Compounds, compositions and methods thereof

Abstract

In particular, the present disclosure provides compounds such as, for example, a compound of Formula I or a salt thereof. In some embodiments, the present disclosure provides methods for modulating the activity of MRGPRX4. In some embodiments, the present disclosure provides methods for preventing or treating a condition, disorder, or disease, for example, a condition, disorder, or disease associated with MRGPRX4.

Description

[Technical Field]

[0001] This application claims priority to PCT Application Nos. PCT / CN2022 / 126550, filed October 21, 2022, and PCT / CN2023 / 077383, filed February 21, 2023, each of which is incorporated by reference in its entirety.

[0002] In some embodiments, the present disclosure provides compounds and compositions useful for, among other things, regulating the activity of MRGPRX4. In some embodiments, the provided compounds and compositions are useful for preventing or treating conditions, disorders, or diseases associated with MRGPRX4, such as pruritus. 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 regulating biological functions and activities. The Mas-related G protein-coupled receptor X4 (MRGPRX4) has numerous biological functions and has been reported to be associated with various pathologies, disorders, or diseases. For example, patients with liver diseases, disorders, or conditions such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and progressive familial intrahepatic cholestasis (PFIC) often suffer from intractable pruritus, which severely impacts their quality of life and can lead to fatigue, tiredness, depression, and even suicidal thoughts. Recently, it has been reported that MRGPRX4 and its agonism by bile acids and their derivatives are likely related to the pruritus that occurs in these diseases (e.g., Meixiong et al. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus, PNAS, 2019, 116(21), 10525-10530; Yu et al. MRGPRX4 is a bile acid receptor for human cholestatic itch, eLife, 2019, 8, e48431).

[0004] MRGPRX4 is reported to be expressed at least in human dorsal root ganglion (hDRG) neurons and co-expressed with the pruritic receptor HRH1. Bile acids or MRGPRX4-specific agonists in the skin activate MRGPRX4 in pruritus-related primary fibers, resulting in Ca uptake. 2+ It has been reported to induce a reaction and induce pruritus in humans.

[0005] Small compounds that are said to function as MRGPRX4 modulators are disclosed in WO2020 / 198537, US2021 / 0032213, WO2021 / 211839, WO2022 / 061008, etc. Summary of the Invention

[0006] In some embodiments, the present disclosure provides various compounds, e.g., compounds having the structure of Formula I or salts thereof, as well as compositions and methods thereof. In some embodiments, the provided compounds are useful as MRGPRX4 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 condition, disorder, or disease associated with MRGPRX4. In some embodiments, the condition, disorder, or disease is or includes pruritus. In some embodiments, the condition, disorder, or disease is associated with the administration of other therapeutic agents, such as an FXR agonist, bile acid, or analogs or derivatives thereof.

[0007] In some embodiments, the disclosure provides compounds having the structure of Formula I, or a pharmaceutically acceptable salt thereof.

[0008] [ka]

[0009] (however, R 1 is —C(O)OH or its equivalent, optionally protected —CHO or R d6 or R 1 is -C(O)OR 11 , -P(O)(OR 12 )(OR 13 ), -C(O)N(R 14 )SO2R 15 , -C(O)NR 16 R 17 ,-CN,

[0010] [ka]

[0011] , halogen, or

[0012] [ka]

[0013] and; R d6 is -CH(OR)2; R 2 and R 3 are each independently R', -OR', halogen, -CN, -NO2, or -N(R') 2 and; Ring A is

[0014] [ka]

[0015] wherein ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms; L ra is an optionally substituted —(CH)N—; n is 1, 2, or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH2-; Z is -N= or -C(R 9 )=and; R 4 , R 5 , R 6 , R 7 and R 9 are each independently R', -OR', halogen, -CN, -NO2, or -N(R')2; Ring B is an optionally substituted ring selected from a 6- to 10-membered aryl ring and a 5- to 10-membered heteroaryl ring having 1-6 heteroatoms; R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16, and R 17 are each independently R', each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)R; each R is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms; or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the atom; 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 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms.

[0016] In some embodiments, the disclosure provides a compound having the structure of Formula I or a salt thereof, wherein R 1 is -C(O)OH or its equivalent, optionally protected -CHO or R d6 or R 1 is -C(O)OR 11 , -P(O)(OR 12 )(OR 13 ), -C(O)N(R 14 )SO2R 15 , -C(O)NR 16 R 17 ,-CN,

[0017] [ka]

[0018] and each other variable is independently as described herein.

[0019] In some embodiments, the disclosure provides compounds having the structure of Formula I or a pharmaceutically acceptable salt thereof, wherein ring A' is an optionally substituted 5-6 membered aromatic ring having 0-4 heteroatoms, and each other variable is independently as described herein.

[0020] 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 delivering a provided compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0021] The provided technology is useful for many purposes. For example, in some embodiments, the present disclosure provides a method for preventing a condition, disorder, or disease, the method comprising administering or delivering an effective amount of a provided compound to a subject susceptible thereto. For example, in some embodiments, the present disclosure provides a method for treating a condition, disorder, or disease, the method comprising administering or delivering an effective amount of a provided compound to a subject suffering therefrom. In some embodiments, the condition, disorder, or disease is a condition, disorder, or disease associated with MRGPRX4. In some embodiments, the condition, disorder, or disease is associated with activation of MRGPRX4. In some embodiments, the condition, disorder, or disease is associated with activation of MRGPRX4 by a drug. In some embodiments, the condition, disorder, or disease is associated with the interaction of MRGPRX4 with a drug. In some embodiments, the condition, disorder, or disease is associated with administration of a drug. In some embodiments, the condition, disorder, or disease is associated with delivery of a drug. In some embodiments, the drug is a therapeutic agent. In some embodiments, the drug is capable of binding to MRGPRX4. In some embodiments, the drug is capable of activating MRGPRX4. In some embodiments, the agent is an FXR agonist. In some embodiments, the agent is a bile acid or an analog or derivative thereof. In some embodiments, the condition, disorder, or disease is pruritus.

[0022] In some embodiments, the present disclosure provides methods for preventing a condition, disorder, or disease, comprising administering or delivering an effective amount of a provided compound and other agents to a subject susceptible thereto. In some embodiments, the present disclosure provides methods for treating a condition, disorder, or disease, comprising administering or delivering an effective amount of a provided compound and other agents to a subject suffering therefrom. For example, in some embodiments, the condition, disorder, or disease is associated with farnesoid X receptor (FXR), and the other agent is an FXR agonist. In some embodiments, the condition, disorder, or disease is associated with TGR5, and the other agent is a TGR5 agonist. In some embodiments, the other agent can activate MRGPRX4. In some embodiments, the other agent is an FXR agonist. In some embodiments, the other agent is a bile acid or an analog or derivative thereof. In some embodiments, the condition, disorder, or disease is a liver condition, disorder, or disease. For example, in some embodiments, the condition, disorder, or disease is nonalcoholic steatohepatitis (NASH).

[0023] In some embodiments, the disclosure provides techniques, such as methods, reagents, etc., for making compounds of formula (I) or pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0024] The techniques of the present disclosure may be more readily understood by reference to the following detailed description of specific embodiments. definition

[0025] As used herein, the following definitions shall apply unless otherwise specified. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, 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., John Wiley & Sons, New York:2001.

[0026] As used in this disclosure, unless otherwise clear from the context, (i) the term "a" or "an" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and / or"; (iii) the terms "comprising," "comprise," "including" (whether or not used in conjunction with "but not limited to"), and "include" (whether or not used in conjunction with "but not limited to") may be understood to encompass the itemized listed component or step, whether presented by itself 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, as understood by those of ordinary skill in the art; and (vi) when ranges are provided, endpoints are included. Unless otherwise clear from the context, isomers of the compounds are included. As will be appreciated by those skilled 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.

[0027] 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, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 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).

[0028] Alkenyl: As used herein, the term "alkenyl" refers to an aliphatic group, as defined herein, having one or more double bonds.

[0029] 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 1-100 carbon atoms. In certain embodiments, a straight-chain or branched-chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C5 for straight chain). 20 , C2-C for branched chain20 ), 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).

[0030] Alkynyl: As used herein, the term "alkynyl" refers to an aliphatic group, as defined herein, having one or more triple bonds.

[0031] 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.

[0032] Aryl: As used herein, the term "aryl," 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 5-30 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 5-14 ring members, wherein at least one ring in the ring system is aromatic, and wherein each ring in the ring system contains 3-7 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, phenanthridinyl, or tetrahydronaphthyl.

[0033] Characteristic portion: As used herein, the term "characteristic portion" refers in its broadest sense to a portion of a substance whose presence (or absence) correlates with the presence (or absence) of a particular characteristic, attribute, or activity of the substance. In some embodiments, a characteristic portion of a substance is a portion that is found in the substance and related substances that share the particular characteristic, attribute, or activity, but is not found in related substances that do not share the particular characteristic, attribute, or activity. In certain embodiments, a characteristic portion shares at least one functional property with the original substance. For example, in some embodiments, a "characteristic portion" of a protein or polypeptide is a portion that includes a contiguous stretch of amino acids, or a collection of amino acids, in some embodiments, a contiguous collection of amino acids, that together are characteristic of the protein or polypeptide. In some embodiments, such a contiguous stretch typically includes at least 2, 5, 10, 15, 20, 50, or more amino acids. Generally, a characteristic portion of a substance (e.g., a protein, antibody, etc.) is a portion that shares at least one functional property with the related original substance in addition to the sequence and / or structural identity identified above. In some embodiments, the characteristic moiety may be biologically active.

[0034] 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 several 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 when they are characterized by a sufficient number and type of substantially identical characteristics to support a reasonable conclusion that differences in the results obtained or the phenomena observed under different sets of conditions or circumstances are caused by or indicate variations in those different characteristics.

[0035] Alicyclic: The terms "alicyclic," "carbocycle," "carbocyclyl," "carbocyclic radical," and "carbocycle" are used interchangeably and, as used herein, unless otherwise specified, refer to a saturated or partially unsaturated, but not aromatic, monocyclic, bicyclic, or polycyclic cycloaliphatic ring system, as described herein, having 3-30 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 3-6 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 a decahydronaphthyl or tetrahydronaphthyl group. 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).

[0036] Heteroaliphatic: As used herein, the term "heteroaliphatic" has its ordinary 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, CH, and CH 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.

[0037] Heteroalkyl: As used herein, the term "heteroalkyl" has its ordinary meaning in the art and refers to any of the alkyl groups 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, and the like.

[0038] 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 5-30 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, a heteroaryl group is a group having 5-10 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, a heteroaryl group has 6, 10, or 14 pi electrons shared in the cyclic arrangement, and has 1-5 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.

[0039] 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.

[0040] 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., 3-30 membered ring) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, the heterocyclic group is a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1-4 heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 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.

[0041] Leaving Group / LG: As used herein, a leaving group or LG is an atom or group of atoms that departs from the main or remaining portion of a substrate during a reaction or at a fundamental step of a reaction. In some embodiments, LG is a halogen. In some embodiments, LG is -Cl. In some embodiments, LG is -OH.

[0042] 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.

[0043] Suitable monovalent substituents include, for example, 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) 0-4 N(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) 0-4 SC(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 1-20 C having 1-5 heteroatoms independently selected from aliphatic, nitrogen, oxygen, sulfur, silicon, and phosphorus 1-20 Heteroaliphatic, -CH2-(C 6-14 aryl), -O(CH2) 0-1 (C 6-14aryl), -CH- (a 5-14 membered heteroaryl ring), a 5-20 membered monocyclic, bicyclic, or polycyclic saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus; or, notwithstanding the above definitions, two independent occurrences of R together with their intervening atoms are a 5-20 membered monocyclic, bicyclic, or polycyclic saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus, which may be optionally substituted as defined below.

[0044] 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 ● (where 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 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0045] Suitable divalent substituents include, for example, the following: =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 hydrogen, optionally substituted as defined below. 1-6 The "optionally substituted" group is selected from the group consisting of aliphatic, unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of the "optionally substituted" group include, for example, -O(CR * 2) 2-3O -, where R * Each independent occurrence of is hydrogen, optionally substituted as defined below. 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0046] R * Suitable substituents for the aliphatic group include, for example, 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 represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0047] In some embodiments, suitable substituents on a substitutable nitrogen include, for example, the following examples: -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, optionally substituted as defined below, 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, regardless of the above definitions, R † two independent occurrences of, taken together with their intervening atoms, form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0048] 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 ● , -NR2, 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 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0049] 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.

[0050] 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, the pharmaceutical composition may be specially formulated for administration in solid or liquid form. These forms include those adapted for the following: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets intended for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue, parenteral administration (e.g., as a sterile solution or suspension, or as a sustained-release formulation, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection), topical application (e.g., as a cream, ointment, or sustained-release patch or spray applied to the skin, lungs, or oral cavity), vaginal or rectal administration (e.g., as a pessary, cream, or foam), sublingual, ophthalmic, transdermal, or nasal, pulmonary, and other mucosal surfaces.

[0051] 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.

[0052] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means 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 part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Examples of materials that can function as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, sucrose, and the like; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; excipients such as tragacanth powder, malt, gelatin, talc, cocoa butter, and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; 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.

[0053] 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, S.M. Berg 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 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, lactobacillus acid salt, and the like. Examples of suitable salts include, but are not limited to, ionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.In some embodiments, provided compounds comprise 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, where 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, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a potassium salt. In some embodiments, the 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 comprise two or more acidic groups. In some embodiments, pharmaceutically acceptable salts, or salts in general, of such compounds comprise 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 acidic groups (e.g., 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 cations.

[0054] 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," T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. The term 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, for example, the following: 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-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethylcarbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethylcarbamate (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-ferrocenylmethylamino (Fcm), N-2-picolylamino 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 (Mt e), 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.

[0055] 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.

[0056] Suitable hydroxyl protecting groups include, for example, the following: 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]-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 -trichloroethyl, 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 dithiocarbonate, 2-iodobenzoate, 4-azidobutyric acid ester, 4-nitro-4-methylpentanoic acid ester, o-(dibromomethyl)benzoate ester, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, Monosacinoate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). Protecting groups for protecting 1,2- or 1,3-diols include, for example, 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 ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidine orthoester, 1,2-dimethicone hydroxyethylidene orthoesters, α-methoxybenzylidene orthoesters, 1-(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.

[0057] 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 attached to the sulfur atom of the phosphorothioate group.In some embodiments, the protecting group is attached to the oxygen atom of the internucleotide phosphorothioate bond. In some embodiments, the protecting group is attached to the oxygen atom of the internucleotide phosphate bond. 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.

[0058] Subject: As used herein, the term "subject" or "test subject" refers to any organism to which a compound or composition is administered in accordance with the present disclosure, 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.

[0059] Substantially / Essentially: As used herein, the term "substantially / essentially" 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 completeness, or achieve or avoid absolute results. Thus, the term "substantially / essentially" is used herein to capture the potential lack of completeness inherent in many biological and / or chemical phenomena.

[0060] 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.

[0061] 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, the relevant population is a population of subjects suffering from and / or susceptible to a disease, disorder, or condition. In some embodiments, the relevant population is a population of model organisms. In some embodiments, the relevant population may be defined by one or more criteria, such as age group, sex, genetic background, pre-existing clinical condition, 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 an agent that has been, or is seeking to be, approved by a government agency before being marketed for administration to humans. In some embodiments, a "therapeutic agent" is a drug that requires a physician's prescription for administration to a human. In some embodiments, a therapeutic agent is a provided compound.

[0062] 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.

[0063] 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.

[0064] Unsaturated: As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0065] 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

[0066] 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:

[0067] [ka]

[0068] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0069] Specific embodiments for various variables in various formulas (e.g., Formula I and formulas in various schemes) are described herein as examples. Those skilled in the art, upon reading this disclosure, can select embodiments for each variable and combine them. Such combinations are within the scope of this disclosure. Those skilled in the art will also appreciate that an embodiment described for one variable (e.g., R) may be combined with other variables (e.g., R′, R ) that may be such a variable. 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 Understand that it can also be used for other things (such as R). Ring A

[0070] In some embodiments, ring A is

[0071] [ka]

[0072] wherein each variable is independently as described herein. In some embodiments, Ring A' is an optionally substituted phenyl ring. In some embodiments, Ring A is

[0073] [ka]

[0074] wherein each variable is independently as described herein. In some embodiments, L ra is an optionally substituted —(CH 2 )N—. In some embodiments, ring A is

[0075] [ka]

[0076] wherein each variable is independently as described herein. In some embodiments, ring A is

[0077] [ka]

[0078] wherein each variable is independently as described herein. In some embodiments, ring A is optionally substituted.

[0079] [ka]

[0080] wherein each variable is independently as described herein. In some embodiments, ring A is optionally substituted.

[0081] [ka]

[0082] wherein each variable is independently as described herein. In some embodiments, ring A is optionally substituted.

[0083] [ka]

[0084] wherein each variable is independently as described herein. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0085] In some embodiments, ring A is

[0086] [ka]

[0087] wherein each variable is independently as described herein. In some embodiments, Ring A' is an optionally substituted phenyl ring. In some embodiments, Ring A is

[0088] [ka]

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

[0090] [ka]

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

[0092] [ka]

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

[0094] [ka]

[0095] where each variable is independently as described herein.

[0096] In some embodiments, ring A is

[0097] [ka]

[0098] wherein each variable is independently as described herein. In some embodiments, ring A is

[0099] [ka]

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

[0101] [ka]

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

[0103] [ka]

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

[0105] [ka]

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

[0107] [ka]

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

[0109] [ka]

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

[0111] [ka]

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

[0113] [ka]

[0114] wherein each variable is independently as described herein. In some embodiments, ring A is optionally substituted.

[0115] [ka]

[0116] wherein each variable is independently as described herein. In some embodiments, ring A is optionally substituted.

[0117] [ka]

[0118] where each variable is independently as described herein.

[0119] Among other things, the present disclosure provides stereochemically pure, e.g., enantiomerically pure, compounds having the purity described herein. In some embodiments, the compounds are stereochemically pure. In some embodiments, the compounds are enantiomerically pure. In some embodiments, the provided compositions are enriched in one enantiomer over the other, or enriched in one configuration about the chiral center over the other. For example, in some embodiments, the percentage of an enantiomer, or one configuration about the chiral center, is about or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5%. In some embodiments, it is about or at least about 60%. In some embodiments, it is about or at least about 65%. In some embodiments, it is about or at least about 70%. In some embodiments, it is about or at least about 75%. In some embodiments, it is about or at least about 80%. In some embodiments, it is about or at least about 85%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 95%. In some embodiments, it is about or at least about 96%. In some embodiments, it is about or at least about 97%. In some embodiments, it is about or at least about 98%. In some embodiments, it is about or at least about 99%. In some embodiments, it is about or at least about 99.5%. In some embodiments, it is enriched in the (S) enantiomer or configuration. In some embodiments, it is enriched in the (R) enantiomer or configuration. In some embodiments, the configuration of the stereocenter is indicated in the chemical structure next to the stereocenter, e.g., as "R," "S," "(R)," "(S)," etc. These configurations are typically determined by commercially available software, such as ChemDraw, when creating chemical structures using such software. In some embodiments, the configuration of the stereocenter is not indicated. One of ordinary skill in the art can readily determine the configuration of a stereocenter according to common practices in the art.

[0120] In some embodiments, R 10 It has been observed that the S configuration of the chiral carbon to which is attached can result in a higher desired activity, e.g., MRGPRX4 inhibition, than the R configuration (for the R / S configuration of this carbon center, the following order of priority 1 to 4 is used: X, ring B, L ra (e.g., -(CH2)N-, and R 10 (e.g., H)). For example, in some embodiments, 52A (S enantiomer) provided much higher MRGPRX4 inhibitory activity than 52B. See, e.g., Table 1.

[0121] Ring A'

[0122] In some embodiments, ring A' is an optionally substituted phenyl ring. In some embodiments, ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms. In some embodiments, ring A' is an optionally substituted 5-6 membered aromatic ring having 1-4 heteroatoms. In some embodiments, ring A' is a 6 membered aromatic ring having 1-2 heteroatoms. In some embodiments, ring A' is a 6 membered aromatic ring having 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is a 6 membered aromatic ring having a heteroatom selected from O, N, and S. In some embodiments, ring A' is a 6 membered aromatic ring having a nitrogen atom. In some embodiments, ring A' is a 6 membered aromatic ring having two heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is a 6 membered aromatic ring having two heteroatoms, each N. In some embodiments, ring A' is a 6-membered aromatic ring having three heteroatoms. In some embodiments, ring A' is a 6-membered aromatic ring having three heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is a 6-membered aromatic ring having three heteroatoms, one of which is N. In some embodiments, ring A' is a 5-membered aromatic ring having 1-2 heteroatoms. In some embodiments, ring A' is a 5-membered aromatic ring having 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is a 5-membered aromatic ring having an oxygen atom. In some embodiments, ring A' is a 5-membered aromatic ring having a nitrogen atom. In some embodiments, ring A' is a 5-membered aromatic ring having a sulfur atom. In some embodiments, ring A' is a 5-membered aromatic ring having two heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is a 5-membered aromatic ring having two heteroatoms, one of which is N. In some embodiments, ring A' is a 5-membered aromatic ring having two heteroatoms independently selected from N and S.In some embodiments, ring A' is a 5-membered aromatic ring having two heteroatoms independently selected from N and O. In some embodiments, ring A' is a 5-membered aromatic ring having two heteroatoms independently selected from O and S. In some embodiments, ring A' is a 5-membered aromatic ring having three heteroatoms. In some embodiments, ring A' is a 5-membered aromatic 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 of the heteroatoms are nitrogen. In some embodiments, all of the heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatoms.

[0123] In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 1-4 heteroatoms. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 4 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 3 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 3 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 3 heteroatoms, one of which is N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 3 heteroatoms independently selected from O and N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 3 heteroatoms independently selected from O and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 3 heteroatoms independently selected from N and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having two heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having two heteroatoms, one of which is N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having two heteroatoms independently selected from O and N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having two heteroatoms independently selected from O and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having two heteroatoms independently selected from N and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having two heteroatoms, both of which are N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having one heteroatom selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring bearing a nitrogen atom.In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having an oxygen atom. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having a sulfur atom. 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.

