Compounds, compositions, and methods thereof

Abstract

The present disclosure provides, among other things, a compound, such as a compound of Formula I or a salt thereof. In some embodiments, the present disclosure provides methods of modulating the activity of MRGPRX4. In some embodiments, the present disclosure provides methods of preventing or treating a condition, disorder or disease, such as an MRGPRX4-related condition, disorder or disease.

Description

Cross - reference to related applications

[0001] This application claims priority to PCT application PCT / CN2022 / 126550 filed on October 21, 2022 and PCT application PCT / CN2023 / 077383 filed on February 21, 2023, the entire content of each application being incorporated herein by reference. Technical field

[0002] In some embodiments, the present disclosure provides compounds and compositions for modulating the activity of MRGPRX4, etc. In some embodiments, the provided compounds and compositions are helpful for preventing or treating conditions, disorders or diseases related to MRGPRX4, such as pruritus. In some embodiments, the present disclosure provides techniques for preparing the provided compounds and compositions. Background art

[0003] Compounds can be used for various purposes, including modulating biological functions and activities. It has been reported that Mas - related G - protein coupled receptor X4 (MRGPRX4) has multiple biological functions and may be associated with various conditions, disorders or diseases. For example, patients with hepatobiliary conditions, disorders or diseases such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or progressive familial intrahepatic cholestasis (PFIC) often suffer from intractable pruritus, which usually seriously affects the quality of life and may lead to lethargy, fatigue, depression and even suicidal thoughts. Recently, it has been reported that the agonist effects of MRGPRX4 and its bile acids and their derivatives may be related to the pruritus that appears in these diseases (such as Meixiong et al., MRGPRX4 is a bile acid - activated protein - coupled receptor that may cause cholestatic pruritus, PNAS, 2019, 116(21), 10525 - 10530; Yu et al., MRGPRX4 is a bile acid receptor for human bile itch, eLife, 2019, 8, e48431).

[0004] It has been reported that MRGPRX4 is expressed at least in human dorsal root ganglion (hDRG) neurons and co - expressed with the itch receptor HRH1. It has been reported that bile acids or MRGPRX4 - specific agonists in the skin can activate MRGPRX4 in itch - related primary fibers, causing a Ca 2+ response and inducing pruritus in human subjects.

[0005] Small compounds that are allegedly MRGPRX4 regulators have been disclosed in WO 2020 / 198537, US2021 / 0032213, WO2021 / 211839, WO 2022 / 061008, etc. SUMMARY OF THE INVENTION

[0006] In some embodiments, the present disclosure provides various compounds, such as compounds having the structure of Formula I or salts thereof, as well as compositions and methods thereof. In some embodiments, the provided compounds can be used as MRGPRX4 regulators. In some embodiments, the provided technologies (such as compounds, compositions, methods, etc.) can be used to prevent or treat various conditions, disorders, or diseases. In some embodiments, the condition, disorder, or disease is a condition, disorder, or disease related to MRGPRX4. In some embodiments, the condition, disorder, or disease is itching or includes itching. In some embodiments, the condition, disorder, or disease is pruritus or includes pruritus. In some embodiments, the condition, disorder, or disease is related to the administration of additional therapeutic agents, such as FXR agonists, bile acids, or their analogs or derivatives, etc.

[0007] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the structure of Formula I: Wherein R 1 is -C(O)OH or its isostere, 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 )SO 2 R 15 , -C(O)NR 16 R 17 , -CN, halogen, or R d6 is -CH(OR) 2 ; R 2 and R 3 are each independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring A is wherein Ring A' is an optionally substituted 5-10 membered aromatic ring having 0-4 heteroatoms; Lra is optionally substituted -(CH 2 ) n -; n is 1, 2 or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH 2 -; Z is -N= or -C(R 9 )=; R 4 , R 5 , R 6 , R 7 and R 9 are each independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring B is an optionally substituted ring selected from 5- to 10-membered heteroaryl rings and 6- to 10-membered aryl rings 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 an optionally substituted group selected from C 1 -C 6 aliphatic optionally, C 1 -C 6 heterocyclic aliphatic, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocyclic group having 1 to 4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, 6- to 10-membered heteroaryl-C 1 -C 6 aliphatic, and 5- to 10-membered heteroaryl-C 1 -C 6 aliphatic; or Two R groups located on the same atom optionally and independently together with that atom form an optionally substituted 3- to 10-membered ring having 0 to 4 heteroatoms in addition to the central atom; or Two R groups located on two atoms may optionally and independently form, together with their intervening atom, an optionally substituted 3- to 10-membered ring which, in addition to the intervening atom, has 0 to 4 heteroatoms.

[0008] In some embodiments, the present disclosure provides a compound, wherein the compound has the structure of Formula I or a salt thereof, wherein R 1 is -C(O)OH or an isostere thereof, 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 )SO 2 R 15 , -C(O)NR 16 R 17 , -CN, and each other variable is independently as described herein.

[0009] In some embodiments, the present disclosure provides a compound, wherein the compound has the structure of Formula I or a pharmaceutically acceptable salt thereof, wherein ring A' is an optionally substituted 5- to 6-membered aromatic ring having 0 to 4 heteroatoms, and each other variable is independently as described herein.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the provided compound. In some embodiments, the present disclosure provides a pharmaceutical composition comprising the provided compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition for delivering the provided compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] The provided technology can be used for a variety of purposes. For example, in some embodiments, the present disclosure provides a method for preventing a disorder, condition, or disease, comprising administering or delivering an effective amount of the provided compound to a susceptible subject. For example, in some embodiments, the present disclosure provides a method for treating a disorder, condition, or disease, comprising administering or delivering an effective amount of the provided compound to a subject having the disorder, condition, or disease. In some embodiments, the disorder, condition, or disease is an MRGPRX4-related disorder, condition, or disease. In some embodiments, the disorder, condition, or disease is related to MRGPRX4 activation. In some embodiments, the disorder, condition, or disease is related to the activation of MRGPRX4 by an agent. In some embodiments, the disorder, condition, or disease is related to the interaction of MRGPRX4 with an agent. In some embodiments, the disorder, condition, or disease is related to the administration of a formulation. In some embodiments, the disorder, condition, or disease is related to the delivery of an agent. In some embodiments, the agent is a therapeutic agent. In some embodiments, the agent can bind to MRGPRX4. In some embodiments, the agent can activate MRGPRX4. In some embodiments, the agent is an FXR agonist. In some embodiments, the agent is a bile acid or an analogue or derivative thereof. In some embodiments, the disorder, condition, or disease is pruritus.

[0012] In some embodiments, the present disclosure provides a method for preventing a disorder, condition, or disease, comprising administering or delivering an effective amount of the provided compound and an additional formulation to a subject susceptible thereto. In some embodiments, the present disclosure provides a method for treating a disorder, condition, or disease, comprising administering or delivering an effective amount of the provided compound and an additional formulation to a subject having the disorder, condition, or disease. For example, in some embodiments, the disorder, condition, or disease is related to the farnesoid X receptor (FXR), and the additional formulation is an FXR agonist. In some embodiments, the disorder, condition, or disease is related to TGR 5 and the additional formulation is a TGR 5 agonist. In some embodiments, the additional formulation can activate MRGPRX4. In some embodiments, the additional formulation is an FXR agonist. In some embodiments, the additional formulation is a bile acid or an analogue or derivative thereof. In some embodiments, the disorder, condition, or disease is a liver disorder, condition, or disease. For example, in some embodiments, the disorder, condition, or disease is non-alcoholic steatohepatitis (NASH).

[0013] In some embodiments, the present disclosure provides techniques for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as methods, reagents, etc. Detailed embodiments

[0014] The technology of the present disclosure can be more easily understood by referring to the following detailed description of some embodiments. Definitions

[0015] Unless otherwise specified, the definitions used herein are as follows. For the purposes of the present disclosure, the identification of chemical elements is based on the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are 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.

[0016] For the terms used in the present disclosure, unless the context indicates otherwise, (i) the term "a" or "an" can be understood as "at least one"; (ii) the term "or" can be understood as "and / or"; (iii) the terms "comprising", "comprises", "include" (whether used with "but not limited to" or not) and "including" (whether used with "but not limited to" or not) can be understood as including the components or steps listed item by item, whether by themselves or in combination with one or more additional components or steps; (iv) the term "another / other" can be understood as at least one more / second or more; (v) the terms "about" and "approximate" can be understood as allowing for standard variations understood by those of ordinary skill in the art; (vi) when a range is provided, the endpoints are included. Unless the context indicates otherwise, isomers of compounds are included. As understood by those of skill in the art, compounds can be provided, administered, or delivered in various forms, such as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, esters, prodrugs, homologs, etc.

[0017] Aliphatic: As used herein, "aliphatic" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units (but no aromatic groups), or a substituted or unsubstituted monocyclic, bicyclic or polycyclic hydrocarbon ring that is completely saturated or contains one or more unsaturated units (but no aromatic groups), or a combination thereof. In some embodiments, the aliphatic group contains 1-50 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-20 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-9 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-8 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-7 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms, and in still other embodiments, the aliphatic group contains 1, 2, 3 or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0018] Alkenyl: As used herein, the term "alkenyl" refers to an aliphatic group as defined herein having one or more double bonds.

[0019] Alkyl: As used herein, the term "alkyl" has its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (cycloaliphatic) groups, alkyl-substituted cycloalkyl groups and cycloalkyl-substituted alkyl groups. In some embodiments, the alkyl has 1-100 carbon atoms. In some embodiments, the straight-chain or branched-chain alkyl has about 1-20 carbon atoms in its backbone (e.g., straight-chain is C 1 -C 20 , branched-chain is C 2 -C 20 ), or about 1-10. In some embodiments, the cycloalkyl ring has about 3-10 carbon atoms in its ring structure, and these rings are monocyclic, bicyclic or polycyclic, or have about 5, 6 or 7 carbon atoms in the cyclic structure. In some embodiments, the alkyl group may be a lower alkyl group, and the lower alkyl group includes 1-4 carbon atoms (e.g., straight-chain lower alkyl is C 1 -C 4 ).

[0020] Alkynyl: As used herein, the term "alkynyl" refers to an aliphatic group as defined herein having one or more triple bonds.

[0021] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In some embodiments, the non-human animal is a mammal (such as 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 can be a transgenic animal, a genetically engineered animal, and / or a cloned animal.

[0022] Aryl: As used herein, the term "aryl", which can be used alone or as part of a larger molecule, such as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic, bicyclic, or polycyclic ring system having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, aryl is a monocyclic, bicyclic, or polycyclic ring system having 5 to 14 ring members, wherein at least one ring is aromatic and each ring in the system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, aryl is biaryl. The term "aryl" can be used interchangeably with the term "aryl ring". In some embodiments of the present disclosure, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, binaphthyl, anthryl, etc., which may be substituted with one or more substituents. The scope of the term "aryl" as used herein also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indenyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc.

[0023] Characteristic moiety: The term "characteristic moiety" as used herein, in a broad sense, refers to a part of a substance, the presence (or absence) of which is associated with the presence (or absence) of a particular characteristic, property, or activity of the substance. In some embodiments, the characteristic moiety of a substance refers to the part found in that substance and a related substance having a particular characteristic, property, or activity, and absent in a substance not having the particular characteristic, property, or activity. In some embodiments, the characteristic moiety shares at least one functional characteristic with the complete substance. For example, in some embodiments, the "characteristic moiety" of a protein or polypeptide refers to the part containing a continuous segment of amino acids or a collection of amino acids (in some embodiments, a collection of continuous segments of amino acids), which together constitute the characteristic of the protein or polypeptide. In some embodiments, each such continuous segment generally contains at least 2, 5, 10, 15, 20, 50 or more amino acids. Generally speaking, the characteristic moiety of a substance (such as a protein, antibody, etc.) refers to the part that, in addition to the above sequence and / or structural identity, also has at least one functional characteristic with the related complete substance. In some embodiments, the characteristic moiety may have biological activity.

[0024] Comparability: The term "comparability" as used herein refers to two (or more) sets of conditions or situations being sufficiently similar to allow comparison of the results obtained or the phenomena observed. In some embodiments, comparable conditions or situations are characterized by having a plurality of substantially identical characteristics and one or a small number of different characteristics. One of ordinary skill in the art will understand that when a set of conditions has a sufficient number and type of substantially identical characteristics, this set of conditions is comparable, such that a reasonable conclusion can be drawn that the differences in the results obtained or the phenomena observed under different conditions or situations are caused by, or indicative of, changes in these characteristics.

[0025] Cycloaliphatic: The terms "cycloaliphatic", "carbocyclic", "carbocyclic group", "carbocyclic moiety", and "carbocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring system, which, as described herein, unless otherwise specified, has 3 to 30 ring members. Cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloaliphatic group has 3 - 6 carbon atoms. In some embodiments, the cycloaliphatic group is a saturated cycloalkyl. The term "cycloaliphatic" may also include an aliphatic ring fused to one or more aromatic or non-aromatic rings (such as decahydronaphthalene or tetrahydronaphthalene). In some embodiments, the cycloaliphatic group is bicyclic. In some embodiments, the cycloaliphatic group is tricyclic. In some embodiments, the cycloaliphatic group is polycyclic. In some embodiments, "cycloaliphatic" refers to C 3-C 6 monocyclic hydrocarbon, or C 8 -C 10 bicyclic or polycyclic hydrocarbon, fully saturated or containing one or more unsaturated units, but not an aromatic hydrocarbon, or fully saturated C 9 -C 16 polycyclic hydrocarbon, or a hydrocarbon containing one or more unsaturated units but not aromatic, having one point of attachment to the remainder of the molecule.

[0026] Heteroaliphatic: As used herein, the term "heteroaliphatic" has its ordinary meaning in the art and refers to an aliphatic group in which one or more of the carbon atoms described herein are independently replaced by one or more heteroatoms (such as oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). In some embodiments, one or more units selected from C, CH, 2 and CH 3 are independently replaced by one or more heteroatoms (including their oxidized and / or substituted forms). In some embodiments, the heteroaliphatic group is a heteroalkyl. In some embodiments, the heteroaliphatic group is a heteroalkenyl.

[0027] Heteroalkyl: As used herein, the term "heteroalkyl" has its ordinary meaning in the art and refers to an alkyl group in which one or more of the carbon atoms described herein are independently replaced by one or more heteroatoms (such as oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). Examples of heteroalkyls include, but are not limited to, alkoxy, polyethylene glycol, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0028] Heteroaryl: As used herein, the terms "heteroaryl" and "heteroaryl-", which may be used alone or as part of a larger molecule (such as "heteroalkyl" or "heteroalkoxy"), refer to a monocyclic, bicyclic or polycyclic system having a total of five to thirty ring members, wherein at least one of the rings in the system is an aromatic ring and at least one aromatic ring atom is a heteroatom. In some embodiments, heteroaryl is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic or polycyclic), and in some embodiments is a group having 5, 6, 9 or 10 ring atoms. In some embodiments, each ring unit of the monocyclic ring is aromatic. In some embodiments, heteroaryl has 6, 10 or 14 π electrons shared in a cyclic array; in addition to carbon atoms, it has 1 to 5 heteroatoms. Heteroaryl includes, but is not limited to, thienyl, furyl, 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 hetero-polyaryl, such as bipyridyl, etc. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaryl ring is fused to one or more aryl rings, cycloaliphatic rings or heterocyclic rings, wherein the linking group or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl can be monocyclic, bicyclic or polycyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", and any of these terms includes optionally substituted rings. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl moieties are each optionally substituted.

