(R′)2, where each of the two R′ is independently as described herein and, together with the intervening nitrogen atom, forms an optionally substituted 3- to 6-membered ring having two heteroatoms in addition to the nitrogen atom. In some embodiments, X 6 -C(R 6 )= and R 6 teeth

[0216] [ka]

[0217] is.

[0218] In some embodiments, X 6 -C(R 6 )= and R 6 is optionally substituted C1-C 10 In some embodiments, X is aliphatic. 6 -C(R 6 )= and R 6 is an optionally substituted C1-C6 aliphatic. In some embodiments, X 6 -C(R 6 )= and R 6 is a C1-C6 aliphatic. In some embodiments, X 6 -C(R 6)= and R 6 is optionally substituted C1-C6 alkyl. In some embodiments, X 6 -C(R 6 )= and R 6 is halogen-substituted C1-C6 alkyl. In some embodiments, X 6 -C(R 6 )= and R 6 is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, X 6 -C(R 6 )= and R 6 is C1-C6 alkyl. In some embodiments, X 6 -C(R 6 )= and R 6 is an optionally substituted C-C alkenyl. In some embodiments, X 6 -C(R 6 )= and R 6 is C2-C6 alkenyl. In some embodiments, X 6 -C(R 6 )= and R 6 is an optionally substituted C2-C6 alkynyl. In some embodiments, X 6 -C(R 6 )= and R 6 is C2-C6 alkynyl. In some embodiments, X 6 -C(R 6 )= and R 6 is methyl. In some embodiments, X 6 -C(R 6 )= and R 6 is ethyl. In some embodiments, X 6 -C(R 6 )= and R 6 is —CF. In some embodiments, X 6 -C(R 6 )= and R 6 is —CHF. In some embodiments, X 6 -C(R 6 )=, where R6 teeth

[0219] [ka]

[0220] In some embodiments, X 6 -C(R 6 )=, where R 6 teeth

[0221] [ka]

[0222] In some embodiments, X 6 -C(R 6 )= and R 6 teeth

[0223] [ka]

[0224] In some embodiments, X 6 -C(R 6 )= and R 6 teeth

[0225] [ka]

[0226] In some embodiments, X 6 -C(R 6 )= and R 6 teeth

[0227] [ka]

[0228] In some embodiments, X 6 -C(R6 )= and R 6 teeth

[0229] [ka]

[0230] In some embodiments, X 6 -C(R 6 )= and R 6 teeth

[0231] [ka]

[0232] In some embodiments, X 6 -C(R 6 )= and R 6 is an optionally substituted 3- to 10-membered alicyclic group. In some embodiments, X 6 -C(R 6 )= and R 6 is an optionally substituted 3- to 6-membered alicyclic group. In some embodiments, X 6 -C(R 6 )= and R 6 is a 3- to 6-membered alicyclic group. 6 -C(R 6 )= and R 6 teeth

[0233] [ka]

[0234] In some embodiments, X 6 -C(R 6 )=, where R 6 teeth

[0235] [ka]

[0236] In some embodiments, X 6 -C(R 6 )=, where R 6 teeth

[0237] [ka]

[0238] In some embodiments, X 6 -C(R 6 )=, where R 6 teeth

[0239] [ka]

[0240] is.

[0241] In some embodiments, X 6 -C(R 6 )= and R 6 is a halogen. In some embodiments, X 6 is -C(F)=. In some embodiments, X 6 is -C(Cl)=. In some embodiments, X 6 is -C(Br)=. In some embodiments, X 6 is -C(I)=.

[0242] X 7

[0243] In some embodiments, X 7 is -N=, -C(R 6 )=, or optionally substituted —CH=, where R6 is as described herein. In some embodiments, X 7 In some embodiments, X 7 -C(R 6 )=, where R 6is as described herein. In some embodiments, R 6 R is as described herein 1 In some embodiments, R 6 is as described herein. In some embodiments, X 7 is optionally substituted -CH=. In some embodiments, X 7 is -CH=. In some embodiments, X 7 is -C(OH)=. In some embodiments, X 7 is -C(OR')=, where R' is an optionally substituted C1-C6 aliphatic. In some embodiments, X 7 is -C(OR')=, where R' is C1-C6 aliphatic. In some embodiments, X 7 is -C(OR')=, where R' is an optionally substituted C1-C6 alkyl. In some embodiments, X 7 is -C(OR')=, and R' is halogen-substituted C1-C6 alkyl. In some embodiments, X 7 is -C(OR')=, R' is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, X 7 is -C(OMe)=. In some embodiments, X 7 is -C(OCF3)=. In some embodiments, X 7 is -C(OCHF2)=. In some embodiments, X 7 is -C(OCHF). In some embodiments, X 7 is -C(OCF2Cl)=. In some embodiments, X 7 is -C(OR')=, where R' is an optionally substituted C1-C6 alkyl, and R', taken together with other R' groups on other atoms and their intervening atoms, forms an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms.

[0244] In some embodiments, X 7 -C(R 6)= and R 6 is optionally substituted C1-C 10 In some embodiments, X is aliphatic. 7 -C(R 6 )= and R 6 is an optionally substituted C1-C6 aliphatic. In some embodiments, X 7 -C(R 6 )= and R 6 is a C1-C6 aliphatic. In some embodiments, X 7 -C(R 6 )= and R 6 is optionally substituted C1-C6 alkyl. In some embodiments, X 7 -C(R 6 )= and R 6 is halogen-substituted C1-C6 alkyl. In some embodiments, X 7 -C(R 6 )= and R 6 is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, X 7 -C(R 6 )= and R 6 is C1-C6 alkyl. In some embodiments, X 7 -C(R 6 )= and R 6 is an optionally substituted C-C alkenyl. In some embodiments, X 7 -C(R 6 )= and R 6 is C2-C6 alkenyl. In some embodiments, X 7 -C(R 6 )= and R 6 is an optionally substituted C2-C6 alkynyl. In some embodiments, X 7 -C(R 6 )= and R 6 is C2-C6 alkynyl. In some embodiments, X 7 -C(R 6 )= and R 6 is methyl. In some embodiments, X7 -C(R 6 )=, where R 6 is ethyl. In some embodiments, X 7 -C(R 6 )= and R 6 is —CF. In some embodiments, X 7 -C(R 6 )= and R 6 is —CHF. In some embodiments, X 7 -C(R 6 )= and R 6 is -CHF2. In some embodiments, X 7 -C(R 6 )= and R 6 is -CF2Cl.

[0245] In some embodiments, X 7 -C(R 6 )= and R 6 is a halogen. In some embodiments, X 7 is -C(F)=. In some embodiments, X 7 is -C(Cl)=. In some embodiments, X 7 is -C(Br)=. In some embodiments, X 7 is -C(I)=.

[0246] X 8

[0247] In some embodiments, X 8 is -N=, -C(R 6 )=, or optionally substituted —CH=, where R6 is as described herein. In some embodiments, X 8 In some embodiments, X 8 -C(R 6 )=, where R 6 is as described herein. In some embodiments, R 6 R is as described herein 1 In some embodiments, R6 is as described herein. In some embodiments, X 8 is optionally substituted -CH=. In some embodiments, X 8 is -CH=. In some embodiments, X 8 is -C(OH)=. In some embodiments, X 8 is -C(OR')=, where R' is an optionally substituted C1-C6 aliphatic. In some embodiments, X 8 is -C(OR')=, where R' is C1-C6 aliphatic. In some embodiments, X 8 is -C(OR')=, where R' is an optionally substituted C1-C6 alkyl. In some embodiments, X 8 is -C(OR')=, and R' is halogen-substituted C1-C6 alkyl. In some embodiments, X 8 is -C(OR')=, R' is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, X 8 is -C(OMe)=. In some embodiments, X 8 is -C(OCF3)=. In some embodiments, X 8 is -C(OCHF2)=. In some embodiments, X 8 is -C(OCHF). In some embodiments, X 8 is -C(OCF2Cl)=. In some embodiments, X 8 is -C(OR')=, where R' is an optionally substituted C1-C6 alkyl, and R', together with other R' groups on other atoms and their intervening atoms, form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. In some embodiments, X 7 and X 8 are both -C(OR')-, and the two R's together with their intervening atoms form an optionally substituted 4-10 (e.g., 5-10, 5-9, 5-6, etc.) membered ring having 0-3 heteroatoms in addition to the intervening atoms. In some embodiments, X 7 and X8 are both -C(R 6 )- and two R 6 together with the intervening atom(s) form an optionally substituted 4-10 (e.g., 5-10, 5-9, 5-6, etc.) membered ring having 0-3 heteroatoms in addition to the intervening atom(s). In some embodiments, the present disclosure provides

[0248] [ka]

[0249] The present invention provides a compound having the structure:

[0250] In some embodiments, X 8 -C(R 6 )= and R 6 is optionally substituted C1-C 10 In some embodiments, X is aliphatic. 8 -C(R 6 )= and R 6 is an optionally substituted C1-C6 aliphatic. In some embodiments, X 8 -C(R 6 )= and R 6 is a C1-C6 aliphatic. In some embodiments, X 8 -C(R 6 )= and R 6 is optionally substituted C1-C6 alkyl. In some embodiments, X 8 -C(R 6 )= and R 6 is halogen-substituted C1-C6 alkyl. In some embodiments, X 8 -C(R 6 )= and R 6 is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, X 8 -C(R 6 )= and R 6 is C1-C6 alkyl. In some embodiments, X 8 -C(R6 )= and R 6 is an optionally substituted C-C alkenyl. In some embodiments, X 8 -C(R 6 )= and R 6 is C2-C6 alkenyl. In some embodiments, X 8 -C(R 6 )= and R 6 is an optionally substituted C2-C6 alkynyl. In some embodiments, X 8 -C(R 6 )= and R 6 is C2-C6 alkynyl. In some embodiments, X 8 -C(R 6 )= and R 6 is methyl. In some embodiments, X 8 -C(R 6 )= and R 6 is ethyl. In some embodiments, X 8 -C(R 6 )= and R 6 is —CF. In some embodiments, X 8 -C(R 6 )= and R 6 is —CHF. In some embodiments, X 8 -C(R 6 )= and R 6 teeth

[0251] [ka]

[0252] In some embodiments, X 8 -C(R 6 )= and R 6 teeth

[0253] [ka]

[0254] is.

[0255] In some embodiments, X 8 -C(R 6 )= and R 6 is a halogen. In some embodiments, X 8 is -C(F)=. In some embodiments, X 8 is -C(Cl)=. In some embodiments, X 8 is -C(Br)=. In some embodiments, X 8 is -C(I)=.

[0256] R 1

[0257] In some embodiments, R 1 is halogen, —CN, —NO, —R′, —OR′, —N(R′)2, —N(R′)C(O)OR′, —C(O)R′, —C(O)OR′, —C(O)N(R′)2, or —OC(O)N(R′)2, where R′ is independently as described herein. In some embodiments, R 1 is —H. In some embodiments, R 1 is not —H. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -NO2 。 In some embodiments, R 1 is R' as described herein. In some embodiments, R 1 Ha-LR ' where each L and R ' and are independently as described herein. In some embodiments, L is optionally substituted C 1-3 In some embodiments, R is alkylene. 1 is —CHR′, where R′ is as described herein. In some embodiments, R 1 is —CHC(O)OR, and R is as described herein. In some embodiments, R 1is as described herein. In some embodiments, R 1 is —N(R′) 2 , where R′ is independently as described herein. 。 In some embodiments, R 1 is —N(R′)C(O)OR′, where each R′ is independently as described herein. In some embodiments, R 1 is —C(O)R′, where R′ is as described herein. In some embodiments, R 1 -C(O)OR ' and R ' is as described herein. In some embodiments, R 1 is —C(O)N(R′) 2 , where R′ is independently as described herein. In some embodiments, R 1 is —OC(O)N(R′) 2 , where R′ is independently as described herein.

[0258] In some embodiments, R 1 is -OR', where R' is as described herein. In some embodiments, R 1 is —OH. In some embodiments, R 1 is -OR', where R' is an optionally substituted C1-C6 aliphatic. In some embodiments, R 1 HA-OR ' and R ' is C1-C6 aliphatic. In some embodiments, R 1 is -OR', where R' is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is -OR', and R' is halogen-substituted C1-C6 alkyl. In some embodiments, R 1 is -OR', R' is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, R 1 is -OMe. In some embodiments, R 1 is -OCF3. In some embodiments, R 1 is -OCHF. In some embodiments, R 1is -OCH2F. In some embodiments, R 1 is -OCF2Cl. In some embodiments, R 1 teeth

[0259] [ka]

[0260] is.

[0261] In some embodiments, R 1 is an optionally substituted C1-C 10 In some embodiments, R 1 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 1 is C1-C6 aliphatic. In some embodiments, R 1 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is halogen-substituted C-C alkyl. In some embodiments, R 1 is a substituted C1-C6 alkyl, and each substituent is -F. In some embodiments, R 1 is C1-C6 alkyl 。 In some embodiments, R 1 is an optionally substituted C2-C6 alkenyl 。 In some embodiments, R 1 is C-C alkenyl. In some embodiments, R 1 is an optionally substituted C-C alkynyl. In some embodiments, R 1 is C2-C6 alkynyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is —CF. In some embodiments, R 1 is -CHF. In some embodiments, R 1 teeth

[0262] [ka]

[0263] In some embodiments, R 1 teeth

[0264] [ka]

[0265] In some embodiments, R 1 is halogen. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.

[0266] R 2

[0267] In some embodiments, R 2 is R as described herein 1 In some embodiments, R 2 is R' as described herein. In some embodiments, R 2 is R as described herein. In some embodiments, R 2 is —H. In some embodiments, R 2 is not —H. In some embodiments, R 2 is an optionally substituted C 1-6 It is aliphatic 。 In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 is an optionally substituted C-C having 1 to 3 (e.g., 1, 2, or 3) heteroatoms 10(For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 In some embodiments, there is one heteroatom. In some embodiments, there are two heteroatoms. In some embodiments, there are three heteroatoms. In some embodiments, the heteroatom is an oxygen atom. In some embodiments, at least two heteroatoms are different. In some embodiments, all heteroatoms are the same.

[0268] In some embodiments, R 2 is -OR', where R' is as described herein. In some embodiments, R 2 is —OH. In some embodiments, R 2 is -OR', where R' is an optionally substituted C 1-6 It is aliphatic.

[0269] In some embodiments, R 2 and other R groups (e.g., if this is R, then R 2 , R 3 (other variables such as ) together with the intervening atoms form a ring, which may be optionally substituted as described herein. In some embodiments, the ring formed is an optionally substituted 3-10, 3-9, 3, 4, 5, 6, 7, 8, 9, or 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms. R 3

[0270] In some embodiments, R 3 is R', where R ' is as described herein. In some embodiments, R 3 is as described herein. In some embodiments, R 3 is H. In some embodiments, R 3 is an optionally substituted C1-C6 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3is methyl. In some embodiments, R 3 is ethyl. R 4

[0271] In some embodiments, R 4 is R' and R ' is as described herein. In some embodiments, R 4 is as described herein. In some embodiments, R 4 is H. In some embodiments, R 4 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 4 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is -CHF. In some embodiments, R 4 is —CHOH. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-hexyl. In some embodiments, R 4 is -(CH2)2CH=CH2 。 In some embodiments, R 4 is —(CH)COOH. In some embodiments, R 4 is an optionally substituted C1-C aryl group having 1 to 3 (e.g., 1, 2, or 3) heteroatoms; 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 ) heteroaliphatic. In some embodiments, R 4 is —CH2OCH3. In some embodiments, R 4 is —CH2OCH2OCH3. In some embodiments, R 4 is an optionally substituted C6 to C 10 Aryl-C1- 10 For example, in some embodiments, R 4 is -(CH2)2Ph. In some embodiments, R4 and R 5 are both R and, together with the intervening atoms, form a ring which may be optionally substituted as described herein. R 5

[0272] In some embodiments, R 5 is R', where R ' is as described herein. In some embodiments, R 5 is as described herein. In some embodiments, R 5 is H. In some embodiments, R 5 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is -CH2OH 。 In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-hexyl. In some embodiments, R5 is -(CH2)2CH=CH2 。 In some embodiments, R 5 is —(CH)COOH. In some embodiments, R 5 is an optionally substituted C1-C aryl group having 1 to 3 (e.g., 1, 2, or 3) heteroatoms; 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 In some embodiments, R 5 is -CH2OCH3 。 In some embodiments, R 5 is —CH2OCH2OCH3. In some embodiments, R 5 is an optionally substituted C6 to C 10 Aryl-C1- 10For example, in some embodiments, R 5 is -(CH2)2Ph. In some embodiments, R 4 and R 5 are both R and, together with the intervening atoms, form a ring which may be optionally substituted as described herein.

[0273] R 6

[0274] In some embodiments, R 6 is the R 1 In some embodiments, R 6 is R' as described herein. In some embodiments, R 6 is R as described herein. In some embodiments, R 6 and other groups which may be R, taken together with their intervening atom(s), form a ring, which may be optionally substituted as described herein. In some embodiments, two R 6 (For example, X 6 and X 7 Each of these independently represents -C(R 6 When )=) is R and taken together with their intervening atom(s) form a ring, which may be optionally substituted as described herein. In some embodiments, R 6 is —H. In some embodiments, R 6 is not -H.

[0275] In some embodiments, R 6 is halogen. In some embodiments, R 6 is -F. In some embodiments, R 6 is -Cl. In some embodiments, R 6 is -Br. In some embodiments, R 6 is -I. In some embodiments, R 6 is -CN. In some embodiments, R 6 is —NO. In some embodiments, R 6is R' as described herein. In some embodiments, R 6 is -OR' as described herein. In some embodiments, R 6 is —OH. In some embodiments, R 6 is -OR', where R' is an optionally substituted C1-6 aliphatic. In some embodiments, R 6 is -OR', where R' is C 1-6 In some embodiments, R 6 is -OR', where R' is an optionally substituted C 1-6 In some embodiments, R 6 is -OR', where R' is C 1-6 is alkyl 。 In some embodiments, R 6 is -OR', where R' is C 1-6 In some embodiments, R 6 is -OR', and R' is a substituent C 1-6 alkyl, and each substituent is -F. In some embodiments, R 6 is -OMe. In some embodiments, R 6 is -OCF3. In some embodiments, R 6 is -OCHF2 。 In some embodiments, R 6 is -OCH2F. In some embodiments, R 6 is -OCF2Cl. In some embodiments, X 6 is -OR', and R', taken together with other R' groups on other atoms and their intervening atoms, forms an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms. In some embodiments, provided compounds, e.g., compounds having the structure of Formula I, or salts thereof, are

[0276] [ka]

[0277] or a salt thereof. In some embodiments, R 6 is -OR', R' is -C(O)R, and R is as defined herein.

[0278] In some embodiments, R 6 is -N(R')2, where each R' is independently as described herein. In some embodiments, two R', taken together with the nitrogen atom to which they are attached, form a ring, which may be optionally substituted as described herein. In some embodiments, one of R' and another R attached to another atom, taken together with the intervening atoms, form a ring, which may be optionally substituted as described herein. In some embodiments, R 6 is —N(R′)C(O)OR′, where each R′ is independently as described herein. In some embodiments, R 6 is —C(O)R′, where R′ is as described herein. In some embodiments, R 6 is —C(O)R′, where R′ is an optionally substituted C 1-6 In some embodiments, R 6 is —C(O)CH. In some embodiments, R 6 is —C(O)OR′, where R′ is as described herein. In some embodiments, R 6 is —C(O)OR′, where R′ is an optionally substituted C 1-6 In some embodiments, R 6 is —C(O)OCH. In some embodiments, R 6 is —C(O)OCH2CH3. In some embodiments, R 6 is —C(O)N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 6 is —OC(O)N(R′) 2 , where each R′ is independently as described herein.

[0279] In some embodiments, R 6is an optionally substituted C1 to C 10 In some embodiments, R 6 is an optionally substituted C 1-6 aliphatic (as will be appreciated by those skilled in the art, 1-n (For example, C 1-6 ) is C1-C n (e.g., C1-C6). In some embodiments, R 6 is C 1-6 In some embodiments, R 6 is an optionally substituted C 1-6 In some embodiments, R 6 is C 1-6 In some embodiments, R 6 is C1-C6 haloalkyl. In some embodiments, R 6 is a C1-C6 aliphatic substituted with one or more -F. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more -F. In some embodiments, R 6 is an optionally substituted C-C alkenyl. In some embodiments, R 6 is an optionally substituted C-C alkynyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is —CF. In some embodiments, R 6 In some embodiments, cr6 is -CHF. In some embodiments, R 6 is —CF2Cl. In some embodiments, R 6 is -CH(CH3)2 。 In some embodiments, R 6 is —C(CH)OH. In some embodiments, R 6 is —C(CH)CN. In some embodiments, R 6is -C(CH3)=CH2. In some embodiments, R 6 is -C≡CH. In some embodiments, R 6 is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered alicyclic ring. In some embodiments, R 6 is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10-membered cycloalkyl. In some embodiments, R 6 is optionally substituted cyclopropyl. In some embodiments, R 6 is optionally substituted cyclobutyl. In some embodiments, R 6 is optionally substituted cyclopentyl. In some embodiments, R 6 is optionally substituted cyclohexyl.

[0280] R s

[0281] In some embodiments, R s is R as described herein 1 In some embodiments, R s is -L-R', where L and R' are each independently as described herein. In some embodiments, L is optionally substituted -CH2-. In some embodiments, L is -CH2-. In some embodiments, R s is R' as described herein. In some embodiments, R s is R as described herein. In some embodiments, R s -C(O)R ' and R ' is as described herein. In some embodiments, Rs is -C(O)R, and R is as described herein. In some embodiments, R s is —C(O)OR, and R is as described herein. In some embodiments, R s is —C(O)OtBu. In some embodiments, Rs is —CHC(O)OR, and R is as described herein. In some embodiments, R s is -CH2C(O)OCH3.

[0282] In some embodiments, two R are R and, together with their intervening atoms, form a ring, which may be optionally substituted as described herein.

[0283] R'

[0284] In some embodiments, R' is R as described herein. In some embodiments, R' is -OR and R is as described herein. In some embodiments, R' is -C(O)R and R is as described herein. In some embodiments, R' is -C(O)OR and R is as described herein. In some embodiments, R' is -S(O)R and R is as described herein.

[0285] In some embodiments, R' is -H. In some embodiments, R' is not -H. In some embodiments, two R' are R and together with their intervening atoms form a ring as described herein.

[0286] R

[0287] In some embodiments, R is -H. In some embodiments, R is not -H.

[0288] In some embodiments, R is an optionally substituted C-C 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 ) aliphatic. In some embodiments, R is an optionally substituted C-C 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 In some embodiments, R is an optionally substituted C 1-6In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is alkyl. For example, in some embodiments, R is optionally substituted hexyl. In some embodiments, R is hexyl. In some embodiments, R is optionally substituted pentyl. In some embodiments, R is pentyl. In some embodiments, R is optionally substituted butyl. In some embodiments, R is butyl. In some embodiments, R is optionally substituted propyl. In some embodiments, R is propyl. In some embodiments, R is isopropyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is ethyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is methyl. In some embodiments, R is -CF3.

[0289] In some embodiments, R is an optionally substituted C1-C1 alkyl group having 1-3 (e.g., 1, 2, or 3) heteroatoms. 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 In some embodiments, R is an optionally substituted C1-C6 heteroaliphatic group having 1-3 (e.g., 1, 2, or 3) heteroatoms. 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 ) heteroalkyl. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is nitrogen. In some embodiments, the nitrogen atom is substituted. In some embodiments, the heteroatom is sulfur. In some embodiments, there is one heteroatom. In some embodiments, there are two heteroatoms. In some embodiments, there are three heteroatoms.