[0124] In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having 1-4 heteroatoms. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having four heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having three heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having three heteroatoms, all of which are N. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having two heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having two heteroatoms, one of which is N. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having two heteroatoms independently selected from O and N. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having two heteroatoms independently selected from O and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having two heteroatoms independently selected from O and S. A' is an optionally substituted 10-membered aromatic ring having two heteroatoms independently selected from N and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having two heteroatoms (both N). In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having one heteroatom selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having a nitrogen atom. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having an oxygen atom. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having a sulfur atom. In some embodiments, the ring has a single heteroatom.In some embodiments, the ring has two or more heteroatoms, at least one of which is nitrogen. In some embodiments, each is nitrogen. In some embodiments, all of the heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatoms.

[0125] In some embodiments, ring A' is an optionally substituted divalent naphthyl ring. In some embodiments, ring A' is an optionally substituted

[0126] [ka]

[0127] In some embodiments, ring A' is

[0128] [ka]

[0129] is.

[0130] X

[0131] In some embodiments, X is —O—, —S—, or —N(R 8 )-, where R 8 is as described herein. In some embodiments, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -N(R 8 )-, where R 8 is as described herein. In some embodiments, X is an optionally substituted —CH—.

[0132] R 8

[0133] In some embodiments, R 8 is R' as described herein. In some embodiments, R8 is R as described herein. In some embodiments, R 8 is H. In some embodiments, R 8 is not H. In some embodiments, R 8 is an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 8 is an optionally substituted C1-C6 aliphatic. In some embodiments, R 8 is an optionally substituted C1-C6 alkyl. In some embodiments, R 8 is an optionally substituted C1-C4 alkyl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is propyl. In some embodiments, R 8 isopropyl (

[0134] [ka]

[0135] In some embodiments, R 8 is butyl. In some embodiments, R 8 isobutyl (

[0136] [ka]

[0137] )

[0138] In some embodiments, R 8 is an optionally substituted C 3- In some embodiments, R 8 is optionally substituted

[0139] [ka]

[0140] In some embodiments, R 8 is optionally substituted

[0141] [ka]

[0142] In some embodiments, R 8 is optionally substituted

[0143] [ka]

[0144] In some embodiments, R 8 is optionally substituted. In some embodiments, R 8 is optionally substituted

[0145] [ka]

[0146] In some embodiments, R 8 teeth,

[0147] [ka]

[0148] In some embodiments, R 8 teeth,

[0149] [ka]

[0150] In some embodiments, R 8 teeth,

[0151] [ka]

[0152] is.

[0153] In some embodiments, R 8 is an optionally substituted 6-10 membered aryl group. In some embodiments, R 8 is an optionally substituted phenyl group. In some embodiments, R 8 is a phenyl group.

[0154] In some embodiments, R 8 is an optionally substituted 6-10 membered aryl-C1-C6 aliphatic ring. In some embodiments, R 8 is an optionally substituted 6-10 membered aryl-C1-C6 alkyl. In some embodiments, R 8 is an optionally substituted phenyl-C1-C6 alkyl. In some embodiments, R 8 is optionally substituted phenyl-C1-C6 alkyl 。 In some embodiments, R 8 is an optionally substituted phenyl-C1-C6 alkyl. In some embodiments, R 8 is optionally substituted

[0155] [ka]

[0156] In some embodiments, R 8 teeth,

[0157] [ka]

[0158] is.

[0159] Z

[0160] In some embodiments, Z is -N= or -C(R 9 )=, where R 9 is as described herein. In some embodiments, Z is -N=. In some embodiments, Z is -C(R 9 )=, where R 9 is as described herein.

[0161] R 9

[0162] In some embodiments, R 9 is H. In some embodiments, R 9 is not H. In some embodiments, R 9 -R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where R' is as described herein. In some embodiments, R 9 is -OR', where R' is as defined herein.

[0163] In some embodiments, R 9 is halogen. In some embodiments, R 9 is F. In some embodiments, R 9 is Cl. In some embodiments, R 9 is Br. In some embodiments, R 9 is I.

[0164] In some embodiments, R 9 is -CN.

[0165] In some embodiments, R 9 is -NO2.

[0166] In some embodiments, R 9 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 9 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 9 is -NHR', where R' is as defined herein.

[0167] In some embodiments, R 9 is R' as described herein. In some embodiments, R 9 is R as described herein.

[0168] In some embodiments, R 9 is selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered cyclic aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered cyclic aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms; 、 is an optionally substituted group. In some embodiments, R 9 is C1-C6 aliphatic. In some embodiments, R 9 is an optionally substituted C1-C6 alkyl. In some embodiments, R 9 is an optionally substituted C1-C4 alkyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is ethyl. In some embodiments, R9 is propyl. In some embodiments, R 9 isopropyl (

[0169] [ka]

[0170] In some embodiments, R 9 is butyl. In some embodiments, R 9 isobutyl (

[0171] [ka]

[0172] )

[0173] R 10

[0174] In some embodiments, R 10 is R' as described herein. In some embodiments, R 10 is R as described herein. In some embodiments, R 10 is H.

[0175] In some embodiments, R 10 is not H. In some embodiments, R 10 is an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms.

[0176] n

[0177] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0178] R 4

[0179] In some embodiments, R 4 is H. In some embodiments, R 4 is not H. In some embodiments, R 4 -R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where R' is as described herein. In some embodiments, R 4 is -OR', where R' is as defined herein.

[0180] In some embodiments, R 4 is halogen. In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is I.

[0181] In some embodiments, R 4 is -CN.

[0182] In some embodiments, R 4 is -NO2.

[0183] In some embodiments, R 4 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 4 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 4 is -NHR', where R' is as defined herein.

[0184] In some embodiments, R 4 is R' as described herein. In some embodiments, R 4 is R as described herein.

[0185] In some embodiments, R 4 is an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 4 is C1-C6 aliphatic. In some embodiments, R 4 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 is an optionally substituted C1-C4 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is C 1-4 In some embodiments, R 4 is -CF3.

[0186] R 5

[0187] In some embodiments, R 5 is H. In some embodiments, R 5 is not H. In some embodiments, R 5-R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where R' is as described herein. In some embodiments, R 5 is -OR', where R' is as defined herein.

[0188] In some embodiments, R 5 is halogen. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I.

[0189] In some embodiments, R 5 is -CN.

[0190] In some embodiments, R 5 is -NO2.

[0191] In some embodiments, R 5 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 5 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 5 is -NHR', where R' is as defined herein.

[0192] In some embodiments, R 5 is R' as described herein. In some embodiments, R 5 is R as described herein.

[0193] In some embodiments, R 5is an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 5 is C1-C6 aliphatic. In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 5 is an optionally substituted C1-C4 alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is propyl. In some embodiments, R 5 is isopropyl. In some embodiments, R 5 is butyl. In some embodiments, R 5 is isobutyl. In some embodiments, R 5 is C 1-4 In some embodiments, R 5 is -CF3.

[0194] In some embodiments, R 4 and R 5 together with their intervening atoms form a ring as described herein. In some embodiments, R 4 and R 5 together with their intervening atoms form an optionally substituted phenyl ring. In some embodiments, R 4 and R 5 together with their intervening atoms form an optionally substituted 5- or 6-membered heteroaryl ring having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0195] R 6

[0196] In some embodiments, R 6 is H. In some embodiments, R 6 is not H. In some embodiments, R 6 -R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where R' is as described herein. In some embodiments, R 6 is -OR', where R' is as defined herein.

[0197] 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.

[0198] In some embodiments, R 6 is -CN.

[0199] In some embodiments, R 6 is -NO2.

[0200] In some embodiments, R 6 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 6 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 6 is -NHR', where R' is as defined herein.

[0201] In some embodiments, R 6 is R' as described herein. In some embodiments, R 6 is R as described herein.

[0202] In some embodiments, R 6 is an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 6 is C1-C6 aliphatic. In some embodiments, R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is an optionally substituted C1-C4 alkyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is propyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is butyl. In some embodiments, R 6 is isobutyl. In some embodiments, R 6 is C 1-4 In some embodiments, R 6 is -CF3.

[0203] In some embodiments, R 6 is -OR, where R is as described herein. In some embodiments, R is H. In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is C 1-6 In some embodiments, R is alkyl. In some embodiments, R is methyl. In some embodiments, R is —CF.

[0204] In some embodiments, R6 is —C(O)OR, where R is as described herein. In some embodiments, R 6 is —C(O)OH.

[0205] In some embodiments, R 6 is —S(O)R, where R is as described herein. In some embodiments, R is C 1-6 In some embodiments, R is C 1-6 In some embodiments, R 6 is -S(O)Me.

[0206] R 7

[0207] In some embodiments, R 7 is H. In some embodiments, R 7 is not H. In some embodiments, R 7 -R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where R' is as described herein. In some embodiments, R 7 is -OR', where R' is as defined herein.

[0208] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is Br. In some embodiments, R 7 is I.

[0209] In some embodiments, R 7 is -CN.

[0210] In some embodiments, R 7 is -NO2.

[0211] In some embodiments, R 7 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 7 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 7 is -NHR', where R' is as defined herein.

[0212] In some embodiments, R 7 is R' as described herein. In some embodiments, R 7 is R as described herein.

[0213] In some embodiments, R 7 is an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 7 is C1-C6 aliphatic. In some embodiments, R 7 is an optionally substituted C1-C6 alkyl. In some embodiments, R 7 is an optionally substituted C1-C4 alkyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is propyl. In some embodiments, R 7 is isopropyl. In some embodiments, R 7 is butyl. In some embodiments, R 7 is isobutyl. In some embodiments, R 7 is C 1-4 In some embodiments, R7 is -CF3.

[0214] In some embodiments, R 4 , R 5 , R 6 , and R 7 are each independently R', -OR', halogen, -CN, -NO2, or -N(R')2, where R' is as described herein.

[0215] In some embodiments, R 4 , R 5 , R 6 , and R 7 Each of is H.

[0216] In some embodiments, R 4 , R 5 , R 6 , and R 7 Each of these is not independently H.

[0217] R 4 , R 5 , R 6 , and R 7 One of them is not H, but R 4 , R 5 , R 6 , and R 7 The remaining three of R are each H. In some embodiments, R 4 , R 5 , R 6 , and R 7 Two of them are R, not H. 4 , R 5 , R 6 , and R 7 The remaining two are H.

[0218] In some embodiments, R 4 , R 5 , and R 7 are H and R 6is selected from R', -OR', halogen, -CN, -NO2, or -N(R')2, where R' is as described herein. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is selected from halogen, —CN, optionally substituted C1-C6 alkyl, —OR (where R is optionally substituted C1-C6 alkyl), optionally substituted 6-10 membered aryl, —C(O)OR (where R is H or optionally substituted C1-C6 alkyl), or —S(O)R (where R is H or optionally substituted C1-C6 alkyl).

[0219] R 4 , R 5 , and R 7 are H and R 6 is halogen. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is F. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is Cl. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is Br. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is I.

[0220] In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 , R5 , and R 7 are H and R 6 is -CF3.

[0221] In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is —OR, where R is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is -OMe. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is -OCF3.

[0222] In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is an optionally substituted 6-10 membered aryl. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is optionally substituted phenyl. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is phenyl.

[0223] In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is —C(O)OR, where R is H or an optionally substituted C1-C6 alkyl. In some embodiments, R 4 , R 5 , and R 7are H and R 6 is —C(O)OH.

[0224] In some embodiments, R 4 , R 5 , and R 7 Each of is H and R 6 is —S(O)R, where R is H or optionally substituted C-C alkyl. In some embodiments, R 4 , R 5 , and R 7 are H and R 6 is -SO2Me.

[0225] In some embodiments, ring A is

[0226] [ka]

[0227] where R 6 , R 8 , and R 9 each independently as described herein.

[0228] In some embodiments, ring A is

[0229] [ka]

[0230] and X and R 6 are each independently as described herein. In some embodiments, ring A is

[0231] [ka]

[0232] and R 6 is as described herein.

[0233] In some embodiments, ring A is

[0234] [ka]

[0235] and R 6 and R 8 are each independently as described herein. In some embodiments, ring A is

[0236] [ka]

[0237] and R 6 is as described herein. In some embodiments, ring A is

[0238] [ka]

[0239] and R 6 is as described herein.

[0240] In some embodiments, R 4 , R 6 , and R 7 are H and R, respectively. 5 is selected from R', -OR', halogen, -CN, -NO2, or -N(R')2, where R' is as described herein. In some embodiments, R 4 , R 6 , and R 7 are H and R 5is selected from halogen, —CN, optionally substituted C1-C6 alkyl, —OR (where R is optionally substituted C1-C6 alkyl), optionally substituted 6-10 membered aryl, —C(O)OR (where R is H or optionally substituted C1-C6 alkyl), or —S(O)R (where R is H or optionally substituted C1-C6 alkyl).

[0241] In some embodiments, R 4 , R 6 , and R 7 are H and R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 , R 6 , and R 7 are H and R 5 is -CF3.

[0242] R 4 , R 6 , and R 7 are H and R 5 is a halogen. In some embodiments, R 4 , R 6 , and R 7 are H and R 5 is F. In some embodiments, R 4 , R 6 , and R 7 are H and R 5 is Cl.

[0243] In some embodiments, ring A is

[0244] [ka]

[0245] and X and R 5 are each independently as described herein. In some embodiments, ring A is

[0246] [ka]

[0247] and R 5 is as described herein.

[0248] In some embodiments, ring A is

[0249] [ka]

[0250] and X and R 5 are each independently as described herein. In some embodiments, ring A is

[0251] [ka]

[0252] and R 5 is as described herein.

[0253] In some embodiments, ring A is

[0254] [ka]

[0255] and X and R 5 are each independently as described herein. In some embodiments, ring A is

[0256] [ka]

[0257] and R 5 is as described herein.

[0258] In some embodiments, R 4 and R 7 are H and R 5 and R 6 are each independently selected from R', -OR', halogen, -CN, -NO2, and -N(R')2, where R' is as described herein. In some embodiments, R 4 and R 7 are H and R 5 and R 6 are each independently selected from halogen, —CN, optionally substituted C-C alkyl, —OR (where R is optionally substituted C-C alkyl), optionally substituted 6-10 membered aryl, —C(O)OR (where R is H or optionally substituted C-C alkyl), and —S(O)R (where R is H or optionally substituted C-C alkyl).

[0259] In some embodiments, R 4 and R 7 are H and R 5 is optionally substituted C1-C6 alkyl, and R 6 is halogen. In some embodiments, R 4 and R 7 are H and R 5 is -CF3, and R 6 is halogen. In some embodiments, R 4 and R 7 are H and R 5 is -CF3, and R 6 is F. In some embodiments, R 4 and R 7 are H and R 5 is -CF3, and R 6 is Cl.

[0260] In some embodiments, ring A is

[0261] [ka]

[0262] where X, R 5 and R 6 each independently as described herein.

[0263] In some embodiments, R 6 and R 7 are H and R 4 and R 5 are each independently selected from R', -OR', halogen, -CN, -NO2, and -N(R')2, where R' is as described herein. In some embodiments, R 6 and R 7 are H and R 4 and R 5 are each independently selected from halogen, —CN, optionally substituted C-C alkyl, —OR (where R is optionally substituted C-C alkyl), optionally substituted 6-10 membered aryl, —C(O)OR (where R is H or optionally substituted C-C alkyl), and —S(O)R (where R is H or optionally substituted C-C alkyl).

[0264] In some embodiments, R 6 and R 7 are H and R 4 is optionally substituted C1-C6 alkyl, and R 5 is halogen. In some embodiments, R 4 and R 7 are H and R 4 is -CF3, and R 5 is halogen. In some embodiments, R 6 and R 7 are H and R 4 is -CF3, and R 5is F. In some embodiments, R 6 and R 7 are H and R 4 is -CF3, and R 5 is Cl.

[0265] In some embodiments, ring A is

[0266] [ka]

[0267] where X, R 4 and R 5 and each of the following is independently as described herein. In some embodiments, ring A is

[0268] [ka]

[0269] where R 4 and R 5 each independently as described herein.

[0270] In some embodiments, R 4 and R 6 are H and R 5 and R 7 are each independently selected from R', -OR', halogen, -CN, -NO2, and -N(R')2, where R' is as described herein. In some embodiments, R 4 and R 6 are H and R 5 and R 7are each independently selected from halogen, —CN, optionally substituted C-C alkyl, —OR (where R is optionally substituted C-C alkyl), optionally substituted 6-10 membered aryl, —C(O)OR (where R is H or optionally substituted C-C alkyl), and —S(O)R (where R is H or optionally substituted C-C alkyl).

[0271] In some embodiments, R 4 and R 6 are H and R 5 is optionally substituted C1-C6 alkyl, and R 7 is halogen. In some embodiments, R 4 and R 6 are H and R 5 is -CF3, and R 7 is halogen. In some embodiments, R 4 and R 6 are H and R 5 is -CF3, and R 7 is F. In some embodiments, R 4 and R 6 are H and R 5 is -CF3, and R 7 is Cl.

[0272] In some embodiments, ring A is

[0273] [ka]

[0274] and X, R 5 , and R 7 are each independently as described herein. In some embodiments, ring A is

[0275] [ka]

[0276] and R 5 and R 7 are each independently as described herein.

[0277] In some embodiments, ring A is

[0278] [ka]

[0279] wherein each variable is independently as described herein. In some embodiments, ring A is

[0280] [ka]

[0281] wherein each variable is independently as described herein. In some embodiments, ring A is

[0282] [ka]

[0283] wherein each variable is independently as described herein. In some embodiments, ring A is

[0284] [ka]

[0285] wherein each variable is independently as described herein. In some embodiments, ring A is

[0286] [ka]

[0287] wherein each variable is independently as described herein. In some embodiments, ring A is

[0288] [ka]

[0289] where each variable is independently as described herein.

[0290] In some embodiments, ring A is

[0291] [ka]

[0292] where each variable is independently as described herein.

[0293] In some embodiments, ring A is

[0294] [ka]

[0295] wherein each variable is independently as described herein. In some embodiments, ring A is

[0296] [ka]

[0297] where each variable is independently as described herein.

[0298] In some embodiments, ring A is

[0299] [ka]

[0300] where each variable is independently as described herein.

[0301] In some embodiments, ring A is

[0302] [ka]

[0303] where each variable is independently as described herein.

[0304] In certain embodiments, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:

[0305] [ka]

[0306] In certain embodiments, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:

[0307] [ka]

[0308] [ka]

[0309] In some embodiments, the present disclosure provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is:

[0310] [ka]

[0311] and may be optionally substituted.

[0312] Ring B

[0313] In some embodiments, ring B is an optionally substituted aryl ring selected from a 6-10 membered aryl ring and a 5-10 membered heteroaryl ring having 1-6 heteroatoms (as will be appreciated by those of skill in the art, R 1 , R 2 and R 3 In addition to this, it is a ring.

[0314] In some embodiments, ring B is an optionally substituted 6-10 membered aryl ring. In some embodiments, ring B is an optionally substituted phenyl ring. In some embodiments, ring B is a phenyl ring. In some embodiments, R 1 is in the o-position (unless otherwise specified, o, m, and p are independent relative to the carbon attached to ring A). In some embodiments, R 1 In some embodiments, R is in the m position. In some embodiments, R is in the p position. 2 is at the o-position. In some embodiments, R 2 is at the m-position. In some embodiments, R 2 In some embodiments, R 3 is at the o-position. In some embodiments, R 3 is at the m-position. In some embodiments, R 3 In some embodiments, R 1 and R 2 are adjacent. In some embodiments, R 1 and R 2 are not adjacent. In some embodiments, R 2 and R 3 are adjacent to each other. In some embodiments, R 2 and R 3 are not adjacent to each other. In some embodiments, R 1 and R 3 are adjacent to each other. In some embodiments, R 1and R 3 are not adjacent to each other.

[0315] In some embodiments, Ring B is an optionally substituted naphthyl.

[0316] In some embodiments, Ring B is an optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms. In some embodiments, Ring B is an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms. In some embodiments, Ring B is an optionally substituted 9 membered bicyclic heteroaryl ring having 1-6 heteroatoms. In some embodiments, Ring B is an optionally substituted 10 membered bicyclic heteroaryl ring having 1-6 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, there are five heteroatoms. In some embodiments, there are six heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen, and sulfur.

[0317] In some embodiments, ring B is

[0318] [ka]

[0319] In some embodiments, ring B is

[0320] [ka]

[0321] In some embodiments, ring B is

[0322] [ka]

[0323] In some embodiments, ring B is

[0324] [ka]

[0325] In some embodiments, ring B is

[0326] [ka]

[0327] In some embodiments, ring B is

[0328] [ka]

[0329] In some embodiments, ring B is

[0330] [ka]

[0331] In some embodiments, ring B is

[0332] [ka]

[0333] In some embodiments, ring B is

[0334] [ka]

[0335] In some embodiments, ring B is

[0336] [ka]

[0337] In some embodiments, ring B is

[0338] [ka]

[0339] In some embodiments, ring B is

[0340] [ka]

[0341] In some embodiments, ring B is

[0342] [ka]

[0343] In some embodiments, ring B is

[0344] [ka]

[0345] In some embodiments, ring B is

[0346] [ka]

[0347] In some embodiments, ring B is

[0348] [ka]

[0349] In some embodiments, ring B is

[0350] [ka]

[0351] is.

[0352] R 1

[0353] In some embodiments, R 1 is -C(O)OR 11 , -P(O)(OR 12 )(OR 13 ), -C(O)N(R 14 )SO2R 15 , -C(O)NR 16 R 17 ,

[0354] [ka]

[0355] , halogen, or

[0356] [ka]

[0357] where each variable is independently as described herein.

[0358] In some embodiments, R 1 is -C(O)OR 11 and R 11 is as described herein. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ) and R12 and R 13 and each independently is as described herein. In some embodiments, R 1 is -C(O)N(R 14 )SO2R 15 and R' and R 15 and each independently is as described herein. In some embodiments, R 1 is -C(O)NR 16 R 17 and R 16 and R 17 and each independently is as described herein. In some embodiments, R 1 teeth,

[0359] [ka]

[0360] is.