[0029] Heteroatom: As used herein, the term "heteroatom" refers to an atom that is not 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 of imino 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.

[0030] Heterocycle: As used herein, the terms "heterocycle", "heterocyclic group", "heterocyclic moiety", and "heterocyclic ring" are used interchangeably and refer to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic molecule (e.g., 3 - 30 membered) having one or more heteroatom ring atoms. In some embodiments, the heterocyclic moiety is a stable 5 - to 7 - membered monocyclic or 7 - to 10 - membered bicyclic heterocyclic molecule, saturated or partially unsaturated, having one or more (preferably 1 to 4) heteroatoms in addition to carbon atoms, as defined above. When referring to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 - 3 heteroatoms selected from oxygen, sulfur, and nitrogen, nitrogen can be N (such as 3,4 - dihydro - 2H - pyrrolyl), NH (such as pyrrolidine), or +NR (such as N - substituted pyrrolidine). The heterocycle can be attached to its pendant group at any heteroatom or carbon atom so as to form a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic moieties include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophene, pyrrolidine, piperidinyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxinyl, dihydroxy, diazepam, oxazolidinyl, thiazinyl, morpholine, and quinuclidinyl. The terms "heterocycle", "heterocyclic group", "heterocyclic ring", "heterocyclic moiety", "heterocyclic molecule", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H - indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The groups of the heterocyclic family can be monocyclic, bicyclic, or polycyclic. The term "heteroalkyl" refers to an alkyl group substituted by a heterocyclic group, where the alkyl and heterocyclic groups are each independently optionally substituted.

[0031] Leaving group / LG: As used herein, a leaving group or LG is an atom or group of atoms that separates from the major or remaining portion of a substrate during a reaction or during an elementary step of a reaction. In some embodiments, LG is a halogen. In some embodiments, LG is - Cl. In some embodiments, LG is - OH.

[0032] Optional substitution: As described herein, the compounds of the present disclosure may include optionally substituted and / or substituted molecules. In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of one or more hydrogens of a designated molecule 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 more than one position in any given structure can be substituted with more than one substituent selected from a designated group, the substituents at each position may be the same or different. In some embodiments, the optionally substituted group is unsubstituted. The combinations of substituents contemplated by the present disclosure are preferably those that form stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that does not undergo substantial change under the conditions of production, testing, and (in some embodiments) recovery, purification, and use for one or more of the purposes disclosed herein. Certain substituents are described below.

[0033] Suitable monovalent substituents include: halogen; -(CH 2 ) 0-4 R o ; -(CH 2 ) 0-4 OR o ; -O(CH 2 ) 0-4 Ro, -O-(CH 2 ) 0- 4 C(O)OR o ; -(CH 2 ) 0-4 CH(OR o ) 2 ; -(CH 2 ) 0-4 Ph, which may be substituted by R o ; -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph, which may be substituted by R o ; -CH=CHPh, which may be substituted by R o ; -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl, which may be substituted by R o ; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R o ) 2 ; -(CH 2 )0-4 N(R o )C(O)R o ; - N(R o )C(S)R o ; -(CH 2 ) 0-4 N(R o )C(O)NR o 2 ; - N(R o )C(S)NR o 2 ; -(CH 2 ) 0-4 N(R o )C(O)OR o ; - N(R o )N(R o )C(O)R o ; - N(R o )N(R o )C(O)NR o 2 ; - N(R o )N(R o )C(O)OR o ; -(CH 2 ) 0-4 C(O)R o ; - C(S)R o ; -(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 C(O)SR o ; -(CH 2 ) 0-4 C(O)OSiR o 3 ; -(CH 2 ) 0- 4 OC(O)R o ; - OC(O)(CH 2 ) 0-4 SR, - SC(S)SR o ; -(CH 2 ) 0-4 SC(O)R o ; -(CH 2 ) 0-4 C(O)NR o 2 ; - C(S)NR o 2 ; - C(S)SR o; -SC(S)SR o , -(CH 2 ) 0-4 OC(O)NR o 2 ; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH 2 C(O)R; -C(NOR o )R; -(CH 2 ) 0-4 SSR o ; -(CH 2 ) 0-4 S(O) 2 R o ; -(CH 2 ) 0-4 S(O) 2 OR o ; -(CH 2 ) 0-4 OS(O) 2 R o ; -S(O) 2 NR o 2 ; -(CH 2 ) 0-4 S(O)R o ; -N(R o )S(O) 2 NR o 2 ; -N(R o )S(O) 2 R o ; -N(OR o )R o ; -C(NH)NR o 2 ; -P(O) 2 R o ; -P(O)R o 2 ; -OP(O)R o 2 ; -OP(O)(OR o ) 2 ; -SiR o 3; -OSiR o 3 ; -(C 1-4 linear or branched alkylene)O-N(R o ) 2 ; or -(C 1-4 linear or branched alkylene)C(O)O-N(Ro ) 2 , wherein each R o may be substituted as defined below and is independently hydrogen, C 1-20 aliphatic, C with 1 - 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus 1-20 heteroaliphatic, -CH 2 -(C 6-14 aryl), -O(CH 2 ) 0-1 (C 6-14 aryl), -CH 2 -(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 definition, two independently occurring Rs, together with the atoms in between them, form 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, and the aryl ring may be substituted as defined below.

[0034] R o (or the ring formed by two independently occurring Rs o together with the atoms in between them) suitable monovalent substituents on it are independently halogen, -(CH 2 ) 0-2 R · ; -(halo - R · ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR · , -(CH 2 ) 0-2 CH(OR · ) 2 ; -O(halo - R · ), -CN, -N3, -(CH 2 ) 0-2 C(O)R · , -(CH 2 ) 0-2 C(O)OH; -(CH 2 ) 0-2 C(O)OR · , -(CH 2 ) 0-2 SR · ; -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH2 ) 0-2 NHR · ;- (CH 2 ) 0-2 NR · 2 , - NO 2 , - 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 when preceded by "halo" is substituted by one or more halogens only, and is independently selected from C 1-4 aliphatic, - CH 2 Ph, - O(CH 2 ) 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. Suitable divalent substituents on saturated carbon atoms include = O and = S. o Suitable divalent substituents include the following: = O, = S, = NNR*,

[0035] = NNHC(O)R*, = NNHC(O)OR*, = NNHS(O) 2 , = NNHC(O)R*, = NR*, = NOR*, - O(C(R* 2 )) 2 O -, or - S(C(R* 2-3 )) 2 S -, where each independently occurring R* is selected from hydrogen, C 2-3 - 6 aliphatic, which may be substituted as defined below, or an unsubstituted 5 - 6 - membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Suitable divalent substituents bonded to ortho - substitutable carbon of an "optionally substituted" group include: - O(CR*[tg1]2)2 - 3O - where each independently occurring R* is selected from hydrogen, C1 - 6 aliphatic which may be substituted as defined below or an unsubstituted 5 - 6 - membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 Suitable substituents on the aliphatic group of R* include halogen, - R

[0036] · · 、- (halo - R · ), - OH, - OR · 、- O(halo - R ·)、 -CN, -C(O)OH, -C(O)OR · 、 -NH 2 、 -NHR · 、 -NR · 2 or -NO 2 、 wherein each R · is unsubstituted or, in the presence of "halo" in front, is substituted only by one or more halogens and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0037] In some embodiments, suitable substituents on nitrogen include wherein each is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or, notwithstanding the above definition, two independently occurring together with the atoms between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0038] Suitable substituents on the aliphatic group are independently halogen, -R · 、 -(haloR · ), -OH, -OR · 、 -O(haloR · ), -CN, -C(O)OH, -C(O)OR · 、 -NH 2 、 -NHR · 、 -NR · 2 or -NO 2 、 wherein each R · is unsubstituted or, in the presence of "halo" in front, is substituted only by one or more halogens and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0- 1 Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0039] Partially Unsaturated: As used herein, the term "partially unsaturated" refers to a cyclic molecule that includes at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but does not include aryl or heteroaryl molecules as defined herein.

[0040] Pharmaceutical Composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the unit dose of the active agent is suitable for administration in a treatment regimen that, when administered to the relevant population, has a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition may be formulated specifically for administration in solid or liquid form, including compositions suitable for the following uses: oral administration, e.g., infusions (aqueous or non-aqueous solutions or suspensions), tablets, such as pills for buccal absorption, sublingual absorption, and systemic absorption, suppositories, powders, granules, lozenges; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained release formulations; topical administration, e.g., as creams, ointments, or controlled release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, e.g., as suppositories, creams, or foams; sublingual; ophthalmic; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0041] Pharmaceutically Acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable, within the reasonable scope of medical judgment, for contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0042] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, used to carry or transport a test compound from one organ or part of the body to another organ or another part of the body. Each carrier must be "acceptable", i.e., compatible with the other ingredients in the formulation and not harmful to the patient. Materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as 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 glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffer solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical formulations.

[0043] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of such compounds that are suitable for use in pharmaceuticals, i.e., salts that are suitable for contact with the tissues of humans and lower animals within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S.M. Berge et al. 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, i.e., salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or amino salts formed by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphor, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonic acid, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoic acid, hydroiodides, 2-hydroxy-ethanesulfonic acid, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. In some embodiments, the provided compounds contain one or more acidic groups, and the pharmaceutically acceptable salts are alkali metals, alkaline earth metals, or ammonium (e.g., N(R) 3ammonium salts, where each R is independently defined as described in the present disclosure) salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. 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, the pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates. In some embodiments, the provided compounds contain two or more acid groups. In some embodiments, the pharmaceutically acceptable salts of such compounds, or salts in general, include two or more cations, which may be the same or different. In some embodiments, in the pharmaceutically acceptable salts (or salts in general), the ionizable hydrogen in all acidic groups (e.g., in aqueous solution, pKa not exceeding about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, not exceeding about 7; in some embodiments, not exceeding about 6; in some embodiments, not exceeding about 5; in some embodiments, not exceeding about 4; in some embodiments, not exceeding about 3) is replaced by cations.

[0044] Protecting groups: The term "protecting group" as used herein is well known in the art and includes protecting groups described in detail in "Protecting Groups in Organic Synthesis" (T.W. Greene and P.G.M. Wuts, Third Edition, John Wiley & Sons, 1999), the entire content of which is incorporated herein by reference. In addition, it also includes protecting groups specifically for nucleoside and nucleotide chemistry described in "Current Protocols in Nucleic Acid Chemistry" edited by Serge L. Beaucage et al. The entire Chapter 2 is incorporated herein by reference. Suitable amino protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenylacetyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,Ethyl N-(dicyclohexylcarbamoyl)carbamate, tert-Butyl carbamate (BOC), Ethyl 1-adamantylcarbamate (Adoc), Vinyl carbamate (Voc), Allyl carbamate (Alloc), Isopropyl 1-carbamate (Ipaoc), Cinnamyl carbamate (Coc), 4-Nitrocinnamyl carbamate (Noc), 8-Quinolyl carbamate, Methyl N-(2-hydroxybenzoate), Alkyl dithiocarbamate, Benzyl carbamate (Cbz), p-Methoxybenzyl carbamate (Moz), p-Nitrobenzyl 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-Dithiol)]methyl carbamate (Dmoc), 4-Methylthiophenyl carbamate (Mtpc), 2,4-Dimethylthiophene carbamate (Bmpc), 2-Phosphonoethyl carbamate (Peoc), 2-Triphenylphosphonylisopropyl carbamate (Ppoc), 1,1-Dimethyl-2-cyanoethyl carbamate, m-Chloro-p-acetyloxybenzyl carbamate, p-(Dihydroxybenzyl)benzyl carbamate, 5-Benzisoxazolylmethyl carbamate, 2-(Trifluoromethyl)-6-bromomethyl carbamate (Tcroc), m-Nitrophenyl carbamate, 3,5-Dimethoxybenzyl carbamate, o-Nitrobenzyl carbamate, 3,4-Dimethoxy-6-nitrobenzyl carbamate, Phenyl(o-nitrophenyl)methyl carbamate, Benzothiazine-(10)-carbonyl derivative, N'-p-Toluenesulfonylaminocarbonyl derivative, N'-Phenylthiocarbamoyl derivative, tert-Amyl carbamate, S-Benzyl thiocarbamate, p-Cyanobenzyl carbamate, Cyclobutyl carbamate, Cyclohexyl carbamate, Cyclopentyl carbamate, Cyclopropylmethyl carbamate, p-Decyloxybenzyl carbamate, 2,2-Dimethoxycarbonylvinyl carbamate, o-(N,N-Dimethylcarbonylamino)benzyl carbamate, 1,1-Dimethyl-3-(N,N-Dimethylcarbonylamino)propyl carbamate, 1,1-Dimethylpropargyl carbamate, Bis(2-pyridyl)methyl carbamate, 2-Furanylmethyl carbamate, 2-Iodoethyl carbamate, Isobutyl carbamate, Isobutyl carbamate, p-(p'-Methoxyphenylazo)benzyl carbamate, 1-Methylcyclobutyl carbamate, 1-Methylcyclohexyl carbamate, 1-Methyl-1-cyclopropylmethyl carbamate, 1-Methyl-1-(3,5-(dimethoxyphenyl)ethyl carbamate, ethyl 1-methyl-1-(phenylazophenyl)carbamate, ethyl 1-methyl-1-phenylethyl carbamate, ethyl 1-methyl-1-(4-pyridyl)carbamate, phenyl carbamate, benzyl p-(phenylazo)carbamate, phenyl 2,4,6-tributylcarbamate, benzyl 4-(trimethylammonium)carbamate, benzyl 2,4,6-trimethylcarbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, pyridinecarboxamide, 3-pyridylcarboxamide, N-benzoyl phenylalanine derivative, benzamide, p-phenylbenzamide, o-nitroacetophenone, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzoxycarbonylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiopyrrolidone (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazacyclopentane 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 salt, N-benzylamine, N-bis(4-methoxyphenyl)methylamine, N-5-dibenzofuranyl amine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethylamine, N-ferrocenylmethylamino (Fcm), N-2-eicosylamine N'-oxide, N-1,1-dimethylthioethyleneimine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethylamine, N-[(2-pyridyl)methyl]methyleneimine, N-(N',N'-dimethylmethylene)amine, N,N'-isopropyldiamine, N-p-nitrobenzylamine, N-salicylideneimine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneimine, N-cyclohexylmethyleneimine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboric acid derivatives, N-[phenyl(pentacarbonylchromium or tungsten)carbonyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphonamide (Dpp), dimethylthiophosphonamide (Mpt), diphenylthiophosphonamide (Ppt), dialkylphosphonamides, dibenzylphosphonamides, diphenylphosphonamides, benzenesulfonamides, o-nitrobenzenesulfonamide (Nps), 2,4-dinitrobenzenesulfonamide, pentachlorobenzenesulfonamide, 2-nitro-4-methoxybenzenesulfonamide, tritylsulfonamide, 3-nitropyridinesulfonamide (Npys), p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylbenzopyran-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthalenemethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethanesulfonamide and benzenesulfonamide.,

[0045] Suitably protected carboxylic acids also include, but are not limited to, silyl, alkyl, alkenyl, aryl and aralkyl protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, etc. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, tert-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl or naphthyl. Suitable aralkyl groups include optionally substituted benzyl (e.g. p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-benzyl, 2,6-dichlorobenzyl, p-cyanobenzyl) and 2- and 4-pyridylmethyl.