[0290] In some embodiments, R is an optionally substituted 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) alicyclic group. In some embodiments, R is an optionally substituted 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) cycloalkyl group. In some embodiments, it is a 3 membered ring. In some embodiments, it is a 4 membered ring. In some embodiments, it is a 5 membered ring. In some embodiments, it is a 6 membered ring. In some embodiments, it is a 7 membered ring. In some embodiments, it is an 8 membered ring. In some embodiments, it is a 9 membered ring. In some embodiments, it is a 10 membered ring. In some embodiments, the ring is monocyclic. In some embodiments, the ring is bicyclic. In some embodiments, the ring is polycyclic. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is pentyl. In some embodiments, R is optionally substituted butyl. In some embodiments, R is butyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl. In some embodiments, R is optionally substituted adamantyl. In some embodiments, R is adamantyl.

[0291] In some embodiments, R is an optionally substituted 3-10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) heterocyclyl having 1-4 (e.g., 1, 2, 3, or 4) heteroatoms. In some embodiments, the heterocyclyl ring is saturated. In some embodiments, it is partially unsaturated. In some embodiments, it is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, the ring is monocyclic. In some embodiments, the ring is bicyclic. In some embodiments, the ring is polycyclic. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is nitrogen. In some embodiments, the nitrogen atom is substituted. In some embodiments, the heteroatom is sulfur. In some embodiments, there is one heteroatom. In some embodiments, there are two heteroatoms. In some embodiments, there are three heteroatoms.

[0292] In some embodiments, R is an optionally substituted 6- to 10-membered aryl. In some embodiments, R is an optionally substituted aryl. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is an optionally substituted 10-membered aryl. In some embodiments, R is an optionally substituted naphthyl. In some embodiments, R is naphthyl.

[0293] In some embodiments, R is an optionally substituted 5-10 (e.g., 5, 9, or 10) heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms. In some embodiments, R is an optionally substituted 5-membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4) heteroatoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4) heteroatoms. In some embodiments, R is an optionally substituted bicyclic 9-membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4) heteroatoms. In some embodiments, R is an optionally substituted bicyclic 10-membered heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms. In some embodiments, there is one heteroatom. In some embodiments, there are two heteroatoms. In some embodiments, there are three heteroatoms. In some embodiments, there are four heteroatoms. In some embodiments, the heteroatom is nitrogen. In some embodiments, the nitrogen atom is substituted. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur. In some embodiments, each heteroatom is the same. In some embodiments, at least one heteroatom is different from at least one other heteroatom.

[0294] In some embodiments, R is an optionally substituted 6-10 (e.g., 6, 10, etc.) membered aryl-C-C 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 ) aliphatic. Optionally substituted 6- to 10-membered aryl and optionally substituted C1-C 10 Particular embodiments of aliphatic groups are described above.

[0295] In some embodiments, R is an optionally substituted 5-10 (e.g., 5, 6, 9, 10, etc.) membered heteroaryl having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms, and is C1-C 10 (For example, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 Optionally substituted 5- to 10-membered heteroaryl having 1 to 6 heteroatoms and optionally substituted C1-C 10 Particular embodiments of aliphatic groups are described above.

[0296] In some embodiments, two R groups (in some embodiments, two groups that can be R, e.g., each independently R) on the same atom are 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R s and two groups selected from) optionally and independently, taken together with their atoms, form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having, in addition to the atoms, 0-4 (0, 1, 2, 3, or 4) heteroatoms. In some embodiments, the two R groups (in some embodiments, two groups that can be R, e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R s (two groups independently selected from) に and independently, together with their intervening atoms, form an optionally substituted 3- to 10-membered (3, 4, 5, 6, 7, 8, 9, or 10-membered) ring having, in addition to the intervening atoms, 0-4 (e.g., 1, 2, 3, or 4) heteroatoms.

[0297] In some embodiments, rings of the present disclosure, such as rings formed by two groups together with an intervening atom, alicyclic rings, heterocyclic rings, aryl rings, heteroaryl rings, etc., are substituted. In some embodiments, they are unsubstituted. In some embodiments, they are saturated. In some embodiments, they are partially substituted. In some embodiments, they are aromatic. In some embodiments, there is a heteroatom in the ring. In some embodiments, there are two heteroatoms in the ring. In some embodiments, there are three heteroatoms in the ring. In some embodiments, there are four atoms in the ring. In some embodiments, there are no heteroatoms. In some embodiments, the ring is a 3-membered ring. In some embodiments, the ring is a 4-membered ring. In some embodiments, the ring is a 5-membered ring. In some embodiments, the ring is a 6-membered ring. In some embodiments, the ring is a 7-membered ring. In some embodiments, the ring is an 8-membered ring. In some embodiments, the ring is a 9-membered ring. In some embodiments, the ring is a 10-membered ring. In some embodiments, they are monocyclic. In some embodiments, they are bicyclic. In some embodiments, they are polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10, 3-9, 3-8, 3-7, 3-6, 3, 4, 5, 6, 7, 8, 9, or 10-membered saturated, partially unsaturated, or aromatic ring having, independently, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-7, 3, 4, 5, 6, or 7-membered saturated, partially unsaturated, or aromatic ring having, independently, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-, 4-, 5-, or 6-membered saturated, partially unsaturated, or aromatic ring having, independently, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms.

[0298] L 1

[0299] In some embodiments, L 1is a covalent bond, -C(O)-, -C(S)-, -S(O)2-, -N(R')C(O)-, -N(R')S(O)2-, -N(R')C(S)-, or

[0300] [ka]

[0301] wherein each R' is independently as described herein. In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is —C(O)—. In some embodiments, L 1 is -C(S)-. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is —N(R′)C(O)—, where R′ is as described herein. In some embodiments, L 1 is —N(R′)C(O)—, where R′ is an optionally substituted C1-C6 alkyl. In some embodiments, L 1 is —N(H)C(O)—. In some embodiments, L 1 is —N(R′)S(O)—, where R′ is as described herein. In some embodiments, L 1 is —N(R′)S(O)—, where R′ is an optionally substituted C-C alkyl. In some embodiments, L 1 is —N(H)S(O)—. In some embodiments, L 1 is -N(R')C(S)-, where R' is as described herein. In some embodiments, L 1 is —N(R′)C(S)—, where R′ is an optionally substituted C1-C6 alkyl. In some embodiments, L 1 is —N(H)C(S)—. In some embodiments, L 1 teeth

[0302] [ka]

[0303] wherein R' is as described herein. In some embodiments, R' is -H. In some embodiments, R' is optionally substituted C 1-6 It is alkyl.

[0304] L

[0305] In some embodiments, L is an optionally substituted C alkylene, wherein one or more methylene units of the alkylene are optionally and independently selected from —O—, —S—, —C(R 4 )(R 5 )-, -N(R 4 )-, optionally substituted -CH=N-, optionally substituted -CH=CH- or -Cy-; and R 4 and R 5 each is independently R' as described herein; and each -Cy- is independently

[0306] [ka]

[0307] wherein ring B is an optionally substituted saturated or partially saturated 3- to 10-membered ring having 0-4 heteroatoms; and t is 0, 1, 2, 3, or 4.

[0308] In some embodiments, L is optionally substituted C 1-3 In some embodiments, L is optionally substituted -CH-. 。In some embodiments, L is -CH2-. In some embodiments, L is an optionally substituted -(CH2)2-. In some embodiments, L is -(CH2)2-. In some embodiments, L is an optionally substituted -(CH2)3-. In some embodiments, L is -(CH2)3-.

[0309] In some embodiments, L is a L as described herein. 2 is.

[0310] L 2

[0311] In some embodiments, L 2 is an optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are optionally and independently selected from —O—, —S—, —C(R 4 )(R 5 )-, -N(R 4 )-, optionally substituted -CH=N-, optionally substituted -CH=CH- or -Cy-; R 4 and R 5 each independently represents R' as described herein; each -Cy- is independently

[0312] [ka]

[0313] wherein ring B is an optionally substituted saturated or partially saturated 3- to 10-membered ring having 0-4 heteroatoms; and t is 0, 1, 2, 3, or 4.

[0314] In some embodiments, L 2 is an optionally substituted C 1-3 In some embodiments, L is alkylene. 2 is an optionally substituted —CH—. In some embodiments, L 2is an optionally substituted —(CH2)2— 。 In some embodiments, L 2 is an optionally substituted —(CH)—. In some embodiments, L is —CH—. In some embodiments, L 2 is -(CH2)2-. In some embodiments, L 2 is -(CH2)3-.

[0315] In some embodiments, L 2 is an optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are independently replaced with -O-. In some embodiments, L 2 is an optionally substituted C 1‐3 alkylene, where one unit of the alkylene is replaced with -O-. In some embodiments, L 2 is optionally substituted

[0316] [ka]

[0317] In some embodiments, L 2 teeth,

[0318] [ka]

[0319] In some embodiments, L 2 is replaced

[0320] [ka]

[0321] In some embodiments, L 2 is optionally substituted

[0322] [ka]

[0323] In some embodiments, L 2 teeth

[0324] [ka]

[0325] In some embodiments, L 2 is replaced

[0326] [ka]

[0327] is.

[0328] In some embodiments, L 2 is an optionally substituted C 2-3 alkylene, where one unit of the alkylene is replaced by -O- and another unit of the alkylene is replaced by -C(R 4 )(R 5 )- and R 4 and R 5 are independently as described herein. In some embodiments, L 2 teeth

[0329] [ka]

[0330] where R 4 and R 5 are independently as described herein. In some embodiments, L 2 teeth

[0331] [ka]

[0332] In some embodiments, L 2 teeth

[0333] [ka]

[0334] In some embodiments, L 2 teeth

[0335] [ka]

[0336] In some embodiments, L 2 teeth

[0337] [ka]

[0338] In some embodiments, L 2 teeth

[0339] [ka]

[0340] In some embodiments, L 2 teeth

[0341] [ka]

[0342] In some embodiments, L 2 teeth

[0343] [ka]

[0344] In some embodiments, L 2 teeth

[0345] [ka]

[0346] In some embodiments, L 2 teeth

[0347] [ka]

[0348] In some embodiments, L 2 teeth

[0349] [ka]

[0350] In some embodiments, L 2 teeth

[0351] [ka]

[0352] In some embodiments, L 2 teeth

[0353] [ka]

[0354] In some embodiments, R 4 and R 5 taken together with the atoms to which they are attached form a ring, which may be optionally substituted as described herein.

[0355] In some embodiments, L 2 is an optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are independently replaced with -S-. 2 is an optionally substituted C 1-3 In some embodiments, L is an alkylene, wherein one methylene unit of the alkylene is replaced with -S-. 2 is optionally substituted

[0356] [ka]

[0357] In some embodiments, L 2 is replaced

[0358] [ka]

[0359] In some embodiments, L 2 teeth,

[0360] [ka]

[0361] In some embodiments, L 2 teeth,

[0362] [ka]

[0363] where R 4 and R 5 are independently as described herein. In some embodiments, R 4 and R 5each independently represents an optionally substituted C 1-6 For example, in some embodiments, R 4 and R 5 are each methyl.

[0364] In some embodiments, L 2 is an optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are independently —C(R 4 )(R 5 )- and R 4 and R 5 are independently as described herein. In some embodiments, R 4 and R 5 taken together with the carbon atoms to which they are attached form a ring, which may be optionally substituted as described herein. 2 is an optionally substituted C 1-3 alkylene, where one methylene unit of the alkylene is —C(R 4 )(R 5 )- and R 4 and R 5 are independently as described herein. In some embodiments, L 2 teeth

[0365] [ka]

[0366] is.

[0367] In some embodiments, L 2 is an optionally substituted C 1‐3 alkylene, wherein one or more methylene units of the alkylene are independently —N(R 4 )-, where R 4 is as described herein. In some embodiments, L 2is an optionally substituted C 1‐3 alkylene, where one methylene unit of the alkylene is —N(R 4 )-, where R 4 is as described herein. In some embodiments, L 2 is optionally substituted

[0368] [ka]

[0369] In some embodiments, L 2 is replaced

[0370] [ka]

[0371] In some embodiments, L 2 teeth,

[0372] [ka]

[0373] In some embodiments, L 2 teeth,

[0374] [ka]

[0375] In some embodiments, L 2 teeth

[0376] [ka]

[0377] and R 4 is C 1‐6In some embodiments, L 2 teeth

[0378] [ka]

[0379] In some embodiments, L 2 teeth

[0380] [ka]

[0381] and each variable is independently as described herein. In some embodiments, L 2 teeth

[0382] [ka]

[0383] In some embodiments, L 2 teeth

[0384] [ka]

[0385] In some embodiments, L 2 teeth

[0386] [ka]

[0387] is.

[0388] In some embodiments, L 2 is an optionally substituted C 1-3alkylene, wherein one or more methylene units of the alkylene are independently replaced with an optionally substituted —CH═N—. In some embodiments, L 2 is an optionally substituted C 1-3 In some embodiments, L is an alkylene, wherein one methylene unit of the alkylene is replaced with an optionally substituted —CH═N—. 2 is an optionally substituted C 1‐3 In some embodiments, L is an alkylene, wherein one methylene unit of the alkylene is replaced with -CH=N-. 2 is an optionally substituted —CH═N—. In some embodiments, L 2 is an optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are independently replaced with an optionally substituted —CH═CH—. In some embodiments, L 2 is an optionally substituted C 1‐3 In some embodiments, L is an alkylene, wherein one methylene unit of the alkylene is replaced with an optionally substituted —CH═CH—. 2 is an optionally substituted C 1‐3 alkylene, wherein one methylene unit of the alkylene is replaced with -CH=CH-. In some embodiments, L 2 is optionally substituted -CH=CH-. In some embodiments, L 2 is -CH=CH-.

[0389] In some embodiments, L 2 is an optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are independently replaced with -Cy-, where -Cy- is as described herein. 2 is an optionally substituted C 1-3alkylene, wherein one methylene unit of the alkylene is replaced with -Cy-, where -Cy- is as defined herein. 2 is -CH2-Cy-, where -CH2- is optionally substituted and -Cy- is as described herein. In some embodiments, two methylene units are independently replaced, one of which is replaced with -Cy-. In some embodiments, L 2 is -Cy-O-, where -Cy- is as defined herein.

[0390] -Cy-

[0391] As described herein, each -Cy- independently represents

[0392] [ka]

[0393] where ring B is ((R s ) in addition to t) is a saturated or partially saturated 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms, which may be optionally substituted (as would be understood by one of ordinary skill in the art). Ring B

[0394] Ring B can be a variety of ring moieties as described herein. In some embodiments, Ring B is (R s ) t In some embodiments, ring B is substituted with (R s ) tIn some embodiments, ring B is saturated. In some embodiments, ring B is partially unsaturated. In some embodiments, ring B is a 3- to 7-membered ring. In some embodiments, ring B is a 3-membered ring. In some embodiments, ring B is a 4-membered ring. In some embodiments, ring B is a 5-membered ring. In some embodiments, ring B is a 6-membered ring. In some embodiments, ring B is a 7-membered ring. In some embodiments, ring B is an 8-membered ring. In some embodiments, ring B is a 9-membered ring. In some embodiments, ring B is a 10-membered ring. In some embodiments, ring B is monocyclic. In some embodiments, ring B is bicyclic. In some embodiments, ring B is polycyclic. In some embodiments, each monocyclic unit is independently a 3- to 7-membered ring, e.g., a 3-, 4-, 5-, 6-, or 7-membered ring. In some embodiments, the ring does not contain heteroatoms. In some embodiments, the ring contains one heteroatom. In some embodiments, the ring contains two heteroatoms. In some embodiments, the ring contains three heteroatoms. In some embodiments, the ring contains four heteroatoms. In some embodiments, ring B is an optionally substituted saturated 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, ring B is an optionally substituted partially unsaturated 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, ring B is an optionally substituted saturated 3-7 membered ring having 0-4 heteroatoms. In some embodiments, ring B is an optionally substituted saturated 3-membered ring having no heteroatoms. In some embodiments, ring B is an optionally substituted saturated 3-membered ring having one heteroatom. In some embodiments, ring B is an optionally substituted saturated 4-membered ring having no heteroatoms. In some embodiments, Ring B is an optionally substituted saturated 4-membered ring having one heteroatom.In some embodiments, ring B is an optionally substituted saturated 5-membered ring having no heteroatoms. In some embodiments, ring B is an optionally substituted saturated 5-membered ring having one heteroatom. In some embodiments, ring B is an optionally substituted saturated 5-membered ring having two heteroatoms. In some embodiments, ring B is an optionally substituted saturated 6-membered ring having no heteroatoms. In some embodiments, ring B is an optionally substituted saturated 6-membered ring having one heteroatom. In some embodiments, ring B is an optionally substituted saturated 6-membered ring having two heteroatoms, wherein each variable is independently as described herein. In some embodiments, ring B is an optionally substituted saturated 7-membered ring having no heteroatoms. In some embodiments, ring B is an optionally substituted saturated 7-membered ring having one heteroatom. In some embodiments, ring B is an optionally substituted saturated 7-membered ring having two heteroatoms, wherein each variable is independently as described herein.

[0395] In some embodiments, the heteroatom is nitrogen. In some embodiments, the nitrogen atom is substituted. In some embodiments, the nitrogen atom is substituted with an R group as described herein. s In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur. In some embodiments, the sulfur atom is substituted (e.g., —S(O)—).

[0396] In some embodiments, Ring B is optionally substituted

[0397] [ka]

[0398] In some embodiments, ring B is optionally substituted

[0399] [ka]

[0400] In some embodiments, ring B is optionally substituted

[0401] [ka]

[0402] In some embodiments, ring B is optionally substituted

[0403] [ka]

[0404] In some embodiments, ring B is optionally substituted

[0405] [ka]

[0406] In some embodiments, ring B is optionally substituted

[0407] [ka]

[0408] In some embodiments, ring B is optionally substituted

[0409] [ka]

[0410] In some embodiments, ring B is optionally substituted

[0411] [ka]

[0412] In some embodiments, ring B is optionally substituted

[0413] [ka]

[0414] In some embodiments, ring B is optionally substituted

[0415] [ka]

[0416] In some embodiments, ring B is optionally substituted

[0417] [ka]

[0418] In some embodiments, ring B is optionally substituted

[0419] [ka]

[0420] In some embodiments, ring B is optionally substituted

[0421] [ka]

[0422] In some embodiments, ring B is optionally substituted

[0423] [ka]

[0424] In some embodiments, ring B is optionally substituted

[0425] [ka]

[0426] In some embodiments, ring B is optionally substituted

[0427] [ka]

[0428] In some embodiments, ring B is optionally substituted

[0429] [ka]

[0430] In some embodiments, ring B is optionally substituted

[0431] [ka]

[0432] is.

[0433] t

[0434] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0435] In some embodiments, -Cy- is attached to the rest of the molecule by a single atom. In some embodiments, -Cy- is spirocyclic. In some embodiments, -Cy- is

[0436] [ka]

[0437] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0438] [ka]

[0439] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0440] [ka]

[0441] where R s and each of t is independently as described herein.

[0442] In some embodiments, -Cy- is

[0443] [ka]

[0444] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0445] [ka]

[0446] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0447] [ka]

[0448] where R s and t are each independently as described herein.

[0449] In some embodiments, -Cy- is

[0450] [ka]

[0451] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0452] [ka]

[0453] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0454] [ka]

[0455] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0456] [ka]

[0457] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0458] [ka]

[0459] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0460] [ka]

[0461] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0462] [ka]

[0463] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0464] [ka]

[0465] where R sand t are each independently as described herein. In some embodiments, -Cy- is

[0466] [ka]

[0467] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0468] [ka]

[0469] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0470] [ka]

[0471] where R s and t are each independently as described herein. In some embodiments, -Cy- is

[0472] [ka]

[0473] where R s and t are each independently as described herein.

[0474] In some embodiments, the present disclosure provides:

[0475] [ka]

[0476] The present invention provides a compound having the structure:

[0477] In some embodiments, L 2 teeth

[0478] [ka]

[0479] and each variable is as described herein. In some embodiments, L 2 teeth

[0480] [ka]

[0481] and each variable is as described herein. In some embodiments, L 2 teeth

[0482] [ka]

[0483] and each variable is as described herein. In some embodiments, L 2 teeth

[0484] [ka]

[0485] In some embodiments, L 2 teeth

[0486] [ka]

[0487] In some embodiments, L 2 teeth

[0488] [ka]

[0489] In some embodiments, L 2 teeth

[0490] [ka]

[0491] In some embodiments, L 2 teeth

[0492] [ka]

[0493] In some embodiments, L 2 teeth

[0494] [ka]

[0495] In some embodiments, L 2 teeth

[0496] [ka]

[0497] In some embodiments, L 2 teeth

[0498] [ka]

[0499] In some embodiments, L 2 teeth

[0500] [ka]

[0501] In some embodiments, L 2 teeth

[0502] [ka]

[0503] In some embodiments, L 2 teeth

[0504] [ka]

[0505] In some embodiments, L 2 teeth

[0506] [ka]

[0507] In some embodiments, L 2 teeth

[0508] [ka]

[0509] In some embodiments, L 2 teeth

[0510] [ka]

[0511] In some embodiments, L 2 teeth

[0512] [ka]

[0513] In some embodiments, L 2 teeth

[0514] [ka]

[0515] In some embodiments, L 2 teeth

[0516] [ka]

[0517] In some embodiments, L 2 teeth

[0518] [ka]

[0519] In some embodiments, L 2 teeth

[0520] [ka]

[0521] In some embodiments, L 2 teeth

[0522] [ka]

[0523] In some embodiments, L 2 teeth

[0524] [ka]

[0525] In some embodiments, L 2 teeth

[0526] [ka]

[0527] In some embodiments, L 2 teeth

[0528] [ka]

[0529] In some embodiments, L 2 teeth

[0530] [ka]

[0531] In some embodiments, L 2 teeth

[0532] [ka]

[0533] In some embodiments, L 2 teeth

[0534] [ka]

[0535] is.

[0536] In some embodiments, L 2 teeth

[0537] [ka]

[0538] where each variable is as described herein. In some embodiments, L 2 teeth

[0539] [ka]

[0540] where each variable is as described herein. In some embodiments, L 2 teeth

[0541] [ka]

[0542] where each variable is as described herein. In some embodiments, L 2 teeth

[0543] [ka]

[0544] In some embodiments, L 2 teeth

[0545] [ka]

[0546] In some embodiments, L 2 teeth

[0547] [ka]

[0548] is.