[0361] In some embodiments, R 1 is -C(O)OR 11 In some embodiments, R 11 is R as described herein. In some embodiments, R 11 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 11 is C 1-6 In some embodiments, R 11 is C 1-6 In some embodiments, R 11 is methyl. In some embodiments, R 11 is ethyl.

[0362] In some embodiments, R 1 is —C(O)OH. In some embodiments, R 1 is -C(O)OR 11 where R 11 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is -C(O)OR 11 where R 11 is an optionally substituted 3- to 10-membered cycloalkyl.

[0363] In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where R 12 and R 13 each independently as described herein.

[0364] In some embodiments, R 12 is R' as described herein. In some embodiments, R 12 is R as described herein. In some embodiments, R 12 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 12 is H. In some embodiments, R 12 is an optionally substituted C 1-6 In some embodiments, R 12 is C 1-6 In some embodiments, R 12 is methyl. In some embodiments, R 12 is ethyl.

[0365] In some embodiments, R 13 is R' as described herein. In some embodiments, R 13 is R as described herein. In some embodiments, R 13 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 13 is H. In some embodiments, R 13 is an optionally substituted C 1-6 In some embodiments, R 13 is C 1-6 In some embodiments, R 13 is methyl. In some embodiments, R 13 is ethyl.

[0366] In some embodiments, R 12 and R 13 are each independently R' as described herein. In some embodiments, R 12 and R 13 are each independently R as described herein.

[0367] In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ) and R 12 and R 13 are each independently H or optionally substituted C1-C6 alkyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ) and R 12 and R 13are each independently H. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ) and R 12 is H and R 13 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ) and R 12 is H and R 13 is ethyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ) and R 12 and R 13 are each independently C1-C6 alkyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ) and R 12 and R 13 are each ethyl.

[0368] In some embodiments, R 1 is -C(O)N(R 14 )SO2R 15 where R 14 and R 15 are each independently as described herein. In some embodiments, R 1 is -C(O)NHSO2R 15 where R 15 is as described herein.

[0369] In some embodiments, R 1 is -CN.

[0370] In some embodiments, R 14 is R' as described herein. In some embodiments, R 14 is R as described herein. In some embodiments, R 14is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 14 is H. In some embodiments, R 14 is an optionally substituted C 1-6 In some embodiments, R 14 is C 1-6 In some embodiments, R 14 is methyl. In some embodiments, R 14 is ethyl.

[0371] In some embodiments, R 15 is R' as described herein. In some embodiments, R 15 is R as described herein. In some embodiments, R 15 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms; 。 In some embodiments, R 15 is H. In some embodiments, R 15 is an optionally substituted C 1-6 In some embodiments, R 15 is C 1-6 In some embodiments, R 15 is methyl. In some embodiments, R 15 is ethyl.

[0372] In some embodiments, R 14 and R 15 are each independently R' as described herein. In some embodiments, R 14 and R 15 are each independently R as described herein.

[0373] In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 and R 17 each independently as described herein.

[0374] In some embodiments, R 16 is R' as described herein. In some embodiments, R 16 is R as described herein. In some embodiments, R 16 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 16 is H. In some embodiments, R 16 is an optionally substituted C 1-6 In some embodiments, R 16 is C 1-6 In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl.

[0375] In some embodiments, R 17 is R' as described herein. In some embodiments, R 17is R as described herein. In some embodiments, R 17 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, R 17 is H. In some embodiments, R 17 is an optionally substituted C 1-6 In some embodiments, R 17 is C 1-6 In some embodiments, R 17 is methyl. In some embodiments, R 17 is ethyl.

[0376] In some embodiments, R 16 and R 17 are each independently R' as described herein. In some embodiments, R 16 and R 17 are each independently R as described herein.

[0377] In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 and R 17 each is independently H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C-C aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms.

[0378] In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 and R 17 Each of is independently H or an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 and R 17 Each of is independently H. In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 is H and R 17 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 is H and R 17 is methyl. In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 and R 17 Each of is independently C-C alkyl. In some embodiments, R 1 is -C(O)NR 16 R 17 where R 16 and R 17 Each of is methyl.

[0379] In some embodiments, R 1 is the equivalent of —C(O)OH. In some embodiments, the compound is a carboxylic acid equivalent of a carboxylic acid compound, e.g., R 1is —C(O)OH. In some embodiments, the carboxylic acid equivalent is one described in WO2020 / 198537, US2021 / 0032213, WO2021 / 211839, or WO2022 / 061008, each of which is independently incorporated herein by reference.

[0380] In some embodiments, the carboxylic acid isosteres are described in Ballatore et al., ChemMedChem. 2013Mar;8(3):385-395, which carboxylic acid isosteres are incorporated herein by reference.

[0381] In some embodiments, the carboxylic acid bioisostere is a hydroxamic acid. 1 is -C(O)N(R 14 )OH and R 14 is as described herein. In some embodiments, R 1 is —C(O)NHOH. In some embodiments, R 1 is -N(OH)C(O)R 11 and R 11 is as described herein. In some embodiments, the carboxylic acid bioisostere is a phosphinic acid. In some embodiments, R 1 is -P(O)H(OR 12 ) and R 12 is as described herein. In some embodiments, the carboxylic acid bioisostere is a phosphonic acid. In some embodiments, the carboxylic acid is N-cyanoacetamide. In some embodiments, R 1 is —C(O)NHCN. In some embodiments, the carboxylic acid bioisostere is a sulfonic acid. In some embodiments, R 1 is -S(O)2OR 11 and R 11 is as described herein. In some embodiments, the carboxylic acid bioisostere is a sulfonamide. In some embodiments, R 1is -S(O)NR 16 R 17 and R 16 and R 17 are each independently as described herein. In some embodiments, the carboxylic acid bioisostere is an acylsulfonamide. In some embodiments, R 1 is -S(O)2N(R 14 )C(O)R 15 and R 14 and R 15 are each independently as described herein. In some embodiments, the carboxylic acid bioisostere is a sulfonylurea. In some embodiments, R 1 is -S(O)2N(R 14 )C(O)NR 16 R 17 and R 14 , R 16 and R 17 are each independently as described herein. In some embodiments, R 1 is -N(R 16 )C(O)(R 14 )S(O)2R 15 where R 14 , R 15 and R 16 are each independently as described herein. In some embodiments, R 1 is -S(O)NR 16 R 17 where R 16 and R 17 are each independently as described herein. In some embodiments, R 1 is -N(R 14 )S(O)2R 15 where R 14 and R 15 are each independently as described herein. In some embodiments, R 14 is —H. In some embodiments, R 16is —H. In some embodiments, the carboxylic acid bioisostere is tetrazole. In some embodiments, R 1 teeth,

[0382] [ka]

[0383] In some embodiments, the carboxylic acid bioisostere is a thiazolidinedione. In some embodiments, R 1 is optionally substituted

[0384] [ka]

[0385] In some embodiments, the carboxylic acid bioisostere is an oxazolidinedione. In some embodiments, R 1 is optionally substituted

[0386] [ka]

[0387] In some embodiments, the carboxylic acid bioisostere is 5'-oxo-1,2,4-oxadiazole. In some embodiments, R 1 is optionally substituted

[0388] [ka]

[0389] In some embodiments, the carboxylic acid bioisostere is 5'-oxo-1,2,4-thiadiazole. In some embodiments, R 1 is optionally substituted

[0390] [ka]

[0391] In some embodiments, the carboxylic acid bioisostere is 5'-thioxo-1,2,4-oxadiazole. In some embodiments, R 1 is optionally substituted

[0392] [ka]

[0393] In some embodiments, the carboxylic acid bioisostere is an isothiazole. In some embodiments, R 1 is optionally substituted

[0394] [ka]

[0395] In some embodiments, the carboxylic acid bioisostere is an isoxazole. In some embodiments, R 1 is optionally substituted

[0396] [ka]

[0397] In some embodiments, the bioisostere of the carboxylic acid is a phenol, and the phenyl ring is optionally substituted. In some embodiments, the bioisostere of the carboxylic acid is a phenol. In some embodiments, R 1 is a substituted phenyl where the substituent is —OH. In some embodiments, R 1 is 4-hydroxyphenyl. In some embodiments, R 1is 3-methyl-4-hydroxyphenyl. In some embodiments, the bioisostere of the carboxylic acid is a polyfluorophenol, e.g., a difluorophenol. In some embodiments, R 1 is phenyl substituted with one or more fluoro and —OH. In some embodiments, R 1 is phenyl substituted with two or more fluoro and -OH. In some embodiments, R 1 is 3,5-difluoro-4-hydroxyphenyl. In some embodiments, the carboxylic acid isostere is tetronic acid. In some embodiments, R 1 is optionally substituted

[0398] [ka]

[0399] In some embodiments, the carboxylic acid isostere is tetronic acid. In some embodiments, R 1 is optionally substituted

[0400] [ka]

[0401] In some embodiments, the carboxylic acid electron equivalent is cyclopentane-1,3-dione. In some embodiments, R 1 is optionally substituted

[0402] [ka]

[0403] In some embodiments, the carboxylic acid electron equivalent is squaric acid. In some embodiments, R 1 teeth,

[0404] [ka]

[0405] In some embodiments, R 1 teeth,

[0406] [ka]

[0407] In some embodiments, the carboxylic acid bioisostere is 3-hydroxypyridin-4(1H)-one. In some embodiments, R 1 is optionally substituted

[0408] [ka]

[0409] In some embodiments, R 1 teeth,

[0410] [ka]

[0411] In some embodiments, the carboxylic acid bioisostere is 6-hydroxy-1,3-dioxin-4-one. In some embodiments, R 1 is optionally substituted

[0412] [ka]

[0413] In some embodiments, R 1 is optionally substituted

[0414] [ka]

[0415] In some embodiments, R 1 is optionally substituted

[0416] [ka]

[0417] In some embodiments, R 1 is optionally substituted

[0418] [ka]

[0419] In some embodiments, R 1 is optionally substituted

[0420] [ka]

[0421] In some embodiments, R 1 is optionally substituted

[0422] [ka]

[0423] In some embodiments, R 1 is optionally substituted

[0424] [ka]

[0425] In some embodiments, R 1 teeth,

[0426] [ka]

[0427] and each of X and W is independently -O-, -S-, -N(R 8 ), or optionally substituted —CH—, and Y is —N═ or —C(R 9 )= and R 8 and R 9 is independently as described herein, and -NH- is optionally substituted. In some embodiments, R 1 teeth,

[0428] [ka]

[0429] and each of X and W is independently -O-, -S-, -N(R 8 ), or optionally substituted —CH—, and Y is —N═ or —C(R 9 )= and R 8 and R 9 is independently as described herein, and -NH- is optionally substituted. In some embodiments, R 1 teeth,

[0430] [ka]

[0431] wherein X and W are each independently -O-, -S-, -N(R 8 ), or optionally substituted —CH—, and Y is —N═ or —C(R 9 )=, where R 8 and R 9 are each independently as described herein, and -NH- is optionally substituted. In some embodiments, R1 teeth,

[0432] [ka]

[0433] wherein X', Y and W' are each independently -N= or -C(R 9 )=, where R 9 is as described herein, and -NH- is optionally substituted. In some embodiments, R 1 teeth,

[0434] [ka]

[0435] wherein X', Y and W' are each independently -N= or -C(R 9 )=, where R 9 is as described herein, and -NH- is optionally substituted. In some embodiments, R 1 teeth,

[0436] [ka]

[0437] wherein X', Y and W' are each independently -N= or -C(R 9 )=, where R 9 is as described herein, and -NH- is optionally substituted. In some embodiments, -NH- is unsubstituted. In some embodiments, -NH- is substituted. In some embodiments, X is -O-. In some embodiments, X is -N(R 8 )-, where R 8is as described herein. In some embodiments, X is optionally substituted -CH2-. In some embodiments, Y is Z as described herein. In some embodiments, Y is -N=. In some embodiments, Y is -C(R 9 )=. In some embodiments, Y is an optionally substituted -CH=. In some embodiments, Y is -CH=. In some embodiments, X' is Z as described herein. In some embodiments, X' is -N=. In some embodiments, X' is -C(R 9 )=. In some embodiments, X' is an optionally substituted -CH=. In some embodiments, X' is -CH=. In some embodiments, W' is Z as described herein. In some embodiments, W' is -N=. In some embodiments, W' is -C(R 9 )=. In some embodiments, W' is an optionally substituted -CH=. In some embodiments, W' is -CH=. In some embodiments, the carboxylic acid equivalent is a hydroxyquinolinone. In some embodiments, the carboxylic acid equivalent is 3-hydroxyquinolin-2-one. In some embodiments, the carboxylic acid equivalent is 4-hydroxyquinolin-2-one. In some embodiments, the R 1 The group is substituted. In some embodiments, it is unsubstituted.

[0438] In some embodiments, R 1 is -CHO. In some embodiments, R 1 is a protected -CHO.

[0439] In some embodiments, R 1 is R d6 In some embodiments, R d6 is -CH(OR). In some embodiments, each R is independently not -H. In some embodiments, each R is independently an optionally substituted C 1-6It is aliphatic. In some embodiments, two R's, taken together with the intervening atoms, form an optionally substituted 4-10 membered ring, e.g., a 5-10 membered ring, a 5-6 membered ring, a 4 membered ring, a 5 membered ring, a 6 membered ring, a 7 membered ring, an 8 membered ring, a 9 membered ring, or a 10 membered ring, having 0-3 heteroatoms in addition to the intervening atoms. In some embodiments, there are no heteroatoms in addition to the intervening atoms. 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 substituted. In some embodiments, the ring is unsubstituted. In some embodiments, the ring is saturated. In some embodiments, the ring is monocyclic. In some embodiments, R d6 is optionally substituted

[0440] [ka]

[0441] In some embodiments, R d6 teeth,

[0442] [ka]

[0443] is.

[0444] 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.

[0445] In some embodiments, R 1 teeth

[0446] [ka]

[0447] is.

[0448] R 2

[0449] In some embodiments, R 2 wherein R' is as described herein. In some embodiments, R 2 is 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 In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is methyl. In some embodiments, R 2 is an optionally substituted C 3-6 Alicyclic 。 In some embodiments, R 2 is an optionally substituted C 3-6 In some embodiments, R 2 is an optionally substituted cyclopropyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is an optionally substituted cyclobutyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is optionally substituted cyclopentyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2is optionally substituted cyclohexyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is an optionally substituted 5-6 membered heteroaryl having 1-4, e.g., 1, 2, 3, or 4 heteroatoms (e.g., independently selected from nitrogen, oxygen, and sulfur). 2 teeth,

[0450] [ka]

[0451] is.

[0452] In some embodiments, R 2 is R', and R' is -C(O)OR. In some embodiments, R 2 is —C(O)OH. In some embodiments, R 2 is —C(O)OR, where R is an optionally substituted C 1-6 It is an aliphatic group.

[0453] In some embodiments, R 2 is -OR', where R' is as described herein. In some embodiments, R' is as described herein. In some embodiments, R' is H. In some embodiments, R' is an optionally substituted C 1-6 In some embodiments, R' is an optionally substituted C 1-6 It is aliphatic. In some embodiments, R' is methyl.

[0454] In some embodiments, R 2 is halogen. In some embodiments, R 2is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br.

[0455] In some embodiments, R 2 is -CN. In some embodiments, R 2 is —NO. In some embodiments, R 2 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 2 is -NHR', where R' is as described herein. In some embodiments, each R' is independently as described herein. In some embodiments, R 2 is -NH2.

[0456] R 3

[0457] In some embodiments, R 3 is R' as described herein. In some embodiments, R 3 is R as described herein. In some embodiments, R 3 is H. In some embodiments, R 3 is not H. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is methyl. In some embodiments, R 3 is an optionally substituted C 3-6 Cycloaliphatic 。 In some embodiments, R 3 is an optionally substituted C 3-6In some embodiments, R 3 is an optionally substituted cyclopropyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is an optionally substituted cyclobutyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is optionally substituted cyclopentyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is optionally substituted cyclohexyl. In some embodiments, R 3 is cyclohexyl. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is phenyl. In some embodiments, R 3 is an optionally substituted 5-6 membered heteroaryl having 1-4, e.g., 1, 2, 3, or 4 heteroatoms (e.g., independently selected from nitrogen, oxygen, and sulfur). 3 teeth,

[0458] [ka]

[0459] is.

[0460] In some embodiments, R 3 is R', and R' is -C(O)OR. In some embodiments, R 3 is —C(O)OH. In some embodiments, R 3 is —C(O)OR, where R is an optionally substituted C 1-6 It is an aliphatic group.

[0461] In some embodiments, R 3is -OR', where R' is as described herein. In some embodiments, R' is as described herein. In some embodiments, R' is H. In some embodiments, R' is an optionally substituted C 1-6 In some embodiments, R' is an optionally substituted C 1-6 It is aliphatic. In some embodiments, R' is methyl.

[0462] In some embodiments, R 3 is halogen. In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br.

[0463] In some embodiments, R 3 is -CN. In some embodiments, R 3 is —NO. In some embodiments, R 3 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 3 is -NHR', where R' is as described herein. In some embodiments, each R' is independently as described herein. In some embodiments, R 3 is -NH2.

[0464] In some embodiments, R 3 and R 3 each independently represents R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where each variable is as described herein. In some embodiments, R 3 and R 3 Each of is H. In some embodiments, R 3 and R 3 One of the two is H and the other is R 3 and R 3の The other is not H. In some embodiments, R3 and R 3 One of the two is H and the other is R 3 and R 3 The other is R, -OR', halogen, -CN, -NO 2、 or -N(R')2, where each variable is as described herein. In some embodiments, R 3 and R 3 and each of R is not H. In some embodiments, R 3 and R 3 Each of these is R, -OR', halogen, -CN, -NO 2、 Or -N(R')2, where each variable is as described herein.

[0465] In some embodiments, ring B is

[0466] [ka]

[0467] where each variable is as described herein.

[0468] In some embodiments, ring B is

[0469] [ka]

[0470] where R 2 and R 11 is independently R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is as described herein. In some embodiments, Ring B is

[0471] [ka]

[0472] where R 2is a halogen and R 11 is H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 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 aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0473] [ka]

[0474] where R 2 is a halogen and R 11 is H. In some embodiments, ring B is

[0475] [ka]

[0476] where R 2 is F and R 11 is H.

[0477] In some embodiments, ring B is

[0478] [ka]

[0479] where R 2 and R 11 is independently R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is as described herein. In some embodiments, Ring B is

[0480] [ka]

[0481] where R 2 is a halogen and R 11 is H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 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 aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0482] [ka]

[0483] where R 2 is a halogen and R 11 is H. In some embodiments, ring B is

[0484] [ka]

[0485] where R 2 is F and R 11 is H.

[0486] In some embodiments, ring B is

[0487] [ka]

[0488] where R 11is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0489] [ka]

[0490] where R 11 is H.

[0491] In some embodiments, ring B is

[0492] [ka]

[0493] where each variable is independently as described herein.

[0494] In some embodiments, ring B is

[0495] [ka]

[0496] where R 2 and R 11 is independently R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is as described herein. In some embodiments, Ring B is

[0497] [ka]

[0498] where R 2 is a halogen and R 11 is H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 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 aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0499] [ka]

[0500] where R 2 is a halogen and R 11 is H. In some embodiments, ring B is

[0501] [ka]

[0502] where R 2 is F and R 11 is H.

[0503] In some embodiments, ring B is

[0504] [ka]

[0505] where R 2 and R 11 each independently represents R', -OR', halogen, -CN, -NO 2、or -N(R')2, where each variable is independently as described herein. In some embodiments, Ring B is

[0506] [ka]

[0507] where R 2 is halogen, optionally substituted C1-C6 alkyl, -OR (wherein R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3- C cycloalkyl or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms, R 11 is H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C-C aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0508] [ka]

[0509] where R 2 is a halogen and R 11is H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C-C aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0510] [ka]

[0511] where R 2 is a halogen and R 11 is H. In some embodiments, ring B is

[0512] [ka]

[0513] where R 2 is F and R 11 is H. In some embodiments, ring B is

[0514] [ka]

[0515] where R 2 is chlorine and R 11 is H. In some embodiments, ring B is

[0516] [ka]

[0517] where R 2 is Br and R 11 is H.

[0518] In some embodiments, ring B is

[0519] [ka]

[0520] where R 2 is -OR, where R is an optionally substituted C1-C6 alkyl, and R 11 is H. In some embodiments, ring B is

[0521] [ka]

[0522] where R 2 is -OMe, and R 11 is H. In some embodiments, ring B is

[0523] [ka]

[0524] where R 2 is -OMe, and R 11 is H.

[0525] In some embodiments, ring B is

[0526] [ka]

[0527] where R 2 is an optionally substituted 6-10 membered aryl, and R 11 is H. In some embodiments, ring B is

[0528] [ka]

[0529] where R 2 is optionally phenyl. In some embodiments, Ring B is

[0530] [ka]

[0531] where R 2 is phenyl and R 11 is H.

[0532] In some embodiments, ring B is

[0533] [ka]

[0534] where R 2 is an optionally substituted C1-C6 alkyl, and R 11 is H. In some embodiments, ring B is

[0535] [ka]

[0536] where R 2 is C1-C6 alkyl. In some embodiments, ring B is

[0537] [ka]

[0538] where R 2 is methyl and R 11 is H. In some embodiments, ring B is

[0539] [ka]

[0540] where R 2 is methyl and R 11 is H.

[0541] In some embodiments, ring B is

[0542] [ka]

[0543] where R 2 is an optionally substituted C 3- C cycloalkyl, and R 11 is H. In some embodiments, ring B is

[0544] [ka]

[0545] where R 2 is C 3- C cycloalkyl, and R 11 is H. In some embodiments, ring B is

[0546] [ka]

[0547] where R 2 teeth,

[0548] [ka]

[0549] and R 11is H. In some embodiments, ring B is

[0550] [ka]

[0551] where R 2 teeth,

[0552] [ka]

[0553] and R 11 is H. In some embodiments, ring B is

[0554] [ka]

[0555] where R 2 teeth,

[0556] [ka]

[0557] and R 11 is H. In some embodiments, ring B is

[0558] [ka]

[0559] where R 2 teeth,

[0560] [ka]

[0561] and R 11 is H.