[0046] Suitable hydroxy protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2-methoxyethoxymethyl (MEM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), p-butoxymethyl, 4-pentenoxymethyl (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-dioxolan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanoinden-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-(phenylseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridyl, 4-pyridyl, N-oxido-3-methyl-2-pyridyl, diphenylmethyl, p,p'-dinitrophenyl, 5-dibenzosuberoyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, 4,4',4”-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4”-tris(levulinoyloxyphenyl)methyl, 4,4',4”-tris(benzoyloxyphenyl)methyl, 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-benzodithiol-2-yl, benzisothiazolyl S,S-dioxo, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, triphenoxysilyl, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid dithioacetal), pivalate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl alkyl carbonate, 2,2,2-trichloroethyl alkyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(benzenesulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonyl)ethyl carbonate (Peoc), isobutyl alkyl carbonate, allyl carbonate, p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 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, diphenylacetyl chloride ester, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-methoxycarbonylbenzoate, α-naphthoate, nitrate, N,N,N',N'-tetramethylphosphorodiamidate alkyl ester, N-phenylcarbamate alkyl ester, borate, dimethylthiophosphate, 2,4-dinitrobenzenesulfonate alkyl ester, sulfate, methanesulfonate (mesylate), benzylsulfonate and p-toluenesulfonate (Ts). Protecting groups for 1,2- or 1,3-diols include methylene acetal, ethylene acetal, 1-tert-butylethylene ketal, 1-phenylethylene ketal, (4-methoxyphenyl)ethylene acetal, 2,2,2-trichloroethylene acetal, acetone, cyclopentyl ketal, cyclohexyl ketal, cycloheptyl 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-ethoxyethylidene orthoester, 1,2-dimethoxyethylidene orthoester, α-methoxybenzylidene orthoester, 1-(N,N-dimethylamino)ethylidene derivative, α-(N,N'-dimethylamino)benzylidene derivative, 2-oxocyclopentylidene orthoester, di-tert-butylsilyl (DTBS), 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-tert-butoxydisiloxane-1,3-diyl derivative (TBDS), cyclic carbonate, cyclic borate, ethyl borate and phenyl borate.,

[0047] In some embodiments, the hydroxyl protecting group is acetyl, tert-butyl, tert-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, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenylmethyl carbonate, mesylate, tosylate, trifluoromethanesulfonate, 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-nitrobenzenesulfonyl)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)trimethylphenyl, diphenylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenyloxanthren-9-yl (pixyl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX). In some embodiments, the hydroxyl protecting groups are each independently selected from acetyl, benzyl, tert-butyldimethylsilyl, tert-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. In some embodiments, the protecting group is attached to the sulfur atom of the thiophosphate group. In some embodiments, the protecting group is attached to the oxygen atom of the internucleotide thiophosphate linkage. In some embodiments, the protecting group is attached to the oxygen atom of the internucleotide phosphate linkage.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-butylformamide)-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.

[0048] Subject: As used herein, the term "subject" or "test subject" refers to any living organism to which a compound or composition according to the present disclosure is administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical test subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms, etc.) and plants. In some embodiments, the subject is a human. In some embodiments, the subject may have and / or be susceptible to a certain disease, disorder, and / or condition.

[0049] Substantially: As used herein, the term "substantially" refers to a property or related attribute that exhibits a complete or nearly complete range or degree in quality. Those of ordinary skill in the biological and / or chemical arts will understand that biological and chemical phenomena rarely (if ever) achieve perfection and / or completeness, or obtain or avoid absolute results. Thus, the term "substantially" is used herein to encompass the potential incompleteness inherent in many biological and / or chemical phenomena.

[0050] Susceptible: An individual who is "susceptible" to a condition, disorder, and / or disease is an individual who has a higher risk of developing the condition, disorder, and / or disease than the general public. In some embodiments, an individual who is susceptible to a condition, disorder, and / or disease has a tendency to develop such condition, disorder, and / or disease. In some embodiments, an individual who is susceptible to a condition, disorder, and / or disease may not have been diagnosed with the condition, disorder, and / or disease. In some embodiments, an individual who is susceptible to a condition, disorder, and / or disease may exhibit symptoms of the condition, disorder, and / or disease. In some embodiments, an individual who is susceptible to a condition, disorder, and / or disease may not exhibit symptoms of the condition, disorder, and / or disease. In some embodiments, a person who is susceptible to a condition, disorder, and / or disease will develop the condition, disorder, and / or disease. In some embodiments, an individual who is susceptible to a condition, disorder, and / or disease will not develop the condition, disorder, and / or disease.

[0051] Therapeutic agent: As used herein, the term "therapeutic agent" generally refers to any preparation that, when administered to a subject, can elicit a desired effect (such as a desired biological, clinical, or pharmacological effect). In some embodiments, a preparation is considered a therapeutic agent if it shows a statistically significant effect in an appropriate population. In some embodiments, the appropriate population refers to a population of subjects suffering from and / or predisposed to a certain condition, disorder, or disease. In some embodiments, the appropriate population is a population of model organisms. In some embodiments, the appropriate population can be defined by one or more criteria, such as age group, gender, genetic background, previous clinical symptoms, previous treatments received, etc. In some embodiments, a therapeutic agent is a substance that, when administered to a subject in an effective amount, can alleviate, improve, relieve, inhibit, prevent, delay the onset, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of the subject's condition, disorder, and / or disease. In some embodiments, a "therapeutic agent" refers to a preparation that has obtained or requires government agency approval before being marketed for human use. In some embodiments, a "therapeutic agent" refers to a preparation that requires a doctor's prescription for administration to humans. In some embodiments, the "therapeutic agent" is the provided compound.

[0052] Therapeutically effective dose: As used herein, the term "therapeutically effective dose" refers to the amount of a substance (such as a therapeutic agent, composition, and / or preparation) that can elicit a desired biological response when administered as part of a treatment regimen. In some embodiments, the therapeutically effective dose of a substance refers to the amount that is sufficient to treat, diagnose, prevent, and / or delay the onset of a condition, disorder, and / or disease when administered to a subject suffering from or predisposed to the condition, disorder, and / or disease. As understood by those of ordinary skill in the art, the effective dose of a substance may vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective dose of a compound in a preparation for treating a condition, disorder, and / or disease refers to the dose that can alleviate, improve, relieve, inhibit, prevent, postpone the onset, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of the condition, disorder, and / or disease. In some embodiments, the therapeutically effective dose is administered as a single dose; in some embodiments, multiple unit doses are required to provide the therapeutically effective dose.

[0053] Treatment: As used herein, the terms "treat", "treatment", or "treating" refer to any method used to partially or completely relieve, improve, relieve, inhibit, prevent, delay the onset, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of a condition, disorder, and / or disease. Treatment can be performed on subjects who do not exhibit the condition, disorder, and / or disease. In some embodiments, treatment can be performed on subjects who exhibit only early symptoms of the condition, disorder, and / or disease, for example, to reduce the risk of lesions associated with the condition, disorder, and / or disease.

[0054] Unsaturated: As used herein, the term "unsaturated" means that a molecule has one or more unsaturated units.

[0055] Those skilled in the art will appreciate that the methods and compositions described herein in connection with the provided compounds generally also apply to pharmaceutically acceptable salts of such compounds. Some embodiments of the compounds

[0056] Among other things, the present disclosure provides compounds that can be used for various purposes. In some embodiments, the provided compounds have the structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0057] In this disclosure, various embodiments are described by way of example for various variables in various formulas (such as Formula I and the formulas in various schemes). Those skilled in the art who read this disclosure can select an embodiment for each variable and combine them; such combinations are within the scope of this disclosure. Those skilled in the art also understand that the embodiments described for one variable (e.g., R) can also be used for other variables that can serve as such a variable (such as R', R 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 , etc.). Ring A

[0058] In some embodiments, Ring A is 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 wherein each variable is independently as described herein. In some embodiments, L ra is optionally substituted -(CH 2 ) n -. In some embodiments, Ring A is wherein each variable is independently as described herein. In some embodiments, Ring A is Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein. In some embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0059] In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A' is an optionally substituted phenyl ring. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein.

[0060] In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein. In some embodiments, ring A is optionally substituted Each variable is independently as described herein.

[0061] Among other things, the present disclosure also provides compounds having stereochemical purity (such as enantiomeric purity) as described herein. In some embodiments, the compounds have stereochemical purity. In some embodiments, the compounds have enantiomeric purity. In some embodiments, one enantiomer of the provided composition is enriched relative to the other enantiomer, or with respect to a chiral center, one configuration is enriched relative to the other configuration. For example, in some embodiments, the percentage of the enantiomer or one configuration with respect to 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, the (S) enantiomer or configuration is enriched. In some embodiments, the (R) enantiomer or configuration is enriched. In some embodiments, the configuration of the stereocenter is shown next to the stereocenter in the chemical structure, such as "R", "S", "(R)", "(S)", etc. When preparing chemical structures using commercial software such as ChemDraw, the configuration is typically determined by such software. In some embodiments, the configuration of the stereocenter is not shown. Those skilled in the art can readily determine the configuration of the stereocenter according to common practices in the art.

[0062] In some embodiments, it was observed that the S configuration of the chiral carbon bonded to R 10 could provide higher expected activity than the R configuration, such as MRGPRX4 inhibition (for the R / S configuration of this carbon center, the following order from priority one to four is used: X, ring B, L ra (e.g., -(CH 2 )n-, and R 10 (e.g., H)). For example, in some embodiments, the MRGPRX4 inhibitory activity of 52A (S enantiomer) is much higher than that of 52B. See Table 1, etc. Ring A'

[0063] In some embodiments, ring A' is an optionally substituted phenyl ring. In some embodiments, ring A' is an optionally substituted 5- to 10-membered aromatic ring having 0 to 4 heteroatoms. In some embodiments, ring A' is an optionally substituted 5- to 6-membered aromatic ring having 1 to 4 heteroatoms. In some embodiments, ring A' is a 6-membered aromatic ring having 1 to 2 heteroatoms. In some embodiments, ring A' is a 6-membered aromatic ring having 1 to 2 heteroatoms independently selected from O, N, and S; in some embodiments, ring A' is a 6-membered aromatic ring having one heteroatom selected from O, N, and S. In some embodiments, ring A' is a 6-membered aromatic ring having one nitrogen atom. In some embodiments, ring A' is a 6-membered aromatic ring having 2 heteroatoms independently selected from O, N, and S; in some embodiments, ring A' is a 6-membered aromatic ring having 2 heteroatoms, each of which is N. In some embodiments, ring A' is a 6-membered aromatic ring having 3 heteroatoms. In some embodiments, ring A' is a 6-membered aromatic ring having 3 heteroatoms independently selected from O, N, and S; in some embodiments, ring A' is a 6-membered aromatic ring having 3 heteroatoms (one of which is N). In some embodiments, ring A' is a 5-membered aromatic ring having 1 to 2 heteroatoms. In some embodiments, ring A' is a 5-membered aromatic ring having 1 to 2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is a 5-membered aromatic ring having one oxygen atom. In some embodiments, ring A' is a 5-membered aromatic ring having one nitrogen atom. In some embodiments, ring A' is a 5-membered aromatic ring having one sulfur atom. In some embodiments, ring A' is a 5-membered aromatic ring having 2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is a 5-membered aromatic ring having 2 heteroatoms (one of which is N). In some embodiments, ring A' is a 5-membered aromatic ring having 2 heteroatoms independently selected from N and S. In some embodiments, ring A' is a 5-membered aromatic ring having 2 heteroatoms independently selected from N and O. In some embodiments, ring A' is a 5-membered aromatic ring having 2 heteroatoms independently selected from O and S; in some embodiments, ring A' is a 5-membered aromatic ring having 3 heteroatoms. In some embodiments, ring A' is a 5-membered aromatic ring having 3 heteroatoms independently selected from O, N, and S. 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 a nitrogen atom. In some embodiments, each heteroatom is nitrogen. In some embodiments, all heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatoms.

[0064] 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, 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 2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 2 heteroatoms, one of which is N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 2 heteroatoms independently selected from O and N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 2 heteroatoms independently selected from O and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 2 heteroatoms independently selected from N and S. Optionally in some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 2 heteroatoms, both of which are N. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having 1 heteroatom selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having one nitrogen atom. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having one oxygen atom. In some embodiments, ring A' is an optionally substituted 9-membered aromatic ring having one 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 a nitrogen atom. In some embodiments, each heteroatom is nitrogen. In some embodiments, all heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatoms.

[0065] 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 4 heteroatoms independently selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having 3 heteroatoms independently selected from O, N, and S. In some embodiments, ring A′ is an optionally substituted 10-membered aromatic ring having 3 heteroatoms, all of which are N. In some embodiments, ring A′ is an optionally substituted 10-membered aromatic ring having 2 heteroatoms independently selected from O, N, and S. In some embodiments, ring A′ is an optionally substituted 10-membered aromatic ring having 2 heteroatoms, one of which is N. Ring A′ is an optionally substituted 10-membered aromatic ring having 2 heteroatoms independently selected from O and N. In some embodiments, ring A′ is an optionally substituted 10-membered aromatic ring having 2 heteroatoms independently selected from O and S. In some embodiments, ring A′ is an optionally substituted 10-membered aromatic ring having 2 heteroatoms independently selected from N and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having 2 heteroatoms, both of which are N. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having 1 heteroatom selected from O, N, and S. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having one nitrogen atom. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having one oxygen atom. In some embodiments, ring A' is an optionally substituted 10-membered aromatic ring having one 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 a nitrogen atom. In some embodiments, each heteroatom is nitrogen. In some embodiments, all heteroatoms are the same. In some embodiments, at least one heteroatom is different from the other heteroatoms.

[0066] In some embodiments, ring A' is an optionally substituted divalent naphthalene ring. In some embodiments, ring A' is optionally substituted In some embodiments, ring A' is X

[0067] 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 optionally substituted -CH 2 -. R 8

[0068] In some embodiments, R 8 is R' as described herein. In some embodiments, R 8 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 cycloaliphatic, 3-10 membered heterocyclic group 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. In some embodiments, R 8 is an optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 8 is an optionally substituted C 1 -C 6 alkyl. In some embodiments, R 8 is an optionally substituted C 1 -C 4 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 is isopropyl In some embodiments, R 8 is butyl. In some embodiments, R 8 is isobutyl

[0069] In some embodiments, R 8 is an optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 8 is an optionally substituted In some embodiments, R 8 is an optionally substituted In some embodiments, R 8 is an optionally substituted In some embodiments, R 8 is an optionally substituted In some embodiments, R 8 is In some embodiments, R 8 is In some embodiments, R 8 is

[0070] 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.