[0549] In some embodiments, L 2 teeth

[0550] [ka]

[0551] where each variable is as described herein. In some embodiments, L 2 teeth,

[0552] [ka]

[0553] where each variable is as described herein. In some embodiments, L 2 teeth,

[0554] [ka]

[0555] where each variable is as described herein. In some embodiments, L 2 teeth,

[0556] [ka]

[0557] where each variable is as described herein. In some embodiments, L 2 teeth,

[0558] [ka]

[0559] where each variable is as described herein. In some embodiments, L2 teeth,

[0560] [ka]

[0561] In some embodiments, L 2 teeth,

[0562] [ka]

[0563] In some embodiments, L 2 teeth,

[0564] [ka]

[0565] In some embodiments, L 2 teeth,

[0566] [ka]

[0567] In some embodiments, L 2 teeth,

[0568] [ka]

[0569] In some embodiments, L 2 teeth,

[0570] [ka]

[0571] In some embodiments, L 2teeth,

[0572] [ka]

[0573] In some embodiments, L 2 teeth,

[0574] [ka]

[0575] In some embodiments, L 2 teeth,

[0576] [ka]

[0577] In some embodiments, L 2 teeth,

[0578] [ka]

[0579] In some embodiments, L 2 teeth,

[0580] [ka]

[0581] In some embodiments, L 2 teeth,

[0582] [ka]

[0583] In some embodiments, L 2 teeth,

[0584] [ka]

[0585] In some embodiments, L 2 teeth

[0586] [ka]

[0587] In some embodiments, L 2 teeth

[0588] [ka]

[0589] In some embodiments, L 2 teeth

[0590] [ka]

[0591] In some embodiments, L 2 teeth

[0592] [ka]

[0593] In some embodiments, L 2 teeth

[0594] [ka]

[0595] In some embodiments, L 2 teeth

[0596] [ka]

[0597] In some embodiments, L 2 teeth

[0598] [ka]

[0599] In some embodiments, L 2 teeth

[0600] [ka]

[0601] In some embodiments, L 2 teeth

[0602] [ka]

[0603] In some embodiments, L 2 teeth

[0604] [ka]

[0605] In some embodiments, L 2 teeth

[0606] [ka] In some embodiments, L 2 teeth

[0607] [ka]

[0608] In some embodiments, L 2 teeth

[0609] [ka]

[0610] In some embodiments, L 2 teeth

[0611] [ka]

[0612] In some embodiments, L 2 teeth

[0613] [ka]

[0614] In some embodiments, L 2 teeth

[0615] [ka] In some embodiments, L 2 teeth

[0616] [ka]

[0617] In some embodiments, L 2 teeth

[0618] [ka]

[0619] In some embodiments, L 2 teeth

[0620] [ka]

[0621] In some embodiments, L 2 teeth

[0622] [ka]

[0623] In some embodiments, L 2 teeth

[0624] [ka]

[0625] In some embodiments, L 2 teeth

[0626] [ka]

[0627] In some embodiments, L 2 teeth

[0628] [ka]

[0629] In some embodiments, L 2 teeth

[0630] [ka]

[0631] In some embodiments, L 2 teeth

[0632] [ka]

[0633] In some embodiments, L 2 teeth

[0634] [ka]

[0635] In some embodiments, L 2 teeth

[0636] [ka]

[0637] where each variable is as described herein.

[0638] In some embodiments, the present disclosure provides a compound having the following structure:

[0639] [ka]

[0640] or a salt thereof, wherein each variable is independently as described herein.

[0641] In some embodiments, the present disclosure provides a compound having the following structure:

[0642] [ka]

[0643] or a salt thereof, wherein each variable is independently as described herein.

[0644] In some embodiments, the present disclosure provides a compound having the following structure:

[0645] [ka]

[0646] or a salt thereof, wherein each variable is independently as described herein.

[0647] In some embodiments, the present disclosure provides a compound having the following structure:

[0648] [ka]

[0649] or a salt thereof, wherein each variable is independently as described herein.

[0650] In some embodiments, the present disclosure provides a compound having the following structure:

[0651] [ka]

[0652] or a salt thereof, wherein each variable is independently as described herein.

[0653] In some embodiments, the present disclosure provides a compound having the following structure:

[0654] [ka]

[0655] or a salt thereof, wherein each variable is independently as described herein.

[0656] In some embodiments, the present disclosure provides a compound having the following structure:

[0657] [ka]

[0658] or a salt thereof, wherein each variable is independently as described herein.

[0659] In some embodiments, the disclosure provides a compound having a structure selected below, or a salt thereof. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the compound may optionally be in the form of a solvate.

[0660] [Table 1-1]

[0661] [Table 1-2]

[0662] [Table 1-3]

[0663] [Table 1-4]

[0664] [Table 1-5]

[0665] [Table 1-6]

[0666] [Table 1-7]

[0667] Table 1-8

[0668] Table 1-9

[0669] Table 1-10

[0670] Table 1-11

[0671] Table 1-12

[0672] Table 1-13

[0673] Table 1-14

[0674] Table 1-15

[0675] Table 1-16

[0676] Table 1-17

[0677] Table 1-18

[0678] Table 1-19

[0679] Table 1-20

[0680] Table 1-21

[0681] Table 1-22

[0682] Table 1-23

[0683] Table 1-24

[0684] Table 1-25

[0685] Table 1-26

[0686] Table 1-27

[0687] [Table 1-28]

[0688] manufacturing industry

[0689] In some embodiments, the present disclosure provides various techniques for preparing the compounds and compositions described herein, e.g., reagents, intermediates, conditions, etc. One of skill in the art will recognize that many techniques are available and can be utilized in accordance with the present disclosure.

[0690] As will be appreciated by those skilled in the art, various groups, such as hydroxyl groups, amino groups, and carboxyl groups, can be protected in chemical reactions to avoid undesired reactions. Many techniques for protection / deprotection are available to those skilled in the art and can be utilized in accordance with the present disclosure. Some of these techniques are described herein and illustrated in the Examples.

[0691] Various chemical reactions are typically carried out in a solvent. In some embodiments, the reaction is carried out in a single solvent, such as DCM, THF, EtO, EtOH, toluene, etc. In some embodiments, the reaction is carried out in a mixture of two or more solvents. In some embodiments, the solvent is polar. In some embodiments, the solvent is non-polar. In some embodiments, the solvent is protic. In some embodiments, the solvent is aprotic. In some embodiments, the solvent is polar but not protic. Suitable solvents for various reactions are available to those of skill in the art and can be utilized in accordance with the present disclosure.

[0692] In some embodiments, the reaction is carried out under an inert atmosphere (e.g., N, Ar, etc.). In some embodiments, the reaction is carried out exposed to air. In some embodiments, the reaction is carried out under anhydrous conditions (e.g., with reagents, solvents, containers, etc., appropriately dried). In some embodiments, the reaction is carried out in the presence of a substantial amount of water (e.g., about 0.1 equivalent, 0.5 equivalents, or 1 equivalent or more).

[0693] In some embodiments, the reaction is carried out at a temperature, or for a period of time, that is above, below, or about standard ambient temperature (25° C.). In some embodiments, the reaction temperature is below standard ambient temperature. In some embodiments, the temperature is about or about −78° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10° C., 0° C., or 10° C. or lower. In some embodiments, the temperature is about 10° C. or lower. In some embodiments, the temperature is about 15° C. or lower. In some embodiments, the temperature is about 20° C. or lower. In some embodiments, the reaction temperature is about standard ambient temperature. In some embodiments, the reaction temperature is above standard ambient temperature. In some embodiments, the reaction temperature is about or at least about 35, 40, 50, 60, 70, 80, 90, 100, or 100° C. In some embodiments, the reaction involves refluxing in a boiling solvent system, such as ether, toluene, or the like. In some embodiments, the temperature is changed during the reaction process, for example, increasing from a lower temperature to a higher temperature, decreasing from a higher temperature to a lower temperature, or both.

[0694] In some embodiments, a product is produced preferentially over other potential products. In some embodiments, a product is produced with chemoselectivity, stereoselectivity, and / or regioselectivity. In some embodiments, selectivity is expressed, for example, as the ratio of one product to another. In some embodiments, the ratio is about or at least about 1.5:1, 2:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 200:1, 500:1, or more.

[0695] The reaction can be carried out for a variety of times. In some embodiments, the reaction is completed instantly. In some embodiments, the reaction time can vary from a few minutes to a few hours to a few days, e.g., 5, 10, 15, 20, 30, 45 minutes, or 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 20, or 22 hours, or one or more days. Those skilled in the art can determine when the reaction is complete using a variety of techniques based on the amount of starting material consumed, the amount of product produced, the amount of by-products produced, etc.

[0696] In some embodiments, the present disclosure provides compounds of high purity. In some embodiments, the purity of the compounds is about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9% or greater. In some embodiments, the purity of the compounds is about 80% or greater. In some embodiments, the purity of the compounds is about 85% or greater. In some embodiments, the purity of the compounds is about 90% or greater. In some embodiments, the purity of the compounds is about 95% or greater. In some embodiments, the purity of the compounds is about 96% or greater. In some embodiments, the purity of the compounds is about 97% or greater. In some embodiments, the purity of the compounds is about 98% or greater. In some embodiments, the purity of the compounds is about 99% or greater. In some embodiments, the purity of the compounds is about 99.5% or greater. In some embodiments, the purity of the compounds is about 99.7% or greater. In some embodiments, the purity of the compounds is about 99.9% or greater.

[0697] In some embodiments, the present disclosure provides compounds having high stereochemical purity. In some embodiments, the stereochemical purity of the compound is about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9% or greater. In some embodiments, the stereochemical purity of the compound is about 80% or greater. In some embodiments, the stereochemical purity of the compound is about 85% or greater. In some embodiments, the stereochemical purity of the compound is about 90% or greater. In some embodiments, the stereochemical purity of the compound is about 95% or greater. In some embodiments, the stereochemical purity of the compound is about 96% or greater. In some embodiments, the stereochemical purity of the compound is about 97% or greater. In some embodiments, the stereochemical purity of the compound is about 98% or greater. In some embodiments, the stereochemical purity of the compound is about 99% or greater. In some embodiments, the stereochemical purity of the compound is about 99.5% or greater. In some embodiments, the stereochemical purity of the compound is about 99.7% or greater. In some embodiments, the stereochemical purity of the compound is about 99.9% or greater.

[0698] In some embodiments, the present disclosure provides compounds having high enantiomeric purity. In some embodiments, the enantiomeric purity of the compound is about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9% or greater. In some embodiments, the enantiomeric purity of the compound is about 80% or greater. In some embodiments, the enantiomeric purity of the compound is about 85% or greater. In some embodiments, the enantiomeric purity of the compound is about 90% or greater. In some embodiments, the enantiomeric purity of the compound is about 95% or greater. In some embodiments, the enantiomeric purity of the compound is about 96% or greater. In some embodiments, the enantiomeric purity of the compound is about 97% or greater. In some embodiments, the enantiomeric purity of the compound is about 98% or greater. In some embodiments, the enantiomeric purity of the compound is about 99% or greater. In some embodiments, the enantiomeric purity of the compound is about 99.5% or greater. In some embodiments, the enantiomeric purity of the compound is about 99.7% or greater, hi some embodiments, the enantiomeric purity of the compound is about 99.9% or greater.

[0699] Stereochemically pure, e.g., enantiomerically pure, compounds and compositions can be prepared according to the present disclosure using a variety of techniques, for example, in some embodiments by separation, including chiral separation, and in some embodiments, by stereoselective synthesis.

[0700] In some embodiments, the method includes one or more steps as described below, where each variable is independently as described herein ("halo" is halogen). In some embodiments, the method is described below by way of example. In some embodiments, the disclosure provides a compound having a structure of a formula selected below, or a salt thereof.

[0701] [ka]

[0702] In some embodiments, the present disclosure provides a method for preparing a compound, such as a compound of Formula I or a salt thereof, e.g., a compound of Formula C or a salt thereof, comprising one or more or all of the steps exemplified above (wherein each variable is independently as described herein). In some embodiments, a compound having the structure of Formula (2) or a salt thereof is contacted with a halogen to obtain a compound having the structure of Formula (3) or a salt thereof. In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, the halogen is I. In some embodiments, a compound having the structure of Formula (3) or a salt thereof is reacted with a suitable compound, such as thiourea or a salt thereof, selenourea or a salt thereof, to obtain a compound having the structure of Formula (4) or a salt thereof. In some embodiments, the reaction from Formula (3) to Formula (4) is carried out in a solvent system including a protic solvent, such as an alcohol. In some embodiments, the reaction from Formula (3) to Formula (4) is carried out in methanol. In some embodiments, the reaction from (3) to (4) is carried out in ethanol. In some embodiments, the reaction of (3) to (4) is carried out or involves reacting at a temperature of about room temperature. In some embodiments, the reaction of (3) to (4) is carried out or involves reacting at a temperature of about 20-25°C. In some embodiments, the reaction of (3) to (4) is carried out or involves reacting at a temperature greater than about 25°C. In some embodiments, the reaction of (3) to (4) is carried out or involves reacting at a temperature of about 40°C or greater. In some embodiments, the reaction of (3) to (4) is carried out or involves reacting at about 40°C. In some embodiments, the reaction of (3) to (4) is carried out or involves reacting at a temperature between about 60°C and about 70°C, optionally with stirring. In some embodiments, the reaction of (3) to (4) is carried out or involves reacting at about 60°C. In some embodiments, the reaction is carried out or involves reacting at about 70°C. In some embodiments, the reaction is carried out or involves reacting at about 100°C.In some embodiments, the reaction from a compound of Formula (2) or a salt thereof to a compound of Formula (4) or a salt thereof is a one-pot reaction. In some embodiments, the method comprises contacting a compound of Formula (2) or a salt thereof with thiourea or a salt thereof and a halogenating reagent (e.g., a halogenating agent such as Br2, I2, etc.). In some embodiments, the method comprises contacting a compound of Formula (2) or a salt thereof with selenourea or a salt thereof and a halogenating reagent (e.g., a halogenating agent such as Br2, I2, etc.). As will be appreciated by those skilled in the art, many reactions are stirred or mixed. In some embodiments, a compound having the structure of Formula (4) or a salt thereof is used to obtain a compound having the structure of Formula (5) or a salt thereof. In some embodiments, the reaction from (4) to (5) is carried out in DCM. In some embodiments, the reaction from (4) to (5) is carried out in DMF. In some embodiments, the reaction from (4) to (5) is carried out or comprises reacting at a temperature about room temperature. In some embodiments, the reaction from (4) to (5) is carried out or comprises reacting at a temperature of about 20-25°C. In some embodiments, the reaction of (4) to (5) is carried out or includes reacting at a temperature above about 25° C. In some embodiments, the reaction of (4) to (5) is carried out or includes reacting at 40° C. or higher. In some embodiments, the reaction of (4) to (5) is carried out or includes reacting at about 40° C. In some embodiments, the reaction is carried out or includes reacting at about 60° C. In some embodiments, the reaction is carried out or includes reacting at about 70° C. In some embodiments, the reaction of (3) to (4) is carried out or includes reacting at about 60° C. to about 70° C., optionally with stirring. In some embodiments, R. 3 is —H, and the compound having the structure of formula (5) or a salt thereof is a compound having the structure of formula I or a salt thereof. In some embodiments, the compound having the structure of formula (5) or a salt thereof is a compound having the structure of formula R 3-LG (LG is a leaving group), or a salt thereof, to provide a compound having the structure of Formula I, or a salt thereof. A variety of leaving groups can be utilized in accordance with the present disclosure. For example, in some embodiments, the leaving group is a halogen. In some embodiments, LG is Cl. In some embodiments, LG is Br. In some embodiments, LG is I. In some embodiments, LG is -S(O)R, where R is as described herein and is not H. In some embodiments, R is an optionally substituted C 1‐6 It is aliphatic. In some embodiments, R is an optionally substituted phenyl. Many suitable conditions can be utilized in accordance with the present disclosure. For example, in some embodiments, the conditions are alkylation conditions. In some embodiments, the reaction is performed in the presence of a base. In some embodiments, the base is NaH. In some embodiments, the reaction of (5) to I is performed in DMF. In some embodiments, the reaction of (5) to I is performed in DMSO. In some embodiments, the reaction of (5) to I is performed in THF.

[0703] In some embodiments, a compound having the structure of Formula (1) or a salt thereof is contacted with a ketone or aldehyde to provide a compound having the structure of Formula (2) or a salt thereof.

[0704] [ka]

[0705] where R 4 ' is R as described herein 4 and each other variable is independently as described herein. In some embodiments, R 4 In some embodiments, R 4 ' is -SH.

[0706] In some embodiments, the present disclosure provides a method comprising: A compound having the structure of formula (5):

[0707] [ka]

[0708] or a salt thereof to provide a compound having the structure of Formula I:

[0709] [ka]

[0710] or a salt thereof, wherein each variable is independently as described herein.

[0711] In some embodiments, the method comprises reacting a compound having the structure of Formula (5) or a salt thereof with R 3 -L G or a salt thereof, to obtain a compound having the structure of Formula I, or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the contacting is performed under alkylating conditions. In some embodiments, the contacting is performed in the presence of a base.

[0712] In some embodiments, L in formula (5) 1 is —C(O)—, and L in formula I 1 is -CH-. In some embodiments, the method includes contacting a compound having the structure of Formula (5) or a salt thereof with a reducing agent to obtain a compound having the structure of Formula I or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reducing agent is LiAlH.

[0713] In some embodiments, the present disclosure provides a method comprising: A compound having the structure of formula (4):

[0714] [ka]

[0715] or a salt thereof to produce a compound having the structure of formula (5):

[0716] [ka]

[0717] or a salt thereof, wherein each variable is independently as described herein.

[0718] In some embodiments, the method comprises reacting a compound having the structure of Formula (4) or a salt thereof:

[0719] [ka]

[0720] or a salt or activated derivative thereof to obtain a compound having the structure of formula (5) or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the method comprises contacting a compound having the structure of formula (4) or a salt thereof with

[0721] [ka]

[0722] or a salt thereof to obtain a compound having the structure of formula (5) or a salt thereof, wherein each variable is independently as described herein. 1 is —C(O)—. In some embodiments, L 1 is -S(O)-. In some embodiments, -L 1-LG is an activated -COOH, e.g., -C(O)Cl. In some embodiments, LG is a halogen. In some embodiments, LG is -F. In some embodiments, LG is -Cl. In some embodiments, LG is -Br. In some embodiments, LG is or includes an optionally substituted heteroaryl. In some embodiments, the reaction of (4) to (5) is an amidation reaction. A variety of amidation techniques can be utilized in accordance with the present disclosure, including activated carboxylic acid derivatives. In some embodiments, the contacting is performed in the presence of a condensing agent (e.g., EFC). In some embodiments, a reagent can facilitate the reaction, e.g., DMAP is present. In some embodiments, the contacting is performed in the presence of a base (e.g., TEA) to neutralize the acid.

[0723] In some embodiments, the present disclosure provides a method comprising: A compound having the structure of formula (3):

[0724] [ka]

[0725] or a salt thereof to produce a compound having the structure of formula (4):

[0726] [ka]

[0727] or a salt thereof, wherein each variable is independently as described herein.

[0728] In some embodiments, the method comprises contacting a compound having the structure of Formula (3) or a salt thereof with thiourea or a salt thereof to obtain a compound having the structure of Formula (4) or a salt thereof. In some embodiments, the method comprises contacting a compound having the structure of Formula (3) or a salt thereof with selenourea or a salt thereof to obtain a compound having the structure of Formula (4) or a salt thereof. In some embodiments, the contacting occurs at about room temperature, e.g., about 25°C. In some embodiments, the contacting occurs at an elevated temperature, e.g., about 100°C. In some embodiments, the contacting occurs at two different temperatures, e.g., first at about room temperature for a period of time and then at an elevated temperature, e.g., about 100°C for a period of time.

[0729] In some embodiments, the present disclosure provides a method comprising: A compound having the structure of formula (2):

[0730] [ka]

[0731] or a salt thereof to produce a compound having the structure of formula (3):

[0732] [ka]

[0733] or a salt thereof, wherein each variable is independently as described herein.

[0734] In some embodiments, the method includes contacting a compound having the structure of Formula (2) or a salt thereof with a halogenating reagent (e.g., a halogenating agent such as Br2, I2, etc.).

[0735] In some embodiments, the present disclosure provides a method comprising: A compound having the structure of formula (2):

[0736] [ka]

[0737] or a salt thereof to produce a compound having the structure of formula (4):

[0738] [ka]

[0739] or a salt thereof, wherein each variable is independently as described herein.

[0740] In some embodiments, the method includes contacting a compound having the structure of Formula (2) or a salt thereof with thiourea or a salt thereof and a halogenating agent (e.g., iodine) to obtain a compound having the structure of Formula (4) or a salt thereof. In some embodiments, the method includes contacting a compound having the structure of Formula (2) or a salt thereof with selenourea or a salt thereof and a halogenating agent (e.g., iodine) to obtain a compound having the structure of Formula (4) or a salt thereof.

[0741] In some embodiments, the present disclosure provides a method comprising: A compound having the structure of formula (1):

[0742] [ka]

[0743] or a salt thereof to produce a compound having the structure of formula (2):

[0744] [ka]

[0745] or a salt thereof, wherein each variable is independently as described herein.

[0746] In some embodiments, the method comprises reacting a compound having the structure of Formula (I) or a salt thereof with R 4 C(O)R 5 or a salt thereof, wherein R 4 and R 5 are each independently as described herein. In some embodiments, R 4 and R 5 In some embodiments, either one of R 4 is R as described herein. In some embodiments, R 4 is —H. In some embodiments, R 4 is not —H. In some embodiments, R 5 is R as described herein. In some embodiments, R 5 is —H. In some embodiments, R 5 is not —H. In some embodiments, R 4 is -H, not R 5 is not —H. In some embodiments, R 4 and R 5 taken together with the carbon atoms to which they are attached form a ring, which may be optionally substituted as described herein. In some embodiments, the method comprises reacting a compound having the structure of formula (I) or a salt thereof with

[0747] [ka]

[0748] wherein each variable is independently as described herein. In some embodiments, =0 is part of a ketone group. In some embodiments, the contacting is performed in the presence of a base, for example, pyrrolidine.

[0749] TRPV3

[0750] Transient receptor potential vanilloid 3 (TRPV3) has been reported to be a nonselective cation channel that is relatively permeable to calcium. In addition to calcium ions, TRPV3 channels have also been reported to be permeable to other cations, such as sodium. Various reports have suggested that TRPV3 channels regulate membrane potential by regulating the flux of cations, such as calcium and sodium ions. Nonselective cation channels, such as TRPV3, specifically regulate calcium ion flux, but in some cases, their mechanism is reported to differ from that of voltage-gated calcium channels. For example, voltage-gated calcium channels have been reported to open in response to membrane depolarization, allowing calcium influx from the extracellular medium, potentially resulting in an increase in intracellular calcium levels or concentrations. Some reports have suggested that TRP channels, which are nonselective cation channels, are signal-transmitting-dependent, at least in some cases, and exhibit longer-lasting, more persistent changes in ion concentration. These mechanistic differences have also been reported to be accompanied by structural differences between voltage-gated and TRP channels. Various channels have been reported to regulate ion flux and membrane potential in various cell types and in response to various stimuli. Significant structural, functional, and / or mechanistic differences have been reported between different classes of ion channels.

[0751] use

[0752] Chronic itch and scratching, a common symptom of various forms of dermatitis, such as senile xerosis and atopic dermatitis (AD), have been reported to affect millions of people worldwide and significantly impact quality of life. In some embodiments, transient receptor potential (TRP) channels have been reported or suggested to play an important role in the perception of pain and itch. In some embodiments, the present disclosure provides techniques for preventing or treating itch. In some embodiments, the present disclosure provides techniques for preventing or treating itch. In some embodiments, the present disclosure provides techniques for preventing or treating pain.