[0562] In some embodiments, ring B is

[0563] [ka]

[0564] where R 2 is an optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms, and R 11 is H. In some embodiments, ring B is

[0565] [ka]

[0566] where R 2 is an optionally substituted 5-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S; R 11 is H. In some embodiments, ring B is

[0567] [ka]

[0568] where R 2 is an optionally substituted 6-membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S; R 11 is H. In some embodiments, ring B is

[0569] [ka]

[0570] where R 2 teeth,

[0571] [ka]

[0572] and R 11 is H.

[0573] In some embodiments, ring B is

[0574] [ka]

[0575] where R 2 and R 11 each independently represents R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where each variable is independently as described herein. In some embodiments, Ring B is

[0576] [ka]

[0577] where R 2 is halogen, optionally substituted C1-C6 alkyl, -OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3- C cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms, and R 11is H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 aliphatic, and 5-10 membered heteroaryl-C having 1-6 heteroatoms-C-C aliphatic. In some embodiments, ring B is

[0578] [ka]

[0579] where R 2 is a halogen and R 11 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0580] [ka]

[0581] where R 2 is a halogen and R 11 is H. In some embodiments, ring B is

[0582] [ka]

[0583] where R 2 is F and R 11 is H. In some embodiments, ring B is

[0584] [ka]

[0585] where R 2 is chlorine and R 11 is H. In some embodiments, ring B is

[0586] [ka]

[0587] where R 2 is Br and R 11 is H.

[0588] In some embodiments, ring B is

[0589] [ka]

[0590] where R 2 is -OR, where R is an optionally substituted C1-C6 alkyl, and R 11 is H. In some embodiments, ring B is

[0591] [ka]

[0592] where R 2 is -OMe, and R 11 is H. In some embodiments, ring B is

[0593] [ka]

[0594] where R 2 is -OMe, and R 11 is H.

[0595] In some embodiments, ring B is

[0596] [ka]

[0597] where R 2 is an optionally substituted C1-C6 alkyl, and R 11 is H. In some embodiments, ring B is

[0598] [ka]

[0599] where R 2 is C1-C6 alkyl. In some embodiments, ring B is

[0600] [ka]

[0601] where R 2 is methyl and R 11 is H. In some embodiments, ring B is

[0602] [ka]

[0603] where R 2 is methyl and R 11 is H.

[0604] In some embodiments, ring B is

[0605] [ka]

[0606] where R 2 and R 11 is independently R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is independently as described herein. In some embodiments, Ring B is

[0607] [ka]

[0608] where R 2 is halogen, optionally substituted C1-C6 alkyl, -OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3- and R is H or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0609] [ka]

[0610] where R 2 is a halogen and R 11is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0611] [ka]

[0612] where R 2 is a halogen and R 11 is H. In some embodiments, ring B is

[0613] [ka]

[0614] where R 2 is F and R 11 is H. In some embodiments, ring B is

[0615] [ka]

[0616] where R 2 is chlorine and R 11 is H. In some embodiments, ring B is

[0617] [ka]

[0618] where R 2 is Br and R 11 is H.

[0619] In some embodiments, ring B is

[0620] [ka]

[0621] where R 11 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0622] [ka]

[0623] where R 11 is H.

[0624] In some embodiments, ring B is

[0625] [ka]

[0626] where each variable is independently as described herein.

[0627] In some embodiments, ring B is

[0628] [ka]

[0629] where R 2and R 11 is independently R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is as described herein.

[0630] In some embodiments, ring B is

[0631] [ka]

[0632] where R 11 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0633] [ka]

[0634] where R 11 is H.

[0635] In some embodiments, ring B is

[0636] [ka]

[0637] wherein each variable is independently as described herein. In some embodiments, ring B is

[0638] [ka]

[0639] wherein each variable is independently as described herein. In some embodiments, ring B is

[0640] [ka]

[0641] where each variable is independently as described herein.

[0642] In some embodiments, ring B is

[0643] [ka]

[0644] where R 12 and R 13 is independently hydrogen or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 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 aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0645] [ka]

[0646] where R 12 and R 13 is independently H or an optionally substituted C1-C6 alkyl. In some embodiments, ring B is

[0647] [ka]

[0648] where R 12 and R 13 Each of is independently H. In some embodiments, ring B is

[0649] [ka]

[0650] and R 12 and R 13 are each independently an optionally substituted C1-C6 alkyl. In some embodiments, ring B is

[0651] [ka]

[0652] and R 12 are H and R 13 is optionally substituted C1-C6 alkyl. In some embodiments, ring B is

[0653] [ka]

[0654] and R 12 are H and R 13 is ethyl. In some embodiments, ring B is

[0655] [ka]

[0656] and R 12 are ethyl, and R 13 is ethyl.

[0657] In some embodiments, ring B is

[0658] [ka]

[0659] wherein each variable is independently as described herein. In some embodiments, ring B is

[0660] [ka]

[0661] wherein each variable is independently as described herein. In some embodiments, ring B is

[0662] [ka]

[0663] where each variable is independently as described herein.

[0664] In some embodiments, ring B is

[0665] [ka]

[0666] where R 2 R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where each variable is independently as described herein; R 16 and R 17each independently represents hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms, or R 16 and R 17 In some embodiments, ring B is a 3-10 membered ring having 0-4 heteroatoms in addition to the optionally substituted nitrogen.

[0667] [ka]

[0668] and R 2 is H or halogen, and R 16 and R 17 is independently hydrogen or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 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 aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0669] [ka]

[0670] where R 2 is a halogen and R 16 and R 17is independently hydrogen or an optionally substituted group selected from C-C aliphatic, C-C heteroaliphatic having 1-3 heteroatoms, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C-C aliphatic, and 5-10 membered heteroaryl-C-C aliphatic having 1-6 heteroatoms. In some embodiments, Ring B is

[0671] [ka]

[0672] where R 2 is a halogen and R 16 and R 17 is independently hydrogen, or optionally C1-C6 alkyl. In some embodiments, ring B is

[0673] [ka]

[0674] and R 2 is a halogen and R 16 and R 17 are each H. In some embodiments, ring B is

[0675] [ka]

[0676] and R 2 is a halogen and R 16 is H and R 17 is optionally C1-C6 alkyl. In some embodiments, ring B is

[0677] [ka]

[0678] and R 2 is a halogen and R 16 is H and R 17 is methyl. In some embodiments, ring B is

[0679] [ka]

[0680] and R 2 is a halogen and R 16 and R 17 and each is optionally C1-C6 alkyl. In some embodiments, ring B is

[0681] [ka]

[0682] and R 2 is a halogen and R 16 and R 17 are each methyl.

[0683] In some embodiments, ring B is

[0684] [ka]

[0685] and R 2 is F and R 16 and R 17 are each independently a hydrogen atom or optionally a C1-C6 alkyl. In some embodiments, ring B is

[0686] [ka]

[0687] and R 2 is Cl and R16 and R 17 are each independently a hydrogen atom or optionally a C1-C6 alkyl. In some embodiments, ring B is

[0688] [ka]

[0689] and R 2 is Br and R 16 and R 17 are each independently a hydrogen atom or optionally a C1-C6 alkyl.

[0690] In some embodiments, ring B is

[0691] [ka]

[0692] wherein each variable is independently as described herein. In some embodiments, ring B is

[0693] [ka]

[0694] where each variable is independently as described herein.

[0695] In some embodiments, ring B is

[0696] [ka]

[0697] wherein each variable is independently as described herein. In some embodiments, ring B is

[0698] [ka]

[0699] where each variable is independently as described herein.

[0700] In some embodiments, ring B is

[0701] [ka]

[0702] wherein each variable is independently as described herein. In some embodiments, ring B is

[0703] [ka]

[0704] wherein each variable is independently as described herein. In some embodiments, ring B is

[0705] [ka]

[0706] where each variable is independently as described herein.

[0707] In some embodiments, ring B is

[0708] [ka]

[0709] where R 2 is R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is independently as described herein.

[0710] In some embodiments, ring B is

[0711] [ka]

[0712] where R 2 is R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is independently as described herein. In some embodiments, ring B is

[0713] [ka]

[0714] where R 2 is H. In some embodiments, ring B is

[0715] [ka]

[0716] where R 2 is halogen, optionally substituted C1-C6 alkyl, -OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3- C cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms; R 11 is H or C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms, C1-C6 aliphatic. In some embodiments, Ring B is

[0717] [ka]

[0718] and R 2 is halogen. In some embodiments, ring B is

[0719] [ka]

[0720] and R 2 is F. In some embodiments, ring B is

[0721] [ka]

[0722] and R 2 is Cl. In some embodiments, ring B is

[0723] [ka]

[0724] and R 2 In some embodiments, ring B is

[0725] [ka]

[0726] and R 2 is I.

[0727] In some embodiments, ring B is

[0728] [ka]

[0729] where R 2 R', -OR', halogen, -CN, -NO 2、 or -N(R')2, where each variable is independently as described herein. In some embodiments, Ring B is

[0730] [ka]

[0731] where R 2 is H. In some embodiments, ring B is

[0732] [ka]

[0733] where R 2 is halogen, optionally substituted C1-C6 alkyl, -OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3- C cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms; R 11 is H or C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms, C1-C6 aliphatic. In some embodiments, Ring B is

[0734] [ka]

[0735] and R 2 is halogen. In some embodiments, ring B is

[0736] [ka]

[0737] and R 2 is F. In some embodiments, ring B is

[0738] [ka]

[0739] and R 2 is Cl. In some embodiments, ring B is

[0740] [ka]

[0741] and R 2 In some embodiments, ring B is

[0742] [ka]

[0743] and R 2 is I.

[0744] In some embodiments, ring B is

[0745] [ka]

[0746] where R 2 is R', -OR', halogen, -CN, -NO2, or -N(R')2, where each variable is independently as described herein. In some embodiments, ring B is

[0747] [ka]

[0748] where R 2 is H. In some embodiments, ring B is

[0749] [ka]

[0750] where R 2 is halogen, optionally substituted C1-C6 alkyl, -OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3- C cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms; R 11 is H or C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C1-C6 aliphatic, and 5-10 membered heteroaryl having 1-6 heteroatoms, C1-C6 aliphatic. In some embodiments, Ring B is

[0751] [ka]

[0752] and R 2 is halogen. In some embodiments, ring B is

[0753] [ka]

[0754] and R 2is F. In some embodiments, ring B is

[0755] [ka]

[0756] and R 2 is Cl. In some embodiments, ring B is

[0757] [ka]

[0758] and R 2 In some embodiments, ring B is

[0759] [ka]

[0760] and R 2 is I.

[0761] In some embodiments, ring B is

[0762] [ka]

[0763] and R 2 is an optionally substituted C1-C6 aliphatic. In some embodiments, ring B is

[0764] [ka]

[0765] and R 2 is optionally substituted C1-C6 alkyl. In some embodiments, ring B is

[0766] [ka]

[0767] and R 2 In some embodiments, ring B is

[0768] [ka]

[0769] and R 2 is an optionally substituted C 3- In some embodiments, ring B is C cycloalkyl.

[0770] [ka]

[0771] and R 2 teeth

[0772] [ka]

[0773] In some embodiments, ring B is

[0774] [ka]

[0775] and R 2 teeth,

[0776] [ka]

[0777] In some embodiments, ring B is

[0778] [ka]

[0779] where R 2 teeth,

[0780] [ka]

[0781] In some embodiments, ring B is

[0782] [ka]

[0783] where R 2 teeth,

[0784] [ka]

[0785] is.

[0786] In some embodiments, ring B is

[0787] [ka]

[0788] and R 2 is —C(O)OR, where each variable is independently as described herein. In some embodiments, Ring B is

[0789] [ka]

[0790] and R 2is —C(O)OR, where R is hydrogen or an optionally substituted C1-C6 aliphatic. In some embodiments, ring B is

[0791] [ka]

[0792] and R 2 is —C(O)OR, and R is hydrogen. In some embodiments, ring B is

[0793] [ka]

[0794] and R 2 is —C(O)OR, where R is an optionally substituted group selected from C1-C6 aliphatic. In some embodiments, ring B is

[0795] [ka]

[0796] and R 2 is —C(O)OR, where R is an optionally substituted group selected from C1-C6 alkyl. In some embodiments, ring B is

[0797] [ka]

[0798] and R 2 is —C(O)OR and R is methyl. In some embodiments, ring B is

[0799] [ka]

[0800] where R 2 is —C(O)OR, where R is ethyl.

[0801] In some embodiments, ring B is

[0802] [ka]

[0803] wherein each variable is independently as described herein. In some embodiments, ring B is

[0804] [ka]

[0805] and R 16 and R 17 are each independently H or an optionally substituted C1-C6 aliphatic. In some embodiments, ring B is

[0806] [ka]

[0807] and R 16 and R 17 are H respectively.

[0808] In some embodiments, ring B is

[0809] [ka]

[0810] where R 2 is -CN.

[0811] In some embodiments, ring B is

[0812] [ka]

[0813] where R 2 and R 3 are independently halogen, —CN, optionally substituted C1-C6 alkyl, or —OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

[0814] In some embodiments, ring B is

[0815] [ka]

[0816] where R 2 and R 3 are each independently halogen, -CN, optionally substituted C1-C6 alkyl, or -OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms. In some embodiments, ring B is

[0817] [ka]

[0818] where R 2 and R 3 are each independently halogen and optionally substituted C1-C6 alkyl. In some embodiments, ring B is

[0819] [ka]

[0820] where R 2 and R 3 are each independently halogen and optionally substituted C1-C6 alkyl. In some embodiments, ring B is

[0821] [ka]

[0822] is.

[0823] In some embodiments, ring B is

[0824] [ka]

[0825] where R 2 and R 3 are independently halogen, —CN, optionally substituted C1-C6 alkyl, or —OR, where R is optionally substituted C1-C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C3-C8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

[0826] In certain embodiments, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:

[0827] [ka]

[0828] [ka]

[0829] In certain embodiments, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:

[0830] [ka]

[0831] In certain embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , n, and X are each independently as described herein.

[0832] [ka]

[0833] In certain embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Z, and X are each independently as described herein.

[0834] [ka]

[0835] In certain embodiments, the present disclosure provides compounds of formula (IV-1-IV-6), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 , and R 10 each of which is independently as described herein.

[0836] [ka]

[0837] In certain embodiments, the present disclosure provides compounds of formula (V-1-V-6), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 each of which is independently as described herein.

[0838] [ka]

[0839] In certain embodiments, the present disclosure provides compounds of the following formula, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , n, and X are each independently as described herein, and each ring is independently optionally substituted. In some embodiments, the present disclosure provides compounds of the following formula, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth

[0840] [ka]

[0841] and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , n, and X are each independently as described herein, and each ring is independently optionally substituted.

[0842] [ka]

[0843] [ka]

[0844] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound having the following structure:

[0845] [ka]

[0846] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0847] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0848] [ka]

[0849] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0850] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0851] [ka]

[0852] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0853] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0854] [ka]

[0855] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 2 is halogen. In some embodiments, R 2 is F. In some embodiments, R 8 is H or optionally substituted C1-C6 alkyl. In some embodiments, R 8 is H. In some embodiments, R 8 is an optionally substituted C1-C6 alkyl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is propyl. In some embodiments, R 8 is isopropyl. In some embodiments, R 8 is isobutyl. In some embodiments, R 8 is butyl. In some embodiments, R 8 is an optionally substituted C-C cycloalkyl. In some embodiments, R 8 is an optionally substituted C-C cycloalkyl. In some embodiments, R8 teeth

[0856] [ka]

[0857] In some embodiments, R 8 teeth

[0858] [ka]

[0859] In some embodiments, R 8 teeth

[0860] [ka]

[0861] In some embodiments, R 8 is an optionally substituted 6-10 membered aryl. In some embodiments, R 8 is phenyl. In some embodiments, R 6 is -CN. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is -CF3.

[0862] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0863] [ka]

[0864] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0865] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0866] [ka]

[0867] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 5 is H. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 5 is -CF3. In some embodiments, R 2 is H. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is an optionally substituted C1-C6 alkyl. In some embodiments, R 2 is an optionally substituted C 3- In some embodiments, R 2 teeth

[0868] [ka]

[0869] In some embodiments, R 2 teeth

[0870] [ka]

[0871] In some embodiments, R 2 teeth

[0872] [ka]

[0873] In some embodiments, R 2 is —OR, where R is an optionally substituted C1-C6 alkyl. In some embodiments, R 2 is -OMe. In some embodiments, R 2 is an optionally substituted 6-10 membered aryl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is an optionally substituted 5-10 membered heteroaryl having 1-3 heteroatoms. In some embodiments, R 2 teeth

[0874] [ka]

[0875] is.

[0876] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0877] [ka]

[0878] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 2 is H. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 4 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 is -CF3. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is a 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 7 is a halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is Br.

[0879] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0880] [ka]

[0881] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 5 is -CF3. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br.

[0882] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0883] [ka]

[0884] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 8 is H. In some embodiments, R 8 is an optionally substituted C1-C6 alkyl. In some embodiments, R 8 is methyl. In some embodiments, R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is -CF3.

[0885] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0886] [ka]

[0887] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 2 is H. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is F. In some embodiments, R 2 is chlorine. In some embodiments, R 2 is Br. In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 5 is -CF3.

[0888] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0889] [ka]

[0890] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 8 is an optionally substituted C1-C6 alkyl. In some embodiments, R 8 is methyl. In some embodiments, R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is -CF3. In some embodiments, R 12 and R 13 Each of is independently H or an optionally substituted C1-C6 alkyl. In some embodiments, R 12 and R13 is independently H. In some embodiments, R 12 and R 13 Each of is independently ethyl.

[0891] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0892] [ka]

[0893] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 2 is halogen. In some embodiments, R 2 is F. In some embodiments, R 2 is chlorine. In some embodiments, R 2 is Br. In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 5 is -CF3. In some embodiments, R 16 and R 17 are each independently H or optionally substituted C1-C6 alkyl. In some embodiments, R 16 and R 17 are each independently an optionally substituted C1-C6 alkyl. In some embodiments, R 16 and R 17 Each is methyl. In some embodiments, R 16 and R 17 together with the nitrogen to form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the nitrogen.

[0894] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is

[0895] [ka]

[0896] or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 2 is halogen. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is an optionally substituted C1-C6 alkyl. In some embodiments, R 2 is -CF3.

[0897] R'

[0898] Various variables are applicable to R' as described herein. In some embodiments, R' is hydrogen.

[0899] 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.

[0900] R

[0901] Various variables are applicable to R described herein. Various embodiments of R may be substituted with other variables that may be R (e.g., R 1 , R 2 , R′, etc.) are described extensively herein.

[0902] In some embodiments, R is -H. In some embodiments, R is not -H.

[0903] In some embodiments, each R is independently 、 hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms.

[0904] In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is alkyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted n-propyl. In some embodiments, R is optionally substituted isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is t-butyl. In some embodiments, R is pentyl. In some embodiments, R is hexyl.

[0905] In some embodiments, R is an optionally substituted C having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-6 In some embodiments, R is an optionally substituted C alkyl group having 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0906] In some embodiments, R is optionally substituted C 3-10 (For example, C 4-10 , C 3-9 , C 3-7 , or 3, 4, 5, 6, 7, 8, 9, or 10-membered) alicyclic groups. In some embodiments, the alicyclic group is a cycloalkyl group. In some embodiments, the alicyclic group is monocyclic. In some embodiments, the alicyclic group is bicyclic. In some embodiments, the alicyclic group is polycyclic. In some embodiments, each monocyclic unit independently has 3-10 (e.g., C 4-10 , C 3-9 , C 3-7 , or 3, 4, 5, 6, 7, 8, 9, or 10-membered alicyclic ring, etc. In some embodiments, the alicyclic group is saturated. In some embodiments, the alicyclic group is partially unsaturated. In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R is an optionally substituted cyclobutyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is an optionally substituted cycloheptyl. In some embodiments, R is cyclopropyl. In some embodiments, R is cyclobutyl. In some embodiments, R is cyclopentyl. In some embodiments, R is cyclohexyl. In some embodiments, R is cycloheptyl.

[0907] In some embodiments, R is an optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered heterocyclyl having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered heterocyclyl having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, the heterocyclyl group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered heterocyclyl ring having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, the heterocyclyl ring has one heteroatom. In some embodiments, the heterocyclyl ring has two or more heteroatoms. In some embodiments, the heterocyclyl ring has three or more heteroatoms. In some embodiments, the heterocyclyl ring has four or more heteroatoms. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0908] In some embodiments, R is optionally substituted C 6-10 (For example, C 6、 C 10 In some embodiments, R is an optionally substituted C 6-10In some embodiments, the aryl ring is aryl. In some embodiments, the aryl ring is monocyclic. In some embodiments, the aryl ring is bicyclic. In some embodiments, the aryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 6-membered aromatic ring. 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.

[0909] In some embodiments, R is an optionally substituted 5-10 (e.g., 5-9, or 5, 6, 7, 8, 9, or 10, etc.) membered heteroaryl having 1-6 (e.g., 1-6, 1-5, 1-4, or 1, 2, 3, 4, 5, or 6, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 5-10 (e.g., 5-9, or 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl ring is monocyclic. In some embodiments, the heteroaryl ring is bicyclic. In some embodiments, the heteroaryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 5- or 6-membered aromatic ring having 0-4 heteroatoms (e.g., independently selected from nitrogen, oxygen, and sulfur), and at least one monocyclic unit contains 1-4 heteroatoms. In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl ring has one heteroatom. In some embodiments, the heteroaryl ring has two or more heteroatoms. In some embodiments, the heteroaryl ring has 3 or more heteroatoms. In some embodiments, the heteroaryl ring has 4 or more heteroatoms. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen.In some embodiments, the heteroatom is sulfur.

[0910] In some embodiments, R is an optionally substituted C 6-10 Aryl-C 1-6 In some embodiments, R is an optionally substituted C 6-10 Aryl-C 1-6 It is an alkyl group.