[0071] In some embodiments, R 8 is an optionally substituted 6-10 membered aryl-C 1 -C 6 aliphatic. In some embodiments, R 8 is an optionally substituted 6-10 membered aryl-C 1 -C 6 alkyl. In some embodiments, R 8 is an optionally substituted phenyl-C 1 -C 6 alkyl. In some embodiments, R 8 is optionally substituted In some embodiments, R 8 is Z

[0072] 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. R 9

[0073] In some embodiments, R 9 is H. In some embodiments, R 9 is not H. In some embodiments, R 9 is -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 described herein.

[0074] In some embodiments, R 9 is halogen. In some embodiments, R 9 is F. In some embodiments, R9 is Cl. In some embodiments, R 9 is Br. In some embodiments, R 9 is I.

[0075] In some embodiments, R 9 is -CN.

[0076] In some embodiments, R 9 is -NO 2 .

[0077] 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 R as described herein. In some embodiments, R 9 is -NHR', where R' is as described herein.

[0078] In some embodiments, R 9 is R' as described herein. In some embodiments, R 9 is R as described herein.

[0079] In some embodiments, R 9 is an optionally substituted group selected from C 1 -C 6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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-C 1 -C 6 aliphatic. In some embodiments, R 9 is C 1 -C 6 aliphatic. In some embodiments, R 9 is an optionally substituted C 1 -C 6 alkyl. In some embodiments, R 9 is an optionally substituted C 1 -C 4 alkyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is ethyl. In some embodiments, R 9 is propyl. In some embodiments, R 9 is isopropyl In some embodiments, R 9 is butyl. In some embodiments, R 9 is isobutyl R 10

[0080] 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.

[0081] In some embodiments, R 10 is not H. In some embodiments, R 10 is an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1 - 3 heteroatoms, 3 - 10 membered cycloaliphatic, 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 1 -C 6 aliphatic and 5 - 10 membered heteroaryl-C 1 -C 6 aliphatic. n

[0082] In some embodiments, n is 1, 2, or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. R 4

[0083] In some embodiments, R 4 is H. In some embodiments, R 4 is not H. In some embodiments, R 4 is -R', -OR', halogen, -CN, -NO 2 or -N(R') 2 wherein R' is as described herein. In some embodiments, R 4 is -OR' wherein R' is as described herein.

[0084] 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, R4 It is I.

[0085] In some embodiments, R 4 is -CN.

[0086] In some embodiments, R 4 is -NO 2 .

[0087] In some embodiments, R 4 is -N(R') 2 . Each R' is independently as described herein. In some embodiments, R 4 is -N(R') 2 , where each R' is independently R as described herein. In some embodiments, R 4 is -NHR', where R' is as described herein.

[0088] In some embodiments, R 4 is R' as described herein. In some embodiments, R 4 is R as described herein.

[0089] In some embodiments, R 4 is an optionally substituted group selected from C 1 -C 6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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-C 1 -C 6 aliphatic. In some embodiments, R 4 is C 1 -C 6 aliphatic. In some embodiments, R 4 is an optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 is an optionally substituted C 1 -C 4 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 4is isobutyl. In some embodiments, R 4 is C 1-4 haloalkyl. In some embodiments, R 4 is -CF 3 . R 5

[0090] In some embodiments, R 5 is H. In some embodiments, R 5 is not H. In some embodiments, R 5 is -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 described herein.

[0091] 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.

[0092] In some embodiments, R 5 is -CN.

[0093] In some embodiments, R 5 is -NO 2 .

[0094] 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 R as described herein. In some embodiments, R 5 is -NHR', where R' is as described herein.

[0095] In some embodiments, R 5 is R' as described herein. In some embodiments, R 5 is R as described herein.

[0096] In some embodiments, R 5 is an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C with 1-3 heteroatoms,6 heteroaliphatic, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocycloaliphatic having 1 to 4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, 6- to 10-membered aryl-C 1 -C 6 aliphatic and 5- to 10-membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, R 5 is C 1 -C 6 aliphatic. In some embodiments, R 5 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 5 is optionally substituted C 1 -C 4 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 haloalkyl. In some embodiments, R 5 is -CF 3 .

[0097] In some embodiments, R 4 and R 5 together with the atoms therebetween form a ring as described herein. In some embodiments, R 4 and R 5 together with the atoms therebetween form an optionally substituted phenyl ring. In some embodiments, R 4 and R 5 together with the atoms therebetween form an optionally substituted 5- or 6-membered heteroaryl ring having 1 to 4 (such as 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. R 6

[0098] In some embodiments, R 6 is H. In some embodiments, R 6 is not H. In some embodiments, R 6 is -R', -OR', halogen, -CN, -NO 2or -N(R') 2 , where R' is as described herein. In some embodiments, R 6 is -OR', where R' is as described herein.

[0099] 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 6 is I.

[0100] In some embodiments, R 6 is -CN.

[0101] In some embodiments, R 6 is -NO 2 .

[0102] 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 R as described herein. In some embodiments, R 6 is -NHR', where R' is as described herein.

[0103] In some embodiments, R 6 is R' as described herein. In some embodiments, R 6 is R as described herein.

[0104] In some embodiments, R 6 is an optionally substituted group selected from C1-C6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocycloaliphatic 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-C 1 -C 6 aliphatic. In some embodiments, R 6 is C 1 -C 6 aliphatic. In some embodiments, R 6 is an optionally substituted C 1 -C 6 alkyl. In some embodiments, R6 is an optionally substituted C 1 -C 4 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 haloalkyl. In some embodiments, R 6 is -CF 3 .

[0105] 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 aliphatic. In some embodiments, R is C 1-6 alkyl. In some embodiments, R is methyl. In some embodiments, R is -CF 3 .

[0106] In some embodiments, R 6 is -C(O)OR, where R is as described herein. In some embodiments, R 6 is -C(O)OH.

[0107] In some embodiments, R 6 is -S(O) 2 R, where R is as described herein. In some embodiments, R is C 1-6 aliphatic. In some embodiments, R is C 1-6 alkyl. In some embodiments, R 6 is -S(O) 2 Me. R 7

[0108] In some embodiments, R 7 is H. In some embodiments, R 7 is not H. In some embodiments, R 7 is -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 described herein.

[0109] 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. In some embodiments, R 7 is I.

[0110] In some embodiments, R 7 is -CN.

[0111] In some embodiments, R 7 is -NO 2 .

[0112] In some embodiments, R 7 is -N(R') 2 . Wherein each R' is independently as described herein. In some embodiments, R 7 is -N(R') 2 , wherein each R' is independently R as described herein. In some embodiments, R 7 is -NHR', where R' is as described herein.

[0113] In some embodiments, R 7 is R' as described herein. In some embodiments, R 7 is R as described herein.

[0114] In some embodiments, R 7 is an optionally substituted group selected from C1-C6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocycloaliphatic 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-C 1 -C 6 aliphatic. In some embodiments, R 7 is C 1 -C 6 aliphatic. In some embodiments, R 7 is an optionally substituted C 1 -C 6 alkyl. In some embodiments, R 7 is an optionally substituted C 1 -C 4 alkyl. In some embodiments, R 7 is methyl. In some embodiments, R7 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 haloalkyl. In some embodiments, R 7 is -CF 3 .

[0115] In some embodiments, each of R 4 , R 5 , R 6 and R 7 is independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where R' is as described herein.

[0116] In some embodiments, each of R 4 , R 5 , R 6 and R 7 is H.

[0117] In some embodiments, each of R 4 , R 5 , R 6 and R 7 is not independently H.

[0118] In some embodiments, one of R 4 , R 5 , R 6 and R 7 is not H, and the remaining three of R 4 , R 5 , R 6 and R 7 are all H. In some embodiments, two of R 4 , R 5 , R 6 and R 7 are not H, and the remaining two of R 4 , R 5 , R 6 and R 7 are both H.

[0119] In some embodiments, each of R 4 , R 5 and R 7 is H, and R6 is selected from R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , wherein R' is as described herein. In some embodiments, R 4 , R 5 and R 7 are each H, and R 6 is selected from halogen, -CN, optionally substituted C 1 -C 6 alkyl, -OR, wherein R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10-membered aryl, -C(O)OR, wherein R is H or optionally substituted C 1 -C 6 alkyl, or -S(O) 2 R, wherein R is H or optionally substituted C 1 -C 6 alkyl.

[0120] In some embodiments, R 4 , R 5 and R 7 are each H, and R 6 is halogen. In some embodiments, R 4 , R 5 and R 7 are each H, and R 6 is F. In some embodiments, R 4 , R 5 and R 7 are each H, and R 6 is Cl. In some embodiments, R 4 , R 5 and R 7 are each H, and R 6 is Br. In some embodiments, R 4 , R 5 and R 7 are each H, and R 6 is I.

[0121] In some embodiments, R 4 , R 5 and R 7 are each H, and R 6 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 , R 5 and R 7Each of them is H, and R 6 is -CF 3 .

[0122] In some embodiments, R 4 , R 5 and R 7 each is H, and R 6 is -OR, where R is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 , R 5 and R 7 each is H, while R 6 is -OMe. In some embodiments, R 4 , R 5 and R 7 each is H, while R 6 is -OCF 3 .

[0123] In some embodiments, R 4 , R 5 and R 7 each is H, while R 6 is an optionally substituted 6- to 10-membered aryl. In some embodiments, R 4 , R 5 and R 7 each is H, while R 6 is an optionally substituted phenyl. In some embodiments, R 4 , R 5 and R 7 each is H, while R 6 is phenyl.

[0124] In some embodiments, R 4 , R 5 and R 7 each is H, and R 6 is -C(O)OR, where R is H or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 , R 5 and R 7 each is H, while R 6 is -C(O)OH.

[0125] In some embodiments, R 4 , R 5 and R 7 each is H, while R 6is -S(O) 2 R, where R is H or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 、R 5 and R 7 each is H, and R 6 is -SO 2 Me.

[0126] In some embodiments, ring A is where R 6 、R 8 and R 9 are each independently as described herein.

[0127] In some embodiments, ring A is where X and R 6 each is independently as described herein. In some embodiments, ring A is where R 6 is as described herein.

[0128] In some embodiments, ring A is where R 6 and R 8 each is independently as described herein. In some embodiments, ring A is where R 6 is as described herein. In some embodiments, ring A is where R 6 is as described herein.

[0129] In some embodiments, R 4 、R 6 and R 7 each is H, R 5 is selected from R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where R' is as described herein. In some embodiments, R 4 、R 6 and R 7 each is H, R 5 is selected from halogen, -CN, optionally substituted C 1 -C 6 alkyl, -OR, where R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, -C(O)OR, where R is H or optionally substituted C 1 -C 6 alkyl, or -S(O)2 R, where R is H or optionally substituted C 1 -C 6 alkyl.

[0130] In some embodiments, each of R 4 , R 6 and R 7 is H, and R 5 is optionally substituted C 1 -C 6 alkyl. In some embodiments, each of R 4 , R 6 and R 7 is H, and R 5 is -CF3.

[0131] In some embodiments, each of R 4 , R 6 and R 7 is H, and R 5 is a halogen. In some embodiments, each of R 4 , R 6 and R 7 is H, and R 5 is F. In some embodiments, each of R 4 , R 6 and R 7 is H, and R 5 is Cl.

[0132] In some embodiments, ring A is wherein X and R 5 are each independently as described herein. In some embodiments, ring A is wherein R 5 is as described herein.

[0133] In some embodiments, ring A is wherein each of X and R 5 is independently as described herein. In some embodiments, ring A is wherein R 5 is as described herein.

[0134] In some embodiments, ring A is wherein each of X and R 5 is independently as described herein. In some embodiments, ring A is wherein R 5 is as described herein.

[0135] In some embodiments, R 4 and R 7Each of them is H, R 5 and R 6 Each independently selected from R', -OR', halogen, -CN, -NO 2 and -N(R') 2 , where R' is as described herein. In some embodiments, R 4 and R 7 Each of them is H, R 5 and R 6 Each independently selected from halogen, -CN, optionally substituted C 1 -C 6 alkyl, -OR, where R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10-membered aryl, -C(O)OR, where R is H or optionally substituted C 1 -C 6 alkyl, and -S(O) 2 R, where R is H or optionally substituted C 1 -C 6 alkyl.

[0136] In some embodiments, R 4 and R 7 Each is H, R 5 is optionally substituted C 1 -C 6 alkyl, R 6 is halogen. In some embodiments, R 4 and R 7 Each is H, R 5 is -CF 3 , R 6 is halogen. In some embodiments, R 4 and R 7 Each is H, R 5 is -CF 3 , R 6 is F. In some embodiments, R 4 and R 7 Each is H, R 5 is -CF 3 , R 6 is Cl.

[0137] In some embodiments, ring A is where X, R 5 and R 6 are each independently as described herein.

[0138] In some embodiments, R 6 and R7 Each of them is H, R 4 and R 5 Each independently selected from R', -OR', halogen, -CN, -NO 2 and -N(R') 2 , where R' is as described herein. In some embodiments, R 6 and R 7 Each of them is H, R 4 and R 5 Each independently selected from halogen, -CN, optionally substituted C 1 -C 6 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, and -S(O)2R, where R is H or optionally substituted C1-C6 alkyl.

[0139] In some embodiments, R 6 and R 7 Each is H, R 4 is optionally substituted C 1 -C 6 alkyl, R 5 is halogen. In some embodiments, R 4 and R 7 Each is H, R 4 is -CF 3 , R 5 is halogen. In some embodiments, R 6 and R 7 Each is H, R 4 is -CF 3 , R 5 is F. In some embodiments, R 6 and R 7 Both are H, and R 4 is -CF 3 , R 5 is Cl.

[0140] In some embodiments, ring A is where X, R 4 and R 5 are each independently as described herein. In some embodiments, ring A is where R 4 and R 5 Each independently as described herein.

[0141] In some embodiments, R 4 and R 6Each of them is H, R 5 and R 7 Each independently selected from R', -OR', halogen, -CN, -NO 2 and -N(R') 2 , where R' is as described herein. In some embodiments, R 4 and R 6 Each of them is H, while R 5 and R 7 Each independently selected from halogen, -CN, optionally substituted C 1 -C 6 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, and -S(O)2R, where R is H or optionally substituted C1-C6 alkyl.

[0142] In some embodiments, R 4 and R 6 Each is H, R 5 is optionally substituted C 1 -C 6 alkyl, R 7 is halogen. In some embodiments, R 4 and R 6 Each is H, R 5 is -CF 3 , R 7 is halogen. In some embodiments, R 4 and R 6 Each is H, R 5 is -CF 3 , R 7 is F. In some embodiments, R 4 and R 6 Both are H, while R 5 is -CF 3 , R 7 is Cl.

[0143] In some embodiments, ring A is where X, R 5 and R 7 are each independently as described herein. In some embodiments, ring A is where R 5 and R 7 Each independently as described herein.

[0144] In some embodiments, ring A is where each variable is independently as described herein. In some embodiments, ring A is wherein each variable is independently as described herein. In some embodiments, Ring A is wherein each variable is independently as described herein. In some embodiments, Ring A is wherein each variable is independently as described herein. In some embodiments, Ring A is wherein each variable is independently as described herein. In some embodiments, Ring A is Each variable is independently as described herein.