[0753] According to several reports, TRP channels are a family of nonselective cation channels that function as sensors for various physical and chemical stimuli. Among them, the vanilloid TRP (TRPV) subfamily is reported to consist of six members (TRPV1-TRPV6), four of which (TRPV1-TRPV4) are reported to be heat-activated and are therefore sometimes classified as thermal TRP channels. TRPV3 is reported to be a calcium-permeable, nonselective cation channel that responds to moderate temperatures (approximately 33°C) and chemical stimuli such as synthetic small molecules (e.g., 2-aminoethoxydiphenylborate, 2-APB) and certain natural compounds (e.g., camphor). TRPV3 is primarily expressed in epidermal and hair follicle keratinocytes and has been reported to play an important role in many aspects of skin function, including pain and itch sensation, skin barrier formation, and hair growth. TRPV3 has also been reported to be localized in non-neuronal tissues, such as the skin. In some embodiments, the present disclosure provides therapeutic approaches for treating diseases that impair the skin barrier, and in some cases, pharmacological modulation techniques for TRPV3 provide additional benefits for conditions other than pain. For example, TRPV3 has been reported to be involved in the development of dry skin pruritus, various forms of dermatitis (e.g., atopic dermatitis, rosacea), and hair growth disorders. In some embodiments, a series of pathogenic mutations in TRPV3, including G573S, G573C, W692G, and G568V, have been reported to be associated with Olmsted syndrome (OS), a rare congenital disorder characterized by alopecia, keratotic plaque formation, and severe pruritus. This may be due to overactivity of the mutant channel in response to various stimuli. Some reports suggest that TRPV3, in contrast to certain other thermal TRP channels, may be sensitized rather than desensitized after repeated stimulation. In some embodiments, the present disclosure provides techniques for inhibiting TRPV3 activity or alleviating TRPV3-related conditions, disorders, or diseases. In some embodiments, compounds capable of modulating one or more functions of TRPV3 provide therapeutic benefit in the treatment of various conditions, disorders, or diseases, including skin conditions, disorders, or diseases.

[0754] In certain embodiments, the present disclosure provides methods for preventing a condition, disorder, or disease, comprising administering an effective amount of a provided compound or composition to a subject susceptible thereto. In certain embodiments, the present disclosure provides methods for treating a condition, disorder, or disease, comprising administering an effective amount of a provided compound or composition to a subject suffering from the condition. In certain embodiments, the present disclosure provides methods for preventing a condition, disorder, or disease, comprising delivering an effective amount of a provided compound or composition to a subject susceptible to the condition. In certain embodiments, the present disclosure provides methods for treating a condition, disorder, or disease, comprising delivering an effective amount of a provided compound or composition to a subject suffering from the condition. In some embodiments, the techniques comprise administering or delivering an effective amount of a provided compound or pharmaceutical composition described herein to a subject suffering from a condition, disorder, or disease, such as itch, pain, etc. In some embodiments, the subject is suffering from itch. In some embodiments, the subject is suffering from chronic itch. In some embodiments, the subject is suffering from pain. In some embodiments, the subject has or has been diagnosed with dermatitis. In some embodiments, the dermatitis is or includes senile xerosis. In some embodiments, the dermatitis is or includes atopic dermatitis. In some embodiments, the condition, disorder, or disease inhibits skin barrier formation. In some embodiments, the condition, disorder, or disease is or includes delayed or abnormal hair growth. In some embodiments, the condition, disorder, or disease is or includes a hair growth disorder. In some embodiments, the condition, disorder, or disease is or includes dry skin pruritus. In some embodiments, the condition, disorder, or disease is or includes rosacea. In some embodiments, the condition, disorder, or disease is or includes Olmsted syndrome. In some embodiments, the condition, disorder, or disease is or includes a congenital condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is or includes alopecia.In some embodiments, the condition, disorder, or disease is or comprises keratinous plaque formation. In some embodiments, the condition, disorder, or disease is or comprises severe itch. In some embodiments, the condition, disorder, or disease is or comprises a skin condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is or comprises migraine, joint pain, cardiac pain due to ischemic myocardium, acute pain, chronic pain, nociceptive pain, neuropathic pain, post-surgical pain, neuralgia (e.g., post-herpetic neuralgia, traumatic neuralgia, fibromyalgia, trigeminal neuralgia), diabetic neuropathy pain, dental pain, cancer pain, or inflammatory pain conditions (e.g., arthritis and osteoarthritis).

[0755] In some embodiments, the condition, disorder or disease is neuropathic pain, nociceptive pain, dental pain, HIV pain, cardiac pain due to ischemic myocardium, migraine pain, joint pain, neuropathy, neurodegeneration, retinopathy, neurocutaneous disorders, stroke, bladder overload, urinary incontinence, vulvodynia, gastrointestinal disorders such as irritable bowel syndrome, gastroesophageal reflux disease, enteritis, ileitis, gastroduodenal ulcers, inflammatory bowel disease, inflammatory diseases such as Crohn's disease, celiac disease, pancreatitis, allergic and non-allergic rhinitis. , respiratory diseases such as asthma or chronic obstructive pulmonary disease, inflammation of the skin, eyes or mucous membranes, atopic dermatitis, eczema, itching, fever, muscle spasms, vomiting, dyskinesia, depression, Huntington's disease, memory impairment, limited brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, hives, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis, anxiety disorder, or benign prostatic hyperplasia.

[0756] In some embodiments, the condition, disorder, or disease is or involves hair loss. In some embodiments, the condition, disorder, or disease is hair loss.

[0757] In some embodiments, the condition, disorder, or disease is or comprises keratosis. In some embodiments, the condition, disorder, or disease is keratosis.

[0758] In some embodiments, the condition, disorder or disease is or includes atopic dermatitis, eczema, seborrheic eczema, pruritus, dermatitis, or psoriasis.

[0759] In some embodiments, the condition, disorder, or disease is pain. In some embodiments, the condition, disorder, or disease is itch. In some embodiments, the condition, disorder, or disease is dermatitis.

[0760] In some embodiments, the condition, disorder, or disease is or comprises acne, hi some embodiments, the condition, disorder, or disease is or comprises rosacea.

[0761] In some embodiments, the condition, disorder, or disease is a condition, disorder, or disease associated with TRPV3. In some embodiments, the condition, disorder, or disease is associated with TRPV3. In some embodiments, the condition, disorder, or disease is associated with activation of TRPV3. In some embodiments, the condition, disorder, or disease is regulated by TRPV3.

[0762] In certain embodiments, the compounds described herein can be used in combination with other therapeutic agents as a combination therapy to prevent or treat a condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is associated with TRPV3 activation. In some embodiments, the other therapeutic agent administered or delivered to a subject can activate TRPV3. In some embodiments, provided compounds can alleviate a condition, disorder, or disease associated with TRPV3 activation. In some embodiments, the condition, disorder, or disease is or includes concurrent TRPV3-associated itch.

[0763] In certain embodiments, the present disclosure provides methods for modulating TRPV3 activity, comprising contacting TRPV3 with an effective amount of a compound or pharmaceutical composition described herein.

[0764] In certain embodiments, the present invention provides a method for modulating TRPV3 activity in a system comprising TRPV3, the method comprising administering or delivering to the system an effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the present invention provides a method for modulating skin function in a system comprising TRPV3, the method comprising administering or delivering to the system an effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the skin function is or comprises pain sensation. In some embodiments, the skin function is or comprises pruritus. In some embodiments, the skin function is or comprises skin barrier formation. In some embodiments, the skin function is or comprises hair growth.

[0765] In some embodiments, the system is or comprises a cell. In some embodiments, the system is or comprises a tissue. In some embodiments, the system is or comprises an organ. In some embodiments, the system is or comprises an organism. In some embodiments, the system is a subject. In some embodiments, the system is an animal. In some embodiments, the system is a human. In some embodiments, the system expresses TRPV3. In some embodiments, the system is or comprises skin. In some embodiments, the system is or comprises a non-neuronal cell or tissue. In some embodiments, the system is or comprises epidermal keratinocytes. In some embodiments, the system is or comprises a hair follicle. In some embodiments, the method reduces TRPV3 activity levels compared to the absence of a provided compound. In some embodiments, the reduction / decrease is about or at least about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

[0766] In some embodiments, the methods increase TRPV3 activity levels compared to the absence of a provided compound, hi some embodiments, the increase is about or at least about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

[0767] In some embodiments, the compound is administered or delivered in the form of a pharmaceutically acceptable salt. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, a prodrug of a provided compound can be administered to deliver the compound.

[0768] In some embodiments, the compound is utilized in racemic form. In some embodiments, the composition is a stereorandom mixture of multiple stereoisomers. For example, in some embodiments, the composition is a stereorandom mixture of two enantiomers. In some embodiments, the compound is utilized in a stereochemically pure form as described herein. In some embodiments, the compound is utilized in an enantiomerically pure form. In some embodiments, the composition is enriched in one or more stereoisomers over others as described herein. In some embodiments, the composition is enriched in one enantiomer as described herein. In some embodiments, the composition is stereochemically pure. In some embodiments, the composition is enantiomerically pure.

[0769] In some embodiments, provided compounds are administered or delivered simultaneously with other therapeutic agents. In some embodiments, provided compounds are administered or delivered in a single composition with other therapeutic agents. In some embodiments, provided compounds are administered or delivered simultaneously with other therapeutic agents but in different compositions. In some embodiments, provided compounds are administered or delivered prior to other therapeutic agents (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months before the other therapeutic agents). In some embodiments, provided compounds are administered or delivered after the other therapeutic agent (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 1, 2, 3, 4, or 5 weeks, or about 1, 2, 3, 4, or 5 months after the other therapeutic agent). In some embodiments, provided compounds are administered or delivered while the subject is receiving the therapeutic effect of the other therapeutic agent.

[0770] In some embodiments, the subject is an adult patient. In some embodiments, the subject is a pediatric patient.

[0771] Certain conditions, disorders or diseases, methods and uses are described in WO2016 / 160938.

[0772] Pharmaceutical Composition

[0773] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a provided compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition capable of delivering a provided compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0774] Various techniques, such as routes of administration, methods of administration, and dosage regimens, can be utilized to administer and / or deliver the compounds and compositions provided in accordance with the present disclosure. In some embodiments, the route and / or method of administration can vary depending on the desired outcome. Those skilled in the art, i.e., physicians, know that they can adjust dosage regimens to achieve a desired response, e.g., a therapeutic response. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intrathecal, intravaginal, transdermal, rectal, inhalation, or topical, particularly to the ear, nose, eye, or skin. In some embodiments, the method of administration is left to the discretion of the physician. For example, in some embodiments, the compound or composition is administered orally. In some embodiments, the compound or composition is administered or delivered topically.

[0775] In some embodiments, the compound can be administered in a pharmaceutical composition. Such pharmaceutical compositions are useful, inter alia, for administration and delivery to a subject in vivo or ex vivo. In some embodiments, the pharmaceutical composition also includes a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier is an agent that does not induce a harmful immune response in the individual receiving the composition and can be administered without undue toxicity. Pharmaceutically acceptable carriers (or excipients) include, but are not limited to, liquids such as water, saline, glycerol, sugars, ethanol, and the like. Additionally, auxiliary substances, such as wetting agents, emulsifying agents, pH buffering agents, and the like, may be present in such vehicles.

[0776] The compound in the pharmaceutical composition may be provided as a pharmaceutically acceptable salt. In some embodiments, the salt may be formed with an acid such as hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, or benzenesulfonic acid. In some embodiments, the salt may be formed with a base. In some embodiments, the salt may be an alkali metal, alkaline earth metal, or ammonium salt, such as sodium, calcium, diethanolamine, ethanolamine, or trialkylamine salt.

[0777] In some embodiments, salts are more soluble in aqueous or other protic solvents than the corresponding free acid or base forms. In some embodiments, the pharmaceutical composition may be a lyophilized powder. In some embodiments, the pharmaceutical composition comprises a provided compound, e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof, dissolved in a pharmaceutically acceptable buffer. In some embodiments, the buffer is a saline buffer. In some embodiments, the pH of the buffer is about 7.4.

[0778] Pharmaceutical compositions can include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonicity agents, and absorption enhancers or delayers compatible with pharmaceutical administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions, and suspensions may also include suspending agents and thickening agents. In some embodiments, the pharmaceutical composition or formulation is a tablet (coated or uncoated), capsule (hard or soft), microbead, powder, granule, and / or crystal. Supplementary active compounds (e.g., preservatives, antibacterial agents, antiviral agents, antifungal agents) can also be incorporated into the pharmaceutical composition.

[0779] Pharmaceutical compositions can be formulated to be compatible with a particular route of administration or delivery as described herein or known to those of skill in the art.

[0780] In some embodiments, the compositions provided are suitable for parenteral delivery. In some embodiments, such compositions include aqueous and non-aqueous solutions, suspensions, or emulsions of the active compound, which are usually sterile and can be isotonic with the subject's blood. Examples include water, buffered saline, Hank's solution, Ringer's solution, dextrose, fructose, ethanol, animal oils, vegetable oils, or synthetic oils. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Additionally, suspensions of the active compound may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or excipients include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Optionally, the suspension may also contain suitable stabilizers or agents that increase solubility, allowing for the preparation of highly concentrated solutions.

[0781] Cosolvents and adjuvants can be added to the compositions and formulations. Non-limiting examples of cosolvents include those having a hydroxyl group or other polar group, such as alcohols such as isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, etc. Examples of adjuvants include surfactants such as soybean lecithin and oleic acid, sorbitan esters such as sorbitan trioleate, polyvinylpyrrolidone, etc.

[0782] After the pharmaceutical composition has been prepared, it is filled into an appropriate container and labeled according to the intended therapeutic purpose, including dosage, frequency, and method of administration.

[0783] A variety of pharmaceutical composition techniques and delivery systems suitable for the compositions, methods and uses of the present disclosure are available (see, e.g., Remington: The Science and Practice of Pharmacy. 23 rdEdition., Academic Press, 2020), may be utilized in accordance with this disclosure.

[0784] In some embodiments, the present disclosure provides methods for delivering provided compounds and compositions to cells, animals, or subjects. In some embodiments, such methods include contacting a provided compound, such as a compound of Formula I or a salt thereof, or a composition thereof, with a subject (e.g., a cell or tissue of a subject) or administering or delivering the compound to a subject (e.g., a subject such as a mammal or human).

[0785] The compounds or compositions described herein can be administered in a sufficient or effective amount to a subject (or to cells, tissues, or organs thereof) in need thereof. Dosages vary and may depend on the type, onset, progression, severity, frequency, duration, or probability of the condition, disorder, or disease being treated, the desired clinical endpoint, previous or concurrent treatments, the subject's general health, age, sex, race, or immunological competence, and other factors understood by those skilled in the art. Dosage, number, frequency, or duration of administration may be proportionally increased or decreased as indicated by the effectiveness of the treatment or therapy, side effects, complications, or other risk factors, and the condition of the subject. Those skilled in the art will understand the factors that may affect the dosage and timing necessary to provide an amount sufficient to produce a therapeutic or prophylactic effect.

[0786] The dosage to achieve a therapeutic effect will vary depending on several factors, including the route of administration, the amount to achieve a therapeutic effect, the particular condition, disorder or disease being treated, the host's immune response to the administered compound or composition, and the stability of the administered compound or composition.

[0787] An effective or sufficient amount may be administered in a single dose or may require multiple doses, and may be administered alone or in combination with other compositions (e.g., compositions containing or delivering other therapeutic agents). For example, dosages may be proportionally increased depending on the needs of the subject, the type, condition, and severity of the condition, disorder, or disease being treated, and / or the side effects of treatment, if any. An amount considered effective also includes an amount that results in the reduced use of other therapies, treatment regimens, or treatment protocols.

[0788] In some embodiments, the pharmaceutical composition contains or delivers an effective amount of an active ingredient, e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof, to achieve its intended purpose, e.g., a therapeutic purpose. Various techniques are available for determining a therapeutically effective amount in accordance with the present disclosure. The therapeutic dose may depend, among other factors, on the subject's age and general condition, the severity of the condition, disorder, or disease, etc. In some embodiments, the therapeutically effective amount in humans may fall within a relatively broad range that can be determined by a physician based on the response of an individual patient.

[0789] In some embodiments, the methods and uses of the present disclosure include systemic, local, or topical delivery and administration, or any route, such as injection, infusion, or oral. In some embodiments, in vivo delivery of pharmaceutical compositions can generally be achieved by injection using a conventional syringe, although other delivery methods, such as convection-enhanced delivery, can also be used. In some embodiments, compounds and compositions can be delivered subcutaneously, epidermally, intradermally, intrathecally, intraorbitally, intramucosally, intraperitoneally, intravenously, intrapleurally, intraarterially, orally, intrahepatically, via the portal vein, or intramuscularly. In some embodiments, modes of administration include oral delivery and pulmonary administration, suppositories, and transdermal administration. A clinician skilled in treating a patient can determine the optimal route of administration for the compounds and compositions described herein.

[0790] Among other things, the present disclosure provides the following embodiments: 1. The compound has the structure of Formula I:

[0791] [ka]

[0792] or a salt thereof, wherein Ring A is an optionally substituted 5- or 6-membered aromatic ring having 0 to 4 heteroatoms, or

[0793] [ka]

[0794] and X 1 , X 2a , X 2b , and X 2c are independently -N=, -C(R 2 )=, or optionally substituted —CH=; X 1a is —O—, —S—, —N(R′)—, —C(R′)—, or optionally substituted —CH— or —NH—; X 3 is —O—, —S—, —Se—, —N(R′)—, or optionally substituted —NH—; X 4 , X 5 , X 6 , X 7 and X 8 are independently -N=, -C(R 6 )=, or optionally substituted —CH=; R 1 , R 2 , R s and R 6 are each independently halogen, —CN, —NO2, —L-R', —OR', —N(R')2, —N(R')C(O)OR', —C(O)R', —C(O)OR', —C(O)N(R')2, or —OC(O)N(R')2; L1 is a covalent bond, -C(O)-, -C(S)-, -S(O)2-, -N(R')C(O)-, -N(R')S(O)2-, -N(R')C(S)-, or

[0795] [ka]

[0796] and R 3 , R 4 and R 5 are each independently R'; L and L 2 each independently represents an optionally substituted C 1‐3 alkylene, wherein one or more methylene units of the alkylene are optionally and independently selected from —O—, —S—, —C(R 4 )(R 5 )-, -N(R 4 )-, optionally substituted -CH=N-, optionally substituted -CH=CH- or -Cy-; Each -Cy- is independently

[0797] [ka]

[0798] wherein ring B is an optionally substituted saturated or partially saturated 3- to 10-membered ring having 0 to 4 heteroatoms; t is 0, 1, 2, 3, or 4; each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)R; Each R is independently hydrogen or C-C 10 Aliphatic, C1-C with 1-3 heteroatoms 10Heteroaliphatic, 3-10-membered cyclic aliphatic, 3-10-membered heterocyclyl having 1-4 heteroatoms, 6-10-membered aryl, 5-10-membered heteroaryl having 1-6 heteroatoms, 6-10-membered aryl-C-C 10 Aliphatic and 5-10 membered heteroaryl-C1-C having 1-6 heteroatoms 10 an optionally substituted group selected from aliphatic, or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3- to 10-membered ring having, in addition to the atom, 0-4 heteroatoms; or A compound characterized in that two R groups on two atoms optionally and independently combine with the intervening atom to form an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atom. 2. The compound is

[0799] [ka]

[0800] or a salt or activated derivative thereof, wherein ring A is as defined in embodiment 1. 3. The compound is

[0801] [ka]

[0802] 3. The compound of embodiment 2, wherein the compound has the structure: 4. The compound is

[0803] [ka]

[0804] or a salt thereof, wherein rings A and L 1are independently as defined in embodiment 1, and LG is a leaving group. 5. The compound according to any one of embodiments 1 to 4, wherein ring A is optionally substituted phenyl. 6. The compound according to any one of embodiments 1 to 4, wherein ring A is phenyl. 7. The compound according to any one of embodiments 1 to 4, wherein ring A is an optionally substituted 5-6 membered heteroaryl ring having 1, 2, 3, or 4 heteroatoms. 8. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 5-membered heteroaryl ring having 1, 2, 3, or 4 heteroatoms. 9. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 5-membered heteroaryl ring having 1 or 2 heteroatoms. 10. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 5-membered heteroaryl ring having two heteroatoms. 11. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 5-membered heteroaryl ring having two nitrogen atoms. 12. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 6-membered heteroaryl ring having 1, 2, 3, or 4 heteroatoms. 13. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 6-membered heteroaryl ring having 1, 2, or 3 heteroatoms. 14. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 6-membered heteroaryl ring having 1 or 2 heteroatoms. 15. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 6-membered heteroaryl ring having two heteroatoms. 16. The compound according to any one of embodiments 1-4, wherein ring A is an optionally substituted 6-membered heteroaryl ring having two nitrogen atoms. 17. Ring A

[0805] [ka]

[0806] The compound of any one of embodiments 1 to 4, wherein: 18. Ring A

[0807] [ka]

[0808] 18. The compound of embodiment 17, wherein 19. Ring A

[0809] [ka]

[0810] 19. The compound of embodiment 17 or 18, wherein 20. Ring A

[0811] [ka]

[0812] 20. The compound of any one of embodiments 17-19, wherein: 21. Ring A

[0813] [ka]

[0814] 21. The compound of any one of embodiments 17-20, wherein 22. Ring A

[0815] [ka]

[0816] 22. The compound of any one of embodiments 17-21, wherein: 23. Ring A

[0817] [ka]

[0818] 21. The compound of any one of embodiments 17-20, wherein 24. Ring A

[0819] [ka]

[0820] 21. The compound of any one of embodiments 17-20, wherein 25. Ring A

[0821] [ka]

[0822] 21. The compound of any one of embodiments 17-20, wherein 26. Ring A

[0823] [ka]

[0824] 21. The compound of any one of embodiments 17-20, wherein 27. Ring A

[0825] [ka]

[0826] 21. The compound of any one of embodiments 17-20, wherein 28. Ring A

[0827] [ka]

[0828] 21. The compound of any one of embodiments 17-20, wherein 29. Ring A

[0829] [ka]

[0830] 18. The compound of embodiment 17, wherein 30. Ring A

[0831] [ka]

[0832] 30. The compound of embodiment 29, wherein 31. Ring A

[0833] [ka]

[0834] The compound of any one of embodiments 29-30, wherein 32. Ring A

[0835] [ka]

[0836] The compound of any one of embodiments 29-31, wherein 33. Ring A

[0837] [ka]

[0838] The compound of any one of embodiments 29-32, wherein 34. Ring A

[0839] [ka]

[0840] The compound of any one of embodiments 29-31, wherein 35. Ring A

[0841] [ka]

[0842] The compound of any one of embodiments 29-31, wherein 36. Ring A

[0843] [ka]

[0844] The compound of any one of embodiments 29-31, wherein 37. Ring A

[0845] [ka]

[0846] The compound of any one of embodiments 29-31, wherein 38. Ring A

[0847] [ka]

[0848] 18. The compound of embodiment 17, wherein 39. Ring A

[0849] [ka]

[0850] 39. The compound of embodiment 38, wherein 40. Ring A

[0851] [ka]

[0852] 40. The compound of any one of embodiments 38-39, wherein: 41. Ring A

[0853] [ka]

[0854] The compound of any one of embodiments 38-40, wherein 42. Ring A

[0855] [ka]

[0856] 18. The compound of embodiment 17, wherein 43. Ring A

[0857] [ka]

[0858] 43. The compound of embodiment 42, wherein 44. Ring A

[0859] [ka]

[0860] 44. The compound of any one of embodiments 42-43, wherein: 45. Ring A

[0861] [ka]

[0862] 45. The compound of any one of embodiments 42-44, wherein: 46. ​​Ring A

[0863] [ka]

[0864] The compound of any one of embodiments 1 to 4, wherein: 47. Ring A

[0865] [ka]

[0866] 47. The compound of embodiment 46, wherein 48. Ring A

[0867] [ka]

[0868] 48. The compound of any one of embodiments 46-47, wherein: 49. Ring A

[0869] [ka]

[0870] 49. The compound of any one of embodiments 46-48, wherein 50. Ring A

[0871] [ka]

[0872] 50. The compound of any one of embodiments 46-49, wherein: 51. Ring A

[0873] [ka]

[0874] The compound of any one of embodiments 46-50, wherein 52. Ring A

[0875] [ka]