[0911] In some embodiments, R is an optionally substituted 5-10 membered heteroaryl-C having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms. 1-6 In some embodiments, R is an optionally substituted 5-10 membered heteroaryl-C having 1-5 heteroatoms. 1-6 In some embodiments, R is an optionally substituted 5-6 membered heteroaryl-C having 1-4 heteroatoms. 1-6 In some embodiments, R is an optionally substituted 5-10 membered heteroaryl-C having 1-6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms. 1-6 alkyl, where heteroaryl and aliphatic are independently as described herein. In some embodiments, R is an optionally substituted 5-10 membered heteroaryl having 1-5 heteroatoms (C 1-6 In some embodiments, R is an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms (C 1-6 alkyl). A variety of suitable heteroaryl and aliphatic groups are as described herein.

[0912] In some embodiments, two R groups on the same atom optionally and independently form, together with the atom, an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having, in addition to the atom, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, two R groups on two atoms optionally and independently form, together with the intervening atoms, an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered ring having, in addition to the intervening atoms, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms.

[0913] As described herein, in various cases, two R groups, or two groups that are or can be R (e.g., R 4 , R 5 , R 6 , R 7etc.), together with their intervening atom(s), can form a ring, which may be optionally substituted as described herein. In some embodiments, the ring formed is substituted (in addition to the groups attached to the intervening atoms). In some embodiments, the ring formed is unsubstituted. In some embodiments, the ring formed is a 3-membered ring. In some embodiments, the ring formed is a 4-membered ring. In some embodiments, the ring formed is a 5-membered ring. In some embodiments, the ring formed is a 6-membered ring. In some embodiments, the ring formed is a 7-membered ring. In some embodiments, the ring formed is an 8-membered ring. In some embodiments, the ring formed is a 9-membered ring. In some embodiments, the ring formed is a 10-membered ring. In some embodiments, the ring formed is saturated. In some embodiments, the ring formed is partially unsaturated. In some embodiments, the ring formed is aromatic. In some embodiments, the ring formed is monocyclic. In some embodiments, the ring formed is bicyclic. In some embodiments, the ring formed is polycyclic. In some embodiments, each monocyclic ring unit is independently a 3-10 (e.g., 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring, is independently saturated, partially unsaturated, or aromatic, and has 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, each monocyclic ring unit is independently a 3-10 (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring, is independently saturated, partially unsaturated, or aromatic, and has 0-4 (e.g., 0, 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic ring unit is independently a 3-7 membered ring. In some embodiments, each monocyclic ring unit is independently a 3-6 membered ring. In some embodiments, each monocyclic ring unit is independently a 5-7 membered ring. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, at least one monocyclic unit is saturated.In some embodiments, at least one monocyclic unit is partially unsaturated. In some embodiments, at least one monocyclic unit is aromatic. In some embodiments, the formed ring has, in addition to the intervening atoms, 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, there are no additional heteroatoms. In some embodiments, there is one additional heteroatom. In some embodiments, there are two additional heteroatoms. In some embodiments, there are three additional heteroatoms. In some embodiments, there are four additional heteroatoms. In some embodiments, there are five additional heteroatoms. In some embodiments, there are six or more additional heteroatoms. In some embodiments, the additional heteroatom is nitrogen. In some embodiments, the additional heteroatom is oxygen. In some embodiments, the additional heteroatom is sulfur. For example, in some embodiments, R. 4 and R 5 taken together with their intervening atoms form a ring as described herein. In some embodiments, R 4 and R 5 together with their intervening atoms form an optionally substituted phenyl ring; in some embodiments, R 4 and R 5 taken together with their intervening atoms form an optionally substituted 5- or 6-membered heteroaryl ring having 1-4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0914] As described herein, various groups may be optionally substituted. Substituents are routinely utilized in chemistry, including the development of various therapeutic agents. Many substituents can be utilized in accordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Substituents are preferred that result in the formation of a compound having desired properties, activity, use, etc., as described herein. In some embodiments, the compound is stable for therapeutic use as described herein. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that allow for the compound's manufacture, detection, and, in certain embodiments, recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, the substituent is a hydrocarbon group. In some embodiments, the substituent includes a heteroatom. In some embodiments, the substituent includes multiple heteroatoms. In some embodiments, each atom in the substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus, and silicon. In some embodiments, each atom in the substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatoms in a substituent is about 1 or less than about 1, in some embodiments, about 2 or less, in some embodiments, about 3 or less, in some embodiments, about 4 or less, in some embodiments, about 5 or less, in some embodiments, about 6 or less, in some embodiments, about 7 or less, in some embodiments, about 8 or less, in some embodiments, about 9 or less, in some embodiments, about 10 or less, and in some embodiments, about 11 or less. In some embodiments, it is about 12 or less, in some embodiments, it is about 13 or less, in some embodiments, it is about 14 or less, and in some embodiments, it is about 15 or less.In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent is independently about 20 or less. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent is independently about 15 or less. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent is independently about 10 or less. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent is independently about 6 or less. In some embodiments, each optional substituent on a substitutable group (e.g., ring A, ring B, R, etc.) is independently selected from the group consisting of halogen, C, CI ... 1-4 Alkyl, -OH, -CN, -NO2, C 1-4 haloalkyl (e.g., -CF3), -OR SB , -N(R SB )2, -C(O)OR SB , -C(O)N(R SB )2, or -S(O)2N(R SB )2, and each R SB are independently -H, C 1-4 Alkyl, or C 1-4 haloalkyl or halogen, C 1-4 Alkyl, -OH, -CN, -NO2, C 1-4 haloalkyl (e.g., -CF3), -OR SB , -N(R SB )2, -C(O)OR SB , -C(O)N(R SB )2, or -S(O)2N(R SB In some embodiments, each optional substituent on a substitutable group (e.g., ring A, ring B, R, etc.) is independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 In some embodiments, each optional substituent on a substitutable group (e.g., ring A, ring B, R, etc.) is independently selected from halogen, C 1-4 Alkyl, or C 1-4 In some embodiments, each halogen is -F.

[0915] In some embodiments, the compound provided is a compound selected from compounds 1-101 in the Examples, or a salt thereof.

[0916] In some embodiments, each heteroatom is independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, each heteroatom is independently selected from oxygen, nitrogen, and sulfur.

[0917] In some embodiments, one or more isotopes may be utilized or enriched at one or more positions in the compounds of the present disclosure. For example, in some embodiments, deuterium is utilized or enriched at one or more positions. In some embodiments, the enrichment is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% of the natural abundance. In some embodiments, the level of an isotope at a position is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% of the total compound molecules. For example, in some embodiments, L ra is -(CD2)n-, and in some embodiments, L ra is -CD2-.

[0918] Manufacturing method

[0919] In some embodiments, the 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.

[0920] 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.

[0921] 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.

[0922] 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).

[0923] 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 -78° C., -60° C., -50° C., -40° C., -30° C., -20° C., -10° C., 0° C., or 10° C. or less. In some embodiments, the temperature is about 10° C. or less. In some embodiments, the temperature is about 15° C. or less. In some embodiments, the temperature is about 20° C. or less. 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 35, 40, 50, 60, 70, 80, 90, 100, or 100° C. or more. 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.

[0924] 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.

[0925] The reaction can be carried out for a variety of times. In some embodiments, the reaction is complete instantaneously. 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.

[0926] In some embodiments, the present disclosure provides compounds of high purity. In some embodiments, the 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 purity of the compound is about 80% or greater. In some embodiments, the purity of the compound is about 85% or greater. In some embodiments, the purity of the compound is about 90% or greater. In some embodiments, the purity of the compound is about 95% or greater. In some embodiments, the purity of the compound is about 96% or greater. In some embodiments, the purity of the compound is about 97% or greater. In some embodiments, the purity of the compound is about 98% or greater. In some embodiments, the purity of the compound is about 99% or greater. In some embodiments, the purity of the compound is about 99.5% or greater. In some embodiments, the purity of the compound is about 99.7% or greater. In some embodiments, the purity of the compound is about 99.9% or greater.

[0927] 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.

[0928] 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.

[0929] 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.

[0930] For example, in some embodiments, the present disclosure provides a method comprising the steps of: Compound of formula B-4:

[0931] [ka]

[0932] or a salt thereof, 8-LG or a salt thereof, or a salt thereof, wherein LG is a leaving group, to produce a compound having the structure of formula B:

[0933] [ka]

[0934] or a salt thereof, wherein each variable is independently as described herein.

[0935] 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 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 carried out in the presence of a base. In some embodiments, the base is NaH.

[0936] In some embodiments, the compound having the structure of formula B-4 or a salt thereof is a compound having the following structure:

[0937] [ka]

[0938] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of Formula B or a salt thereof is a compound having the following structure:

[0939] [ka]

[0940] or a salt thereof, wherein each variable is independently as described herein.

[0941] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula B-3:

[0942] [ka]

[0943] or a salt thereof to produce a compound having the structure of formula B-4:

[0944] [ka]

[0945] or a salt thereof, wherein each variable is independently as described herein.

[0946] In some embodiments, the compound having the structure of formula B-3 or a salt thereof is a compound having the following structure:

[0947] [ka]

[0948] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of B-4 or a salt thereof is a compound having the structure:

[0949] [ka]

[0950] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is a metal complex. In some embodiments, the metal complex is a Pd complex. In some embodiments, the metal complex is PdCl. In some embodiments, the suitable solvent is CHCN.

[0951] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula B-1:

[0952] [ka]

[0953] or a salt thereof, with a compound having the structure of formula B-2:

[0954] [ka]

[0955] or a salt thereof to produce a compound having the structure of formula B-3:

[0956] [ka]

[0957] or a salt thereof, wherein Hal is a halogen, and wherein each variable is independently as described herein.

[0958] In some embodiments, Hal is Cl. In some embodiments, Hal is Br. In some embodiments, Hal is I. In some embodiments, the compound having the structure B-3, or a salt thereof, is

[0959] [ka]

[0960] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of B-2, or a salt thereof, is

[0961] [ka]

[0962] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reaction is performed in the presence of a metal. In some embodiments, the metal is a metal complex. In some embodiments, the metal is Pd. In some embodiments, the Pd is a complex. In some embodiments, the Pd complex is PdCl2(PPh3)2. In some embodiments, the metal is Cu. In some embodiments, the metal is Cu(I). In some embodiments, the Cu(I) complex is CuI. In some embodiments, the reaction is performed in the presence of Pd and Cu. In some embodiments, the reaction is performed in the presence of Pd and Cu(I). In some embodiments, the reaction is performed in the presence of a base. In some embodiments, the base is N(R)3, where each R is independently as described herein. In some embodiments, the base is NEt3.

[0963] In some embodiments, the method is as set forth in Scheme 1, by way of example. Scheme 1

[0964] [ka]

[0965] A method for preparing a provided compound, e.g., a compound of Formula I or a salt thereof, e.g., a compound of Formula B or a salt thereof, is shown by way of example in Scheme 1, where each variable is independently as described herein. In some embodiments, an aniline compound of Formula B-1 or a salt thereof (wherein Hal is Cl, Br, or I) is treated with an alkyne compound of Formula B-2 or a salt thereof under Sonogashira coupling conditions, such as PdCl2(PPh3)2Cl2 / CuI / Et3N, to provide an alkyne compound of Formula B-3 or a salt thereof. In some embodiments, a compound of Formula B-3 or a salt thereof is cyclized using a transition metal catalyst, such as PdCl2, to provide an indole compound of Formula B-4 or a salt thereof. In some embodiments, a compound of Formula B-4 or a salt thereof is cyclized using NaH / R 8 Treatment under alkylating conditions such as -Hal affords a compound of formula I or a salt thereof, for example a compound of formula B or a salt thereof.

[0966] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula B-5:

[0967] [ka]

[0968] or a salt thereof to form a compound having the structure of Formula B:

[0969] [ka]

[0970] or a salt thereof, wherein each variable is independently as described herein.

[0971] In some embodiments, the compound having the structure of formula B-5 or a salt thereof is a compound having the following structure:

[0972] [ka]

[0973] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of B, or a salt thereof, is

[0974] [ka]

[0975] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is a metal complex. In some embodiments, the metal complex is a Pd complex. In some embodiments, the metal complex is PdCl2. In some embodiments, the suitable solvent is CH3CN.

[0976] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula B-3:

[0977] [ka]

[0978] or a salt thereof to produce a compound having the structure of formula B-5:

[0979] [ka]

[0980] or a salt thereof, wherein each variable is independently as described herein.

[0981] In some embodiments, the compound having the structure of B-5 or a salt thereof is a compound having the structure:

[0982] [ka]

[0983] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of B-3 or a salt thereof is a compound having the structure:

[0984] [ka]

[0985] or a salt thereof, wherein each variable is independently as described herein.

[0986] In some embodiments, the method comprises reacting a compound of formula B-3 or a salt thereof with R 8 The method includes reacting a compound having the structure -LG, or a salt thereof, where LG is a leaving group. 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 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 carried out in the presence of a base. In some embodiments, the base is NaH.

[0987] In some embodiments, the method comprises reacting a compound of formula B-3 or a salt thereof with R 8’ -CHO, or a salt thereof, wherein R 8is bonded to -NH- via -CH2-, and R 8’ is R 8 '-CH 2- R 8 For example, in some embodiments, R 8 is -CH2CH3, and R 8 In some embodiments, the reaction is a reductive amination reaction. In some embodiments, the reaction is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is a borohydride agent, e.g., NaBHCN. In some embodiments, the reaction is carried out in the presence of a protic solvent, e.g., an alcohol, such as methanol.

[0988] In some embodiments, the method is described, by way of example, in Scheme 2. Scheme 2

[0989] [ka]

[0990] A method for preparing a provided compound, e.g., a compound of Formula I or a salt thereof, e.g., a compound of Formula B or a salt thereof, is illustratively shown in Scheme 2, where each variable is independently as described herein. In some embodiments, a compound of Formula B-3 or a salt thereof (where each variable is independently as described herein) is reacted with a compound of Formula B-3 or a salt thereof under reductive amination conditions such as NaBHCN / MeOH, or NaH / R 8 -Hal to afford a compound of formula B-5 or a salt thereof (Scheme 2). In some embodiments, cyclization of a compound of formula B-5 or a salt thereof with a transition metal catalyst such as PdCl affords a compound having the structure of Formula I or a salt thereof, for example, an indole compound of formula B or a salt thereof.

[0991] In some embodiments, the method comprises reacting a compound having the structure of formula B-3, or a salt thereof, with R 8with a compound having the structure of formula B or a salt thereof.

[0992] In some embodiments, the method is described, by way of example, in Scheme 3. Scheme 3

[0993] [ka]

[0994] A method for preparing a provided compound, e.g., a compound of Formula I or a salt thereof, e.g., a compound of Formula B or a salt thereof, is shown, by way of example, in Scheme 3, where each variable is independently as described herein. In some embodiments, a compound of Formula B-3 or a salt thereof can be prepared by reacting a compound of Formula B-3 with a group consisting of R 8 By treatment under Chan-Lam cup ring conditions such as B(OH)2 / Cu(OAc)2, a compound of formula I or a salt thereof, such as a compound having the structure of formula B, or a salt thereof, can be obtained in one step (Scheme 3).

[0995] In some embodiments, the present disclosure provides R 1 -C(O)OR 11 and R 11 is not —H (e.g., optionally substituted C 1-6 aliphatic) a first compound of formula I or a salt thereof, 1 is —C(O)OH to a second compound of formula I or a salt thereof. In some embodiments, the first compound of formula I or a salt thereof has the following structure:

[0996] [ka]

[0997] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the second compound of formula I or a salt thereof has the following structure:

[0998] [ka]

[0999] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reaction is carried out in the presence of a base. In some embodiments, the base is LiOH. In some embodiments, the reaction is carried out in the presence of water, for example, in THF / HO.

[1000] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula C-4:

[1001] [ka]

[1002] or a salt thereof to produce a compound having the structure of formula C-5:

[1003] [ka]

[1004] or a salt thereof, wherein Hal is a halogen and each other variable is independently as described herein.

[1005] In some embodiments, the compound having the structure of formula C-4 or a salt thereof is

[1006] [ka]

[1007] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula C-5, or a salt thereof, is

[1008] [ka]

[1009] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, R 11 is not —H. In some embodiments, R 11 is an optionally substituted C 1-6 In some embodiments, Hal is Cl. In some embodiments, Hal is Br. In some embodiments, Hal is I.

[1010] In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is a metal complex. In some embodiments, the metal is Pd. In some embodiments, the Pd is a complex. In some embodiments, the Pd complex is Pd(OAc)2. In some embodiments, the reaction is carried out in the presence of a phosphine compound, for example, having a structure of formula P(R)3, or a salt thereof, where each R is independently as described herein and is not H. In some embodiments, the compound is

[1011] [ka]

[1012] In some embodiments, the metal is Cu. In some embodiments, the metal is Cu(I). In some embodiments, the Cu(I) complex is CuCl. In some embodiments, the reaction is carried out in the presence of Pd and Cu. In some embodiments, the reaction is carried out in the presence of Pd and Cu(I). In some embodiments, the reaction is carried out before the base. In some embodiments, the base is Cs2CO3. In some embodiments, the base is NaH.

[1013] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula C-2:

[1014] [ka]

[1015] or a salt thereof, by reacting the compound having the structure of formula C-3:

[1016] [ka]

[1017] A compound having the structure of formula C-4:

[1018] [ka]

[1019] or a salt thereof (wherein Hal is a halogen and R si is —Si(R)3, where each variable is independently as described herein.

[1020] As described herein, in some embodiments, Hal is Cl, in some embodiments, Hal is Br, and in some embodiments, Hal is I. In some embodiments, R siis —Si(R)3, where each R is independently as described herein and is not —H. In some embodiments, each R is independently —C 1-6 Aliphatic and C 6-10 In some embodiments, each R is independently selected from C 1-6 is an optionally substituted group selected from aliphatic and phenyl. In some embodiments, the compound having the structure of formula C-4 or a salt thereof has the following structure:

[1021] [ka]

[1022] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula C-3, or a salt thereof, is

[1023] [ka]

[1024] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of C-2 or a salt thereof is

[1025] [ka]

[1026] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reaction is carried out under desilylation conditions. In some embodiments, the reaction is carried out in the presence of a fluoride agent. In some embodiments, the fluoride agent is TBAF.

[1027] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula C-1:

[1028] [ka]

[1029] or a salt thereof to produce a compound having the structure of formula C-2:

[1030] [ka]

[1031] or a salt thereof (wherein Hal is a halogen and R si is —Si(R)3, where each variable is independently as described herein.

[1032] As described herein, in some embodiments, Hal is Cl, in some embodiments, Hal is Br, and in some embodiments, Hal is I. In some embodiments, R si is —Si(R)3, where each R is independently as described herein and is not —H. In some embodiments, each R is independently —C 1-6 Aliphatic and C 6-10 In some embodiments, each R is independently an optionally substituted group selected from C1 -6 C-2 is an optionally substituted group selected from aliphatic and phenyl. In some embodiments, the compound having the structure C-2 or a salt thereof is

[1033] [ka]

[1034] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reaction is carried out in the presence of a base. In some embodiments, the base is LDA. In some embodiments, the reaction is carried out with a silylating agent, such as a compound of formula R si -LG, or a salt thereof, where LG is a leaving group, e.g., Cl, OTf, etc. In some embodiments, the reaction is carried out at low temperature, e.g., -100°C.

[1035] In some embodiments, the method is described, by way of example, in Scheme 4. Scheme 4

[1036] [ka]

[1037] A method for preparing a provided compound, e.g., a compound of Formula I or a salt thereof, e.g., a compound of Formula C or a salt thereof, is shown, by way of example, in Scheme 4, where each variable is independently as described herein. In some embodiments, a compound having the structure of Formula C-1 or a salt thereof is silylated under conditions such as LDA / TMSCl / THF to provide a compound having the structure of Formula C-2 or a salt thereof. In some embodiments, a compound having the structure of Formula C-2 or a salt thereof and an aldehyde compound having the structure of Formula C-3 or a salt thereof are treated under desilylation conditions such as TBAF / THF to provide an alcohol compound having the structure of Formula C-4 or a salt thereof. In some embodiments, a compound having the structure of Formula C-4 or a salt thereof is cyclized under transition metal-catalyzed intramolecular CO-coupling conditions such as NaH / CuCl / PhMe or Pd(OAc)2 / TRixiePhos / Cs2CO3 to provide a compound having the structure of Formula C-5 or a salt thereof. A compound having the structure of formula C-5, or a salt thereof, can be subjected to hydrolysis conditions such as LiOH / THF / HO to provide a compound having the structure of formula I, or a salt thereof, such as a compound having the structure of formula C, or a salt thereof.

[1038] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D-7:

[1039] [ka]

[1040] or a salt thereof to provide a compound having the structure of Formula I, or a salt thereof, where each variable is independently as described herein.

[1041] In some embodiments, the compound having the structure of formula D-7, or a salt thereof, is

[1042] [ka]

[1043] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of Formula I, or a salt thereof, has the following structure:

[1044] [ka]

[1045] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the reaction is carried out under oxidizing conditions (e.g., Pinnick oxidation conditions). A variety of techniques can be utilized to convert an aldehyde to a carboxylic acid in accordance with the present disclosure.

[1046] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D-6:

[1047] [ka]

[1048] or a salt thereof to produce a compound having the structure of formula D-7:

[1049] [ka]

[1050] or a salt thereof (wherein R d6 is —CH(OR) 2 , where each variable is independently as described herein.

[1051] In some embodiments, the compound having the structure of formula D-6 or a salt thereof has the following structure:

[1052] [ka]

[1053] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D-7, or a salt thereof, has the following structure:

[1054] [ka]

[1055] or a salt thereof, wherein each variable is independently as described herein.

[1056] In some embodiments, R d6 is —CH(OR) 2 , where each R is independently as described herein and is not —H. In some embodiments, each R is independently —C 1-6It is aliphatic. In some embodiments, two R's together with the intervening atoms form an optionally substituted 4-10 membered ring, e.g., a 5-10 membered ring, a 5-6 membered ring, a 4 membered ring, a 5 membered ring, a 6 membered ring, a 7 membered ring, an 8 membered ring, a 9 membered ring, or a 10 membered ring, having 0-3 heteroatoms in addition to the intervening atoms. In some embodiments, there are no heteroatoms in addition to the intervening atoms. 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 substituted. In some embodiments, the ring is unsubstituted. In some embodiments, the ring is saturated. In some embodiments, the ring is monocyclic. In some embodiments, R d6 is optionally substituted

[1057] [ka]

[1058] In some embodiments, R d6 teeth

[1059] [ka]

[1060] is.