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

[0146] In some embodiments, Ring A is wherein each variable is independently as described herein. In some embodiments, Ring A is wherein each variable is independently as described herein.

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

[0148] In some embodiments, Ring A is wherein each variable is independently as described herein.

[0149] In certain embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

[0150] In certain embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

[0151] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from And optional replacement. Ring B

[0152] In some embodiments, Ring B is an optionally substituted (as will be appreciated by those skilled in the art, in addition to R 1 , R 2 and R 3 The (except) ring is selected from a 6-10 membered aryl ring and a 5-10 membered heteroaryl ring having 1-6 heteroatoms.

[0153] In some embodiments, ring B is an optionally substituted 6- to 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 located at the ortho position (unless otherwise specified, ortho, meta, and para are independent with respect to the carbon bonded to ring A). In some embodiments, R 1 is located at the meta position. In some embodiments, R 1 is located at the para position. In some embodiments, R 2 is located at the ortho position. In some embodiments, R 2 is located at the meta position. In some embodiments, R 2 is located at the para position. In some embodiments, R 3 is located at the ortho position. In some embodiments, R 3 is located at the meta position. In some embodiments, R 3 is located at the para position. In some embodiments, R1 and R2 are adjacent to each other. In some embodiments, R 1 and R 2 are not adjacent to each other. 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 1 and R 3 are not adjacent to each other.

[0154] In some embodiments, ring B is an optionally substituted naphthyl.

[0155] In some embodiments, ring B is an optionally substituted 5- to 10-membered heteroaryl having 1 to 6 heteroatoms. In some embodiments, ring B is an optionally substituted 5- to 6-membered heteroaryl having 1 to 4 heteroatoms. In some embodiments, ring B is an optionally substituted 9-membered bicyclic heteroaryl ring having 1 to 6 heteroatoms. In some embodiments, ring B is an optionally substituted 10-membered bicyclic heteroaryl ring having 1 to 6 heteroatoms. In some embodiments, there is one heteroatom. In some embodiments, there are two heteroatoms. In some exemplary 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.

[0156] In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is In some embodiments, ring B is R 1

[0157] In some embodiments, R 1 is -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 , halogen, or wherein each variable is independently as described herein.

[0158] In some embodiments, R 1 is -C(O)OR 11 , where R 11 is as described herein. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where R 12 and R 13 are each independently as described herein. In some embodiments, R 1 is -C(O)N(R 14 )SO 2 R 15 , where R' and R 15 are both independently as described herein. In some embodiments, R 1 is -C(O)NR 16 R17 , wherein R 16 and R 17 are each independently as described herein. In some embodiments, R 1 is

[0159] In some embodiments, R 1 is -C(O)OR 11 . In some embodiments, R 11 is the R as described herein. In some embodiments, R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocycloaliphatic 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-C 1 -C 6 aliphatic. In some embodiments, R 11 is C 1-6 aliphatic. In some embodiments, R 11 is C 1-6 alkyl. In some embodiments, R 11 is methyl. In some embodiments, R 11 is ethyl.

[0160] In some embodiments, R 1 is -C(O)OH. In some embodiments, R 1 is -C(O)OR 11 , wherein R 11 is an optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is -C(O)OR 11 , wherein R 11 is an optionally substituted 3-10 membered cycloalkyl.

[0161] In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), wherein each R 12 and R 13 is independently as described herein.

[0162] In some embodiments, R 12 is the R' as described herein. In some embodiments, R 12is R as described herein. In some embodiments, R 12 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C with 1-3 heteroatoms 1 -C 6 heteroaliphatic, 3-10 membered cycloaliphatic, 3-10 membered heterocycloaliphatic with 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl with 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic and 5-10 membered heteroaryl-C with 1-6 heteroatoms 1 -C 6 aliphatic. In some embodiments, R 12 is H. In some embodiments, R 12 is an optionally substituted C 1-6 aliphatic. In some embodiments, R 12 is C 1-6 alkyl. In some embodiments, R 12 is methyl. In some embodiments, R 12 is ethyl.

[0163] 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 C 1 -C 6 aliphatic, C with 1-3 heteroatoms 1 -C 6 heteroaliphatic, 3-10 membered cycloaliphatic, 3-10 membered heterocycloaliphatic with 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl with 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic and 5-10 membered heteroaryl-C with 1-6 heteroatoms 1 -C 6 aliphatic. In some embodiments, R 13 is H. In some embodiments, R 13 is an optionally substituted C 1-6 aliphatic. In some embodiments, R 13 is C 1-6 alkyl. In some embodiments, R 13 is methyl. In some embodiments, R 13 is ethyl.

[0164] In some embodiments, R12 and R 13 each independently is R' as described herein. In some embodiments, R 12 and R 13 each independently is R as described herein.

[0165] In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where each R 12 and R 13 is independently H or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where each R 12 and R 13 is independently H. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where R 12 is H, and R 13 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where R 12 is H, and R 13 is ethyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where R 12 and R 13 are each independently C 1 -C 6 alkyl. In some embodiments, R 1 is -P(O)(OR 12 )(OR 13 ), where each R 12 and R 13 are both ethyl.

[0166] In some embodiments, R 1 is -C(O)N(R 14 )SO 2 R 15 , where R 14 and R 15 each independently is as described herein. In some embodiments, R1 is -C(O)NHSO 2 R 15 , wherein R 15 is as described herein.

[0167] In some embodiments, R 1 is -CN.

[0168] In some embodiments, R 14 is R' as described herein. In some embodiments, R 14 is R as described herein. In some embodiments, R 14 is H or an optionally substituted group selected from C 1 -C 6 -aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocycloaliphatic 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-C 1 -C 6 -aliphatic. In some embodiments, R 14 is H. In some embodiments, R 14 is an optionally substituted C 1-6 -aliphatic. In some embodiments, R 14 is C 1-6 -alkyl. In some embodiments, R 14 is methyl. In some embodiments, R 14 is ethyl.

[0169] 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 C 1 -C 6 -aliphatic, C 1 -C 6 -heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocycloaliphatic having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 -aliphatic and 5-10 membered heteroaryl-C 1 -C 6 -aliphatic. In some embodiments, R 15 is H. In some embodiments, R 15 is an optionally substituted C1-6 Aliphatic. In some embodiments, R 15 is C 1-6 alkyl. In some embodiments, R 15 is methyl. In some embodiments, R 15 is ethyl.

[0170] In some embodiments, each of R 14 and R 15 is independently R' as described herein. In some embodiments, each of R 14 and R 15 is independently R as described herein.

[0171] In some embodiments, R 1 is -C(O)NR 16 R 17 , where R 16 and R 17 are each independently as described herein.

[0172] 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 C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1 - 3 heteroatoms, 3 - 10 - membered cycloaliphatic, 3 - 10 - membered heterocycloaliphatic having 1 - 4 heteroatoms, 6 - 10 - membered aryl, 5 - 10 - membered heteroaryl having 1 - 6 heteroatoms, 6 - 10 - membered aryl - C 1 -C 6 aliphatic and 5 - 10 - membered heteroaryl - C 1 -C 6 aliphatic having 1 - 6 heteroatoms. In some embodiments, R 16 is H. In some embodiments, R 16 is an optionally substituted C 1-6 aliphatic. In some embodiments, R 16 is C 1-6 alkyl. In some embodiments, R 16 is methyl. In some embodiments, R 16 is ethyl.

[0173] In some embodiments, R 17 is R' as described herein. In some embodiments, R 17 is R as described herein. In some embodiments, R 17is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C with 1 - 3 heteroatoms 1 -C 6 heteroaliphatic, 3 - 10 - membered cycloaliphatic, 3 - 10 - membered heterocyclic with 1 - 4 heteroatoms, 6 - 10 - membered aryl, 5 - 10 - membered heteroaryl with 1 - 6 heteroatoms, 6 - 10 - membered aryl - C 1 -C 6 aliphatic and 5 - 10 - membered heteroaryl - C with 1 - 6 heteroatoms 1 -C 6 aliphatic. In some embodiments, R 17 is H. In some embodiments, R 17 is optionally substituted C 1-6 aliphatic. In some embodiments, R 17 is C 1-6 alkyl. In some embodiments, R 17 is methyl. In some embodiments, R 17 is ethyl.

[0174] In some embodiments, each of R 16 and R 17 is independently R' as described herein. In some embodiments, each of R 16 and R 17 is independently R as described herein.

[0175] In some embodiments, R 1 is -C(O)NR 16 R 17 where each R 16 and R 17 is independently H or an optionally substituted group selected from C 1 -C 6 aliphatic, C with 1 - 3 heteroatoms 1 -C 6 heteroaliphatic, 3 - 10 - membered cycloaliphatic, 3 - 10 - membered heterocyclic with 1 - 4 heteroatoms, 6 - 10 - membered aryl, 3 - 10 - membered heterocyclic with 1 - 6 heteroatoms, 5 - 10 - membered heteroaryl with 1 - 6 heteroatoms, 6 - 10 - membered aryl - C 1 -C 6 aliphatic, and 5 - 10 - membered heteroaryl - C with 1 - 6 heteroatoms 1 -C 6 aliphatic.

[0176] In some embodiments, R 1 is -C(O)NR 16 R17 , wherein R 16 and R 17 each independently is H or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is -C(O)NR 16 R 17 , wherein R 16 and R 17 are each independently H. In some embodiments, R 1 is -C(O)NR 16 R 17 , wherein R 16 is H, R 17 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is -C(O)NR 16 R 17 , wherein R 16 is H, R 17 is methyl. In some embodiments, R 1 is -C(O)NR 16 R 17 , wherein R 16 and R 17 each independently are C 1 -C 6 alkyl. In some embodiments, R 1 is -C(O)NR 16 R 17 , wherein R 16 and R 17 each are methyl.

[0177] In some embodiments, R 1 is an isostere of -C(O)OH. In some embodiments, the compound is a carboxylic acid isostere of a carboxylic acid compound, e.g., wherein R 1 is -C(O)OH. In some embodiments, the carboxylic acid isostere is a carboxylic acid isostere described in WO 2020 / 198537, US2021 / 0032213, WO 2021 / 211839 or WO 2022 / 061008, each of which is incorporated herein by reference independently.

[0178] In some embodiments, Ballatore et al. described a carboxylic acid isostere in ChemMedChem. March 2013; 8(3): 385-395, the carboxyl isostere of which is incorporated herein by reference.

[0179] In some embodiments, the carboxylic acid bioisostere is a hydroxamic acid. In some embodiments, R 1 is -C(O)N(R 14 )OH, where 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 , where R 11 is as described herein. In some embodiments, the carboxylic acid bioisostere is phosphonic acid. In some embodiments, R 1 is -P(O)H(OR 12 ), where R 12 is as described herein. In some embodiments, the carboxylic acid bioisostere is 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 sulfonic acid. In some embodiments, R 1 is -S(O) 2 OR 11 , where R 11 is as described herein. In some embodiments, the carboxylic acid bioisostere is a sulfonamide. In some embodiments, R 1 is -S(O) 2 NR 16 R 17 , where R 16 and R 17 are each independently as described herein. In some embodiments, the carboxylic acid bioisostere is acylsulfonamide. In some embodiments, R 1 is -S(O) 2 N(R 14 )C(O)R 15 , where R 14 and R 15 are each independently as described herein. In some embodiments, the carboxylic acid bioisostere is sulfonylurea. In some embodiments, R 1 is -S(O) 2 N(R 14 )C(O)NR 16 R 17 , where R 14 、R 16 and R 17 are each independently as described herein. In some embodiments, R 1 is -N(R 16 )C(O)(R14 )S(O) 2 R 15 , wherein R 14 , R 15 and R 16 each independently is as described herein. In some embodiments, R 1 is -S(O) 2 NR 16 R 17 , wherein R 16 and R 17 each independently is as described herein. In some embodiments, R 1 is -N(R 14 )S(O) 2 R 15 , wherein R 14 and R 15 each independently is as described herein. In some embodiments, as described herein, R 14 is -H. In some embodiments, R 16 is -H. In some embodiments, the carboxylic acid bioisostere is tetrazole. In some embodiments, R 1 is In some embodiments, the carboxylic acid bioisostere is thiazolidinedione. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is oxazolidinedione. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is 5'-oxo-1,2,4-oxadiazole. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is 5'-oxo-1,2,4-thiadiazole. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is 5'-thiono-1,2,4-oxadiazole. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is isothiazole. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is isoxazole. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is phenol, wherein the phenyl ring is optionally substituted. In some embodiments, the carboxylic acid bioisostere is phenol. In some embodiments, R 1 is a substituted phenyl, wherein one substituent is -OH. In some embodiments, R 1 is 4-hydroxyphenyl. In some embodiments, R 1 is 3-methyl-4-hydroxyphenyl. In some embodiments, the carboxylic acid bioisostere is a polyfluorophenol, such as difluorophenol. In some embodiments, R 1 is a phenyl substituted with one or more fluorines and -OH. In some embodiments, R 1 is a phenyl substituted with two or more fluorines and -OH. In some embodiments, R 1 is 3,5-difluoro-4-hydroxyphenyl. In some embodiments, the carboxylic acid bioisostere is carbamic acid. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is a tetracarboxylic acid. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is cyclopentane-1,3-dione. In some embodiments, R 1 is optionally substituted In some embodiments, the carboxylic acid bioisostere is squaric acid. In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, the carboxylic acid bioisostere is 3-hydroxypyridin-4(1H)-one. In some embodiments, R 1 is optionally substituted In some embodiments, R 1 is In some embodiments, the carboxylic acid bioisostere is 6-hydroxy-1,3-dioxin-4-one. In some embodiments, R 1 is optionally substituted In some embodiments, R 1 is optionally substituted In some embodiments, R 1 is optionally substituted In some embodiments, R 1 is optionally substituted In some embodiments, R 1 is optionally substituted In some embodiments, R1 is optionally substituted In some embodiments, R 1 is optionally substituted In some embodiments, R 1 is wherein each of X and W is independently -O-, -S-, -N(R 8 ), or optionally substituted -CH 2 -, Y is -N= or -C(R 9 ), wherein R 8 and R 9 are each independently as described herein, and -NH- is optionally substituted. In some embodiments, R 1 is wherein each of X and W is independently -O-, -S-, -N(R 8 ), or optionally substituted -CH 2 -, Y is -N= or -C(R 9 ), wherein R 8 and R 9 are each independently as described herein, and -NH- is optionally substituted. In some embodiments, R 1 is wherein each of X and W is independently -O-, -S-, -N(R 8 ), or optionally substituted -CH 2 -, Y is -N= or -C(R 9 ), wherein R 8 and R 9 are each independently as described herein, and -NH- is optionally substituted. In some embodiments, R 1 is wherein each of X', Y and W' is independently -N= or -C(R 9 ), wherein R 9 is as described herein, and -NH- is optionally substituted. In some embodiments, R 1 is wherein each of X', Y and W' is independently -N= or -C(R 9 ), wherein R 9 is as described herein, and -NH- is optionally substituted. In some embodiments, R 1 is wherein each of X', Y and W' is independently -N= or -C(R 9 ), wherein R 9As described herein, -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 8 is as described herein. In some embodiments, X is optionally substituted -CH 2 -. 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 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 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 optionally substituted -CH=. In some embodiments, W' is -CH=. In some embodiments, the carboxylic acid bioisostere is hydroxyquinolinone. In some embodiments, the carboxylic acid bioisostere is 3-hydroxyquinolin-2-one. In some embodiments, the carboxylic acid bioisostere is 4-hydroxyquinolin-2-one. In some embodiments, the R 1 group described herein is substituted. In some embodiments, it is unsubstituted.