[0876] 50. The compound of any one of embodiments 46-49, wherein: 53. Ring A

[0877] [ka]

[0878] 53. The compound of any one of embodiments 46-52, wherein 54. Ring A

[0879] [ka]

[0880] and R 1 and R 2 The compound of any one of embodiments 46-47, wherein each of is independently an optionally substituted C1-C6 alkyl. 55. Ring A

[0881] [ka]

[0882] and R 1 and R 2 The compound of any one of embodiments 46-47, wherein each of is independently an optionally substituted C1-C6 alkyl. 56. Ring A

[0883] [ka]

[0884] 48. The compound of any one of embodiments 46-47, wherein: 57. The compound is

[0885] [ka]

[0886] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 58. The compound is

[0887] [ka]

[0888] or a salt thereof, wherein halo is halogen and each other variable is independently as described in any one of the preceding embodiments. 59. The compound is

[0889] [ka]

[0890] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 60. The compound of embodiment 58, wherein halo is -Cl. 61. The compound of embodiment 58, wherein halo is -Br. 62. The compound of embodiment 58, wherein halo is -I. 63.X 1 The compound of any one of embodiments 1-4, 17, and 46, wherein is -N=. 64.X 1 -C(R 2 )=. 65.X 1 The compound of any one of embodiments 1-4, 17, and 46, wherein is optionally substituted —CH═. 66.X 1 The compound of any one of embodiments 1-4, 17, and 46, wherein is -CH=. 67.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is -N=. 68.X 2a -C(R 2 )=. 69.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is -C(OR')=. 70.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is —C(OH)═. 71.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is -C(OR')= and R' is optionally substituted C1-C6 alkyl. 72.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is —C(OMe)═. 73.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is —C(N(R′)2)═. 74.X 2aThe compound of any one of embodiments 1-4, 17, and 63-66, wherein is -C(NH2)=. 75.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is —C(N(R′)2)═, and each R′ is independently an optionally substituted C1-C6 alkyl. 76.X 2a -C(R 2 )= and R 2 The compound of any one of embodiments 1-4, 17, and 63-66, wherein is optionally substituted C1-C6 alkyl. 77.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is optionally substituted —CH═. 78.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is -CH=. 79.X 2a The compound of any one of embodiments 1-4, 17, and 63-66, wherein is -C(Me)=. 80.X 2b The compound of any one of embodiments 1-4, 17, and 63-79, wherein is -N=. 81.X 2b -C(R 2 )=. 82.X 2b The compound of any one of embodiments 1-4, 17, and 63-79, wherein is -C(OR')=. 83.X 2b The compound of any one of embodiments 1-4, 17, and 63-79, wherein is -C(OR')= and R' is optionally substituted C1-C6 alkyl. 84.X 2b The compound of any one of embodiments 1-4, 17, and 63-79, wherein is optionally substituted —CH═. 85.X 2bThe compound of any one of embodiments 1-4, 17, and 63-79, wherein is optionally substituted —CH═. 86.X 2b The compound of any one of embodiments 1-4, 17, and 63-79, wherein is -CH=. 87.X 2b The compound of any one of embodiments 1-4, 17, and 63-79, wherein is -C(halogen)=. 88.X 2b The compound of any one of embodiments 1-4, 17, and 63-79, wherein is -C(Cl)=. 89.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is -N=. 90.X 2c -C(R 2 )=. 91.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is optionally substituted —CH═. 92.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is —CH═. 93.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is -C(OR')=. 94.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is —C(OH)═. 95.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is -C(OR')=, and R' is an optionally substituted C1-C6 aliphatic. 96.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is -C(OR')= and R' is C1-C6 aliphatic. 97.X 2cThe compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is -C(OR')= and R' is an optionally substituted C1-C6 alkyl. 98.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is —C(OMe)═. 99.X 2c but

[0891] [ka]

[0892] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 100.X 2c but

[0893] [ka]

[0894] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 101.X 2c teeth

[0895] [ka]

[0896] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 102.X 2c teeth

[0897] [ka]

[0898] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 103.X2c teeth

[0899] [ka]

[0900] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 104.X 2c teeth

[0901] [ka]

[0902] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 105.X 2c -C(R 2 )= and R 2 The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is an optionally substituted C1-C6 aliphatic. 106.X 2c -C(R 2 )= and R 2 The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is C1-C6 aliphatic. 107.X 2c -C(R 2 )= and R 2 The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is optionally substituted C1-C6 alkyl. 108.X 2c but

[0903] [ka]

[0904] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 109.X2c but

[0905] [ka]

[0906] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 110.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is —C(N(R′)2)═. 111.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is —C(N(R′)2)═ and each R′ is independently an optionally substituted C1-C6 alkyl. 112.X 2c but

[0907] [ka]

[0908] The compound of any one of embodiments 1-4, 17, 46 and 63-88, wherein 113. The compound of embodiment 110 or 112, wherein one R′ and another R group on another atom, together with their intervening atoms, form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 114. One R' and R on another atom 3 taken together with their intervening atoms to form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 115. The compound is

[0909] [ka]

[0910] 80. The compound of any one of embodiments 1 and 63-79, wherein the compound has the structure: 116. The compound is

[0911] [ka]

[0912] 80. The compound of any one of embodiments 1 and 63-79, wherein the compound has the structure: 117.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is -C(halogen)=. 118.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is —C(Cl)═. 119.X 2c The compound of any one of embodiments 1-4, 17, 46, and 63-88, wherein is —C(Br)═. 120.X 1a The compound of any one of embodiments 1-4, 17, 46, and 63-119, wherein is —N(R′)—. 121.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is -N(R')-, and R' is an optionally substituted C1-C6 aliphatic. 122.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is -N(R')- and R' is C1-C6 aliphatic. 123.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is -N(R')-, and R' is an optionally substituted C1-C6 alkyl. 124.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is -N(Me)-. 125.X 1aThe compound of any one of embodiments 1-4, 46, and 63-119, wherein is —O—. 126.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is -S-. 127.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is optionally substituted —CH 2 —. 128.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is —C(R′)2—. 129.X 1a The compound of any one of embodiments 1-4, 46, and 63-119, wherein is optionally substituted —NH—. 130.X 3 The compound of any one of embodiments 1 and 5-129, wherein is -S-. 131.X 3 The compound of any one of embodiments 1 and 5-129, wherein is -Se-. 132.X 3 The compound of any one of embodiments 1 and 5-129, wherein is —O—. 133.X 3 The compound of any one of embodiments 1 and 5-129, wherein is —N(R′)—. 134.X 3 The compound of any one of embodiments 1 and 5-129, wherein is -N(R')-, and R' is an optionally substituted C1-C6 aliphatic. 135.X 3 The compound of any one of embodiments 1 and 5-129, wherein is -N(R')-, and R' is an optionally substituted C1-C6 alkyl. 136.X 3 The compound of any one of embodiments 1 and 5-129, wherein is -N(R')-, and R' is an optionally substituted C1-C6 alkyl. 137.X 3The compound of any one of embodiments 1 and 5-129, wherein is optionally substituted —NH—. 138.X 3 The compound of any one of embodiments 1 and 5-129, wherein is —N(Me)—. 139.X 4 The compound of any one of embodiments 1 and 5-138, wherein is -N=. 140.X 4 The compound of any one of embodiments 1 and 5-138, wherein is optionally substituted —CH═. 141.X 4 -C(R 6 )=. 142.X 5 The compound of any one of embodiments 1 and 5-141, wherein is -N=. 143.X 5 The compound of any one of embodiments 1 and 5-141, wherein is optionally substituted —CH═. 144.X 5 The compound of any one of embodiments 1 and 5-141, wherein is —CH═. 145.X 5 -C(R 6 )=. 146.X 5 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-141, wherein is an optionally substituted C1-C6 aliphatic group. 147.X 5 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-141, wherein is an optionally substituted C1-C6 alkyl group. 148.X 5 -C(R 6 )= and R 6The compound of any one of embodiments 1 and 5-141, wherein is an optionally substituted C1-C6 alkyl group. 149.X 5 The compound of any one of embodiments 1 and 5-141, wherein is —C(CF 3 )═. 150.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -N=. 151.X 6 The compound of any one of embodiments 1 and 5-149, wherein is optionally substituted —CH═. 152.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -CH=. 153.X 6 -C(R 6 )=. 154.X 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(OR′)═. 155.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(OH)=. 156.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(OR')=, and R' is an optionally substituted C1-C6 aliphatic. 157.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(OR')= and R' is C1-C6 aliphatic. 158.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(OR')= and R' is optionally substituted C1-C6 alkyl. 159.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(OR')= and R' is C1-C6 alkyl. 160.X 6The compound of any one of embodiments 1 and 5-149, wherein is -C(OR')=, R' is substituted C1-C6 alkyl, and each substituent is -F. 161.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(OMe)=. 162.X 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(OCF3)═. 163.X 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(OCHF2)═. 164.X 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(OCH 2 F)═. 165.X 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(OCF 2 Cl)═. 166.X 6 The compound of any one of embodiments 1 and 5-149, wherein R' is -C(OR')= and R' taken together with other atoms and other R' groups on those intervening atoms form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 167. Compound

[0913] [ka]

[0914] 150. The compound of any one of embodiments 1-149, which is a compound having the structure: or a salt thereof. 168.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(OR')= and R' is -C(O)R. 169.X 6 The compound of any one of embodiments 1 and 5-149, wherein R is -C(OR')=, R' is -C(O)R, and R is an optionally substituted C1-C6 aliphatic. 170.X6 but

[0915] [ka]

[0916] The compound of any one of embodiments 1 and 5-149, wherein 171.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(O)OR′. 172.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(O)OR', and R' is an optionally substituted C1-C6 aliphatic compound. 173.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(O)OCH 3 . 174.X 6 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-149, wherein is —C(O)OCH 2 CH 3 . 175.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(O)R. 176.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(O)R, and R is an optionally substituted C1-C6 aliphatic. 177.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(O)CH 3 . 178.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —CN. 179.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —NO 2 . 180.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —N(R′) 2 . 181.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is -N(R')2 and each R' is independently an optionally substituted C1-C6 aliphatic. 182.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is -N(R')2 and each R' is independently an optionally substituted C1-C6 alkyl. 183.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is -N(R')2 and each R' is independently an optionally substituted C1-C6 alkyl. 184.X 6 -C(R 6 )= and R 6 is —N(R′) 2 , and the two R′s, taken together with the intervening nitrogen atom, form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the nitrogen atom. 185.X 6 -C(R 6 )= and R 6is —N(R′)2, and the two R′s, taken together with the intervening nitrogen atom, form an optionally substituted 3- to 6-membered ring having zero heteroatoms in addition to the nitrogen atom. 186.X 6 -C(R 6 )= and R 6 is —N(R′)2, and the two R′s, together with the intervening nitrogen atom, form an optionally substituted 3- to 6-membered ring having one heteroatom in addition to the nitrogen atom. 187.X 6 -C(R 6 )= and R 6 is —N(R′)2, and the two R′, taken together with the intervening nitrogen atom, form an optionally substituted 3- to 6-membered ring having two heteroatoms in addition to the nitrogen atom. 188.X 6 -C(R 6 )= and R 6 but

[0917] [ka]

[0918] The compound of any one of embodiments 1 and 5-149, wherein 189.X 6 -C(R 6 )= and R 6 optionally substituted C1-C 10 The compound of any one of embodiments 1 and 5-149, which is aliphatic. 190.X 6 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-149, wherein is an optionally substituted C1-C6 aliphatic. 191.X 6 -C(R 6)= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is C1-C6 aliphatic. 192.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is optionally substituted C1-C6 alkyl. 193.X 6 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-149, wherein is C1-C6 haloalkyl. 194.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is substituted C1-C6 alkyl and each substituent is -F. 195.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is C1-C6 alkyl. 196.X 6 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-149, wherein is optionally substituted C2-C6 alkenyl. 197.X 6 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-149, wherein is C2-C6 alkenyl. 198.X 6 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-149, wherein is optionally substituted C2-C6 alkynyl. 199.X 6 -C(R 6 )= and R 6The compound according to any one of embodiments 1 and 5-149, wherein is C2-C6 alkynyl. 200.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is methyl. 201.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is an ethyl group. 202.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —CF 3 . 203.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —CH 2 F. 204.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —CHF 2 . 205.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —CF 2 Cl. 206.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —CH(CH 3 ) 2 . 207.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(CH 3 ) 2 OH. 208.X 6 -C(R 6 )= and R 6The compound of any one of embodiments 1 and 5-149, wherein is —C(CH 3 ) 2 CN. 209.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(CH 3 )═CH 2 . 210.X 6 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-149, wherein is —C≡CH. 211.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is an optionally substituted 3-10 membered cyclic aliphatic. 212.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is an optionally substituted 3-6 membered cyclic aliphatic. 213.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is a 3-6 membered alicyclic group. 214.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is a cyclopropyl group. 215.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is a cyclobutyl group. 216.X 6 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-149, wherein is a cyclopentyl group. 217.X 6 -C(R 6 )= and R6 The compound of any one of embodiments 1 and 5-149, wherein is a cyclohexyl group. 218.X 6 -C(R 6 )=(R 6 The compound of any one of embodiments 1 and 5-149, wherein: 219.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(F)=. 220.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(Cl)=. 221.X 6 The compound of any one of embodiments 1 and 5-149, wherein is —C(Br)═. 222.X 6 The compound of any one of embodiments 1 and 5-149, wherein is -C(I)=. 223.X 7 The compound of any one of embodiments 1 and 5-222, wherein is -N=. 224.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is optionally substituted —CH═. 225.X 7 -C(R 6 )=. 226.X 7 The compound of any one of embodiments 1 and 5-222, wherein is -CH=. 227.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(OH)=. 228.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(OR')= and R' is an optionally substituted C1-C6 aliphatic. 229.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(OR')= and R' is C1-C6 aliphatic. 230.X7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(OR')= and R' is optionally substituted C1-C6 alkyl. 231.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(OR')= and R' is C1-C6 haloalkyl. 232.X 7 The compound of any one of embodiments 1 and 5-222, wherein is -C(OR')=, R' is substituted C1-C6 alkyl, and each substituent is -F. 233.X 7 The compound of any one of embodiments 1 and 5-222, wherein is —C(OMe)═. 234.X 7 The compound of any one of embodiments 1 and 5-222, wherein is —C(OCF 3 )═. 235.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(OCHF2)=. 236.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is —C(OCH 2 F)═. 237.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(OCF2Cl)=. 238.X 7 The compound of any one of embodiments 1 and 5-222, wherein R′ is —C(OR′)═, and R′, taken together with the other atoms and other R′ groups on those intervening atoms, forms an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 239.X 7 -C(R 6 )= and R 6 optionally substituted C1-C 10 The compound of any one of embodiments 1 and 5-222, which is aliphatic. 240.X 7 -C(R 6 )= and R 6The compound according to any one of embodiments 1 and 5-222, wherein is an optionally substituted C1-C6 aliphatic. 241.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is optionally substituted C1-C6 alkyl. 242.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is optionally substituted C1-C6 alkyl. 243.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is halogen substituted C1-C6 alkyl. 244.X 7 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-222, wherein is substituted C1-C6 alkyl and each substituent is -F. 245.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is C1-C6 alkyl. 246.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is optionally substituted C2-C6 alkenyl. 247.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is C2-C6 alkenyl. 248.X 7 -C(R 6 )= and R 6The compound according to any one of embodiments 1 and 5-222, wherein is optionally substituted C2-C6 alkynyl. 249.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is C2-C6 alkynyl. 250.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is methyl. 251.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is ethyl. 252.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is -CF3. 253.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is —CH 2 F. 254.X 7 -C(R 6 )=, where R 6 The compound of any one of embodiments 1 and 5-222, wherein is —CHF 2 . 255.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is -CF2Cl. 256.X 7 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-222, wherein is halogen. 257.X 7 The compound of any one of embodiments 1 and 5-222, wherein is -C(F)=. 258.X7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(Cl)=. 259.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(Br)=. 260.X 7 The compound according to any one of embodiments 1 and 5-222, wherein is -C(I)=. 261.X 8 The compound of any one of embodiments 1 and 5-260, wherein is -N=. 262.X 8 The compound of any one of embodiments 1 and 5-260, wherein is optionally substituted —CH═. 263.X 8 -C(R 6 )=. 264.X 8 The compound of any one of embodiments 1 and 5-260, wherein is -CH=. 265.X 8 The compound of any one of embodiments 1 and 5-260, wherein is -C(OH)=. 266.X 8 The compound according to any one of embodiments 1 and 5-260, wherein is -C(OR')= and R' is an optionally substituted C1-C6 aliphatic. 267.X 8 The compound of any one of embodiments 1 and 5-260, wherein is -C(OR')= and R' is C1-C6 aliphatic. 268.X 8 The compound according to any one of embodiments 1 and 5-260, wherein is -C(OR')= and R' is optionally substituted C1-C6 alkyl. 269.X 8 The compound according to any one of embodiments 1 and 5-260, wherein is -C(OR')= and R' is halogen substituted C1-C6 alkyl. 270.X 8The compound of any one of embodiments 1 and 5-260, wherein is -C(OR')=, R' is substituted C1-C6 alkyl, and each substituent is -F. 271.X 8 The compound of any one of embodiments 1 and 5-260, wherein is —C(OMe)═. 272.X 8 The compound of any one of embodiments 1 and 5-260, wherein is —C(OCF 3 )═. 273.X 8 The compound according to any one of embodiments 1 and 5-260, wherein is —C(OCHF2)═. 274.X 8 The compound according to any one of embodiments 1 and 5-260, wherein is —C(OCH 2 F)═. 275.X 8 The compound according to any one of embodiments 1 and 5-260, wherein is -C(OCF2Cl)=. 276.X 8 The compound of any one of embodiments 1 and 5-260, wherein R′ is —C(OR′)═, and R′ together with the other atoms and other R′ groups on those intervening atoms form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 277. Compound

[0919] [ka]

[0920] or a salt thereof. 278.X 8 -C(R 6 )= and R 6 optionally substituted C1-C 10 The compound of any one of embodiments 1 and 5-260 which is aliphatic. 279.X 8 -C(R 6 )= and R 6The compound according to any one of embodiments 1 and 5-260, wherein is an optionally substituted C1-C6 aliphatic. 280.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is optionally substituted C1-C6 alkyl. 281.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is optionally substituted C1-C6 alkyl. 282.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is halogen substituted C1-C6 alkyl. 283.X 8 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-260, wherein is substituted C1-C6 alkyl and each substituent is -F. 284.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is C1-C6 alkyl. 285.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is optionally substituted C2-C6 alkenyl. 286.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is C2-C6 alkenyl. 287.X 8 -C(R 6 )= and R 6The compound according to any one of embodiments 1 and 5-260, wherein is optionally substituted C2-C6 alkynyl. 288.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is C2-C6 alkynyl. 289.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is methyl. 290.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is ethyl. 291.X 8 -C(R 6 )= and R 6 The compound according to any one of embodiments 1 and 5-260, wherein is —CF 3 . 292.X 8 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-260, wherein is —CH 2 F. 293.X 8 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-260, wherein is —CHF 2 . 294.X 8 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-260, wherein is —CF 2 Cl. 295.X 8 -C(R 6 )= and R 6 The compound of any one of embodiments 1 and 5-260, wherein is halogen. 296.X 8 The compound of any one of embodiments 1 and 5-260, wherein is -C(F)=. 297.X 8The compound of any one of embodiments 1 and 5-260, wherein is -C(Cl)=. 298.X 8 The compound of any one of embodiments 1 and 5-260, wherein is -C(Br)=. 299.X 8 The compound of any one of embodiments 1 and 5-260, wherein is -C(I)=. 300.R 1 The compound of any one of embodiments 1-4 and 17-299, wherein is -OR'. 301.R 1 The compound of any one of embodiments 1-4 and 17-299, wherein is —OH. 302.R 1 The compound of embodiment 300, wherein is -OR' and R' is an optionally substituted C1-C6 aliphatic. 303.R 1 The compound of embodiment 300, wherein is -OR' and R' is C1-C6 aliphatic. 304.R 1 The compound of embodiment 300, wherein is -OR' and R' is optionally substituted C1-C6 alkyl. 305.R 1 The compound of embodiment 300, wherein is -OR' and R' is C1-C6 alkyl. 306.R 1 The compound of embodiment 300, wherein R is -OR' and R' is halogen-substituted C1-C6 alkyl. 307.R 1 The compound of embodiment 300, wherein is -OR', R' is substituted C1-C6 alkyl, and each substituent is -F. 308.R 1 The compound of embodiment 300, wherein is -OMe. 309.R 1 The compound of embodiment 300, wherein is -OCF3. 310.R 1 The compound of embodiment 300, wherein is -OCHF2. 311.R 1 The compound of embodiment 300, wherein is -OCH2F. 312.R1 The compound of embodiment 300, wherein is -OCF2Cl. 313.R 1 The compound of embodiment 300, wherein is -OCH2CF3. 314.R 1 C1 to C, which may be optionally substituted 10 The compound of any one of embodiments 1-4 and 17-299, which is aliphatic. 315.R 1 The compound of embodiment 314, wherein is an optionally substituted C1-C6 aliphatic. 316.R 1 The compound of embodiment 314, wherein is C1-C6 aliphatic. 317.R 1 The compound of embodiment 314, wherein is optionally substituted C1-C6 alkyl. 318.R 1 The compound of embodiment 314, wherein is halogen-substituted C1-C6 alkyl. 319.R 1 The compound of embodiment 314, wherein is substituted C1-C6 alkyl and each substituent is -F. 320.R 1 The compound of embodiment 314, wherein is C1-C6 alkyl. 321.R 1 The compound of embodiment 314, wherein is optionally substituted C2-C6 alkenyl. 322.R 1 The compound of embodiment 314, wherein is C2-C6 alkenyl. 323.R 1 The compound of embodiment 314, wherein is optionally substituted C2-C6 alkynyl. 324.R 1 The compound of embodiment 314, wherein is C2-C6 alkynyl. 325.R 1 The compound of embodiment 314, wherein is methyl. 326.R 1 The compound of embodiment 314, wherein is ethyl. 327.R 1 The compound of embodiment 314, wherein is -CF3. 328.R 1The compound of embodiment 314, wherein is -CH2F. 329.R 1 The compound of embodiment 314, wherein is -CHF2. 330.R 1 The compound of embodiment 314, wherein is -CF2Cl. 331.R 1 The compound of any one of embodiments 1-4 and 17-299, wherein is halogen. 332.R 1 The compound of embodiment 331, wherein is -F. 333.R 1 The compound of embodiment 331, wherein is -Cl. 334.R 1 The compound of embodiment 331, wherein is -Br. 335.R 1 The compound of embodiment 331, wherein is -I. 336.L 1 The compound of any one of embodiments 1 and 4-335, wherein is a covalent bond. 337.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —C(O)—. 338.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —C(S)—. 339.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —S(O)2—. 340.L 1 The compound of any one of embodiments 1 and 4-335, wherein is optionally substituted —CH 2 —. 341.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —CH 2 —. 342.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(R′)C(O)—. 343.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(R′)C(O)— and R′ is C1-C6 alkyl. 344.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(H)C(O)—. 345.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(R′)S(O)2—. 346.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(R′)S(O)2— and R′ is C1-C6 alkyl. 347.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(H)S(O)2—. 348.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(R′)C(S)—. 349.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(R′)C(S)— and R′ is C1-C6 alkyl. 350.L 1 The compound of any one of embodiments 1 and 4-335, wherein is —N(H)C(S)—. 351.L 1 but

[0921] [ka]