[1061] A variety of techniques are available for converting a compound having the structure of formula D-6, or a salt thereof, to a compound having the structure of formula D-7, or a salt thereof, and can be utilized in accordance with the present disclosure. In some embodiments, useful conditions are acidic conditions. In some embodiments, the reaction is carried out in the presence of an acid.

[1062] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D-5:

[1063] [ka]

[1064] or a salt thereof to produce a compound having the structure of formula D-6:

[1065] [ka]

[1066] or a salt thereof (wherein Hal 1 is Hal as described herein, and each other variable is independently as described herein).

[1067] In some embodiments, the compound having the structure of formula D-5 or a salt thereof has the following structure:

[1068] [ka]

[1069] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D-6, or a salt thereof, has the following structure:

[1070] [ka]

[1071] or a salt thereof, wherein each variable is independently as described herein. 1 is Cl. In some embodiments, Hal 1 is Br. In some embodiments, Hal 1 is I.

[1072] In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is a metal complex. In some embodiments, the metal is Pd. In some embodiments, the Pd is a complex. In some embodiments, the Pd complex is Pd(OAc)2. In some embodiments, the reaction is carried out in the presence of a phosphine compound, for example, having a structure of formula P(R)3, or a salt thereof, where each R is independently as described herein and is not H. In some embodiments, the compound is

[1073] [ka]

[1074] In some embodiments, the metal is Cu. In some embodiments, the metal is Cu(I). In some embodiments, the Cu(I) complex is CuCl. In some embodiments, the reaction is carried out in the presence of Pd and Cu. In some embodiments, the reaction is carried out in the presence of Pd and Cu(I). In some embodiments, the reaction is carried out before the base. In some embodiments, the base is Cs2CO3. In some embodiments, the base is NaH.

[1075] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D-4:

[1076] [ka]

[1077] or a salt thereof to produce a compound having the structure of formula D-5:

[1078] [ka]

[1079] or a salt thereof, wherein each variable is independently as described herein.

[1080] In some embodiments, the compound having the structure of formula D-5 or a salt thereof has the following structure:

[1081] [ka]

[1082] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D-4, or a salt thereof, has the following structure:

[1083] [ka]

[1084] or a salt thereof, wherein each variable is independently as described herein.

[1085] In some embodiments, useful reaction conditions are reducing conditions. A variety of techniques can be utilized to reduce ketones to alcohols in accordance with the present disclosure. In some embodiments, the reaction is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is borohydride. In some embodiments, the reducing agent is NaBH4.

[1086] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D-2:

[1087] [ka]

[1088] or a salt thereof, with a compound having the structure of formula D-3:

[1089] [ka]

[1090] or a salt thereof to produce a compound having the structure of formula D-4:

[1091] [ka]

[1092] or a salt thereof (wherein each Hal 2 is Hal as described herein, and R d21 and R d22 is independently R as described herein, and each other variable is independently as described herein).

[1093] In some embodiments, R d21 is an optionally substituted C 1-6 In some embodiments, R d21 is an optionally substituted C 1-6 In some embodiments, R d21 is a methyl group. In some embodiments, R d22 is an optionally substituted C 1-6 In some embodiments, R d22 is an optionally substituted C 1-6 In some embodiments, R d22 is a methyl group.

[1094] In some embodiments, the compound having the structure of formula D-2 or a salt thereof has the following structure:

[1095] [ka]

[1096] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D-3, or a salt thereof, has the following structure:

[1097] [ka]

[1098] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D-4, or a salt thereof, has the following structure:

[1099] [ka]

[1100] or a salt thereof, wherein each variable is independently as described herein.

[1101] In some embodiments, Hal 2 is Cl. In some embodiments, Hal 2 is Br. In some embodiments, Hal 2 is I.

[1102] In some embodiments, the reaction is carried out in the presence of an organometallic agent. In some embodiments, the agent is a Li agent, e.g., n-BuLi. In some embodiments, the agent is a Mg agent, e.g., i-PrMgBr. In some embodiments, a compound having the structure of Formula D-3, or a salt thereof, is contacted with the organometallic agent, and the resulting agent is contacted with a compound having the structure of Formula D-2, or a salt thereof.

[1103] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D-1:

[1104] [ka]

[1105] or a salt thereof, d21 ) OR d22 or a salt thereof to produce a compound having the structure of formula D-2:

[1106] [ka]

[1107] or a salt thereof, wherein each variable is independently as described herein.

[1108] In some embodiments, the compound having the structure of formula D-2, or a salt thereof, is

[1109] [ka]

[1110] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound has the structure of d21 ) OR d22 or a salt thereof is MeNHOMe or a salt thereof, such as MeNHOMe-HCl.

[1111] In some embodiments, the reaction is carried out under cup ring conditions. A variety of cup ring techniques are available and can be utilized in accordance with the present disclosure.

[1112] In some embodiments, the method is described, by way of example, in Scheme 5. Scheme 5

[1113] [ka]

[1114] A method for preparing a provided compound, e.g., a compound of Formula I or a salt thereof, e.g., a compound of Formula D or a salt thereof, is shown, by way of example, in Scheme 5. Each variable is independently as described herein. In some embodiments, an acid compound of Formula D-1 or a salt thereof (in some embodiments, Hal 1 is Cl, Br, or I) with MeNHOMe-HCl under amide coupling conditions such as HATU / DIPEA to provide a compound of formula D-2, or a salt thereof. In some embodiments, a compound of formula D-3, or a salt thereof, can be converted to a protected aldehyde (in some embodiments, Hal) using an organometallic reagent such as n-BuLi or i-PrMgBr. 2 is Br or I), and addition of the resulting arylmetal intermediate to a compound of formula D-2, or a salt thereof, provides a ketone compound of formula D-4, or a salt thereof. In some embodiments, reduction of a ketone of formula D-4, or a salt thereof, with a reducing reagent such as NaBH4, provides an alcohol compound of formula D-5, as described herein. In some embodiments, cyclization of a compound of formula D-5 under transition metal-catalyzed intramolecular CO-coupling conditions (such as NaH / CuCl / PhMe or Pd(OAc)2 / TRixiePhos / Cs2CO3) provides a compound of formula D-6, or a salt thereof. In some embodiments, subjecting a compound of formula D-6, or a salt thereof, to acid hydrolysis conditions such as HCl, followed by oxidation of the resulting aldehyde compound of formula D-7, or a salt thereof, under conditions such as Pinnick oxidation conditions, provides a compound of formula I, or a salt thereof, e.g., a compound of formula D, or a salt thereof.

[1115] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D'-5:

[1116] [ka]

[1117] or a salt thereof to produce a compound having the structure of formula D'-6:

[1118] [ka]

[1119] or a salt thereof, wherein each variable is independently as described herein.

[1120] In some embodiments, the compound having the structure of formula D'-5 or a salt thereof has the following structure:

[1121] [ka]

[1122] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D'-6, or a salt thereof, has the following structure:

[1123] [ka]

[1124] or a salt thereof, wherein each variable is independently as described herein.

[1125] A variety of techniques can be utilized to convert a compound having the structure of Formula D'-5, or a salt thereof, to a compound having the structure of Formula D-6, or a salt thereof. In some embodiments, the conditions are Mitsunobu conditions. In some embodiments, the reaction is carried out in the presence of a phosphine compound. In some embodiments, the reaction is carried out in the presence of an azodicarboxylate compound. In some embodiments, the phosphine compound has the structure P(R)3, where each R is independently as described herein and is not -H. In some embodiments, each R is independently an optionally substituted phenyl. In some embodiments, the phosphine compound is PPh3. In some embodiments, the azodicarboxylate compound is R a1O2C-N=N-CO2R a2 or a salt thereof, wherein R a1 and R a2 are each independently R. In some embodiments, R a1 and R a2 and each is not —H. In some embodiments, R a1 is C 1-6 In some embodiments, R a1 is ethyl. In some embodiments, R a1 is isopropyl. In some embodiments, R a2 is C 1-6 In some embodiments, R a2 is ethyl. In some embodiments, R a2 is isopropyl. In some embodiments, the azodicarboxylate compound is DIAD. In some embodiments, the azodicarboxylate compound is DEAD.

[1126] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D'-4:

[1127] [ka]

[1128] or a salt thereof to produce a compound having the structure of formula D'-5:

[1129] [ka]

[1130] or a salt thereof, where PG is a protecting group and each other variable is independently as described herein.

[1131] In some embodiments, the compound having the structure of formula D'-4 or a salt thereof is

[1132] [ka]

[1133] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D'-5, or a salt thereof, is

[1134] [ka]

[1135] or a salt thereof, wherein each variable is independently as described herein. Those skilled in the art will appreciate that many techniques are available for protecting and deprotecting phenol groups and can be utilized in accordance with the present disclosure. For example, in some embodiments, PG is a suitable protecting group such as Bn, MEM, or allyl.

[1136] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D'-3:

[1137] [ka]

[1138] or a salt thereof to produce a compound having the structure of formula D'-4:

[1139] [ka]

[1140] or a salt thereof, wherein each variable is independently as described herein.

[1141] In some embodiments, the compound having the structure of formula D'-3 or a salt thereof has the following structure:

[1142] [ka]

[1143] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D'-4, or a salt thereof, has the following structure:

[1144] [ka]

[1145] or a salt thereof, wherein each variable is independently as described herein.

[1146] In some embodiments, useful reaction conditions are reducing conditions. A variety of techniques for reducing ketones to alcohols can be utilized in accordance with the present disclosure.

[1147] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D'-1:

[1148] [ka]

[1149] or a salt thereof, with a compound having the structure of formula D'-2:

[1150] [ka]

[1151] or a salt thereof to produce a compound having the structure of formula D'-3:

[1152] [ka]

[1153] or a salt thereof (wherein each Hal 3 is Hal as described herein, and each other variable is independently as described herein).

[1154] In some embodiments, the compound having the structure of formula D'-1 or a salt thereof has the following structure:

[1155] [ka]

[1156] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D'-2, or a salt thereof, has the following structure:

[1157] [ka]

[1158] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D'-3, or a salt thereof, has the following structure:

[1159] [ka]

[1160] or a salt thereof, wherein each variable is independently as described herein.

[1161] In some embodiments, Hal 3 is Cl. In some embodiments, Hal 3 is Br. In some embodiments, Hal 3 is I.

[1162] In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is a metal complex. In some embodiments, the metal complex is a Pd complex. In some embodiments, the metal complex is XPhos Pd G3. In some embodiments, the suitable solvent is dioxane. In some embodiments, the reaction is carried out in the presence of a base. In some embodiments, the base is Cs2CO3.

[1163] In some embodiments, the present disclosure provides a method comprising the steps of: A compound having the structure of formula D'-0:

[1164] [ka]

[1165] or a salt thereof, with a compound having the structure of formula D-3:

[1166] [ka]

[1167] or a salt thereof to form a compound having the structure of formula D'-1:

[1168] [ka]

[1169] or a salt thereof, wherein each variable is independently as described herein.

[1170] In some embodiments, the compound having the structure of formula D'-0 or a salt thereof is

[1171] [ka]

[1172] In some embodiments, the compound having the structure of formula D-3, or a salt thereof, is

[1173] [ka]

[1174] or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula D'-1, or a salt thereof, is

[1175] [ka]

[1176] or a salt thereof, wherein each variable is independently as described herein.

[1177] In some embodiments, the reaction is carried out in the presence of an organometallic agent. In some embodiments, the agent is a Li agent, e.g., n-BuLi. In some embodiments, the agent is a Mg agent, e.g., i-PrMgBr. In some embodiments, a compound having the structure of Formula D-3, or a salt thereof, is contacted with the organometallic agent, and the resulting agent is contacted with a compound having the structure of Formula D'-0, or a salt thereof.

[1178] In some embodiments, the method is described, by way of example, in Scheme 6. Scheme 6

[1179] [ka]

[1180] A method for preparing a provided compound, e.g., a compound of Formula I or a salt thereof, e.g., a compound of Formula D' or a salt thereof, is shown, by way of example, in Scheme 6. Each variable is independently as described herein. In some embodiments, a halide-metal exchange reaction of a compound of Formula D-3 or a salt thereof with an organometallic reagent, such as n-BuLi or i-PrMgBr, followed by addition of the resulting aryl metal intermediate to N-methoxy-N-methylacetamide, provides a ketone compound of Formula D'-1 or a salt thereof. In some embodiments, treatment of a compound of Formula D'-1 or a salt thereof with an aryl halide or a salt thereof with an aryl halide of Formula D'-2 under appropriate conditions, e.g., Pd-catalyzed ketone α-arylation conditions, such as XPhos Pd G3 / Cs2CO3 / dioxane, provides an α-aryl ketone of Formula D'-3 or a salt thereof. In some embodiments, reduction of a ketone of Formula D'-3 or a salt thereof with a reducing reagent, such as NaBH4, provides an alcohol compound of Formula D'-4 or a salt thereof. In some embodiments, removal of the phenol protecting group provides a compound of Formula D'-5 or a salt thereof. In some embodiments, cyclization of a compound of formula D'-5 or a salt thereof under appropriate conditions, e.g., Mitsunobu conditions such as DIAD / PPh3, provides a compound of formula D'-6 or a salt thereof. In some embodiments, subjecting a compound of formula D'-6 or a salt thereof to acid hydrolysis conditions such as HCl, and oxidizing (e.g., Pinnick oxidation) the resulting aldehyde compound of formula D'-7 or a salt thereof, provides a compound of formula I or a salt thereof, e.g., a compound of formula D' or a salt thereof.

[1181] In some embodiments, the method is described, by way of example, in Scheme 7. Scheme 7

[1182] [ka]

[1183] A method for preparing a provided compound, e.g., a compound of Formula I or a salt thereof, e.g., a compound of Formula E (e.g., Formula E-8) or a salt thereof, is shown, by way of example, in Scheme 7, where each variable is independently as described herein. In some embodiments, a provided method includes performing a halide-metal exchange of a compound of Formula E-1 or a salt thereof using an organometallic reagent, such as n-BuLi or i-PrMgBr, to obtain an aryl metal compound. In some embodiments, a provided method includes adding the aryl metal compound to N-methoxy-N-methylacetamide to obtain a ketone compound of Formula E-2 or a salt thereof. In some embodiments, a method includes treating a compound of Formula E-2 or a salt thereof with an aryl halide of Formula E-3 or a salt thereof under appropriate conditions, e.g., Pd-catalyzed ketone α-arylation conditions, such as XPhos Pd G3 / Cs2CO3 / dioxane, to obtain an α-aryl ketone of Formula E-4 or a salt thereof. In some embodiments, the method includes reducing a ketone of formula E-4 or a salt thereof with a reducing reagent such as NaBH4 to obtain an alcohol compound of formula E-5 or a salt thereof. In some embodiments, the method includes removing a protecting group on the phenol to obtain a compound of formula E-6 or a salt thereof. In some embodiments, the method includes cyclizing the compound of formula E-6 or a salt thereof under appropriate conditions, e.g., Mitsunobu conditions such as DIAD / PPh3, to obtain a compound of formula E-7 or a salt thereof. In some embodiments, the provided method includes contacting the compound of formula E-7 or a salt thereof with an azide compound (e.g., TMSN3) to obtain a compound of formula I or a salt thereof, e.g., a compound of formula E-8 or a salt thereof.

[1184] In some embodiments, the method is as set forth in Scheme 8, for example. Scheme 8

[1185] [ka]

[1186] Methods for preparing provided compounds, e.g., compounds of Formula I or salts thereof, e.g., compounds of Formula F-7, Formula F-8, Formula F-9, or Formula F, or salts thereof, are shown, by way of example, in Scheme 8, where each variable is independently as described herein. In some embodiments, Hal 1 , Hal 2 , and Hal 3 are each independently F, Cl, Br, or I. In some embodiments, Hal 1 In some embodiments, Hal is -Br. 2 In some embodiments, Hal is -Br. 3is -F. In some embodiments, the metal is Na. In some embodiments, the method includes reacting a compound of Formula F-1, or a salt thereof, with a Zn reagent to obtain a compound of Formula F-2, or a salt thereof. In some embodiments, the Zn reagent is or includes Zn. In some embodiments, the reaction is performed in the presence of a salt, e.g., a lithium salt, such as LiCl. In some embodiments, the method includes reacting a compound of Formula F-3, or a salt thereof, with, e.g., SOCl2, under appropriate conditions to obtain a compound of Formula F-4, or a salt thereof. In some embodiments, a provided method includes reacting a compound of Formula F-2, or a salt thereof, with a compound of Formula F-4, or a salt thereof (e.g., transition cup ring) to form a compound of Formula F-5, or a salt thereof. In some embodiments, the cup ring between a compound of Formula F-2, or a salt thereof, and a compound of Formula F-4, or a salt thereof, is formed using a metal reagent, e.g., CuCN. In some embodiments, such reaction is performed in the presence of a salt, e.g., a lithium salt, such as LiCl. In some embodiments, the method includes reducing a compound of Formula F-5, or a salt thereof, to obtain a compound of Formula F-6, or a salt thereof. In some embodiments, the reduction is or includes hydrogenation. In some embodiments, the hydrogenation uses H. In some embodiments, the hydrogenation is an in situ hydrogen exchange reaction. In some embodiments, the hydrogenation uses a metal catalyst. In some embodiments, the hydrogenation uses a metal catalyst and HCOOH. In some embodiments, the metal catalyst is or includes a transition metal complex. In some embodiments, the metal catalyst is or includes a Ru complex. In some embodiments, the metal catalyst is RuCl(p-cymene)[(S,S)-Ts-DPEN]. In some embodiments, the hydrogenation uses RuCl(p-cymene)[(S,S)-Ts-DPEN] and HCOOH. A variety of reduction techniques are available and can be utilized in accordance with the present disclosure. In some embodiments, the method includes reacting a compound of formula F-6, or a salt thereof, under appropriate conditions, for example, with a base, to provide a compound of formula F-7, or a salt thereof. In some embodiments, the base is t-BuOK.In some embodiments, the base is t-BuONa. In some embodiments, the base is a metal alkoxide. In some embodiments, the method includes reacting a compound of Formula F-7, or a salt thereof, with a cyanide reagent to obtain a compound of Formula F-8, or a salt thereof. In some embodiments, the cyanide reagent is CuCN. In some embodiments, the method includes reacting a compound of Formula F-8, or a salt thereof, with an azide reagent to obtain a compound of Formula F-9, or a salt thereof. In some embodiments, the azide reagent is TMSN3. In some embodiments, the azide reagent is NaN3. In some embodiments, such reaction is carried out in the presence of a catalyst. In some embodiments, the catalyst is Bu2SnO. In some embodiments, the method includes reacting a compound of Formula F-8, or a salt thereof, with TMSN3 and Bu2SnO to obtain a compound of Formula F-9, or a salt thereof. In some embodiments, the reaction is carried out in the presence of a base and / or a salt of a base (e.g., TEA-HCl). In some embodiments, the base is an amine base. In some embodiments, the method includes reacting a compound of Formula F-8, or a salt thereof, with NaN. 3、and NMP to obtain a compound of formula F-9 or a salt thereof. In some embodiments, methods are provided that include reacting a compound of formula F-8 or a salt thereof with an azide reagent to obtain a compound of formula F-9 or a salt thereof on a scale of about 1 mmol, 5 mmol, 10 mmol, 20 mmol, 50 mmol, 100 mmol, 250 mmol, 500 mmol, 1 mol, 5 mol, 10 mol, 1000 mol, or 2000 mmol or more. In some embodiments, methods are provided that include reacting a compound of formula F-8 or a salt thereof with an azide reagent to obtain a compound of formula F-9 or a salt thereof on a scale of less than about 1 mmol, 5 mmol, 10 mmol, 20 mmol, 50 mmol, 100 mmol, 250 mmol, 500 mmol, 1 mol, 5 mol, 10 mol, 100 mol, 1000 mol, or 2000 mmol. In some embodiments, a compound of formula F-9 or a salt thereof is reacted with a base to obtain a compound of formula F or a salt thereof. In some embodiments, the base is NaOH. In some embodiments, the base is KOH.

[1187] In some embodiments, the present disclosure provides a compound of formula I or a salt thereof, wherein R 1 is -C(O)OR 11 , -P(O)(OR 12 )(OR 13 ),or

[1188] [ka]

[1189] where R 11 is hydrogen and R 12 and R 13wherein at least one of is hydrogen) with a base to prepare such a salt of the compound of Formula I. In some embodiments, the base is an alkaline hydroxide. In some embodiments, the base is NaOH. In some embodiments, the base is an amine base. A variety of bases are useful for preparing salts, including pharmaceutically acceptable salts, and can be utilized in accordance with the present disclosure.