[0180] In some embodiments, R 1 is -CHO. In some embodiments, R 1 is protected -CHO.

[0181] In some embodiments, R 1 is R d6 . In some embodiments, R d6 is -CH(OR) 2 . In some embodiments, each R is independently not -H. In some embodiments, each R is independently optionally substituted C 1-6 aliphatic. In some embodiments, two Rs together with their intervening atom form an optionally substituted 4- to 10-membered ring, such as a 5- to 10-, 5- to 6-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered ring, having 0 to 3 heteroatoms in addition to the intervening atom. In some embodiments, there are no heteroatoms in addition to the intervening atom. 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 a saturated ring. In some embodiments, the ring is monocyclic. In some embodiments, R d6 is optionally substituted In some embodiments, R d6 is

[0182] 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.

[0183] In some embodiments, R 1 is R 2

[0184] In some embodiments, R 2 is R' as described herein. In some embodiments, R 2 is R as described herein. In some embodiments, R 2 is H. In some embodiments, R 2 is not H. In some embodiments, R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R 2 is C 1-6 aliphatic. In some embodiments, R 2 is optionally substituted C 1-6 alkyl. In some embodiments, R 2 is C 1-6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is optionally substituted C 3 -6 cycloaliphatic. In some embodiments, R 2 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 2is 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 an optionally substituted cyclopentyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is an optionally substituted cyclohexyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is an 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 heteroatoms, such as 1, 2, 3, or 4 heteroatoms, such as independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is

[0185] In some embodiments, R 2 is R', where 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 aliphatic.

[0186] In some embodiments, R 2 is -OR', where R' is as described herein. In some embodiments, R' is R as described herein. In some embodiments, R' is H. In some embodiments, R' is an optionally substituted C 1-6 aliphatic. In some embodiments, R' is an optionally substituted C 1-6 aliphatic. In some embodiments, R' is methyl.

[0187] 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.

[0188] In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NO 2 . 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 an R as described herein. In some embodiments, R 2 is -NH 2 . R 3

[0189] In some embodiments, R 3 is an R' as described herein. In some embodiments, R 3 is an 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 aliphatic. In some embodiments, R 3 is C 1-6 aliphatic. In some embodiments, R 3 is an optionally substituted C 1-6 alkyl. In some embodiments, R 3 is C 1-6 alkyl. 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 3-6 cycloalkyl. In 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 an optionally substituted cyclopentyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is an optionally substituted cyclohexyl. In some embodiments, R 3 is cyclohexyl. In some embodiments, R 3 is an optionally substituted phenyl. In some embodiments, R 3 is phenyl. In some embodiments, R 3 is an optionally substituted 5- to 6-membered heteroaryl having 1 to 4 heteroatoms, such as 1, 2, 3, or 4 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 is

[0190] In some embodiments, R 3 is R', where 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 optionally substituted C 1 -6 aliphatic.

[0191] In some embodiments, R 3 is -OR', where R' is as described herein. In some embodiments, R' is R as described herein. In some embodiments, R' is H. In some embodiments, R' is optionally substituted C 1-6 aliphatic. In some embodiments, R' is optionally substituted C 1-6 aliphatic. In some embodiments, R' is methyl.

[0192] 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.

[0193] In some embodiments, R 3 is -CN. In some embodiments, R 3 is -NO 2 . 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 R as described herein. In some embodiments, R 3 is -NH 2 .

[0194] In some embodiments, where R 3 and R 3 are both independently 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 are H. In some embodiments, one of R 3 and R 3 is H, R 3 and R 3Another one in is not H. In some embodiments, R 3 and R 3 One of is H, R 3 and R 3 The other one 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 None of them is H. In some embodiments, R 3 and R 3 Each of them is R, -OR', halogen, -CN, -NO 2 or -N(R') 2 , where each variable is as described herein.

[0195] In some embodiments, ring B is where each variable is as described herein.

[0196] In some embodiments, ring B is where R 2 and R 11 Each is independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where each variable is as described herein. In some embodiments, ring B is where R 2 is halogen, R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1 - 3 heteroatoms, 3 - 10 - membered cycloaliphatic, 3 - 10 - membered heterocyclic having 1 - 4 heteroatoms, 6 - 10 - membered aryl, 6 - 10 - membered heteroaryl having 1 - 6 heteroatoms, 5 - 10 - membered heteroaryl having 1 - 6 heteroatoms, 6 - 10 - membered aryl - C 1 -C 6 aliphatic and 5 - 10 - membered heteroaryl - C 1 -C 6 aliphatic having 1 - 6 heteroatoms. In some embodiments, ring B is where R 2 is halogen, and R 11 is H. In some embodiments, ring B is where R 2 is F, and R 11 is H.

[0197] In some embodiments, ring B is wherein R 2 and R 11 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where each variable is as described herein. In some embodiments, ring B is wherein R 2 is halogen, R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 1 -C 6 aliphatic and 5-10 membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is halogen, R 11 is H. In some embodiments, ring B is wherein R 2 is F, R 11 is H.

[0198] In some embodiments, ring B is wherein R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 1 -C 6 aliphatic, 5-10 membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 11 is H.

[0199] In some embodiments, ring B is where each variable is independently as described herein.

[0200] In some embodiments, ring B is wherein R 2 and R 11 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , wherein each variable is as described herein. In some embodiments, ring B is wherein R 2 is halogen, R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 1 -C 6 aliphatic and 5-10 membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is halogen, and R 11 is H. In some embodiments, ring B is wherein R 2 is F, and R 11 is H.

[0201] In some embodiments, ring B is wherein R 2 and R 11 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , wherein each variable is independently as described herein. In some embodiments, ring B is wherein R 2 is halogen, optionally substituted C 1 -C 6 alkyl, -OR, wherein R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C 8 cycloalkyl or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms, R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6Heteroaliphatic, 3-10 membered cycloaliphatic, 3-10 membered heterocyclic with 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl with 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 Aliphatic and 5-10 membered heteroaryl-C with 1-6 heteroatoms 1 -C 6 Aliphatic. In some embodiments, ring B is wherein R 2 is halogen, R 11 is H or an optionally substituted group selected from C 1 -C 6 Aliphatic, C1-C6 heteroaliphatic with 1-3 heteroatoms, 3-10 membered cycloaliphatic, 3-10 membered heterocyclic with 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl with 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 Aliphatic and 5-10 membered heteroaryl-C with 1-6 heteroatoms 1 -C 6 Aliphatic. In some embodiments, ring B is wherein R 2 is halogen, R 11 is H. In some embodiments, ring B is wherein R 2 is F, R 11 is H. In some embodiments, ring B is wherein R 2 is Cl, R 11 is H. In some embodiments, ring B is wherein R 2 is Br, R 11 is H.

[0202] In some embodiments, ring B is wherein R 2 is -OR, where R is optionally substituted C 1 -C 6 alkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is -OMe, R 11 is H. In some embodiments, ring B is wherein R 2 is -OMe, R 11 is H.

[0203] In some embodiments, ring B is wherein R 2is an optionally substituted 6-10-membered aryl, and R 11 is H. In some embodiments, ring B is wherein R 2 is an optionally substituted phenyl, R 11 is H. In some embodiments, ring B is wherein R 2 is phenyl, R 11 is H.

[0204] In some embodiments, ring B is wherein R 2 is an optionally substituted C 1 -C 6 alkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is C 1 -C 6 alkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is methyl, R 11 is H. In some embodiments, ring B is wherein R 2 is methyl, R 11 is H.

[0205] In some embodiments, ring B is wherein R 2 is an optionally substituted C 3 -C 8 cycloalkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is C 3 -C 8 cycloalkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is R 11 is H. In some embodiments, ring B is wherein R 2 is R 11 is H. In some embodiments, ring B is wherein R 2 is R 11 is H. In some embodiments, ring B is wherein R 2 is R 11 is H.

[0206] In some embodiments, ring B is wherein R 2 is an optionally substituted 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, and R 11 is H. In some embodiments, ring B is wherein R 2 is an optionally substituted 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, and R 11 is H. In some embodiments, ring B is wherein R 2 is an optionally substituted 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, and R 11 is H. In some embodiments, ring B is wherein R 2 is R 11 is H.

[0207] In some embodiments, ring B is wherein each of R 2 and R 11 is independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where each variable is independently as described herein. In some embodiments, ring B is wherein R 2 is halogen, an optionally substituted C 1 -C 6 alkyl, -OR, where R is an optionally substituted C 1 -C 6 alkyl, an optionally substituted 6- to 10-membered aryl, an optionally substituted C 3 -C 8 cycloalkyl, or an optionally substituted 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, and R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1 to 3 heteroatoms, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocycloaliphatic having 1 to 4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, 6- to 10-membered aryl-C 1 -C 6 aliphatic, and 5- to 10-membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R2 is a halogen, R 11 is H or an optionally substituted group selected from C 1 -C 6 -aliphatic, C with 1 - 3 heteroatoms 1 -C 6 -heteroaliphatic, 3 - 10 - membered cycloaliphatic, 3 - 10 - membered heterocyclic with 1 - 4 heteroatoms, 6 - 10 - membered aryl, 5 - 10 - membered heteroaryl with 1 - 6 heteroatoms, 6 - 10 - membered aryl - C 1 -C 6 -aliphatic and 5 - 10 - membered heteroaryl - C with 1 - 6 heteroatoms 1 -C 6 -aliphatic. In some embodiments, ring B is wherein R 2 is a halogen, R 11 is H. In some embodiments, ring B is wherein R 2 is F, R 11 is H. In some embodiments, ring B is wherein R 2 is Cl, R 11 is H. In some embodiments, ring B is wherein R 2 is Br, R 11 is H.

[0208] In some embodiments, ring B is wherein R 2 is - OR, where R is an optionally substituted C 1 -C 6 -alkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is - OMe, R 11 is H. In some embodiments, ring B is wherein R 2 is - OMe, R 11 is H.

[0209] In some embodiments, ring B is wherein R 2 is an optionally substituted C 1 -C 6 -alkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is C 1 -C 6 -alkyl, R 11 is H. In some embodiments, ring B is wherein R 2 is methyl and R 11 is H. In some embodiments, ring B is wherein R 2 is methyl and R 11 is H.

[0210] In some embodiments, ring B is wherein each of R 2 and R 11 is independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where each variable is independently as described herein. In some embodiments, ring B is wherein R 2 is halogen, optionally substituted C 1 -C 6 alkyl, -OR, where R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, and R 11 is H or an optionally substituted optional substituent selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1 to 3 heteroatoms, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocyclic having 1 to 4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, 6- to 10-membered aryl-C 1 -C 6 aliphatic, and 5- to 10-membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is halogen, R 11 is H or an optionally substituted substituent selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1 to 3 heteroatoms, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocyclic having 1 to 4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1 to 6 heteroatoms, 6- to 10-membered aryl-C 1 -C 6 aliphatic, and 5- to 10-membered heteroaryl-C1 -C 6 Aliphatic. In some embodiments, ring B is wherein R 2 is halogen and R 11 is H. In some embodiments, ring B is wherein R 2 is F and R 11 is H. In some embodiments, ring B is wherein R 2 is Cl and R 11 is H. In some embodiments, ring B is wherein R 2 is Br and R 11 is H.

[0211] In some embodiments, ring B is wherein R11 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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, 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, ring B is 1 -C 6 heteroaliphatic, 3-10 membered cycloaliphatic, 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, 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, ring B is wherein R 11 is H.

[0212] In some embodiments, ring B is wherein each variable is independently as described herein.

[0213] In some embodiments, ring B is wherein R 2 and R 11 are each independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , wherein each variable is as described herein.

[0214] In some embodiments, ring B is wherein R11 is H or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 1 -C 6 aliphatic, 5-10 membered heteroaryl-C 1 -C6 Aliphatic. In some embodiments, ring B is wherein R 11 is H.

[0215] In some embodiments, ring B is wherein each variable is independently as described herein. In some embodiments, ring B is wherein each variable is independently as described herein. In some embodiments, ring B is wherein each variable is independently as described herein.

[0216] In some embodiments, ring B is wherein R 12 and R 13 each independently is hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1 - 3 heteroatoms, 3 - 10 membered cycloaliphatic, 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 1 -C 6 aliphatic and 5 - 10 membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein each R 12 and R 13 independently is H or optionally substituted C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 12 and R 13 each independently is H. In some embodiments, ring B is wherein R 12 and R 13 each independently is optionally substituted C 1 -C 6 alkyl. In some embodiments, ring B is wherein each R 12 is H, R 13 is optionally substituted C 1 -C 6 alkyl. In some embodiments, ring B is wherein each R 12 is H, R 13 is ethyl. In some embodiments, ring B is wherein each R12 is ethyl, R 13 is ethyl.

[0217] In some embodiments, ring B is where each variable is independently as described herein. In some embodiments, ring B is where each variable is independently as described herein. In some embodiments, ring B is where each variable is independently as described herein.

[0218] In some embodiments, ring B is where R 2 is R', -OR', halogen, -CN, -NO 2 , or -N(R') 2 , where each variable is independently as described herein, each R 16 and R 17 is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 1 -C 6 aliphatic and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms, or R 16 and R 17 together with nitrogen form an optionally substituted 3-10 membered ring having 0-4 heteroatoms in addition to nitrogen. In some embodiments, ring B is where R 2 is H or halogen, each R 16 and R 17 is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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 1 -C 6 aliphatic and 5-10 membered heteroaryl-C1-C6 aliphatic. In some embodiments, ring B is where R 2 is halogen, each R 16 and R 17Independently is hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C 1 -C 6 heteroaliphatic, 3-10 membered cycloaliphatic, 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 1 -C 6 aliphatic and 5-10 membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms. In some embodiments, ring B is wherein R 2 is halogen, each R 16 and R 17 is independently hydrogen or optionally C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 2 is halogen, each R 16 and R 17 are both H. In some embodiments, ring B is wherein R 2 is halogen, R 16 is H, and R 17 is optionally C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 2 is halogen, R 16 is H, and R 17 is methyl. In some embodiments, ring B is wherein R 2 is halogen, each R 16 and R 17 is optionally C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 2 is halogen, each R 16 and R 17 are both methyl.

[0219] In some embodiments, ring B is wherein R 2 is F, each R 16 and R 17 is independently hydrogen or is optionally C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 2 is Cl, each R 16 and R 17Independently hydrogen or optionally C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 2 is Br, each R 16 and R 17 are independently hydrogen or optionally C 1 -C 6 alkyl.

[0220] In some embodiments, ring B is wherein each variable is independently as described herein. In some embodiments, ring B is wherein each variable is independently as described herein.

[0221] In some embodiments, ring B is wherein each variable is independently as described herein. In some embodiments, ring B is wherein each variable is independently as described herein.