[0922] The compound of any one of embodiments 1 and 4-335, wherein 352.R 3 The compound of any one of embodiments 1 and 5-351, wherein is H. 353.R 3 The compound of any one of embodiments 1 and 5-351, wherein is an optionally substituted C1-C6 aliphatic. 354.R 3 354. The compound of embodiment 353, wherein is optionally substituted C1-C6 alkyl. 355.R 3The compound of embodiment 353, wherein is C1-C6 alkyl. 356.R 3 The compound of embodiment 353, wherein is methyl. 357.R 3 The compound of embodiment 353, wherein is ethyl. 358.L 2 The compound of any one of embodiments 1 and 5-357, wherein is optionally substituted C1-3 alkylene. 359.L 2 359. The compound of embodiment 358, wherein is C1-3 alkylene. 360.L 2 359. The compound of embodiment 358, wherein is optionally substituted —CH 2 —. 361.L 2 359. The compound of embodiment 358, wherein is optionally substituted -CH2CH2-. 362.L 2 359. The compound of embodiment 358, wherein is optionally substituted -CH2CH2CH2-. 363.L 2 The compound of embodiment 358, wherein is -CH2-. 364.L 2 The compound of embodiment 358, wherein is -CH2CH2-. 365.L 2 The compound of embodiment 358, wherein is -CH2CH2CH2-. 366.L 2 The compound of any one of embodiments 1 and 5-357, wherein is an optionally substituted C1-3 alkylene, wherein one or more methylene units of said alkylene are independently replaced with -O-. 367.L 2 The compound according to any one of embodiments 1 and 5-357, wherein is optionally substituted C1-3 alkylene, and one unit of said alkylene is replaced with -O-. 368.L 2 The compound of embodiment 366, wherein is optionally substituted —CH 2 O—. 369.L 2 The compound of embodiment 366, wherein is —CH 2 O—. 370.L 2 The compound of embodiment 366, wherein is substituted —CH 2 O—. 371.L 2 The compound of embodiment 366, wherein is optionally substituted -CH2CH2O-. 372.L 2 The compound of embodiment 366, wherein is —CH 2 CH 2 O—. 373.L 2 The compound of embodiment 366, wherein is substituted -CH2CH2O-. 374.L 2 optionally substituted C 2-3 alkylene, wherein one unit of the alkylene is replaced by —O— and another unit of the alkylene is —C(R 4 )(R 5 The compound of any one of embodiments 1 and 5-357, wherein R is substituted with )-. 375.L 2 but

[0923] [ka]

[0924] The compound of any one of embodiments 1 and 5-357, wherein 376.L 2 optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are independently —C(R 4 )(R 5 The compound of any one of embodiments 1 and 5-357, wherein R is substituted with )-. 377.L 2 optionally substituted C 1-3 alkylene, wherein one methylene unit of the alkylene is —C(R 4 )(R 5 The compound of any one of embodiments 1 and 5-357, wherein R is substituted with )-. 378.L 2 but

[0925] [ka]

[0926] The compound of any one of embodiments 1 and 5-357, wherein 379.L 2 optionally substituted C 1-3 alkylene, wherein one or more methylene units of the alkylene are independently —N(R 4 The compound of any one of embodiments 1 and 5-357, wherein R is substituted with )-. 380.L 2 optionally substituted C 1-3 alkylene, wherein one methylene unit of the alkylene is —N(R 4 The compound of any one of embodiments 1 and 5-357, wherein R is substituted with )-. 381.L 2 -CH2-N(R 4 )-, wherein -CH2- is optionally substituted. 382.L 2 -CH2-N(R 4 )-, wherein -CH2- is substituted. 383.L 2 -CH2-N(R 4 )-, and -CH2- is unsubstituted. 384.L 2 -C(R 4 )(R 5 )-N(R 4 )-. 385.L 2 -C(R 4 )(R 5 The compound of any one of embodiments 1 and 5-357, wherein: 386.L 2 -C(R 4 )(R5 375. The compound of embodiment 374, wherein R is —O—. 387.R 4 The compound of any one of embodiments 1 and 5-386, wherein is R. 388.R 4 388. The compound of embodiment 387, wherein is —H. 389.R 4 388. The compound of embodiment 387, wherein is not —H. 390.R 4 optionally substituted C1-C 10 388. The compound of embodiment 387, which is aliphatic. 391.R 4 optionally substituted C 1-6 388. The compound of embodiment 387, which is aliphatic. 392.R 4 optionally substituted C 1-6 The compound of embodiment 387, wherein the aryl group is alkyl. 393.R 4 C 1-6 The compound of embodiment 387, wherein the aryl group is alkyl. 394.R 4 The compound of embodiment 387, wherein is methyl. 395.R 4 The compound of embodiment 387, wherein is -CH2F. 396.R 4 The compound of embodiment 387, wherein is ethyl. 397.R 4 The compound of embodiment 387, wherein is -CH2CH2CH=CH2. 398.R 4 The compound of embodiment 387, wherein is optionally substituted phenyl. 399.R 4 and R 5 are taken together with the atoms to which they are attached to form an optionally substituted 3-10 membered ring having 0-4 heteroatoms. 400.R 4 and R 5are taken together with the atoms to which they are attached to form an optionally substituted 3- to 10-membered ring, e.g., a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring, containing no heteroatoms. 401.R 4 and R 5 taken together with the atoms to which they are attached form an optionally substituted three-membered ring containing no heteroatoms. 402.R 4 and R 5 are taken together with the atoms to which they are attached to form an optionally substituted 4-membered ring containing no heteroatoms. 403.R 4 and R 5 are taken together with the atoms to which they are attached to form an optionally substituted 6-membered ring containing no heteroatoms. 404.R 4 and R 5 The compound of embodiment 387, wherein together with the atoms to which they are attached form an optionally substituted cyclohexyl ring. 405.R 4 and R 5 are taken together with the atoms to which they are attached to form an optionally substituted 3- to 10-membered ring having 1 to 4 heteroatoms. 406.R 4 and R 5 are taken together with the atoms to which they are attached to form an optionally substituted 3-10 membered ring having one heteroatom. 407.R 4 and R 5 are taken together with the atoms to which they are attached to form an optionally substituted 3-membered ring (1 heteroatom). 408.R 4 and R 5are taken together with the atoms to which they are attached to form an optionally substituted 4-membered ring (1 heteroatom). 409. A compound of embodiment 387, wherein R4 and R5, together with the atoms to which they are attached, form an optionally substituted 6-membered ring (1 heteroatom). 410. A compound according to any one of embodiments 405-409, wherein the ring formed has a nitrogen atom. 411. A compound according to any one of embodiments 405-409, wherein the ring formed contains an oxygen atom. 412.R 5 The compound of any one of embodiments 1 and 5-398, wherein is R. 413.R 5 The compound of embodiment 412, wherein is —H. 414.R 5 The compound of embodiment 412, wherein is not —H. 415.R 5 optionally substituted C1-C 10 The compound of embodiment 412, which is aliphatic. 416.R 5 optionally substituted C 1-6 The compound of embodiment 412, which is aliphatic. 417.R 5 The compound of embodiment 412, wherein is methyl. 418.R 5 The compound of embodiment 412, wherein is -CH2F. 419.R 5 The compound of embodiment 412, wherein is ethyl. 420.R 5 The compound of embodiment 412, wherein is -CH2CH2CH=CH2. 421.R 5 413. The compound of embodiment 412, wherein is optionally substituted phenyl. 422.L 2 but

[0927] [ka]

[0928] The compound of any one of embodiments 1 and 5-357, wherein 423.L 2 but

[0929] [ka]

[0930] The compound of any one of embodiments 1 and 5-357, wherein 424.L 2 but

[0931] [ka]

[0932] The compound of any one of embodiments 1 and 5-357, wherein 425.L 2 but

[0933] [ka]

[0934] The compound of any one of embodiments 1 and 5-357, wherein 426.L 2 but

[0935] [ka]

[0936] The compound of any one of embodiments 1 and 5-357, wherein 427.L 2 but

[0937] [ka]

[0938] The compound of any one of embodiments 1 and 5-357, wherein 428.L 2 but

[0939] [ka]

[0940] The compound of any one of embodiments 1 and 5-357, wherein 429.L 2 but

[0941] [ka]

[0942] The compound of any one of embodiments 1 and 5-357, wherein 430.L 2 but

[0943] [ka]

[0944] The compound of any one of embodiments 1 and 5-357, wherein 431.L 2 but

[0945] [ka]

[0946] The compound of any one of embodiments 1 and 5-357, wherein 432.L 2 but

[0947] [ka]

[0948] The compound of any one of embodiments 1 and 5-357, wherein 433.L 2 but

[0949] [ka]

[0950] The compound of any one of embodiments 1 and 5-357, wherein 434.L 2 optionally substituted C 1-3 The compound of any one of embodiments 1 and 5-357, wherein the compound is alkylene, wherein one or more methylene units of the alkylene are independently replaced with -S-. 435.L 2 optionally substituted C 1-3 The compound of any one of embodiments 1 and 5-357, wherein the alkylene is one methylene unit replaced with -S-. 436.L 2 The compound of any one of embodiments 1 and 5-357, wherein is optionally substituted —CH 2 S—. 437.L 2 The compound of any one of embodiments 1 and 5-357, wherein is —CH 2 S—. 438.L 2 The compound of any one of embodiments 1 and 5-357, wherein is a substituted —CH 2 S—. 439.L 2 The compound of any one of embodiments 1 and 5-357, wherein is —CH 2 —NH—. 440.L 2 but

[0951] [ka]

[0952] The compound of any one of embodiments 1 and 5-357, wherein 441.L 2 but

[0953] [ka]

[0954] The compound of any one of embodiments 1 and 5-357, wherein 442.L 2 but

[0955] [ka]

[0956] The compound of any one of embodiments 1 and 5-357, wherein 443.L 2 but

[0957] [ka]

[0958] The compound of any one of embodiments 1 and 5-357, wherein 444.L 2 optionally substituted C 1-3 The compound of any one of embodiments 1 and 5-357, wherein the alkylene is alkylene, and one or more methylene units of the alkylene are independently replaced with an optionally substituted —CH═N—. 445.L 2 optionally substituted C 1-3 The compound of any one of embodiments 1 and 5-357, which is alkylene, wherein one methylene unit of the alkylene is replaced with an optionally substituted —CH═N—. 446.L 2 optionally substituted C 1-3The compound according to any one of embodiments 1 and 5-357, which is alkylene, wherein one methylene unit of the alkylene is replaced with -CH=N-. 447.L 2 The compound of any one of embodiments 1 and 5-357, wherein is optionally substituted —CH═N—. 448.L 2 The compound of any one of embodiments 1 and 5-357, wherein is -CH=N-. 449.L 2 optionally substituted C 1-3 The compound of any one of embodiments 1 and 5-357, which is alkylene, wherein one or more methylene units of the alkylene are independently replaced with an optionally substituted —CH═CH—. 450.L 2 optionally substituted C 1-3 The compound of any one of embodiments 1 and 5-357, which is alkylene, wherein one methylene unit of the alkylene is replaced with an optionally substituted -CH=CH-. 451.L 2 optionally substituted C 1-3 The compound according to any one of embodiments 1 and 5-357, which is alkylene, wherein one methylene unit of the alkylene is replaced with -CH=CH-. 452.L 2 The compound of any one of embodiments 1 and 5-357, wherein is optionally substituted -CH=CH-. 453.L 2 The compound of any one of embodiments 1 and 5-357, wherein is -CH=CH-. 454.L 2 optionally substituted C 1-3 The compound of any one of embodiments 1 and 5-357, wherein the alkylene is alkylene and one or more methylene units of the alkylene are independently replaced with an optionally substituted -Cy-. 455.L 2 optionally substituted C 1-3The compound of any one of embodiments 1 and 5-357, wherein is alkylene, one methylene unit of said alkylene is replaced with -Cy-. 456.L 2 The compound of any one of embodiments 1 and 5-357, wherein is optionally substituted -CH2-CH2-, and one methylene unit of -CH2-CH2- is replaced with -Cy-. 457. The compound according to any one of embodiments 1 and 5-357, wherein L2 is -Cy-O-. 458. Compound

[0959] [ka]

[0960] or a salt thereof. 459. Compound

[0961] [ka]

[0962] or a salt thereof. 460. Compound

[0963] [ka]

[0964] or a salt thereof. 461. The compound according to any one of embodiments 454-460, wherein ring B in -Cy- is an optionally substituted saturated 3-10 membered ring having 0-4 heteroatoms. 462. The compound according to any one of embodiments 454-460, wherein ring B in -Cy- is an optionally substituted partially unsaturated 3-10 membered ring having 0-4 heteroatoms. 463. The compound according to any one of embodiments 461-462, wherein ring B is a 3- to 7-membered ring. 464. The compound according to any one of embodiments 461-462, wherein ring B is a 3-membered ring. 465. The compound according to any one of embodiments 461-462, wherein ring B is a 4-membered ring. 466. The compound according to any one of embodiments 461-462, wherein ring B is a 5-membered ring. 467. The compound according to any one of embodiments 461-462, wherein ring B is a 6-membered ring. 468. The compound according to any one of embodiments 461-467, wherein ring B has no heteroatoms. 469. Compounds according to any one of embodiments 461-467, wherein ring B has one heteroatom. 470. Compounds according to any one of embodiments 461-467, wherein ring B has two heteroatoms. 471. Ring B is optionally substituted

[0965] [ka]

[0966] The compound of any one of embodiments 461-462, wherein 472. Ring B is optionally substituted

[0967] [ka]

[0968] The compound of any one of embodiments 461-462, wherein 473. Ring B is optionally substituted

[0969] [ka]

[0970] The compound of any one of embodiments 461-462, wherein 474. Ring B is optionally substituted

[0971] [ka]

[0972] The compound of any one of embodiments 461-462, wherein 475. Ring B is optionally substituted

[0973] [ka]

[0974] The compound of any one of embodiments 461-462, wherein 476. Ring B is optionally substituted

[0975] [ka]

[0976] The compound of any one of embodiments 461-462, wherein 477. Ring B is optionally substituted

[0977] [ka]

[0978] The compound of any one of embodiments 461-462, wherein 478. Ring B is optionally substituted

[0979] [ka]

[0980] The compound of any one of embodiments 461-462, wherein 479. Ring B is optionally substituted

[0981] [ka]

[0982] The compound of any one of embodiments 461-462, wherein 480. Ring B is optionally substituted

[0983] [ka]

[0984] The compound of any one of embodiments 461-462, wherein 481. Ring B is optionally substituted

[0985] [ka]

[0986] The compound of any one of embodiments 461-462, wherein 482. Ring B is optionally substituted

[0987] [ka]

[0988] The compound of any one of embodiments 461-462, wherein 483. Ring B is optionally substituted

[0989] [ka]

[0990] The compound of any one of embodiments 461-462, wherein 484. Ring B is optionally substituted

[0991] [ka]

[0992] The compound of any one of embodiments 461-462, wherein 485. Ring B is optionally substituted

[0993] [ka]

[0994] The compound of any one of embodiments 461-462, wherein 486. Ring B is optionally substituted

[0995] [ka]

[0996] The compound of any one of embodiments 461-462, wherein 487. Ring B is optionally substituted

[0997] [ka]

[0998] The compound of any one of embodiments 461-462, wherein 488. Ring B is optionally substituted

[0999] [ka]

[1000] The compound of any one of embodiments 461-462, wherein 489. The compound according to any one of embodiments 454-488, wherein -Cy- is a spiro ring. 490.L 2 but

[1001] [ka]

[1002] The compound of any one of embodiments 1 and 5-357, wherein 491.L 2 but

[1003] [ka]

[1004] The compound of any one of embodiments 1 and 5-357, wherein 492.L 2 but

[1005] [ka]

[1006] The compound of any one of embodiments 1 and 5-357, wherein 493.L 2 but

[1007] [ka]

[1008] The compound of any one of embodiments 1 and 5-357, wherein 494.L 2 but

[1009] [ka]

[1010] The compound of any one of embodiments 1 and 5-357, wherein 495.L 2 but

[1011] [ka]

[1012] The compound of any one of embodiments 1 and 5-357, wherein 496.L 2 but

[1013] [ka]

[1014] The compound of any one of embodiments 1 and 5-357, wherein 497.L 2 but

[1015] [ka]

[1016] The compound of any one of embodiments 1 and 5-357, wherein 498.L 2 but

[1017] [ka]

[1018] The compound of any one of embodiments 1 and 5-357, wherein 499.L 2 but

[1019] [ka]

[1020] The compound of any one of embodiments 1 and 5-357, wherein 500.L 2 but

[1021] [ka]

[1022] The compound of any one of embodiments 1 and 5-357, wherein 501.L 2 but

[1023] [ka]

[1024] The compound of any one of embodiments 1 and 5-357, wherein 502.L 2 but

[1025] [ka]

[1026] The compound of any one of embodiments 1 and 5-357, wherein 503. Compound

[1027] [ka]

[1028] or a salt thereof. 504. Compound

[1029] [ka]

[1030] or a salt thereof. 505. Compound

[1031] [ka]

[1032] or a salt thereof. 506. Compound

[1033] [ka]

[1034] or a salt thereof. 507. Compound

[1035] [ka]

[1036] or a salt thereof. 508. The compound of any one of embodiments 1 and 5-507, wherein t is 0. 509. The compound of any one of embodiments 1 and 5-507, wherein t is 1. The compound of any one of embodiments 1 and 5-507, wherein 510.t is 2. The compound of any one of embodiments 1 and 5-507, wherein 511.t is 3. 512. The compound of any one of embodiments 1 and 5-507, wherein t is 4. 513.R s The compound of any one of embodiments 1 and 5-512, wherein each occurrence of is -L-R'. 514.R sThe compound of any one of embodiments 1 and 5-512, wherein each occurrence of is -L-R', where L is an optionally substituted -CH2-. 515.R s The compound of any one of embodiments 1 and 5-512, wherein is -L-R', L is an optionally substituted -CH2-, and R' is -C(O)OR. 516.R s The compound of any one of embodiments 1 and 5-512, wherein is -CH2-R'. 517.R s The compound of any one of embodiments 1 and 5-512, wherein is —R′. 518.R s The compound of any one of embodiments 1 and 5-512, wherein is —H. 519.R s optionally substituted C 1-6 The compound of any one of embodiments 1 and 5-512, which is aliphatic. 520.R s optionally substituted C 1-6 The compound of any one of embodiments 1 and 5-512, wherein R is alkyl. 521.R s optionally substituted C 3-6 The compound of any one of embodiments 1 and 5-512, wherein the cycloalkyl. 522.R s The compound according to any one of embodiments 1 and 5-512, wherein is —C(O)OR′. 523.R s is —C(O)OR′, and R′ is an optionally substituted C 1-6 The compound of any one of embodiments 1 and 5-512, wherein the group is an aliphatic group. 524.R s is —C(O)OR′, and R′ is an optionally substituted C 1-6 The compound of any one of embodiments 1 and 5-512, wherein R is alkyl. 525.L 2 but

[1037] [ka]

[1038] The compound of any one of embodiments 1 and 5-357, wherein 526.L 2 but

[1039] [ka]

[1040] The compound of any one of embodiments 1 and 5-357, wherein 527.L 2 but

[1041] [ka]

[1042] The compound of any one of embodiments 1 and 5-357, wherein 528.L 2 but

[1043] [ka]

[1044] The compound of any one of embodiments 1 and 5-357, wherein 529.L 2 but

[1045] [ka]

[1046] The compound of any one of embodiments 1 and 5-357, wherein 530.L 2 but

[1047] [ka]

[1048] The compound of any one of embodiments 1 and 5-357, wherein 531.L 2 but

[1049] [ka]

[1050] The compound of any one of embodiments 1 and 5-357, wherein 532.L 2 but

[1051] [ka]

[1052] The compound of any one of embodiments 1 and 5-357, wherein 533.L 2 but

[1053] [ka]

[1054] The compound of any one of embodiments 1 and 5-357, wherein 534.L 2 but

[1055] [ka]

[1056] The compound of any one of embodiments 1 and 5-357, wherein 535.L 2 but

[1057] [ka]

[1058] The compound of any one of embodiments 1 and 5-357, wherein 536.L 2 but

[1059] [ka]

[1060] The compound of any one of embodiments 1 and 5-357, wherein 537.L 2 but

[1061] [ka]

[1062] The compound of any one of embodiments 1 and 5-357, wherein 538.L 2 but

[1063] [ka]

[1064] The compound of any one of embodiments 1 and 5-357, wherein 539.L 2 but

[1065] [ka]

[1066] The compound of any one of embodiments 1 and 5-357, wherein 540.L 2 but

[1067] [ka]

[1068] The compound of any one of embodiments 1 and 5-357, wherein 541.L 2 but

[1069] [ka]

[1070] The compound of any one of embodiments 1 and 5-357, wherein 542.L 2 but

[1071] [ka]

[1072] The compound of any one of embodiments 1 and 5-357, wherein 543.L 2 but

[1073] [ka]

[1074] The compound of any one of embodiments 1 and 5-357, wherein 544.L 2 but

[1075] [ka]

[1076] The compound of any one of embodiments 1 and 5-357, wherein 545.L 2 but

[1077] [ka]

[1078] The compound of any one of embodiments 1 and 5-357, wherein 546.L 2 but

[1079] [ka]

[1080] The compound of any one of embodiments 1 and 5-357, wherein 547.L 2 but

[1081] [ka]

[1082] The compound of any one of embodiments 1 and 5-357, wherein 548.L 2 but

[1083] [ka]

[1084] The compound of any one of embodiments 1 and 5-357, wherein 549.L 2 but

[1085] [ka]

[1086] The compound of any one of embodiments 1 and 5-357, wherein 550.L 2 but

[1087] [ka]

[1088] The compound of any one of embodiments 1 and 5-357, wherein 551.L 2 but

[1089] [ka]

[1090] The compound of any one of embodiments 1 and 5-357, wherein 552.L 2 but

[1091] [ka]

[1092] The compound of any one of embodiments 1 and 5-357, wherein 553.L 2 but

[1093] [ka]

[1094] The compound of any one of embodiments 1 and 5-357, wherein 554.L 2 but

[1095] [ka]

[1096] The compound of any one of embodiments 1 and 5-357, wherein 555.L 2 but

[1097] [ka]

[1098] The compound of any one of embodiments 1 and 5-357, wherein 556.L 2 but

[1099] [ka]

[1100] The compound of any one of embodiments 1 and 5-357, wherein 557.L 2 but

[1101] [ka]

[1102] The compound of any one of embodiments 1 and 5-357, wherein 558.L 2 but

[1103] [ka]

[1104] The compound of any one of embodiments 1 and 5-357, wherein 559.L 2 but

[1105] [ka]

[1106] The compound of any one of embodiments 1 and 5-357, wherein 560.L 2 but

[1107] [ka]

[1108] The compound of any one of embodiments 1 and 5-357, wherein 561.L 2 but

[1109] [ka]

[1110] The compound of any one of embodiments 1 and 5-357, wherein 562.L 2 but

[1111] [ka]

[1112] The compound of any one of embodiments 1 and 5-357, wherein 563.L 2 but

[1113] [ka]

[1114] The compound of any one of embodiments 1 and 5-357, wherein 564.L 2 but

[1115] [ka]

[1116] The compound of any one of embodiments 1 and 5-357, wherein 565.L 2 but

[1117] [ka]

[1118] The compound of any one of embodiments 1 and 5-357, wherein 566.L 2 but

[1119] [ka]

[1120] The compound of any one of embodiments 1 and 5-357, wherein 567.L 2 but

[1121] [ka]

[1122] The compound of any one of embodiments 1 and 5-357, wherein 568.L 2 but

[1123] [ka]

[1124] The compound of any one of embodiments 1 and 5-357, wherein 569.L 2 but

[1125] [ka]