[1190] One of skill in the art reading this disclosure will appreciate that in some embodiments, the compound of formula F-1 or a salt thereof may be a compound of formula F-1′:

[1191] [ka]

[1192] or a salt thereof, where each variable is as defined herein. In some embodiments, Hal 3 is F. In some embodiments, Hal 2 is Br. In some embodiments, the compound of formula F-1 or F-1′

[1193] [ka]

[1194] In some embodiments, the compound of formula F-2 or a salt thereof is a compound of formula F-2':

[1195] [ka]

[1196] or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound F-2 or F-2' is

[1197] [ka]

[1198] In some embodiments, the compound of F-2 or F-2' is

[1199] [ka]

[1200] In some embodiments, the compound of formula F-3 is

[1201] [ka]

[1202] In some embodiments, the compound of formula F-4 is

[1203] [ka]

[1204] In some embodiments, the compound of formula F-5 or a salt thereof is a compound of formula F-5':

[1205] [ka]

[1206] or a salt thereof, where each variable is as described herein. In some embodiments, Hal 1 is Br. In some embodiments, the compound of formula F-5 or F-5′

[1207] [ka] In some embodiments, the compound of formula F-6 or a salt thereof is a compound of formula F-6':

[1208] [ka]

[1209] or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F-6 or F-6'

[1210] [ka]

[1211] In some embodiments, the compound of formula F-6 or F-6′ is

[1212] [ka]

[1213] In some embodiments, the compound of formula F-7 or a salt thereof is a compound of formula F-7′

[1214] [ka]

[1215] or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F-7 or F-7′

[1216] [ka]

[1217] In some embodiments, the compound of formula F-7 or F-7′ is

[1218] [ka]

[1219] In some embodiments, the compound of formula F-8 or a salt thereof is a compound of formula F-8':

[1220] [ka]

[1221] or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F-8 or F-8'

[1222] [ka]

[1223] In some embodiments, the compound of formula F-8 or F-8' is

[1224] [ka]

[1225] In some embodiments, the compound of formula F-9 or a salt thereof is a compound of formula F-9′

[1226] [ka]

[1227] or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F-9 or F-9′, or a salt thereof, is

[1228] [ka]

[1229] or a salt thereof. In some embodiments, the compound of formula F-9 or F-9′ or a salt thereof is

[1230] [ka]

[1231] or a salt thereof. In some embodiments, the compound of formula F or a salt thereof is

[1232] [ka]

[1233] or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F or F', or a salt thereof, is

[1234] [ka]

[1235] In some embodiments, the compound of formula F or F′ or a salt thereof is

[1236] [ka]

[1237] In some embodiments, ring A' in formula F-1, F-2, F-5, F-6, F-7, F-8, F-9, or F is independently an optionally substituted ring.

[1238] [ka]

[1239] In some embodiments, ring A' in formula F-1, F-2, F-5, F-6, F-7, F-8, F-9, or F is independently

[1240] [ka]

[1241] In some embodiments, ring A' in formula F-1, F-2, F-5, F-6, F-7, F-8, F-9, or F is independently an optionally substituted ring.

[1242] [ka]

[1243] In some embodiments, ring A' in formula F-1, F-2, F-5, F-6, F-7, F-8, F-9, or F is independently an optionally substituted ring.

[1244] [ka]

[1245] In some embodiments, ring A' of formula F-1, F-2, F-5, F-6, F-7, F-8, F-9, or F is independently

[1246] [ka]

[1247] is.

[1248] In some embodiments, the present disclosure provides compounds having the structure of Formula I, where R 1 is —CN), or a salt thereof, to form a compound having the structure of Formula I, 1 teeth,

[1249] [ka]

[1250] or a salt thereof. A variety of techniques are available for such reactions and can be utilized in accordance with the present disclosure. For example, in some embodiments, a compound having the structure of Formula I, where R 1 In some embodiments, the azide is TMSN3. In some embodiments, the tin oxide has the structure R2Sn(O) or a salt thereof. In some embodiments, each R is an optionally substituted C 1-6 In some embodiments, each R is independently C 1-6 In some embodiments, each R is independently C 1-6 In some embodiments, the tin oxide is dibutyltin oxide. In some embodiments, the reaction is carried out at a temperature above ambient temperature, for example, about 100° C., 110° C., or higher. In some embodiments, the reaction is carried out in a solvent, for example, toluene. In some embodiments, the reaction time is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours, or more.

[1251] In some embodiments, the present disclosure provides compounds having the structure of Formula I, where R 1 is —C(O)NH2), or a salt thereof, to form a compound having the structure of Formula I, 1 is —CN). A variety of techniques are available for such reactions and can be utilized in accordance with the present disclosure. For example, in some embodiments, a compound having the structure of Formula I (wherein R 1 is —C(O)NH2), or a salt thereof, is contacted with an anhydride. In some embodiments, a compound having the structure of Formula I, 1is —C(O)NH2) or a salt thereof is contacted with TFAA. In some embodiments, the contacting is carried out in the presence of a base, e.g., Et3N. In some embodiments, the reaction is carried out in a suitable solvent, e.g., DCM. In some embodiments, the reaction is carried out at a temperature below ambient temperature, e.g., about 0° C.

[1252] In some embodiments, the present disclosure provides a compound having the structure of Formula I, wherein R 1 is —C(O)OH, or a salt thereof, to form a compound having the structure of Formula I, 1 is —C(O)NH2. A variety of techniques are available for such reactions, such as amidation techniques, and can be utilized in accordance with the present disclosure. For example, in some embodiments, a compound having the structure of Formula I, wherein R 1 is —C(O)OH, or a salt thereof. In some embodiments, a compound having the structure of Formula I, wherein R 1 is —C(O)OH, or a salt thereof, is contacted with SOCl. In some embodiments, a compound having the structure of Formula I, wherein R 1 is —C(O)OH, or a salt thereof, or an activated form thereof, is contacted with NH (e.g., NH in MeOH). 1 is —C(O)OH, or a salt thereof, to form R 1 providing a compound having the structure of Formula I, wherein is —CN.

[1253] In some embodiments, the formulation or composition is stereoisomerically enriched. In some embodiments, the formulation or composition is diastereomerically enriched. In some embodiments, the formulation or composition is enantiomerically enriched. In some embodiments, the formulation or composition is diastereomerically pure. In some embodiments, the formulation or composition is enantiomerically pure. Stereochemically enriched or pure formulations and compositions can be prepared in accordance with the present disclosure using various stereoselective techniques, such as chiral auxiliaries, stereoselective reactions, stereoselective catalysts, etc. For example, in some embodiments, a compound of formula F-5 or F-5′, or a salt thereof, can be stereoselectively reduced to provide a compound of formula F-6 or F-6′, or a salt thereof. In some embodiments, the stereogenic carbon formed by the reduction is R. In some embodiments, it is S. In some embodiments, the reduction is performed in the presence of a chiral metal catalyst, such as RuCl(p-cymene)[(S,S)-Ts-DPEN].

[1254] Specific techniques for preparing the provided compounds are illustrated in the Examples. use

[1255] In certain embodiments, the present disclosure provides methods of modulating the activity of MRGPRX4 by contacting MRGPRX4 with an effective amount of a compound or pharmaceutical composition described herein.

[1256] In certain embodiments, the present disclosure provides a method for modulating the activity of MRGPRX4 in a system comprising MRGPRX4, the method comprising administering or delivering to the system an effective amount of a compound or pharmaceutical composition described herein. 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 MRGPRX4. In some embodiments, the method reduces the activity level of MRGPRX4 compared to the absence of a provided compound. In some embodiments, the reduction is about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% or more.

[1257] In certain embodiments, the present disclosure provides a method 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 a method 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, disorder, or disease. In certain embodiments, the present disclosure provides a method for preventing a condition, disorder, or disease, comprising delivering an effective amount of a provided compound or composition to a subject susceptible thereto. In certain embodiments, the present disclosure provides a method 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, disorder, or disease. 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.

[1258] 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.

[1259] In some embodiments, the condition, disorder, or disease is or comprises itch. In some embodiments, the condition, disorder, or disease is itch. In some embodiments, the condition, disorder, or disease is a condition, disorder, or disease associated with MRGPRX4. In some embodiments, the condition, disorder, or disease is associated with activation of MRGPRX4.

[1260] In some embodiments, the condition, disorder, or disease is chronic pruritus, cholestatic pruritus, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, cholestasis, end-stage renal failure, hemodialysis, contact dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eczema, erythema, folliculitis, fungal skin infections, hemorrhoids, herpes, HIV infection. The following conditions are considered to be causes of death: rhesus macular degeneration, Hodgkin's disease, hyperthyroidism, iron deficiency anemia, kidney disease, leukemia, liver disease, lymphoma, malignant tumors, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia rubra, pruritus true, pruritus ani, pseudorabies, psoriasis, rectal prolapse, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus, or urticaria.

[1261] In some embodiments, the condition, disorder, or disease is MRGPRX4-associated pruritus. In some embodiments, the condition, disorder, or disease is MRGPRX4-associated acute or chronic pruritus associated with a liver condition, disorder, or disease.

[1262] In certain embodiments, the MRGPRX4-associated pruritus is acute or chronic pruritus associated with a hepatobiliary condition, disorder, or disease. In some embodiments, the hepatobiliary condition, disorder, or disease is intrahepatic cholestasis of pregnancy (ICP), estrogen-, progesterone-, or testosterone-induced cholestasis, toxin-, or other drug-induced hepatocellular cholestasis, benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC), chronic viral hepatitis C, chronic hepatitis B, alcoholic or non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), secondary sclerosing cholangitis (SSC), sarcoidosis, ABCB4 deficiency, Alagille syndrome, drug-induced canalicular cholangiopathy, cholelithiasis, IgG4-related cholangitis, biliary atresia, cholangiocarcinoma, benign biliary adenoma, or other obstructive cholestasis.

[1263] In some embodiments, the condition, disorder, or disease is a liver condition, disorder, or disease. In some embodiments, the liver condition, disorder, or disease is NASH. In some embodiments, the liver condition, disorder, or disease is NAFLD. In some embodiments, the liver condition, disorder, or disease is ICP. In some embodiments, the liver condition, disorder, or disease is PBC. In some embodiments, the liver condition, disorder, or disease is PFIC. In some embodiments, the liver condition, disorder, or disease is PSC. In some embodiments, the liver condition, disorder, or disease is BRIC. In some embodiments, the liver condition, disorder, or disease is chronic hepatitis B.

[1264] In some embodiments, the condition, disorder, or disease is nonalcoholic steatohepatitis (NASH). In some embodiments, the condition, disorder, or disease is a bile acid synthesis condition, disorder, or disease. In some embodiments, the bile acid synthesis condition, disorder, or disease is due to a single enzyme deficiency (SED). In some embodiments, the condition, disorder, or disease is a peroxisomal condition, disorder, or disease, e.g., a Zellweger spectrum disorder. In some embodiments, the condition, disorder, or disease is a liver condition, disorder, or disease, steatorrhea, or complications due to reduced absorption of fat-soluble vitamins.

[1265] In some embodiments, the condition, disorder or disease is cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic liver disease, gastrointestinal disease, renal disease, metabolic disease, cancer (i.e., colon cancer), or a neurological manifestation such as stroke. In certain embodiments, the condition, disorder, or disease is primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, enteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplant-associated graft-versus-host disease, living donor liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or alpha 1-antitrypsin deficiency. In certain embodiments, the gastrointestinal disease is inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, or microscopic colitis. In certain embodiments, the renal disease is diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, or polycystic kidney disease. In certain embodiments, the cardiovascular disease is atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, or hypertriglyceridemia. In certain embodiments, the metabolic disease is insulin resistance, type I and type II diabetes, or obesity. In some embodiments, the condition, disorder, or disease is an inflammatory condition, disorder, or disease, such as allergy, osteoarthritis, appendicitis, bronchial asthma, pancreatitis, allergic rash, psoriasis, etc. In some embodiments, the condition, disorder, or disease is an autoimmune condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is rheumatoid arthritis, multiple sclerosis, and type 1 diabetes.In some embodiments, the condition, disorder, or disease is a gastrointestinal disease, such as inflammatory bowel disease (Crohn's disease, ulcerative colitis), short bowel syndrome (post-radiation colitis), microscopic colitis, irritable bowel syndrome (malabsorption), and bacterial overgrowth. In some embodiments, the condition, disorder, or disease is cancer. In some embodiments, the cancer is colon cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, renal cancer, gastric cancer, pancreatic cancer, prostate cancer, or pancreatic islet cancer. In some embodiments, the condition, disorder, or disease is FXR-mediated. In some embodiments, the condition, disorder, or disease is TGR5-mediated. In some embodiments, subjects susceptible to and / or suffering from these would benefit from increased activity levels of FXR and / or TGR5. In some embodiments, the condition, disorder, or disease is chronic kidney disease. In some embodiments, the condition, disorder, or disease is uremic pruritus.

[1266] In some embodiments, the condition, disorder, or disease is associated with the administration or delivery of a drug that can activate MRGPRX4. Many techniques for assessing MRGPRX4 activation (e.g., in vivo, in vitro, etc.) are available for assessing whether a drug can activate MRGPRX4. Specific useful techniques are described, for example, in Meixiong et al. MRGPRX4 is a G protein-coupled receptor activated by bile acid or analogs or derivatives that may contribute to cholestatic prutritus, PNAS, 2019, 116(21), 10525-10530; Yu et al. MRGPRX4 is a bile acid receptor for human cholestatic itch, eLife, 2019, 8, e48431.

[1267] In some embodiments, the condition, disorder, or disease is associated with the administration or delivery of an agent that can activate MRGPRX4 but also provide another activity or can be used as a therapeutic agent to treat the condition, disorder, or disease. In some embodiments, the present disclosure provides a method for preventing or treating a condition, disorder, or disease associated with the administration of an agent, comprising administering or delivering an effective amount of a provided compound or composition to a subject. In some embodiments, the present disclosure provides a method for preventing a condition, disorder, or disease associated with the administration of an agent, comprising administering an effective amount of a provided compound or composition to a subject. In some embodiments, the present disclosure provides a method for preventing a condition, disorder, or disease associated with the administration of an agent, comprising delivering an effective amount of a provided compound or composition to a subject. In some embodiments, the present disclosure provides a method for treating a condition, disorder, or disease associated with the administration of an agent, comprising administering an effective amount of a provided compound or composition to a subject. In some embodiments, the present disclosure provides a method for treating a condition, disorder, or disease associated with the administration of an agent, comprising delivering an effective amount of a provided compound or composition to a subject. In some embodiments, the agent can activate MRGPRX4. In some embodiments, the agent is a bile acid or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the agent is a bile acid analog or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the agent is a bile acid derivative or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the agent is a bile acid conjugate, such as a taurine conjugate, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the bile acid is cholic acid. In some embodiments, the bile acid is ursodeoxycholic acid (UDCA). In some embodiments, the bile acid is ursocholic acid. In some embodiments, the bile acid is chenodeoxycholic acid. In some embodiments, the bile acid or an analog or derivative thereof is obeticholic acid.In some embodiments, the bile acid or analog or derivative thereof is taurursodiol or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, it is taurursodiol. In some embodiments, it is taurursodiol sodium. In some embodiments, the agent is an FXR agonist. In some embodiments, the agent is a TGR5 agonist. In some embodiments, the agent is a therapeutic agent. In some embodiments, the agent is, for example, a therapeutic agent approved by the U.S. Food and Drug Administration (e.g., cholic acid, obeticholic acid, taurursodiol, ursodeoxycholic acid, etc.), used alone or in combination with other therapeutic agents. In some embodiments, the agent is obeticholic acid used in combination with ursodeoxycholic acid. In some embodiments, the agent is taursodiol in combination with sodium phenylbutyrate. In some embodiments, the condition, disorder, or disease associated with administration of the agent is or includes itch. In some embodiments, the provided methods can improve patient compliance with the agent. In some embodiments, provided methods can increase the single dose, total dose, frequency of administration, and / or length of administration regimen of the agent. In some embodiments, provided compounds can reduce the severity of side effects, such as pruritus. In some embodiments, provided compounds are administered or delivered 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 administration of the agent. In some embodiments, provided compounds are administered or delivered 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 administration of the agent. In some embodiments, provided compounds are administered or delivered simultaneously with the administration of the agent.

[1268] In certain embodiments, the compounds described herein can be used in combination therapy with other therapeutic agents to prevent or treat a condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is associated with activation of MRGPRX4. In some embodiments, a therapeutic agent administered or delivered to a subject can activate MRGPRX4. In some embodiments, provided compounds can alleviate a condition, disorder, or disease associated with activation of MRGPRX4. In some embodiments, the condition, disorder, or disease involves or includes pruritus associated with MRGPRX4. In certain embodiments, the therapeutic agent is a farnesoid X receptor (FXR) agonist, such as obeticholic acid (OCA), cilofexor (GS-9674), tropifexor (LJN452), EDP-305, EDP-297, nidufexor, TERN-101 (LY2562175), MET-409, BAr704, BAr502, EYP-001, RDX-023, AGN-242266, HPG-1860, AGN-242256, IOT-022, M-480, or INV-33. In certain embodiments, the therapeutic agent is an ileal bile acid transport (IBAT) inhibitor, such as odevixibat or maralixibat. In certain embodiments, the therapeutic agent is ursocholic acid. In certain embodiments, the therapeutic agent is a thyroid hormone receptor beta (THR-β) agonist, such as resmetirom (MGL-3196), GC-24, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid], MB07811 (2R,4S)-4-(3-chlorophenyl)-2-((3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxide-[1,3,2]-dioxaphosphonan). In certain embodiments, the therapeutic agent is a peroxisome proliferator-activated receptor (PPAR) agonist, such as elafibranor, lanifibranor, saroglitazar, pioglitazone, or rosiglitazone.In certain embodiments, the therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist, such as semaglutide, exenatide, dulaglutide, liraglutide, lixisenatide, danugliplon (PF-06882961), or PF-07081532. In certain embodiments, the therapeutic agent is a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, such as tirzepatide. In certain embodiments, the therapeutic agent is an α-cetyl-CoA carboxylase (ACC) inhibitor, such as filscostat, PF-05221304, or WZ66. In certain embodiments, the therapeutic agent is a diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor, such as PF-06865571. In certain embodiments, the other therapeutic agent is a ketohexokinase (KHK) inhibitor, such as PF-06835919. In some embodiments, the therapeutic agent is a drug approved (e.g., by the U.S. Food and Drug Administration (FDA)) for the treatment of a condition, disorder, or disease, either alone or in combination. Various approved drugs and their uses are publicly available and can be used in combination with the compounds provided in accordance with the present disclosure. For example, in some embodiments, the drug is obeticholic acid, which is approved for the treatment of adult patients with primary biliary cholangitis (PBC) without cirrhosis or compensated cirrhosis without evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) for patients with an inadequate response to UDCA or as monotherapy in patients who cannot tolerate UDCA. In some embodiments, the drug is cholic acid, which is approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies (SEDs) or as adjunctive therapy for peroxisomal disorders (PDs), including Zellweger syndrome, for patients with complications due to liver disease, steatorrhea, or reduced absorption of fat-soluble vitamins. In some embodiments, the agent is tauursodiol, a combination therapy with sodium phenylbutyrate (Relyvrio), which is approved for the treatment of amyotrophic lateral sclerosis (ALS).

[1269] 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 administration of 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 administration of 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.

[1270] In some embodiments, the bile acid or analog or derivative thereof is selected from the group consisting of bile acids, as reported in Meixiong et al., "MRGPRX4 is a Gprotein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus," PNAS, 2019, 116(21), 10525-10530; Yu et al., "MRGPRX4 is bile acid receptor for human cholestatic itch," eLife, 2019, 8, e48431.In some embodiments, the bile acid or analog or derivative thereof is selected from the group consisting of WO2016086169, US10519191, WO2016130809, US10246483, WO2017147174, WO2017147159, WO2017147137, US10364267, US10323061, US10323060, WO2017189663, WO2017 189652, WO2017189651, US10080743, US10080742, US10080741, WO2017201155, WO2017201152, WO2017 201150, US10144729, US10138228, WO2018067704, US10450306, WO2018081285, US10597391, WO201810 2418, US10584145, WO2018152171, US10472386, WO2018187804, US10676500, WO2019118571, US106893 91, WO2020231917, WO2016073767, US10266560, WO2016086134, US10208081, WO2016086218, US106967 13, US10968249, WO2016086115, WO2016161003, US10457703, US11040998, US11034684, US10947264, US10961272, WO2019160813, or US10829486, each of which bile acids and analogs or derivatives thereof are incorporated herein by reference.In some embodiments, the FXR agonist is selected from the group consisting of WO2016086169, US10519191, WO2016130809, US10246483, WO2017147174, WO2017147159, WO2017147137, US10364267, US10323061, US10323060, WO2017189663, WO2017189652, WO20171 89651, US10080743, US10080742, US10080741, WO2017201155, WO2017201152, WO2017201153, WO2017201 154, WO2017201155, WO2017201150, US10144729, US10138228, WO2018067704, US10450306, WO2018081285 , US10597391, WO2018102418, US10584145, WO2018152171, US10472386, WO2018187804, US10676500, WO2 019118571, US10689391, WO2020231917, WO2016073767, US10266560, WO2016086134, US10208081, WO2016 086218, US10696713, US10968249, WO2016086115, WO2016161003, US10457703, US11040998, US11034684, US10947264, US10961272, WO2019160813, or US10829486, each of which is incorporated herein by reference.

[1271] In some embodiments, the condition, disorder, or disease is primary biliary cholangitis (PBC). In some embodiments, the condition, disorder, or disease is primary biliary cholangitis (PBC) without cirrhosis or with compensated cirrhosis without evidence of portal hypertension. In some embodiments, the other therapeutic agent is or is delivered obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the other therapeutic agent is or is delivered ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating primary biliary cholangitis (PBC), the method comprising administering or delivering an effective amount of a provided compound to a subject suffering from PBC, wherein the subject is administered, exposed to, or under the influence of another therapeutic agent (e.g., UDCA or a salt thereof). In some embodiments, the other therapeutic agent is administered or delivered simultaneously with a provided compound. In some embodiments, the other therapeutic agent is administered or delivered via the same pharmaceutical composition as a provided compound. In some embodiments, a provided compound is administered before or after another therapeutic agent. In some embodiments, a subject is exposed to therapeutically important levels of a provided compound and another therapeutic agent simultaneously. In some embodiments, a subject is exposed to therapeutically important effects of a provided compound and another therapeutic agent simultaneously.

[1272] In some embodiments, the condition, disorder, or disease is a bile acid synthesis disorder. In some embodiments, the condition, disorder, or disease is a bile acid synthesis disorder caused by a single enzyme deficiency (SED). In some embodiments, the condition, disorder, or disease is a peroxisomal disorder (PD). In some embodiments, the condition, disorder, or disease is a peroxisomal disorder (PD), including a Zellweger spectrum disorder. In some embodiments, the subject exhibits signs of liver disease, steatorrhea, or complications. In some embodiments, the other therapeutic agent is cholic acid.

[1273] In some embodiments, the condition, disorder, or disease is a neurodegenerative condition, disorder, or disease. In some embodiments, the condition, disorder, or disease is ALS. In some embodiments, the other therapeutic agent is a combination of tauursodiol and sodium phenylbutyrate (Relyvrio).