[0222] In some embodiments, ring B is wherein each variable is independently as described herein. In some embodiments, ring B is wherein each variable is independently as described herein. In some embodiments, ring B is wherein each variable is independently as described herein.

[0223] In some embodiments, ring B is wherein R 2 is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , wherein each variable is independently as described herein.

[0224] In some embodiments, ring B is wherein R 2 is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , wherein each variable is independently as described herein. In some embodiments, ring B is wherein R 2 is H. In some embodiments, ring B is wherein R 2 is halogen, optionally substituted C 1 -C 6 alkyl, -OR, where R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C8 a cycloalkyl group, or an optionally substituted 5-10 membered heteroaryl group having 1-6 heteroatoms, and R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C having 1-3 heteroatoms 1 -C 6 heteroaliphatic, 3-10 membered cycloaliphatic, 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-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is a halogen. In some embodiments, ring B is wherein R 2 is F. In some embodiments, ring B is wherein R 2 is Cl. In some embodiments, ring B is wherein R 2 is Br. In some embodiments, ring B is wherein R 2 is I.

[0225] In some embodiments, ring B is wherein R 2 is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where each variable is independently as described herein. In some embodiments, ring B is wherein R 2 is H. In some embodiments, ring B is wherein R 2 is halogen, optionally substituted C 1 -C 6 alkyl, -OR, where R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or an optionally substituted 5-10 membered heteroaryl group having 1-6 heteroatoms, and R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C having 1-3 heteroatoms 1 -C 6Heteroaliphatic, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocyclic with 1 to 4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl with 1 to 6 heteroatoms, 6- to 10-membered aryl-C1-C6 aliphatic, and 5- to 10-membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is halogen. In some embodiments, ring B is wherein R 2 is F. In some embodiments, ring B is wherein R 2 is Cl. In some embodiments, ring B is wherein R 2 is Br. In some embodiments, ring B is wherein R 2 is I.

[0226] In some embodiments, ring B is wherein R 2 is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 , where each variable is independently as described herein. In some embodiments, ring B is wherein R 2 is H. In some embodiments, ring B is wherein R 2 is halogen, optionally substituted C 1 -C 6 alkyl, -OR, where R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 5- to 10-membered heteroaryl with 1 to 6 heteroatoms, and R 11 is H or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 heteroaliphatic with 1 to 3 heteroatoms, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocyclic with 1 to 4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl with 1 to 6 heteroatoms, 6- to 10-membered aryl-C 1 -C 6 aliphatic, and 5- to 10-membered heteroaryl-C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is a halogen. In some embodiments, ring B is wherein R 2 is F. In some embodiments, ring B is wherein R 2 is Cl. In some embodiments, ring B is wherein R 2 is Br. In some embodiments, ring B is wherein R 2 is I.

[0227] In some embodiments, ring B is wherein R 2 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is optionally substituted C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 2 is methyl. In some embodiments, ring B is wherein R 2 is optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, ring B is wherein R 2 is In some embodiments, ring B is wherein R 2 is In some embodiments, ring B is wherein R 2 is In some embodiments, ring B is wherein R 2 is

[0228] In some embodiments, ring B is wherein R 2 is -C(O)OR, and each variable is independently as described herein. In some embodiments, ring B is wherein R 2 is -C(O)OR, R is hydrogen or optionally substituted C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is -C(O)OR, R is hydrogen. In some embodiments, ring B is wherein R 2 is -C(O)OR, and R is an optionally substituted group selected from C 1 -C 6 aliphatic. In some embodiments, ring B is wherein R 2 is -C(O)OR, and R is an optionally substituted group selected from C 1 -C 6 alkyl. In some embodiments, ring B is wherein R 2 is -C(O)OR, and R is methyl. In some embodiments, ring B is wherein R 2 is -C(O)OR, and R is ethyl.

[0229] In some embodiments, ring B is wherein each variable is independently as described herein. In some embodiments, ring B is wherein each R 16 and R 17 are independently H or optionally substituted C 1 -C 6 aliphatic. In some embodiments, ring B is wherein each R 16 and R 17 are both H.

[0230] In some embodiments, ring B is wherein R 2 is -CN.

[0231] In some embodiments, ring B is wherein each R 2 and R 3 are independently halogen, -CN, optionally substituted C 1 -C 6 alkyl, -OR, wherein R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

[0232] In some embodiments, ring B is wherein each R 2 and R 3 are independently halogen, -CN, optionally substituted C 1 -C 6 alkyl, -OR, wherein R is optionally substituted C 1 -C6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms. In some embodiments, Ring B is wherein each R 2 and R 3 are independently halogen and optionally substituted C 1 -C 6 alkyl. In some embodiments, Ring B is wherein each R 2 and R 3 are independently halogen and optionally substituted C 1 -C 6 alkyl, and in some embodiments, Ring B is

[0233] In some embodiments, Ring B is wherein each R 2 and R 3 are independently halogen, -CN, optionally substituted C 1 -C 6 alkyl, -OR, wherein R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

[0234] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from: In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from:

[0235] In some 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 independently as described herein.

[0236] In some 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.

[0237] In some embodiments, the present disclosure provides a compound of formula (IV-1 to IV-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 10 are each independently as described herein.

[0238] In some embodiments, the present disclosure provides a compound of formula (V-1 to 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 are each independently as described herein.

[0239] In some embodiments, the present disclosure provides a compound 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 independently as described herein, and each ring is independently optionally substituted. In some embodiments, the present disclosure provides a compound of the following formula or a pharmaceutically acceptable salt thereof, wherein R 1 is while R 2 , R 3 , R4 , R5, R6, R7, R8, R 9 , R 10 , n, and X are each independently as described herein, and each ring is independently optionally substituted.

[0240] In some embodiments, the structure of the compound of formula (I) or a pharmaceutically acceptable salt thereof is: or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0241] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0242] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0243] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, 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 C 1 -C 6 alkyl. In some embodiments, R 8 is H. In some embodiments, R 8 is optionally substituted C 1 -C 6 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 optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 8 is optionally substituted C3 -C 8 cycloalkyl. In some embodiments, R 8 is In some embodiments, R 8 is In some embodiments, R 8 is In some embodiments, R 8 is an optionally substituted 6- to 10-membered aryl group. 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 C 1 -C 6 alkyl. In some embodiments, R 6 is -CF 3 .

[0244] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein.

[0245] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, 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 C 1 -C 6 alkyl. In some embodiments, R 5 is -CF 3 . 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 2is Br. In some embodiments, R 2 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 2 is optionally substituted C 3 -C 8 cycloalkyl. In some embodiments, R 2 is In some embodiments, R 2 is In some embodiments, R 2 is In some embodiments, R 2 is -OR, where R is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 2 is -OMe. In some embodiments, R 2 is optionally substituted 6-10 membered aryl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is optionally substituted 5-10 membered heteroaryl having 1-3 heteroatoms. In some embodiments, R 2 is

[0246] In some embodiments, the structure of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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 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 optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 is -CF 3。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 C 1 -C 6 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. 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.

[0247] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, 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 C 1 -C 6 alkyl. In some embodiments, R 5 is -CF 3 <. 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.

[0248] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, 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 -C 6 alkyl. In some embodiments, R 8 is methyl. In some embodiments, R 6 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 6 is -CF 3 .

[0249] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure, 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 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 optionally substituted C 1 -C 6 alkyl. In some embodiments, R 5 is -CF 3 .

[0250] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure, or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein. In some embodiments, R 8 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 8 is methyl. In some embodiments, R 6 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 6 is -CF 3 . In some embodiments, each R 12 and R 13 is independently H or optionally substituted C 1 -C 6 alkyl. In some embodiments, each R 12 and R 13 is independently H. In some embodiments, each R 12 and R 13 is independently ethyl. In some embodiments, R12 is H, R 13 is ethyl

[0251] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, 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 5 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 5 is -CF3. In some embodiments, each R 16 and R 17 is independently H or optionally substituted C 1 -C 6 alkyl. In some embodiments, each R 16 and R 17 is independently optionally substituted C 1 -C 6 alkyl. In some embodiments, each R 16 and R 17 are both methyl. In some embodiments, R 16 is H, R 17 is methyl. In some embodiments, R 16 and R 17 together with nitrogen form an optionally substituted 3- to 10-membered ring having 0 to 4 heteroatoms in addition to nitrogen.

[0252] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of, 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 optionally substituted C 1 -C 6 alkyl. In some embodiments, R 2 is -CF 3 . R'

[0253] The various variables can be R' as described herein. In some embodiments, R' is hydrogen.

[0254] In some embodiments, R' is R as described herein. In some embodiments, R' is -OR, where R is as described herein. In some embodiments, R' is -C(O)R, where R is as described herein. In some embodiments, R' is -C(O)OR, where R is as described herein. In some embodiments, R' is -S(O) 2 R, where R is as described herein. R

[0255] The various variables can be R as described herein. Various embodiments of R are described extensively herein, including other variables that can be R described in various sections (e.g., R 1 、R 2 、R', etc.).

[0256] In some embodiments, R is -H. In some embodiments, R is not -H.

[0257] In some embodiments, each R is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3-10 membered cycloaliphatic, 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-C 1 -C 6 aliphatic.

[0258] In some embodiments, R is optionally substituted C 1 -6 aliphatic. In some embodiments, R is optionally substituted C 1 -6 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 tert-butyl. In some embodiments, R is pentyl. In some embodiments, R is hexyl.

[0259] In some embodiments, R is an optionally substituted C 1-6 heteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 3 (such as 1, 2, or 3) heteroatoms independently selected from nitrogen, oxygen, and sulfur 1 -6 heteroaliphatic. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0260] In some embodiments, R is an optionally substituted C 3-10 (e.g., C 4-10 、C 3-9 、C 3-7 or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered) cycloaliphatic. In some embodiments, the cycloaliphatic group is a cycloalkyl group. In some embodiments, the cycloaliphatic 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- to 10- (e.g., C 4-10 、C 3-9 、C 3-7 or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered cycloaliphatic ring. In some embodiments, the cycloaliphatic group is saturated. In some embodiments, it 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.

[0261] In some embodiments, R is an optionally substituted 3- to 10- (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10-membered) heterocycle having 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 3- to 10- (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10-membered) heterocycle having 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, the heterocyclic 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- to 10- (e.g., 3, 4, 5, 6, 7, 8, 9, or 10-membered) heterocycle having 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, the heterocycle has one heteroatom. In some embodiments, the heterocycle has two or more heteroatoms. In some embodiments, the heterocycle has three or more heteroatoms. In some embodiments, the heterocycle 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.

[0262] In some embodiments, R is an optionally substituted C 6-10 (e.g., C 6 , C 10 etc.) aryl. In some embodiments, R is an optionally substituted C 6-10 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.

[0263] In some embodiments, R is an optionally substituted 5- to 10-membered heteroaryl (such as 5-9 or 5, 6, 7, 8, 9, or 10 etc.) having 1-6 (such as 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- to 10-membered heteroaryl (such as 5-9, or 5, 6, 9, 10 etc.) having 1-4 (such as 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 aryl ring having 0-4 heteroatoms (e.g., independently selected from nitrogen, oxygen, and sulfur), wherein 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 three or more heteroatoms. In some embodiments, the heteroaryl 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.

[0264] In some embodiments, R is an optionally substituted C 6-10 aryl-C 1-6 aliphatic, wherein the aryl and aliphatic are independently as described herein. In some embodiments, R is an optionally substituted C 6-10 aryl-C 1-6 alkyl.

[0265] In some embodiments, R is an optionally substituted 5- to 10-membered heteroaryl-C 1-6 aliphatic having 1-6 (such as 1, 2, 3, 4, 5, or 6) heteroatoms, wherein the heteroaryl and aliphatic are independently as described herein. In some embodiments, R is an optionally substituted 5- to 10-membered heteroaryl-C 1-6 aliphatic having 1-5 heteroatoms. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl-C 1-6Aliphatic. In some embodiments, R is an optionally substituted 5- to 10-membered heteroaryl-C having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms 1-6 alkyl, wherein the heteroaryl and aliphatic are each independently as described herein. In some embodiments, R is an optionally substituted 5- to 10-membered heteroaryl-C having 1 to 5 heteroatoms 1-6 alkyl. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl-C having 1 to 4 heteroatoms 1-6 alkyl. Various suitable heteroaryl and aliphatic groups are as described herein.

[0266] In some embodiments, two R groups on the same atom are optionally and independently joined with the atom to form an optionally substituted 3- to 10- (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring having 0 to 4 (e.g., 0, 1, 2, 3, or 4) heteroatoms in addition to the atom. In some embodiments, two R groups on two atoms are optionally and independently joined with their intervening atom to form an optionally substituted 3- to 10- (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring having 0 to 4 (e.g., 0, 1, 2, 3, or 4) heteroatoms in addition to the intervening atom.

[0267] As described herein, in various instances, two R groups or two groups that belong to or can be R (e.g., R 4 , R 5 , R 6 R 7etc.) can together with their intervening atom form an optionally substituted ring as described herein. In some embodiments, the formed ring is substituted (except for the group attached to the intervening atom). In some embodiments, the formed ring is unsubstituted. In some embodiments, the formed ring is a three-membered ring. In some embodiments, the formed ring is a 4-membered ring. In some embodiments, the formed ring is a 5-membered ring. In some embodiments, the formed ring is a 6-membered ring. In some embodiments, the formed ring is a 7-membered ring. In some embodiments, the formed ring is an 8-membered ring. In some embodiments, the formed ring is a 9-membered ring. In some embodiments, the formed ring is a 10-membered ring. In some embodiments, the formed ring is a saturated ring. In some embodiments, the formed ring is a partially unsaturated ring. In some embodiments, the formed ring is an aromatic ring. In some embodiments, the formed ring is a monocyclic ring. 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., 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring, which ring is independently a saturated ring, a partially unsaturated ring, or an aromatic ring and has 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms. In some embodiments, each monocyclic 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, which ring is independently a saturated ring, a partially unsaturated ring, or an aromatic ring and has 0-4 (such as 0, 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently 3-7 membered. In some embodiments, each monocyclic unit is independently 3-6 membered. In some embodiments, each monocyclic unit is independently 5-7 membered. 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 an aromatic unit. In some embodiments, the formed monocyclic ring, in addition to the intervening atom, has 0-4 (such as 0, 1, 2, 3, or 4, etc.) 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 2 additional heteroatoms. In some embodiments, there are 3 additional heteroatoms. In some embodiments, there are 4 additional heteroatoms. In some embodiments, there are 5 additional heteroatoms. In some embodiments, there are 6 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, R4 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.