[1126] The compound of any one of embodiments 1 and 5-357, wherein 570.L 2 but

[1127] [ka]

[1128] The compound of any one of embodiments 1 and 5-357, wherein 571.L 2 but

[1129] [ka]

[1130] The compound of any one of embodiments 1 and 5-357, wherein 572.L 2 but

[1131] [ka]

[1132] The compound of any one of embodiments 1 and 5-357, wherein 573.L 2 but

[1133] [ka]

[1134] The compound of any one of embodiments 1 and 5-357, wherein 574.L 2 but

[1135] [ka]

[1136] The compound of any one of embodiments 1 and 5-357, wherein 575.L 2 but

[1137] [ka]

[1138] The compound of any one of embodiments 1 and 5-357, wherein 576.L 2 but

[1139] [ka]

[1140] The compound of any one of embodiments 1 and 5-357, wherein 577.L 2 but

[1141] [ka]

[1142] The compound of any one of embodiments 1 and 5-357, wherein 578.L 2 but

[1143] [ka]

[1144] The compound of any one of embodiments 1 and 5-357, wherein 579.L 2 but

[1145] [ka]

[1146] The compound of any one of embodiments 1 and 5-357, wherein 580.L 2 but

[1147] [ka]

[1148] The compound of any one of embodiments 1 and 5-357, wherein 581.L 2 but

[1149] [ka]

[1150] The compound of any one of embodiments 1 and 5-357, wherein 582.L 2 but

[1151] [ka]

[1152] The compound of any one of embodiments 1 and 5-357, wherein 583.L 2 but

[1153] [ka]

[1154] The compound of any one of embodiments 1 and 5-357, wherein 584.L 2 but

[1155] [ka]

[1156] The compound of any one of embodiments 1 and 5-357, wherein 585.L 2 but

[1157] [ka]

[1158] The compound of any one of embodiments 1 and 5-357, wherein 586.L 2 but

[1159] [ka]

[1160] The compound of any one of embodiments 1 and 5-357, wherein 587.L 2 but

[1161] [ka]

[1162] The compound of any one of embodiments 1 and 5-357, wherein 588.L 2 but

[1163] [ka]

[1164] The compound of any one of embodiments 1 and 5-357, wherein 589.L 2 but

[1165] [ka]

[1166] The compound of any one of embodiments 1 and 5-357, wherein 590.L 2 but

[1167] [ka]

[1168] The compound of any one of embodiments 1 and 5-357, wherein 591.L 2 but

[1169] [ka]

[1170] The compound of any one of embodiments 1 and 5-357, wherein 592.L 2 but

[1171] [ka]

[1172] The compound of any one of embodiments 1 and 5-357, wherein 593. A compound selected from the following or a salt thereof:

[1173] [Table 2-1]

[1174] [Table 2-2]

[1175] [Table 2-3]

[1176] [Table 2-4]

[1177] [Table 2-5]

[1178] Table 2-6

[1179] Table 2-7

[1180] Table 2-8

[1181] Table 2-9

[1182] Table 2-10

[1183] Table 2-11

[1184] Table 2-12

[1185] Table 2-13

[1186] Table 2-14

[1187] Table 2-15

[1188] Table 2-16

[1189] Table 2-17

[1190] Table 2-18

[1191] Table 2-19

[1192] Table 2-20

[1193] Table 2-21

[1194] Table 2-22

[1195] Table 2-23

[1196] Table 2-24

[1197] Table 2-25

[1198] Table 2-26

[1199] [Table 2-27] 594. The compound according to any one of the preceding embodiments, wherein the compound is a pharmaceutically acceptable salt. 595. The compound according to any one of the preceding embodiments, wherein the compound has an enantiomeric purity of about 80% or greater. 596. The compound according to any one of the preceding embodiments, wherein the compound has an enantiomeric purity of about 90% or greater. 597. The compound according to any one of the preceding embodiments, wherein the compound has an enantiomeric purity of about 95% or greater. 598. The compound according to any one of the preceding embodiments, wherein the compound has an enantiomeric purity of about 98% or greater. 599. The compound of any one of the preceding embodiments, wherein the compound has a purity of about 90% or greater. 600. The compound of any one of the preceding embodiments, wherein the compound has a purity of about 95% or greater. 601. The compound of any one of the preceding embodiments, wherein the compound has a purity of about 98% or greater. 602. The compound of any one of the preceding embodiments, wherein the compound has a purity of about 98% or greater. 603. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments and a pharmaceutically acceptable carrier. 604. A method for treating a condition, disorder, or disease, comprising administering to a subject suffering from the condition, disorder, or disease an effective amount of a compound or pharmaceutical composition according to any one of embodiments 1 to 603. 605. A method for treating a condition, disorder, or disease, comprising delivering to a subject suffering from the condition, disorder, or disease an effective amount of a compound or pharmaceutical composition according to any one of embodiments 1 to 603. 606. A method for preventing a condition, disorder, or disease, comprising administering to a subject susceptible to the condition, disorder, or disease an effective amount of a compound or pharmaceutical composition according to any one of embodiments 1-603. 607. A method for preventing a condition, disorder, or disease, comprising delivering to a subject susceptible to the condition, disorder, or disease an effective amount of a compound or pharmaceutical composition according to any one of embodiments 1-603. 608. The method of any one of embodiments 604-607, wherein the condition, disorder, or disease is associated with TRPV3. 609. The method of any one of embodiments 604-607, wherein said condition, disorder, or disease is regulated by TRPV3. 610. The method of any one of embodiments 604-607, wherein the compound or pharmaceutical composition is administered in combination with one or more additional compounds or agents. 611. The method of any one of embodiments 604-607, wherein the compound or pharmaceutical composition is delivered in combination with one or more additional compounds or agents. 612. The method of any one of embodiments 604-611, wherein the condition, disorder, or disease is or comprises migraine, arthralgia, cardiac pain due to ischemic myocardium, acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, neuralgia pain (e.g., post-herpetic neuralgia, traumatic neuralgia, fibromyalgia, trigeminal neuralgia), diabetic neuropathy pain, dental pain, cancer pain, or an inflammatory pain condition (e.g., arthritis and osteoarthritis). 613. A method wherein the condition, disorder or disease is or comprises neuropathic pain, nociceptive pain, toothache, HIV pain, cardiac pain due to ischemic myocardium, migraine pain, joint pain, neuropathy, neurodegeneration, retinopathy, neurocutaneous disorders, stroke, bladder overload, urinary incontinence, vulvodynia, gastrointestinal disorders such as irritable bowel syndrome, inflammatory diseases such as gastroesophageal reflux disease, enteritis, ileitis, gastroduodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, pancreatitis, respiratory diseases such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, inflammation of the skin, eyes or mucous membranes. 612. The method of any one of embodiments 604-611, wherein the treatment is or comprises mucous membranes, atopic dermatitis, eczema itching, fever, muscle spasms, vomiting, dyskinesia, depression, Huntington's disease, memory impairment, brain function limitation, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, hyperkeratosis gravis, alopecia, Meniere's disease, tinnitus, hyperacusis, anxiety disorder, or benign prostatic hyperplasia. 614. The method of any one of embodiments 604-611, wherein the condition, disorder, or disease is or comprises atopic dermatitis, eczema, seborrheic dermatitis, pruritus, dermatitis, or psoriasis. 615. The method of any one of embodiments 604-611, wherein the condition, disorder, or disease is acne. 616. The method of any one of embodiments 604-611, wherein the condition, disorder or disease is rosacea. 617. The method of any one of embodiments 604-611, wherein the condition, disorder or disease is pain. 618. The method of any one of embodiments 604-611, wherein the condition, disorder or disease is itch. 619. The method of any one of embodiments 604-611, wherein the condition, disorder or disease is dermatitis. 620. The method of any one of embodiments 604-611, wherein the condition, disorder, or disease comprises or is hair loss. 621. The method of any one of embodiments 604-611, wherein the condition, disorder, or disease comprises or is keratosis. 622. The method of any one of embodiments 604-621, wherein the compound or composition is administered or delivered orally. 623. The method of any one of embodiments 604-621, wherein the compound or composition is administered or delivered locally. 624. A method, including: A compound having the structure of formula (5):

[1200] [ka]

[1201] or a salt thereof to form a compound having the structure of Formula I:

[1202] [ka]

[1203] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 625. A method including: A compound having the structure of formula (5):

[1204] [ka]

[1205] or a salt thereof, 3 -LG, or a salt thereof, to produce a compound having the structure of Formula I:

[1206] [ka]

[1207] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 626. A method including: A compound having the structure of formula (4):

[1208] [ka]

[1209] or a salt thereof to produce a compound having the structure of formula (5):

[1210] [ka]

[1211] where each variable is independently as described in any one of the preceding embodiments. 627. A method including: A compound having the structure of formula (4):

[1212] [ka]

[1213] or a salt thereof,

[1214] [ka]

[1215] or a salt or activated derivative thereof, or [ka]

[1216] or a salt thereof to produce a compound having the structure of formula (5):

[1217] [ka]

[1218] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 628. A compound or method according to any one of the preceding embodiments, wherein LG is a halogen. 629. A compound or method according to any one of the preceding embodiments, wherein LG is -Cl. 630. A compound or method according to any one of the preceding embodiments, wherein LG is -Br. 631. A compound or method according to any one of the preceding embodiments, wherein LG is -I. 632. The method of any one of embodiments 624-625, including the method of any one of embodiments 626-631. 633. A method including: A compound having the structure of formula (3):

[1219] [ka]

[1220] or a salt thereof to produce a compound having the structure of formula (4):

[1221] [ka]

[1222] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 634. A method including: A compound having the structure of formula (3):

[1223] [ka]

[1224] or a salt thereof with thiourea or a salt thereof, or selenourea or a salt thereof to produce a compound having the structure of formula (4):

[1225] [ka]

[1226] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 635. The method of any one of embodiments 624 to 634, including the method of embodiment 633 or 634. 636. A method including: A compound having the structure of formula (2):

[1227] [ka]

[1228] or a salt thereof to produce a compound having the structure of formula (3):

[1229] [ka]

[1230] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 637. The method of any one of embodiments 624 to 635, including the method of embodiment 636. 638. A method including: A compound having the structure of formula (2):

[1231] [ka]

[1232] or a salt thereof to produce a compound having the structure of formula (4):

[1233] [ka]

[1234] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 639. The method of any one of embodiments 624 to 630, including the method of embodiment 638. 640. A method comprising: A compound having the structure of formula (1):

[1235] [ka]

[1236] or a salt thereof to produce a compound having the structure of formula (2):

[1237] [ka]

[1238] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 641. A method including: A compound having the structure of formula (1):

[1239] [ka]

[1240] or a salt thereof, 4 C(O)R 5 or a salt thereof to produce a compound having the structure of formula (2):

[1241] [ka]

[1242] or a salt thereof, wherein each variable is independently as described in any one of the preceding embodiments. 642. The method of any one of embodiments 624 to 639, including the method of embodiment 640 or 641. 643. A method for preparing a compound of any one of embodiments 1-602, comprising the method of any one of embodiments 624-642. 644. A compound or composition prepared by the method of any one of embodiments 624-642. 645. A compound, composition, or method described herein. Example

[1243] This specification describes specific examples of the provided technology (e.g., compounds, compositions, methods (methods of preparation, methods of use, methods of evaluation, etc.), etc.). One of skill in the art reading this disclosure will understand that a variety of techniques, including the techniques described below, as well as modifications, variations, and derivatives thereof, are available for making, characterizing, and / or evaluating the provided technology in accordance with this disclosure.

[1244] Specific abbreviations used in the examples below: EA = ethyl acetate; DMF = N,N-dimethylformamide; Dess-Martin periodinane = 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one; DCM = dichloromethane; THF = tetrahydrofuran LAH = lithium aluminum hydride DME = 1,2-dimethoxyethane; TEA = triethylamine EIPEA = ethyldiisopropylamine; DEAD = diethyl azodicarboxylate; DIAD = diisopropyl azodicarboxylate; HATU = 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; EDCI = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HOBt = 1-hydroxybenzotriazole; DIBAL-H = diisobutylaluminum hydride; Bn = benzyl; DMSO = dimethyl sulfoxide; RT=room temperature; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; NCS = N-chlorosuccinimide; LiHMDS = lithium bis(trimethylsilyl)amide; DMAP = 4-dimethylaminopyridine; n-BuLi = n-butyllithium; ACN = acetonitrile; TCFH = chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; NMI = 1-methylimidazole;

[1245] Specific Useful Materials and Experiments: Various reagents are reported and purchased from commercial suppliers (e.g., Sigma-Aldrich, Alfa, Across, etc.) and can be used without further purification unless otherwise noted. THF can be continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen, and DCM can be continuously refluxed and freshly distilled from CaH under nitrogen. In some embodiments, reactions were monitored by TLC, e.g., silica gel 60HSGF254 percolate plates (0.15-0.2 mm SiO2), and visualized by staining with UV light and / or DNP solution (12 g 2,4-dinitrophenylhydrazine, 60 mL H2SO4 concentrate, 80 mL HO, 200 mL EtOH), followed by heating. In some embodiments, the reaction is monitored by LCMS (e.g., Chromolith SpeedROD, RP-18e, 50x4.6 mm, mobile phase: Solvent A: CHCN / H2O / HCOOH = 10 / 90 / 0.05, Solvent B: CHCN / H2O / HCOOH = 90 / 10 / 0.05, 0.8 min @ 10% B, 2.7 min gradient (10-95% B), then 0.8 min @ 95% B, flow rate: 3 mL / min, temperature: 40°C; and Chromolith SpeedROD, RP-18e, 50x4.6 mm, mobile phase: Solvent A: CHCN / H2O / HCOOH = 10 / 90 / 0.05, Solvent B: CHCN / H2O / HCOOH = 90 / 10 / 0.05, 0.8 min @10% B, 2.7 min gradient (10-95% B), then 0.8 min @ 95% B, flow rate: 3 mL / min, temperature: 40°C. In some embodiments, separation was performed by Prep-HPLC (Column: Xbridge BEHC18 OBD column, 5 uM, 10 mm x 250 mm, Mobile phase: [water (0.05% FA)-ACN], B%: 10%-90% over 20 min). In some embodiments, separation was performed by Prep-TLC (NuoTai® pre-coated silica gel 60F254 plates, visualization under UV (λ254 nm, λ366 nm). In some embodiments, 1H spectra were recorded on a JEOL® 400 MHz. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane (δ = 0.000 ppm), and spectra were calibrated to the residual solvent signal of chloroform (δ = 7.26 for 1H). 1 H NMR spectral data are reported as chemical shifts (multiplicity, number of hydrogens). The abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), quant (quintet), m (multiple), and br (broad).

[1246] Useful Procedures: In some embodiments, compounds of formula (I) can be prepared using one or more of the steps set forth below, where each variable is independently as described herein.

[1247] [ka]

[1248] In some embodiments, ketone compound (1) can be contacted with a ketone or aldehyde to prepare ketone (2), which can then be treated with a halogen (e.g., Br, I, etc.) to provide haloketone (3). Haloketone compound (3) can be contacted with a thiourea or selenourea reactant to prepare amine (4). Ketone compound (2) can be contacted with a halogen (e.g., Br, I, etc.) reactant to prepare amine (4) in a one-pot reaction. In some embodiments, halo is chloro, bromo, or iodo. The cyclization reaction can be carried out in a solvent such as an alcohol (e.g., methanol, ethanol, etc.) at room temperature or at an elevated temperature (e.g., above about 40°C, e.g., about 60°C to about 70°C), optionally with stirring.

[1249] Amine (4) can be contacted with suitable reactants (e.g., those described in the Examples) to give compound (5). In some embodiments, the coupling reaction can be carried out in a solvent such as methylene chloride, and / or THF, and / or DMF at room temperature or at elevated temperatures (e.g., above about 40°C, e.g., about 60°C to about 70°C), optionally with stirring. In some embodiments, N-alkylation of compound (5) can be carried out, for example, by reacting R 3 I or R 3Br to provide a compound having the structure of formula (I) or a salt thereof.

[1250] Below are given specific examples of the preparation of particular compounds.

[1251] Example 1: 4,6-Dimethoxy-N-(7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-yl)pyrimidine-5-carboxamide

[1252] [ka]

[1253] Example 1A: 7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-amine

[1254] [ka]

[1255] To a stirred solution of 7-(trifluoromethyl)chroman-4-one (50 mg, 0.23 mmol, 1.00 equiv.) in EtOH (1 mL), thiourea (53 mg, 0.69 mmol, 3.00 equiv.) and iodine (71 mg, 0.28 mmol, 1.20 equiv.) were added at room temperature. The resulting mixture was stirred at 100° C. overnight. After cooling to room temperature, the resulting mixture was extracted with EA (2×10 mL). The combined organic layers were washed with 1N NaOH (1×3 mL) and brine (1×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA=4:1) to give the title compound (13 mg, 21%) as a yellow solid. ESI-MS m / z=272.93 [M+H] + ;Calculated MW: 272.02.

[1256] Example 1B: 4,6-Dimethoxy-N-(7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-yl)pyrimidine-5-carboxamide

[1257] [ka]

[1258] To a suspension of 4,6-dimethoxypyrimidine-5-carboxylic acid (11 mg, 0.057 mmol, 1.20 equiv.) in CHCl (0.5 mL) and a catalytic amount of DMF, oxalyl chloride (12 mg, 0.095 mmol, 2.0 equiv.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and dissolved in CHCl (0.5 mL). 7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-amine (13 mg, 0.048 mmol, 1.0 equiv.), TEA (84 mg, 0.191 mmol, 4.0 equiv.), and DMAP (0.58 mg, 0.0048 mmol, 0.1 equiv.) were added, and the mixture was stirred at room temperature overnight. The resulting mixture was extracted with EA (2 × 10 mL) and washed with saturated NaHCO (1 × 5 mL). The combined organic layer was washed with saturated brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 3:1) to give the title compound (10 mg, 62%) as a yellow solid. ESI-MS m / z = 438.98 [M+H] + ;Calculated MW: 438.06. 1 H NMR (400 MHz, chloroform-d) δ 11.09 (s, 1H), 8.32 (s, 1H), 7.58 (dd, J = 8.2, 1.1 Hz, 1H), 7.16 (d, J = 6.6 Hz, 2H), 5.50 (s, 2H), 3.99 (s, 6H).

[1259] Example 2: N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1260] [ka]

[1261] Example 2A: 4,5-dihydronaphtho[1,2-d]thiazol-2-amine

[1262] [ka]

[1263] To a solution of 3,4-dihydronaphthalen-1(2H)-one (100 mg, 0.68 mmol, 1.00 equiv) in EtOH (1 mL) was added thiourea (156 mg, 2.05 mmol, 3.00 equiv) and iodine (209 mg, 0.82 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the resulting mixture was extracted with EA (2 × 15 mL). The combined organic layer was washed with 1 N NaOH (1 × 5 mL) and brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to afford the title compound (100 mg, 72%) as a purple solid. 1 H NMR (400 MHz, chloroform-d) δ 7.69-7.64 (m, 1H), 7.24-7.21 (m, 1H), 7.18-7.10 (m, 2H), 4.92 (s, 2H), 3.01 (dd, J = 8.8, 6.8 Hz, 2H), 2.91-2.77 (m, 2H).

[1264] Example 2B: N-(4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1265] [ka]

[1266] To a suspension of 4,6-dimethoxypyrimidine-5-carboxylic acid (27 mg, 0.148 mmol, 1.20 equiv.) in CHCl (0.5 mL) and a catalytic amount of DMF, oxalyl chloride (32 mg, 0.248 mmol, 2.0 equiv.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated in vacuo and dissolved in CHCl (0.5 mL). 4,5-dihydronaphtho[1,2-d]thiazol-2-amine (25 mg, 0.124 mmol, 1.0 equiv.), TEA (50 mg, 0.495 mmol, 4.0 equiv.), and DMAP (1.5 mg, 0.012 mmol, 0.1 equiv.) were added, and the mixture was stirred at room temperature overnight. The resulting mixture was then extracted with EA (2 × 10 mL) and washed with saturated NaHCO (1 × 5 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to give the title compound (4.8 mg, 11%) as a yellow solid. ESI-MS m / z = 369.06 [M+H] + ;Calculated MW: 368.09. 1 H NMR (400 MHz, chloroform-d) δ 11.80 (s, 1H), 8.13 (s, 1H), 7.57-7.48 (m, 1H), 7.19-7.12 (m, 3H), 3.86 (s, 6H), 3.08-2.90 (m, 4H).

[1267] Example 3: N-(8-chloro-4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1268] [ka]

[1269] Example 3A: 8-chloro-4,5-dihydronaphtho[1,2-d]thiazol-2-amine

[1270] [ka]

[1271] To a solution of 7-chloro-3,4-dihydronaphthalen-1(2H)-one (100 mg, 0.56 mmol, 1.00 equiv) in EtOH (1 mL) was added thiourea (127 mg, 1.67 mmol, 3.00 equiv) and iodine (169 mg, 0.67 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the resulting mixture was extracted with EA (2 × 15 mL). The combined organic layer was washed with 1 N NaOH (1 × 5 mL) and brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to afford the title compound (100 mg, 31%) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ 7.66(d, J=1.8Hz, 1H), 7.13-7.04(m, 2H), 4.87(s, 2H), 2.97(dd, J=9.1, 6.9Hz, 2H), 2.88-2.79(m, 2H).

[1272] Example 3B: N-(8-chloro-4,5-dihydronaphtho[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1273] [ka]

[1274] To a suspension of 4,6-dimethoxypyrimidine-5-carboxylic acid (24 mg, 0.127 mmol, 1.20 equiv.) in CHCl (0.5 mL) and catalytic DMF, oxalyl chloride (27 mg, 0.212 mmol, 2.0 equiv.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo, dissolved in CHCl (0.5 mL), and 8-chloro-4,5-dihydronaphtho[1,2-d]thiazol-2-amine (25 mg, 0.106 mmol, 1.0 equiv.), TEA (43 mg, 0.424 mmol, 4.0 equiv.), and DMAP (1.3 mg, 0.011 mmol, 0.1 equiv.) were added and stirred at room temperature overnight. The resulting mixture was extracted with EA (2 × 10 mL) and washed with saturated NaHCO (1 × 5 mL). The combined organic layer was washed with saturated brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to give the title compound (7.7 mg, 18%) as a yellow solid. ESI-MS m / z = 403.04 [M+H] + ;Calculated MW: 402.05. 1 H NMR (400 MHz, chloroform-d) δ 12.00 (s, 1H), 8.09 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.11 (t, J = 1.6 Hz, 2H), 3.83 (s, 6H), 3.03-2.91 (m, 4H).

[1275] Example 4: N-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1276] [ka]

[1277] Example 4A: 5,6-Dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-amine

[1278] [ka]

[1279] To a solution of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (100 mg, 0.625 mmol, 1.00 equiv.) in EtOH (1 mL) was added thiourea (143 mg, 1.875 mmol, 3.00 equiv.) and iodine (191 mg, 0.75 mmol, 1.20 equiv.) at room temperature. The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the resulting mixture was extracted with EA (2 × 15 mL). The combined organic layer was washed with 1 N NaOH (1 × 5 mL) and brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to afford the title compound (47 mg, 35%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.89 (dd, J = 7.6, 1.3 Hz, 1H), 7.25-7.22 (m, 1H), 7.19-7.11 (m, 2H), 4.85 (s, 2H), 2.84-2.78 (m, 4H), 2.12 (dtd, J = 11.7, 7.0, 6.4, 2.7 Hz, 2H).