[1274] In some embodiments, the subject is an adult patient. In some embodiments, the subject is a pediatric patient.

[1275] Pharmaceutical Compositions and Administration

[1276] 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. In some embodiments, the compound is provided in the form of a pharmaceutically acceptable salt.

[1277] Various techniques, e.g., routes of administration, methods of administration, dosage regimens, etc., can be utilized to administer and / or deliver 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 result. One skilled in the art, i.e., a physician, knows that dosage regimens can be adjusted to obtain 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 compound is administered or delivered topically. In some embodiments, the composition is or comprises a topical composition. In some embodiments, the composition is or comprises a solution. In some embodiments, the composition is or comprises an emulsion. In some embodiments, the composition is or comprises a lotion. In some embodiments, the composition is or comprises an ointment. In some embodiments, the composition is or comprises a cream. In some embodiments, the composition is or comprises a gel. In some embodiments, the method of administration is left to the discretion of the practitioner.

[1278] 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.

[1279] The compound in the pharmaceutical composition may be provided as a pharmaceutically acceptable salt. In some embodiments, salts can be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, benzenesulfonic acid, etc. In some embodiments, salts can be formed with bases. In some embodiments, the salt is an alkali metal, alkaline earth metal, or ammonium salt, such as sodium, calcium, diethanolamine, ethanolamine, trialkylamine salt, etc.

[1280] 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.

[1281] Pharmaceutical compositions 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 suspending media, coatings, isotonicity agents, and absorption enhancers or delayers, making them compatible for 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.

[1282] 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.

[1283] In some embodiments, the compositions provided are suitable for parenteral administration. 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. Non-limiting 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 can 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 contain suitable stabilizers or agents to increase solubility, allowing for the preparation of highly concentrated solutions.

[1284] 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.

[1285] 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.

[1286] A variety of pharmaceutical compositions and delivery systems suitable for the compositions, methods and uses of the present disclosure are known in the art (see, e.g., Remington: The Science and Practice of Pharmacy. 21st Edition. Philadelphia, PA. Lippincott Williams & Wilkins, 2005) and can be utilized in accordance with the present disclosure.

[1287] 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 subject (e.g., a cell or tissue of a subject) with, or administering or delivering to a subject (e.g., a subject such as a mammal or human) a provided compound, such as a compound of Formula I or a salt thereof, or a composition thereof.

[1288] 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. Dosage amounts 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 of skill in the art. The 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 of skill 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.

[1289] 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.

[1290] 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.

[1291] In some embodiments, the pharmaceutical composition contains or delivers an effective amount of an active ingredient, such as 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.

[1292] 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, the 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 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.

[1293] Among other things, the present disclosure provides the following embodiments: 1. A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof:

[1294] [ka]

[1295] however, R 1 is -C(O)OR 11 , -P(O)(OR 12 )(OR 13 ), -C(O)N(R 14 )SO2R 15 , -C(O)NR 16 R 17 ,-CN,

[1296] [ka]

[1297] and; R 2 and R 3 are each independently R', -OR', halogen, -CN, or -NO 2、 or -N(R')2; Ring A is

[1298] [ka]

[1299] wherein ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms; L ra is an optionally substituted —(CH)N—; n is 1, 2, or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH2-; Z is -N= or -C(R 9 )=and; R 4, R 5 , R 6 , R 7 and R 9 are each independently R', -OR', halogen, -CN, -NO2, or -N(R')2; Ring B is an optionally substituted ring selected from a 6- to 10-membered aryl ring and a 5- to 10-membered heteroaryl ring having 1-6 heteroatoms; R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are each independently R'; Each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)R. Each R is independently hydrogen or C 1- C6 aliphatic, C with 1-3 heteroatoms 1- an optionally substituted group selected from C6 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms; or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the atom; 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 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 2. A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof:

[1300] [ka]

[1301] however, R 1 is -C(O)OR 11 , -P(O)(OR 12 )(OR 13 ), -C(O)N(R 14 )SO2R 15 , -C(O)NR 16 R 17 ,-CN,

[1302] [ka]

[1303] , halogen, or

[1304] [ka]

[1305] and; R 2 and R 3 are each independently R', -OR', halogen, -CN, or -NO 2、 or -N(R')2; Ring A is

[1306] [ka]

[1307] wherein ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms; L ra is an optionally substituted —(CH)N—; n is 1, 2, or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH2-; Z is -N= or -C(R 9 )=and; R 4 , R 5 , R 6 , R 7 and R 9 are each independently R', -OR', halogen, -CN, -NO2, or -N(R')2; Ring B is an optionally substituted ring selected from a 6- to 10-membered aryl ring and a 5- to 10-membered heteroaryl ring having 1-6 heteroatoms; R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are each independently R', Each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)R. each R is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms; or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the atom; 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 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 3. A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof:

[1308] [ka]

[1309] however, R 1 is —C(O)OH or its equivalent, optionally protected —CHO or R d6 and; R d6 is -CH(OR)2; R 2 and R 3 are each independently R', -OR', halogen, -CN, or -NO 2、 or -N(R')2; Ring A is

[1310] [ka]

[1311] wherein ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms; L ra is an optionally substituted —(CH)N—; n is 1, 2, or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH2-; Z is -N= or -C(R 9 )=and; R 4 , R 5 , R 6 , R 7 and R 9 are each independently R', -OR', halogen, -CN, -NO2, or -N(R')2; Ring B is an optionally substituted ring selected from a 6- to 10-membered aryl ring and a 5- to 10-membered heteroaryl ring having 1-6 heteroatoms; R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16, and R 17 are each independently R'; each R' is independently R, -OR, -C(O)R, -C(O)OR, or -S(O)R; each R is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 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-C1-C6 aliphatic, and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms; or two R groups on the same atom optionally and independently combine with the atom to form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to the atom; 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 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms. 4. The compound according to any one of the preceding embodiments, wherein Ring A' is an optionally substituted 5-6 membered aromatic ring having 0-4 heteroatoms. 5. Ring A is

[1312] [ka]

[1313] The compound of any one of embodiments 1-3, wherein 6. Ring A is

[1314] [ka]

[1315] The compound of any one of embodiments 1-4, wherein 7. Compounds according to embodiment 6, wherein ring A' is an optionally substituted 5-6 membered aromatic ring having 1, 2, 3 or 4 heteroatoms. 8. Compounds according to embodiment 6, wherein ring A' is an optionally substituted 5-membered aromatic ring having 1 or 2 heteroatoms. 9. The compound according to embodiment 6, wherein ring A' is an optionally substituted phenyl ring. 10. The compound according to embodiment 6, wherein ring A' is an optionally substituted 6-membered aromatic ring having 1 or 2 heteroatoms. 11. The compound of embodiment 6, wherein ring A' is an optionally substituted 9-membered aromatic ring having 1, 2, 3, or 4 heteroatoms. 12. The compound according to embodiment 6, wherein ring A' is an optionally substituted 9-membered aromatic ring having 1 or 2 heteroatoms. 13. The compound according to embodiment 6, wherein ring A' is an optionally substituted 10-membered aromatic ring having 1, 2, 3, or 4 heteroatoms. 14. The compound according to embodiment 6, wherein ring A' is an optionally substituted 10-membered aromatic ring having 1 or 2 heteroatoms. 15. The compound according to embodiment 6, wherein ring A' is an optionally substituted divalent naphthyl ring. 16. Ring A' is optionally substituted

[1316] [ka]

[1317] 7. The compound of embodiment 6, wherein: 17. Ring A' is

[1318] [ka]

[1319] 7. The compound of embodiment 6, wherein: 18.Z is -C(R 9 )=. 19.R 9 The compound of any one of embodiments 1-11, wherein 20.R 9 The compound of any one of embodiments 1-11, wherein is halogen. 21.R 9 The compound of any one of embodiments 1-11, wherein is F. 22.R 9 The compound of any one of embodiments 1-11, wherein is an optionally substituted C1-C6 aliphatic group. 23.R 9 The compound of any one of embodiments 1-11, wherein is optionally substituted C1-C6 alkyl. 24.R 9 The compound of any one of embodiments 1-11, wherein is methyl. 25. Ring A

[1320] [ka]

[1321] The compound of any one of embodiments 1-4, wherein 26. Ring A

[1322] [ka]

[1323] The compound of any one of embodiments 1-4, wherein 27. Ring A

[1324] [ka]

[1325] The compound of any one of embodiments 1-4, wherein 28. Ring A

[1326] [ka]

[1327] The compound of any one of embodiments 1-4, wherein 29. Ring A

[1328] [ka]

[1329] The compound of any one of embodiments 1-4, wherein 30. Ring A

[1330] [ka]

[1331] The compound of any one of embodiments 1-4, wherein 31. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted 5-6 membered aromatic ring having 1, 2, 3 or 4 heteroatoms. 32. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted 5-membered aromatic ring having 1 or 2 heteroatoms. 33. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted phenyl ring. 34. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted 6-membered aromatic ring having 1 or 2 heteroatoms. 35. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted 9-membered aromatic ring having 1, 2, 3, or 4 heteroatoms. 36. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted 9-membered aromatic ring having 1 or 2 heteroatoms. 37. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted 10-membered aromatic ring having 1, 2, 3, or 4 heteroatoms. 38. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted 10-membered aromatic ring having 1 or 2 heteroatoms. 39. The compound according to any one of embodiments 25-30, wherein ring A' is an optionally substituted divalent naphthyl ring. 40. Ring A' is optionally substituted

[1332] [ka]

[1333] The compound of any one of embodiments 25-30, wherein 41. Ring A' is

[1334] [ka]

[1335] The compound of any one of embodiments 25-30, wherein 42. Ring A

[1336] [ka]

[1337] 3. The compound of embodiment 1 or 2, wherein 43. Ring A

[1338] [ka]

[1339] 3. The compound of embodiment 1 or 2, wherein 44. Ring A

[1340] [ka]

[1341] 3. The compound of embodiment 1 or 2, wherein 45. Ring A

[1342] [ka]

[1343] 3. The compound of embodiment 1 or 2, wherein 46. ​​Ring A

[1344] [ka]

[1345] 3. The compound of embodiment 1 or 2, wherein 47. Ring A

[1346] [ka]

[1347] 3. The compound of embodiment 1 or 2, wherein 48. The compound according to any one of embodiments 25-197, wherein n is 1. 49. The compound according to any one of embodiments 25-197, wherein n is 2. 50. The compound according to any one of embodiments 25-197, wherein n is 3. 51.R 10 The compound of any one of embodiments 25-50, wherein is H. 52.X is -N(R 8)-. 53. The compound has the structure of formula B-5:

[1348] [ka]

[1349] or a salt thereof, wherein each variable is independently as described in embodiment 1 or 2. A compound characterized by: 54.R 8 is H. 55.R 8 The compound of any one of embodiments 1-53, wherein is not H. 56.R 8 The compound of any one of embodiments 1-53, wherein is optionally substituted C1-C6 alkyl. 57.R 8 The compound of embodiment 56, wherein is methyl. 58.R 8 The compound of embodiment 56, wherein is propyl. 59.R 8 The compound of embodiment 56, wherein is isopropyl. 60.R 8 The compound of embodiment 56, wherein is isobutyl. 61.R 8 The compound of any one of embodiments 1-53, wherein is optionally substituted C3-C8 cycloalkyl. 62.R 8 but

[1350] [ka]

[1351] 62. The compound of embodiment 61, wherein 63.R 8 but

[1352] [ka]

[1353] 62. The compound of embodiment 61, wherein 64.R 8 but

[1354] [ka]

[1355] 62. The compound of embodiment 61, wherein 65.R 8 The compound according to any one of embodiments 1-53, wherein is an optionally substituted 6-10 membered aryl. 66.R 8 The compound of embodiment 65, wherein is phenyl. 67.R 8 optionally substituted 6-10 membered aryl-C1 - The compound of any one of embodiments 1-53, wherein the C6 alkyl. 68.R 8 but

[1356] [ka]

[1357] 68. The compound of embodiment 67, wherein 69. A compound according to any one of embodiments 1-51, wherein X is -O-. 70. A compound according to any one of embodiments 1-51, wherein X is optionally substituted -CH2-. 71. A compound according to any one of embodiments 1-51, wherein X is -CH2-. 72. A compound according to any one of embodiments 1-51, wherein X is -S-. 73....

Claims

1. A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however, R １ but, 【Chemistry 2】 and R ２ and R ３ each independently represents R', -OR', halogen, -CN, or -NO ２、 or -N(R') ２ and Ring A is 【Transformation 3】 wherein ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms; L ｒａ is an optionally substituted —(CH ２ ) N-; n is 1, 2, or 3; X is -O-, -S-, -N(R ８ )- or optionally substituted -CH ２ - and Z is -N= or -C(R ９ ) = and R ４ , R ５ , R ６ , R ７ and R ９ each independently represents R', -OR', halogen, -CN, or -NO ２ , or —N(R′) ２ and Ring B is an optionally substituted ring selected from a 6- to 10-membered aryl ring and a 5- to 10-membered heteroaryl ring having 1 to 6 heteroatoms; R ８ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , and R １７ are each independently R'; 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 ６ Aliphatic, C with 1-3 heteroatoms １ -C ６ Heteroaliphatic, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered cyclic aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered cyclic aryl-C １ -C ６ Aliphatic and 5-10 membered heteroaryl-C having 1-6 heteroatoms １ -C ６ 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 3-10 membered ring having 0-4 heteroatoms in addition to the atom; 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 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms.

2. A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof. 【Chemistry 4】 (however, R １ is —C(O)OH or its equivalent, optionally protected —CHO or R ｄ６ or R １ But -C(O)OR １１ , -P(O)(OR １２ ) (OR １３ ), —C(O)N(R １４ ) SO ２ R １５ , —C(O)NR １６ R １７ , -CN, 【Transformation 5】 , halogen, or 【Transformation 6】 and R ｄ６ But -CH(OR) ２ and R ２ and R ３ each independently represents R', -OR', halogen, -CN, or -NO ２、 or -N(R') ２ and Ring A is 【Transformation 7】 wherein ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms; L ｒａ is an optionally substituted —(CH ２ ) N-; n is 1, 2, or 3; X is -O-, -S-, -N(R ８ )- or optionally substituted -CH ２ - and; Z is -N= or -C(R ９ ) = and R ４ , R ５ , R ６ , R ７ and R ９ each independently represents R', -OR', halogen, -CN, or -NO ２ , or —N(R′) ２ and Ring B is an optionally substituted ring selected from a 6- to 10-membered aryl ring and a 5- to 10-membered heteroaryl ring having 1 to 6 heteroatoms; R ８ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , and R １７ are each independently R'; 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 ６ Aliphatic, C with 1-3 heteroatoms １ -C ６ Heteroaliphatic, 3-10 membered cyclic aliphatic, 3-10 membered heterocyclyl having 1-4 heteroatoms, 6-10 membered cyclic aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered cyclic aryl-C １ -C ６ Aliphatic and 5-10 membered heteroaryl-C having 1-6 heteroatoms １ -C ６ 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 3-10 membered ring having 0-4 heteroatoms in addition to the atom; 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 3-10 membered ring having 0-4 heteroatoms in addition to the intervening atoms.

3. Ring A is 【Transformation 8】 The compound according to claim 1, characterized in that:

4. Ring A is 【Chemistry 9】 The compound according to claim 1, characterized in that:

5. L ｒａ Ga-CH ２ The compound according to any one of claims 1 to 4, characterized in that it is -.

6. R １０ The compound of claim 5, wherein is H.

7. Ring A is 【Chemistry 10】 The compound according to claim 1, characterized in that:

8. The compound according to any one of claims 4 to 7, wherein ring A' is an optionally substituted 5- or 6-membered aromatic ring having 1, 2, 3 or 4 heteroatoms.

9. The compound according to any one of claims 4 to 7, wherein ring A' is an optionally substituted phenyl ring.

10. Ring A is 【Chemistry 11】 The compound according to claim 1, characterized in that:

11. R ５ is halogen or optionally substituted C １ -C ６ The compound according to claim 10, characterized in that it is alkyl.

12. R ５ Ga-CF ３ The compound according to claim 11, characterized in that

13. Ring B is 【Chemistry 12】 The compound according to any one of claims 10 to 12, characterized in that it is

14. Ring B is 【Chemistry 13】 The compound according to any one of claims 10 to 12, characterized in that it is

15. R ２ 15. The compound of claim 14, wherein is a halogen.

16. R ２ The compound of claim 14, wherein is -F.

17. R ２ The compound according to any one of claims 1 to 14, characterized in that is R.

18. R ２ The compound according to any one of claims 1 to 14, characterized in that is H.

19. R ２ is —C(O)OR, where R is H or optionally substituted C １－６ A compound according to any one of claims 1 to 14, characterized in that it is aliphatic.

20. R ２ is —OR, where R is an optionally substituted C １ -C ６ alkyl, optionally substituted 6-10 membered aryl, optionally substituted C ３ -C ８ A compound according to any one of claims 1 to 14, characterized in that it is a cycloalkyl or an optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

21. R ３ The compound according to any one of claims 1 to 12, characterized in that is halogen.

22. R ３ The compound according to any one of claims 1 to 12, characterized in that is R.

23. R ３ The compound according to any one of claims 1 to 12, characterized in that is H.

24. R ３ is —C(O)OR, where R is H or optionally substituted C １－６ A compound according to any one of claims 1 to 12, characterized in that it is aliphatic.

25. R ３ is —OR, where R is an optionally substituted C １ -C ６ alkyl, optionally substituted 6-10 membered aryl, optionally substituted C ３ -C ８ A compound according to any one of claims 1 to 12, characterized in that it is a cycloalkyl or an optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

26. A compound selected from Table 1 or a salt thereof.

27. The compound is 【Chemistry 14】 or a pharmaceutically acceptable salt thereof.

28. The compound is 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

29. The compound is 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

30. The compound is 【Chemistry 17】 or a pharmaceutically acceptable salt thereof.

31. The compound is [Chemistry 18] or a pharmaceutically acceptable salt thereof.

32. The compound is 【Chemistry 19】 or a pharmaceutically acceptable salt thereof.

33. The compound is 【Chemistry 20】 or a pharmaceutically acceptable salt thereof.

34. The compound is 【Chemistry 21】 or a pharmaceutically acceptable salt thereof.

35. The compound is 【Chemistry 22】 or a pharmaceutically acceptable salt thereof.

36. The compound is 【Chemistry 23】 or a pharmaceutically acceptable salt thereof.

37. The compound is 【Chemistry 24】 or a pharmaceutically acceptable salt thereof.

38. The compound is 【Chemistry 25】 or a pharmaceutically acceptable salt thereof.

39. The compound is 【Chemistry 26】 or a pharmaceutically acceptable salt thereof.

40. The compound is 【Chemistry 27】 or a pharmaceutically acceptable salt thereof.

41. The compound is 【Chemistry 28】 or a pharmaceutically acceptable salt thereof.

42. 10. The compound according to any one of the preceding claims, characterized in that the compound is a pharmaceutically acceptable salt.

43. 10. The compound according to any one of the preceding claims, characterized in that it is a sodium salt.

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

45. 45. The composition of claim 44, wherein the composition is a topical composition.

46. 10. A method for modulating Mas-related G protein-coupled receptor X4 (MRGPRX4) activity, comprising contacting MRGPRX4 with an effective amount of a compound or pharmaceutical composition according to any one of the preceding claims; or A method for modulating the activity of MRGPRX4 in a system containing MRGPRX4, comprising administering or delivering to said system an effective amount of a compound or pharmaceutical composition according to any one of the preceding claims.

47. 46. ​​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 1-45.

48. 46. ​​A method of 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 claims 1-45.

49. 49. The method of any one of claims 47-48, wherein the condition, disorder or disease is associated with MRGPRX4.

50. 49. The method of any one of claims 47-48, wherein the symptom, disorder or disease is or includes itch.

51. 49. The method of any one of claims 47-48, wherein the symptom, disorder or disease is or comprises pruritus.

52. The condition, disorder or disease is selected from the group consisting of chronic pruritus, cholestatic pruritus, contact dermatitis, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, candidiasis, chickenpox, cholestasis, end-stage renal failure, hemodialysis, contact dermatitis, dermatitis herpetiformis, diabetes, drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, eczema, erythema, folliculitis, fungal skin infections, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iron deficiency anemia, renal failure, and the like.

49. The method of any one of claims 47-48, wherein the condition is or comprises liver disease, leukemia, liver disease, lymphoma, malignant tumor, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia rubra vera, pruritus ani, pseudorabies, psoriasis, rectal prolapse, scabies, schistosomiasis, subcutaneous dermatitis, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus, or urticaria.

53. 52. The method of claim 51, wherein the pruritus is acute or chronic pruritus associated with a liver condition, disorder, or disease.

54. 49. The method of any one of claims 47-48, wherein the condition, disorder or disease is a liver condition, disorder or disease.

55. 55. The method of claim 53 or 54, wherein the liver condition, disorder or disease is intrahepatic cholestasis of pregnancy (ICP), estrogen, progesterone or testosterone-induced cholestasis, toxin or other drug-induced hepatocellular cholestasis, benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC), chronic viral hepatitis C, chronic hepatitis B, alcoholic or non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), secondary sclerosing cholangitis (SSC), sarcoidosis, ABCB4 deficiency, Alagille syndrome, drug-induced canalicular cholangiopathy, cholelithiasis, IgG4-associated cholangitis, biliary atresia, cholangiocarcinoma, benign biliary adenoma, or other obstructive cholestasis.

56. 49. The method of any one of claims 47-48, wherein the condition, disorder or disease is or comprises primary biliary cholangitis (PBC).

57. 57. The method of any one of claims 47 to 56, wherein the compound or composition is used in combination with another therapeutic agent.

58. 58. The method of claim 57, wherein the additional therapeutic agent is or delivers ursodeoxycholic acid or a pharmaceutically acceptable salt thereof.

59. 59. The method of any one of claims 57-58, wherein the compound or composition is administered simultaneously with, before, or after another therapeutic agent.

60. A compound, composition, or method described herein or according to any one of embodiments 1-1178.

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