[1280] Example 4B: N-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1281] [ka]

[1282] To a suspension of 4,6-dimethoxypyrimidine-5-carboxylic acid (26 mg, 0.139 mmol, 1.20 equiv.) in CHCl (0.5 mL) and catalytic DMF, oxalyl chloride (29 mg, 0.231 mmol, 2.0 equiv.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and dissolved in CHCl (0.5 mL). 5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-amine (25 mg, 0.116 mmol, 1.0 equiv.), TEA (47 mg, 0.463 mmol, 4.0 equiv.), and DMAP (1.4 mg, 0.012 mmol, 0.1 equiv.) were added, and the mixture was stirred at room temperature overnight. The resulting mixture was extracted with EA (2 × 10 mL) and washed with saturated NaHCO (1 × 5 mL). The combined organic layer was washed with saturated brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to give the title compound (9.8 mg, 22%) as a yellow solid. ESI-MS m / z = 383.09 [M+H] + ;Calculated MW: 382.11. 1 H NMR (400 MHz, chloroform-d) δ 12.45 (s, 1H), 8.14 (s, 1H), 7.77-7.65 (m, 1H), 7.17-7.08 (m, 3H), 3.74 (s, 6H), 2.94 (t, J = 7.1 Hz, 2H), 2.82-2.69 (m, 2H), 2.25-2.09 (m, 2H).

[1283] Example 5: N-(8-chloro-4H-thiochromeno[4,3-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1284] [ka]

[1285] Example 5A: 8-chloro-4H-thiochromeno[4,3-d]thiazol-2-amine

[1286] [ka]

[1287] To a stirred solution of 6-chlorothiochroman-4-one (100 mg, 0.505 mmol, 1.00 equiv) in EtOH (1 mL) was added thiourea (115 mg, 1.515 mmol, 3.00 equiv) and iodine (154 mg, 0.606 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the resulting mixture was extracted with EA (2 × 15 mL). The combined organic layers were washed with 1 N NaOH (1 × 5 mL) and brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to afford the title compound (47 mg, 16%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.78 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.07 (dd, J = 8.3, 2.3 Hz, 1H), 4.92 (s, 2H), 3.99 (s, 2H).

[1288] Example 5B: N-(8-chloro-4H-thiochromeno[4,3-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1289] [ka]

[1290] To a suspension of 4,6-dimethoxypyrimidine-5-carboxylic acid (17 mg, 0.094 mmol, 1.20 equiv.) in CHCl (0.5 mL) and a catalytic amount of DMF, oxalyl chloride (20 mg, 0.157 mmol, 2.0 equiv.) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated in vacuo and dissolved in CHCl (0.5 mL). 8-chloro-4H-thiochromeno[4,3-d]thiazol-2-amine (20 mg, 0.079 mmol, 1.0 equiv.), TEA (32 mg, 0.315 mmol, 4.0 equiv.), and DMAP (1 mg, 0.0079 mmol, 0.1 equiv.) were added, and the mixture was stirred at room temperature overnight. The resulting mixture was then extracted with EA (2 × 10 mL) and washed with saturated NaHCO (1 × 5 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to give the title compound (9.8 mg, 8%) as a yellow solid. ESI-MS m / z = 420.97 [M+H] + ;Calculated MW: 420.01. 1 H NMR (400 MHz, chloroform-d) δ 8.45 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 8.3, 2.3 Hz, 1H), 4.13 (s, 2H), 4.10 (s, 6H).

[1291] Example 6: N-(7-bromo-4H-chromeno[4,3-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1292] [ka]

[1293] Example 6A: 7-Bromo-4H-chromeno[4,3-d]thiazol-2-amine

[1294] [ka]

[1295] To a stirred solution of 6-chlorothiochroman-4-one (100 mg, 0.442 mmol, 1.00 equiv.) in EtOH (1 mL), thiourea (101 mg, 1.327 mmol, 3.00 equiv.) and iodine (134 mg, 0.529 mmol, 1.20 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the resulting mixture was extracted with EA (2 × 15 mL). The combined organic layers were washed with 1 N NaOH (1 × 5 mL) and brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to give the title compound (20 mg, 16%) as a yellow solid. ESI-MS m / z = 282.92 [M+H] + ;Calculated MW: 281.94.

[1296] Example 6B: N-(7-bromo-4H-chromeno[4,3-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1297] [ka]

[1298] To a solution of 7-bromo-4H-chromeno[4,3-d]thiazol-2-amine (5 mg, 0.035 mmol, 1.00 equiv.), 4,6-dimethoxypyrimidine-5-carboxylic acid (16 mg, 0.089 mmol, 2.50 equiv.), and NMI (15 mg, 0.177 mmol, 5.00 equiv.) in ACN (0.2 mL) and DMF (0.2 mL) was added TCFH (25 mg, 0.089 mmol, 2.50 equiv.) at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was then extracted with EA (2 × 10 mL). The combined organic layer was washed with saturated NaHCO (1 × 5 mL) and brine (1 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA=4:1) to give the title compound (3.3 mg, 21%) as a yellow solid. ESI-MS m / z=448.97 [M+H] +;Calculated MW: 447.98.

[1299] 1 H NMR (400 MHz, chloroform-d) δ 10.87 (s, 1H), 8.37 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.09-7.03 (m, 2H), 5.44 (s, 2H), 4.02 (s, 6H).

[1300] Example 7: N-(5-chloro-8H-indeno[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1301] [ka]

[1302] Example 7A: 5-chloro-8H-indeno[1,2-d]thiazol-2-amine

[1303] [ka]

[1304] To a solution of 6-chloro-2,3-dihydro-1H-inden-1-one (100 mg, 0.602 mmol, 1.00 equiv.) in EtOH (1 mL) was added thiourea (137 mg, 1.807 mmol, 3.00 equiv.) and iodine (184 mg, 0.723 mmol, 1.20 equiv.) at room temperature. The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the resulting mixture was extracted with EA (2 × 15 mL). The combined organic layer was washed with 1 N NaOH (1 × 5 mL) and saturated brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA = 4:1) to give the title compound (25 mg, 19%) as a yellow solid. ESI-MS m / z = 222.96 [M+H] + ;Calculated MW: 222.00.

[1305] Example 7B: N-(5-chloro-8H-indeno[1,2-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1306] [ka]

[1307] To a solution of 5-chloro-8H-indeno[1,2-d]thiazol-2-amine (15 mg, 0.068 mmol, 1.00 equiv.), 4,6-dimethoxypyrimidine-5-carboxylic acid (31 mg, 0.169 mmol, 2.50 equiv.), and NMI (28 mg, 0.338 mmol, 5.00 equiv.) in ACN (0.2 mL) and DMF (0.2 mL) was added TCFH (48 mg, 0.169 mmol, 2.50 equiv.) at 0 °C. The resulting mixture was stirred at room temperature overnight, and then extracted with EA (2 × 10 mL). The combined organic layer was washed with saturated NaHCO (1 × 5 mL) and brine (1 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by pre-TLC (PE:EA=4:1) to give the title compound (5.1 mg, 19%) as a yellow solid. ESI-MS m / z=389.00 [M+H] + ;Calculated MW: 388.04. 1 H NMR (400MHz, chloroform-d) δ10.99(s,1H),8.28(s,1H),7.45-7.36(m,2H),7.19(dd,J=8.0,2.0Hz,1H),4.02(s,6H),3.81(d,J=0.8Hz,2H).

[1308] Example 8: N-(4,4-dimethyl-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1309] [ka]

[1310] Example 8A: 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethan-1-one

[1311] [ka]

[1312] To a stirred solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (1.00 g, 4.85 mmol, 1.00 equiv.) in THF (10.00 mL) was added MeLi (9.1 mL, 14.56 mmol, 3.00 equiv., 1.6 M in diethoxymethane) in small portions at 0 °C. The resulting mixture was stirred at room temperature under an argon atmosphere for 4 h. The pH of the resulting mixture was adjusted to 5 with HCl (1 M) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to afford the title compound (780 mg, 78% yield) as a colorless liquid. 1 H NMR (400 MHz, chloroform-d) δ 12.27 (s, 1H), 7.87-7.81 (m, 1H), 7.25-7.23 (m, 1H), 7.13 (ddd, J = 8.3, 1.8, 0.7 Hz, 1H), 2.67 (s, 3H).

[1313] Example 8B: 2,2-Dimethyl-7-(trifluoromethyl)chroman-4-one

[1314] [ka]

[1315] To a stirred solution of 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethan-1-one (130.0 mg, 0.637 mmol, 1.00 equiv) and propan-2-one (37 mg, 0.637 mmol, 1.00 equiv) in MeOH (2.00 mL) was added pyrrolidine (91.0 mg, 1.27 mmol, 2.00 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature under an argon atmosphere for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE / EtOAc (10:1)) to afford the title compound (115 mg, 74% yield) as a pale yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.93 (dp, J = 7.9, 1.0 Hz, 1H), 7.21-7.16 (m, 2H), 2.75 (s, 2H), 1.46 (s, 6H).

[1316] Example 8C: 4,4-dimethyl-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-amine

[1317] [ka]

[1318] To a 10 mL round-bottom flask, 2,2-dimethyl-7-(trifluoromethyl)chroman-4-one (115 mg, 0.471 mmol, 1.00 equiv.), EtOH (2 mL), thiourea (107 mg, 1.41 mmol, 3.00 equiv.), and I2 (144 mg, 0.565 mmol, 1.20 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under an argon atmosphere for 16 h. The resulting mixture was cooled to room temperature, adjusted to pH 9 with 1 M NaOH, and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE / ethyl acetate (2:1)) to give the title compound (15 mg, 10% yield) as a pale yellow solid. ESI-MS m / z = 301.03 [M+H] + ;Calculated MW: 300.05.

[1319] Example 8D: N-(4,4-dimethyl-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-yl)-4,6-dimethoxypyrimidine-5-carboxamide

[1320] [ka]

[1321] To a solution of 4,6-dimethoxypyrimidine-5-carboxylic acid (10.0 mg, 0.055 mmol, 1.10 equiv) in DCM (1.00 mL) was added (COCl) (14.0 mg, 0.011 mmol, 2.20 equiv) and DMF (1 mg) in DCM (0.1 mL) portionwise at 0° C. The resulting mixture was stirred at room temperature under an argon atmosphere for 3 hours and concentrated under reduced pressure. A solution of 4,4-dimethyl-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-amine (15.0 mg, 0.050 mmol, 1.00 equiv.), TEA (20.0 mg, 0.200 mmol, 4.00 equiv.), and DMAP (6.0 mg, 0.050 mmol, 1.00 equiv.) in DCM (1.00 mL) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature under an argon atmosphere for 16 h. The reaction mixture was diluted with DCM (20 mL), washed with water (2 × 5 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE / EtOAc 3:1) to afford the title compound (5.5 mg, 23% yield) as an off-white solid. ESI-MS m / z = 467.09 [M+H] + ;Calculated MW: 466.09; 1 H NMR (400 MHz, chloroform-d) δ 11.35 (s, 1H), 8.26 (s, 1H), 7.52 (dd, J = 7.9, 1.0 Hz, 1H), 7.16-7.07 (m, 2H), 3.94 (s, 6H), 1.72 (s, 6H).

[1322] Example 9: 4,6-Dimethoxy-N-(4-oxo-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-yl)pyrimidine-5-carboxamide

[1323] [ka]

[1324] Example 9A: Ethyl 3-(2-hydroxy-4-(trifluoromethyl)phenyl)-3-oxopropanoate

[1325] [ka]

[1326] To a stirred solution of NaH (330.0 mg, 7.84 mmol, 4.00 equiv) in diethyl carbonate (1.50 mL) was added 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethan-1-one (400.0 mg, 1.96 mmol, 1.00 equiv) in diethyl carbonate (1.50 mL) dropwise at 0 °C. The resulting mixture was stirred at 80 °C for 16 h under an argon atmosphere. The reaction was diluted with water (50 mL), adjusted to pH 5 with 1 M HCl (aq), and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EtOAc (10:1) to afford the title compound (370 mg, 68% yield) as a pale yellow oil. 1 H NMR (400MHz, chloroform-d) δ11.88(s, 1H), 7.83-7.76(m, 1H), 7.27(dt, J=1.9, 0.6Hz, 1H), 7.15(ddd , J=8.4, 1.8, 0.7Hz, 1H), 4.21(dq, J=12.3, 7.2Hz, 2H), 4.02(s, 2H), 1.27(td, J=7.2, 1.9Hz, 3H).

[1327] Example 9B: 7-(trifluoromethyl)chroman-2,4-dione

[1328] [ka]

[1329] To a stirred solution of ethyl 3-(2-hydroxy-4-(trifluoromethyl)phenyl)-3-oxopropanoate (270.0 mg, 0.978 mmol, 1.00 equiv.) in EtOH (5 mL) was added NaOH (78.0 mg, 1.956 mmol, 2.00 equiv.) in portions at 0 °C. The resulting mixture was stirred at 80 °C under an argon atmosphere for 3 h. The reaction was cooled to room temperature, diluted with water (40 mL), adjusted to pH 5 with 1 M HCl (aq.), and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. 1 H NMR (400MHz, DMSO-d6) δ 7.98 (d, J=8.2Hz, 1H), 7.76 (d, J=1.7Hz, 1H), 7.65 (dd, J=8.5, 1.7Hz, 1H), 5.66 (s, 1H).

[1330] Example 9C: 2-amino-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-4-one

[1331] [ka]

[1332] A 10 mL round-bottom flask was charged with 7-(trifluoromethyl)chroman-2,4-dione (180 mg, 0.783 mmol, 1.00 equiv.), EtOH (2 mL), thiourea (180 mg, 2.34 mmol, 3.00 equiv.), and I2 (240 mg, 0.939 mmol, 1.20 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under an argon atmosphere. The resulting mixture was cooled to room temperature, adjusted to pH 9 with 1 M NaOH, and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-TLC (PE / EtOAc (2:1)) to afford the title compound (15 mg, 6.6% yield) as a pale yellow solid.

[1333] Example 9D: 4,6-Dimethoxy-N-(4-oxo-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-2-yl)pyrimidine-5-carboxamide

[1334] [ka]

[1335] To a solution of 4,6-dimethoxypyrimidine-5-carboxylic acid (12.0 mg, 0.063 mmol, 1.20 equiv) in DCM (1.00 mL) was added a solution of (COCl) (16.0 mg, 0.125 mmol, 2.40 equiv) and DMF (1 mg) in DCM (0.1 mL) in small portions at 0° C. The resulting mixture was stirred at room temperature under an argon atmosphere for 3 h, then concentrated under reduced pressure and dissolved in DCM (1 mL). A solution of 2-amino-7-(trifluoromethyl)-4H-chromeno[4,3-d]thiazol-4-one (15.0 mg, 0.052 mmol, 1.00 equiv.), TEA (22.0 mg, 0.209 mmol, 4.00 equiv.), and DMAP (10.0 mg, 0.024 mmol, 0.50 equiv.) in DCM (1.00 mL) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature under an argon atmosphere for 16 h. The reaction mixture was diluted with DCM (20 mL), washed with water (2 × 5 mL), and dr...

Claims

1. The compound has the structure of Formula I: 【Chemistry 1】 or a salt thereof, wherein Ring A is an optionally substituted 5- to 6-membered aromatic ring having 0-4 heteroatoms, or 【Chemistry 2】 and X １ , X ２ａ , X ２ｂ , and X ２ｃ are each independently -N=, -C(R ２ )=, or optionally substituted —CH=; X １ａ is -O-, -S-, -N(R')-, -C(R') ２ - or optionally substituted -CH ２ - or -NH-, X ３ is —O—, —S—, —Se—, —N(R′)—, or optionally substituted —NH—; X ４ , X ５ , X ６ , X ７ , and X ８ are each independently -N=, -C(R ６ )=, or optionally substituted —CH=; R １ , R ２ , R ｓ and R ６ are each independently a halogen, -CN, or -NO ２ , -L-R', -OR', -N(R') ２ , -N(R')C(O)OR', -C(O)R', -C(O)OR', -C(O)N(R') ２ or —OC(O)N(R′) ２ and L １ is a covalent bond, -C(O)-, -C(S)-, -S(O) ２ -, -N(R')C(O)-, -N(R')S(O) ２ -, -N(R')C(S)-, or 【Transformation 3】 and R ３ , R ４ and R ５ are each independently R'; L and L ２ each independently represents an optionally substituted C １ - ３ alkylene, provided that one or more methylene units of said alkylene are optionally and independently selected from -O-, -S-, -C(R ４ ) (R ５ ) -, -N(R ４ )-, optionally substituted -CH=N-, optionally substituted -CH=CH-, or -Cy-; Each -Cy- is independently 【Chemistry 4】 wherein Ring B is an optionally substituted saturated or partially saturated 3- to 10-membered ring having 0-4 heteroatoms; t is 0, 1, 2, 3, or 4; Each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O) ２ R, Each R is independently hydrogen or C １ -C １０ Aliphatic, C with 1-3 heteroatoms １ -C １０ Heteroaliphatic, 3- to 10-membered cyclic aliphatic, 3- to 10-membered heterocyclyl having 1-4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1-6 heteroatoms, 6- to 10-membered aryl-C １ -C １０ Aliphatic and 5-10 membered heteroaryl-C having 1-6 heteroatoms １ -C １０ an optionally substituted group selected from aliphatic, or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3- to 10-membered ring having, in addition to the atom, 0-4 heteroatoms; or A compound characterized in that two R groups on two atoms are optionally and independently joined together with their intervening atoms to form an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms.

2. The compound according to claim 1, wherein ring A is an optionally substituted 5- to 6-membered heteroaryl ring having 1, 2, 3, or 4 heteroatoms.

3. Ring A may be optionally substituted 【Transformation 5】 3. The compound according to claim 1 or 2, characterized in that it is

4. X １ -N= or -C(R ２ 4. The compound according to claim 1, wherein:

5. X ２ａ -N= or -C(R ２ 5. The compound according to claim 1, wherein:

6. X ２ｂ -N= or -C(R ２ 6. The compound according to claim 1, wherein:

7. X ２ｃ -N= or -C(R ２ 7. The compound according to claim 1, wherein:

8. X １ａ is -N(R')-, -O-, -S-, or -C(R') ２ The compound according to any one of claims 1 to 7, characterized in that:

9. Ring A is 【Transformation 6】 The compound according to any one of claims 1 to 8, characterized in that it is

10. Ring A is 【Transformation 7】 The compound according to any one of claims 1 to 9, characterized in that it is

11. Ring A is 【Transformation 8】 The compound according to any one of claims 1 to 8, wherein

12. Ring A is 【Chemistry 9】 The compound according to claim 11, characterized in that

13. X ３ The compound according to any one of claims 1 to 12, wherein is -S-, -Se-, -O-, or -N(R')-.

14. X ４ -N= or -C(R ６ 14. The compound according to claim 1, wherein:

15. X ５ -N= or -C(R ６ 15. The compound according to claim 1, wherein:

16. X ６ -N= or -C(R ６ 16. The compound according to claim 1, wherein:

17. X ６ 17. The compound of any one of claims 1 to 16, characterized in that: is -C(OR')=, where R', taken together with other R' groups on other atoms and their intervening atoms, forms an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms.

18. X ７ -N= or -C(R ６ 18. The compound according to claim 1, wherein:

19. X ７ is -C(OR')=, where R' together with other R' groups on other atoms and their intervening atoms form an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms.

20. X ８ -N= or -C(R ６ 20. The compound according to claim 1, wherein:

21. X ８ 21. The compound of any one of claims 1 to 20, characterized in that: is -C(OR')=, where R', taken together with other R' groups on other atoms and their intervening atoms, forms an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms in addition to the intervening atoms.

22. R １ is —OR′, optionally substituted C １ -C １０ A compound according to any one of claims 1 to 21, characterized in that it is aliphatic or halogen.

23. L １ is a covalent bond, -C(O)-, -C(S)-, -S(O) ２ -, optionally substituted -CH ２ -, -N(R')C(O)-, -N(R')S(O) ２ -, -N(R')C(S)-, or 【Chemistry 10】 The compound according to any one of claims 1 to 22, characterized in that it is

24. R ３ is H or optionally substituted C １ -C ６ A compound according to any one of claims 1 to 23, characterized in that it is aliphatic.

25. L ２ is optionally substituted C １‐３ A compound according to any one of claims 1 to 24, characterized in that it is alkylene.

26. L ２ is optionally substituted C １‐３ alkylene, wherein one or more methylene units of the alkylene are independently selected from -O-, -N(R ４ 25. The compound according to claim 1, wherein the compound is substituted with -, -S-, -CH=N-, or -CH=CH-.

27. L ２ -C(R ４ ) (R ５ )-N(R ４ ) -, or -C(R ４ ) (R ５ 25. The compound according to claim 1, wherein the aryl group is —O—.

28. R ４ and R ５ The compound of claim 27, wherein, together with the atoms to which they are attached, form an optionally substituted 3- to 10-membered ring having 0-4 heteroatoms.

29. R ５ 28. The compound of claim 27, wherein is R.

30. L ２ is optionally substituted C １‐３ 30. The compound of any one of claims 1 to 29, wherein one or more methylene units of the alkylene are independently substituted with an optionally substituted -Cy-.

31. L ２ The compound according to any one of claims 1 to 30, characterized in that is -Cy-O-.

32. The compound is 【Chemistry 11】 The compound according to any one of claims 1 to 31, which is a compound having the structure: or a salt thereof.

33. The compound according to claim 32, wherein ring B in -Cy- is an optionally substituted saturated 3- to 10-membered ring having 0 to 4 heteroatoms.

34. The compound is 【Chemistry 12】 The compound according to claim 1, characterized in that it is a compound having the structure:

35. The compound is 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 or a salt thereof.

36. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier.

37. 37. A method for treating a condition, disorder or disease, comprising administering to a subject suffering from the condition, disorder or disease an effective amount of a compound or pharmaceutical composition according to any one of claims 1 to 36.

38. 38. The method of claim 37, wherein the condition, disorder or disease is or comprises migraine, arthralgia, cardiac pain due to ischemic myocardium, acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, neuralgia pain (e.g., post-herpetic neuralgia, traumatic neuralgia, fibromyalgia, trigeminal neuralgia), diabetic neuropathy pain, dental pain, cancer pain, or an inflammatory pain condition (e.g., arthritis and osteoarthritis).

39. wherein the condition, disorder or disease is or comprises neuropathic pain, nociceptive pain, dental pain, HIV pain, cardiac pain due to ischemic myocardium, migraine pain, joint pain, neuropathy, neurodegeneration, retinopathy, neurocutaneous disorders, stroke, bladder overload, urinary incontinence, vulvodynia, gastrointestinal disorders such as irritable bowel syndrome, inflammatory diseases such as gastroesophageal reflux disease, enteritis, ileitis, gastroduodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, pancreatitis, allergic and non-allergic rhinitis, respiratory diseases such as asthma or chronic obstructive pulmonary disease, inflammation of the skin, eyes or mucous membranes, atopic dermatitis.

38. The method of claim 37, wherein the condition is or includes dermatitis, itchy eczema, fever, muscle spasms, vomiting, dyskinesia, depression, Huntington's disease, memory impairment, limited brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis, anxiety disorder, or benign prostatic hyperplasia.

40. 38. The method of claim 37, wherein the condition, disorder or disease is or comprises atopic dermatitis, eczema, seborrheic dermatitis, pruritus, dermatitis, or psoriasis.

41. 38. The method of claim 37, wherein the condition, disorder or disease is acne.

42. 38. The method of claim 37, wherein the condition, disorder or disease is rosacea.

43. 43. The method of any one of claims 37 to 42, wherein the compound or composition is delivered orally.

44. 43. The method of any one of claims 37 to 42, wherein the compound or composition is administered or delivered topically.

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