[0268] As described herein, various groups may be optionally substituted. Substituents are commonly used in the chemical arts, including the development of various therapeutic agents. According to the present disclosure, many substituents may be used. In some embodiments, the optionally substituted group is unsubstituted. In some embodiments, the optionally substituted group is substituted. The substituents are preferably those that enable the compound to form the desired properties, activities, uses, etc. described herein. In some embodiments, the compound has a stable therapeutic use as described herein. The term "stable" as used herein refers to a compound that does not undergo substantial change under the conditions of production, testing, and (in some embodiments) recovery, purification, and use for one or more of the 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 the 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 each substituent is about or no more than about 1; in some embodiments, it is no more than about 2; in some embodiments, it is no more than about 3; in some embodiments, it is no more than about 4; in some embodiments, it is no more than about 5; in some embodiments, it is no more than about 6; in some embodiments, it is no more than about 7; in some embodiments, it is no more than about 8; in some embodiments, it is no more than about 9; in some embodiments, it is no more than about 10; in some embodiments, it is no more than about 11; in some embodiments, it is no more than about 12; in some embodiments, it is no more than about 13; in some embodiments, it is no more than about 14; in some embodiments, it is no more than about 15; in some embodiments, it is no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent does not exceed 20. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent does not exceed 15. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent does not exceed 10. In some embodiments, the total number of carbon and non-halogen heteroatoms in each substituent does not exceed 6. In some embodiments, each optional substituent on the optionally substitutable group (such as ring A, ring B, R, etc.) is independently halogen, C 1-4 alkyl, -OH, -CN, -NO 2 , C 1-4 haloalkyl (such as -CF 3 ), -OR SB , -N(R SB )2 , -C(O)OR SB , -C(O)N(R SB ) 2 , or -S(O) 2 N(R SB ) 2 , wherein each RSB is independently -H, C 1-4 alkyl or C 1 -4 haloalkyl, or is halogen, C 1-4 alkyl, -OH, -CN, -NO 2 , C 1-4 haloalkyl (such as -CF 3 ), -OR SB , -N(R SB ) 2 , -C(O)OR SB , -C(O)N(R SB ) 2 , or -S(O) 2 N(R SB ) 2 optionally substituted phenyl. In some embodiments, each optional substituent on a substitutable group (such as ring A, ring B, R, etc.) is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl or -OH. In some embodiments, each optional substituent on a substitutable group (such as ring A, ring B, R, etc.) is independently halogen, C 1-4 alkyl or C 1-4 haloalkyl. In some embodiments, each halogen is -F.

[0269] In some embodiments, the provided compound is a compound selected from compounds 1 - 101 in the examples or a salt thereof.

[0270] 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.

[0271] In some embodiments, the compounds of the present disclosure may utilize or enrich one or more isotopes at one or more positions. For example, in some embodiments, deuterium is utilized or enriched at one or more positions. In some embodiments, the enrichment level is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95% or 99% higher than the applicable natural enrichment level. In some embodiments, the isotopic content at a certain 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 all compound molecules. For example, in some embodiments, L ra is -(CD 2 ) n -; in some embodiments, L ra is -CD 2 -. Preparation methods

[0272] In some embodiments, the present disclosure provides various techniques for preparing the compounds and compositions described herein, such as reagents, intermediates, conditions, etc. Those skilled in the art understand that, based on the disclosure of the present disclosure, many techniques are available for selection and use.

[0273] As those skilled in the art understand, in chemical reactions, various groups such as hydroxyl, amino, carboxyl, etc. may be protected to avoid unwanted reactions. Many protection / deprotection techniques are available to those skilled in the art and can be utilized based on the disclosure of the present disclosure. Some such techniques are described herein and illustrated in the examples.

[0274] 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, Et2O, 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 a protic solvent. In some embodiments, the solvent is an aprotic solvent. In some embodiments, the solvent is polar but not a protic solvent. Suitable solvents for various reactions are available to those skilled in the art and can be utilized based on the content of the present disclosure.

[0275] In some embodiments, the reaction is carried out under an inert atmosphere, such as N2, Ar, etc. In some embodiments, the reaction is carried out in air. In some embodiments, the reaction is carried out under anhydrous conditions, for example, the reagents, solvents, containers, etc. are properly dried. In some embodiments, the reaction is carried out in the presence of a large amount of water (such as about or more than about 0.1, 0.5, or 1 equivalent).

[0276] In some embodiments, the reaction is carried out or continued for a period of time at a temperature above or below or close to the standard ambient temperature (25 °C). In some embodiments, the reaction temperature is lower than the standard ambient temperature. In some embodiments, the temperature is about or not more than about -78, -60, -50, -40, -30, -20, -10, 0, or 10 °C. In some embodiments, the temperature is about or not more than about 10 °C. In some embodiments, the temperature is about or not more than about 15 °C. In some embodiments, the temperature is about or not more than about 20 °C. In some embodiments, the reaction temperature is about the standard ambient temperature. In some embodiments, the reaction temperature is higher than the standard ambient temperature. In some embodiments, the reaction temperature is about or at least about 35, 40, 50, 60, 70, 80, 90, 100, or 100 °C. In some embodiments, the reaction includes refluxing in a boiling solvent system, such as in a solvent system of ether, toluene, etc. In some embodiments, the temperature changes during the reaction, for example, rising from a lower temperature to a higher temperature, dropping from a higher temperature to a lower temperature, or both.

[0277] In some embodiments, one product is selectively produced rather than another potential product. In some embodiments, the product formed has chemoselectivity, stereoselectivity, and / or regioselectivity. In some embodiments, the selectivity is expressed as a ratio, for example, the ratio of one product to another product. 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 higher.

[0278] The reaction can be carried out for various lengths of time. In some embodiments, the reaction is completed instantaneously. In some embodiments, the reaction time varies from a few minutes to a few hours to a few days, such as 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 two days or longer. Those skilled in the art can use various techniques to determine when to terminate the reaction, for example, based on the consumption of starting materials, the formation of products, the formation of by-products, etc.

[0279] In some embodiments, the present disclosure provides compounds of high purity. In some embodiments, the purity of the compound is greater than or equal to about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7% or 99.9%. In some embodiments, the purity of the compound is greater than or equal to about 80%. In some embodiments, the purity of the compound is greater than or equal to about 85%. In some embodiments, the purity of the compound is greater than or equal to about 90%. In some embodiments, the purity of the compound is greater than or equal to about 95%. In some embodiments, the purity of the compound is greater than or equal to about 96%. In some embodiments, the purity of the compound is greater than or equal to about 97%. In some embodiments, the purity of the compound is greater than or equal to about 98%. In some embodiments, the purity of the compound is greater than or equal to about 99%. In some embodiments, the purity of the compound is greater than or equal to about 99.5%. In some embodiments, the purity of the compound is greater than or equal to about 99.7%. In some embodiments, the purity of the compound is greater than or equal to about 99.9%.

[0280] In some embodiments, the present disclosure provides compounds with high stereochemical purity. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7% or 99.9%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 80%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 85%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 90%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 95%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 96%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 97%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 98%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 99%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 99.5%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 99.7%. In some embodiments, the stereochemical purity of the compound is greater than or equal to about 99.9%.

[0281] In some embodiments, the present disclosure provides compounds with high enantiomeric purity. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7% or 99.9%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 80%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 85%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 90%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 95%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 96%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 97%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 98%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 99%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 99.5%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 99.7%. In some embodiments, the enantiomeric purity of the compound is greater than or equal to about 99.9%.

[0282] According to the present disclosure, various techniques can be utilized to prepare compounds and compositions with high stereochemical purity (e.g., enantiomeric purity). For example, in some embodiments, they can be prepared by separation (including chiral separation); in some embodiments, they can be prepared by stereoselective synthesis.

[0283] For example, in some embodiments, the present disclosure provides a method comprising: reacting a compound of formula B-4 or a salt thereof with a compound of formula R 8 -LG or a salt thereof, wherein LG is a leaving group, to provide a compound having formula B: or a salt thereof, wherein each variable is independently as described herein.

[0284] According to the present disclosure, various leaving groups can be used. 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) 2 R, where R is as described herein and is not H. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. According to the present disclosure, many suitable conditions can be utilized. 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.

[0285] In some embodiments, the compound of formula B-4 or a salt thereof is a compound of formula or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound of formula B or a salt thereof is a compound of formula or a salt thereof, wherein each variable is independently as described herein.

[0286] In some embodiments, the present disclosure provides a method comprising: reacting a compound of formula B-3 or a salt thereof to provide a compound of formula B-4: or a salt thereof, wherein each variable is independently as described herein.

[0287] In some embodiments, the compound of formula B-3 or a salt thereof is a compound of formula A compound of the structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound of the B-4 structure or a salt thereof is a compound having a structure of a compound 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 present in a metal complex. In some embodiments, the metal complex is a palladium complex. In some embodiments, the metal complex is PdCl 2 . In some embodiments, a suitable solvent is CH 3 CN.

[0288] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of formula B-1: or a salt thereof and a compound having the structure of formula B-2: or a salt thereof to obtain a compound having the structure of formula B-3: or a salt thereof, wherein Hal is a halogen and each variable is independently as described herein.

[0289] In some embodiments, Hal is Cl. In some embodiments, Hal is Br. In some embodiments, Hal is I. In some embodiments, the compound of the B-3 structure or a salt thereof is a compound having a structure of a compound or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound of the B-2 structure or a salt thereof is a compound having a structure of a compound 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 present in a metal complex. In some embodiments, the metal is palladium. In some embodiments, palladium is in a complex. In some embodiments, the palladium 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 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 N(R) 3 , wherein each R is independently as described herein. In some embodiments, the base is NEt 3 .

[0290] In some embodiments, a method is described by taking Scheme 1 as an example: Scheme 1

[0291] A method for preparing the provided compound, such as a compound of Formula I or a salt thereof, such as a compound of Formula B or a salt thereof, is illustrated by taking Scheme 1 as an example, wherein each variable is independent as described herein. In some embodiments, under Sonogashira coupling conditions (such as PdCl 2 (PPh 3 ) 2 Cl 2 / CuI / Et 3 N), treating an aniline compound of Formula B-1 or a salt thereof (wherein Hal is Cl, Br, or I) and an alkyne compound of Formula B-2 or a salt thereof can obtain an alkyne compound of Formula B-3 or a salt thereof. In some embodiments, using a transition metal catalyst (such as PdCl 2 ) to cyclize a compound of Formula B-3 or a salt thereof can obtain an indole compound of Formula B-4 or a salt thereof. In some embodiments, under alkylation conditions (such as NaH / R 8 -Hal), treating a compound of Formula B-4 or a salt thereof can obtain a compound of Formula I or a salt thereof, such as a compound of Formula B or a salt thereof.

[0292] In some embodiments, the present disclosure provides a method, comprising: reacting a compound having the structure of Formula B-5: or a salt thereof, thereby obtaining a compound having the structure of Formula B: or a salt thereof, wherein each variable is independently as described herein.

[0293] In some embodiments, the compound having the structure of B-5 or a salt thereof is a compound having the structure 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 a compound having the structure 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 present in a metal complex. In some embodiments, the metal complex is a palladium complex. In some embodiments, the metal complex is PdCl 2 . In some embodiments, a suitable solvent is CH 3 CN.

[0294] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of B-3: or a salt thereof to provide a compound having the structure of B-5: or a salt thereof, wherein each variable is independently as described herein.

[0295] In some embodiments, the compound having the structure of B-5 or a salt thereof is a compound having the structure 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 or a salt thereof, wherein each variable is independently as described herein.

[0296] In some embodiments, a method comprises reacting a compound of formula B-3 or a salt thereof with a compound having the R 8 -LG structure or a salt thereof, wherein LG is a leaving group. Various leaving groups can be used according to 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) 2 R, where R is as described herein and is not H. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted phenyl. According to the present disclosure, many suitable conditions can be utilized. 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.

[0297] In some embodiments, a method comprises reacting a compound of formula B-3 or a salt thereof with a compound having the R 8 '-CHO structure or a salt thereof, wherein R 8 is bonded to -NH through -CH 2 -, and the structure of R 8 ' makes R 8 '-CH 2 - be R 8 . For example, in some embodiments, R 8 is -CH 2 CH 3 , while R 8 ' is -CH 3. 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 boron hydride agent such as NaBH 3 CN. In some embodiments, the reaction is carried out in the presence of a protic solvent such as an alcohol such as methyl.

[0298] In some embodiments, a method is described by taking Scheme 2 as an example: Scheme 2

[0299] A method for preparing the provided compound, such as a compound of formula I or a salt thereof, such as a compound of formula B or a salt thereof, is illustrated by taking Scheme 2 as an example, where each variable is independent as described herein. In some embodiments, under reductive amination conditions (such as NaBH 3 CN / MeOH) or alkylation conditions (such as NaH / R 8 -Hal), treating a compound of formula B-3 or a salt thereof, where each variable is independent as described herein, can obtain a compound of formula B-5 or a salt thereof (Scheme 2). In some embodiments, using a transition metal catalyst (such as PdCl 2 ) to cyclize a compound of formula B-5 or a salt thereof can obtain a compound of formula I or a salt thereof, such as an indole compound of formula B or a salt thereof.

[0300] In some embodiments, a method includes reacting a compound of formula B-3 or a salt thereof with a compound of formula R 8 -B(OH) 2 or a salt thereof to provide a compound of formula B or a salt thereof.

[0301] In some embodiments, a method is described by taking Scheme 3 as an example: Scheme 3

[0302] A method for preparing the provided compound, such as a compound of formula I or a salt thereof, such as a compound of formula B or a salt thereof, is illustrated by taking Scheme 3 as an example, where each variable is independent as described herein. In some embodiments, under Chan-Lam coupling conditions (such as R 8 B(OH) 2 / Cu(OAc) 2 ), treating a compound of formula B-3 or a salt thereof can obtain a compound of formula I or a salt thereof in one step, such as a compound of formula B or a salt thereof (Scheme 3).

[0303] In some embodiments, the present disclosure provides a method including reacting a first compound of formula I or a salt thereof (where R1 is -C(O)OR 11 , wherein R 11 is not -H (e.g., optionally substituted C 1-6 aliphatic)) is converted to a second compound of formula I or a salt thereof (wherein R 1 is -C(O)OH). In some embodiments, the first compound of formula I or a salt thereof has a structure 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 a structure 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, such as in THF / H 2 O.

[0304] In some embodiments, the present disclosure provides a method comprising: reacting a compound having a C-4 structure: or a salt thereof to provide a compound having a C-5 structure: or a salt thereof, wherein Hal is a halogen, and each other variable is independently as described herein.

[0305] In some embodiments, the compound having a C-4 structure or a salt thereof has a structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having a C-5 structure or a salt thereof has a structure 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 optionally substituted C 1-6 aliphatic. In some embodiments, Hal is Cl. In some embodiments, Hal is Br. In some embodiments, Hal is I.

[0306] In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is present in a metal complex. In some embodiments, the metal is palladium. In some embodiments, palladium is a complex. In some embodiments, the palladium complex is Pd(OAc) 2 . In some embodiments, the reaction is carried out in the presence of a phosphine compound, such as having the formula P(R) 3A phosphine compound or a salt thereof, wherein each R is independently as described herein and is not H. In some embodiments, the compound is 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 Cs 2 CO 3 . In some embodiments, the base is NaH.

[0307] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the C-2 structure: or a salt thereof with a compound having the C-3 structure: to provide a compound having the C-4 structure: or a salt thereof, wherein Hal is a halogen, Rsi is -Si(R) 3 , and each variable is independently as described herein.

[0308] 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, Rsi is -Si(R) 3 , wherein each R is independently as described herein and is not -H. In some embodiments, each R is independently selected from C 1-6 aliphatic and C 6-10 aryl optional substituents. In some embodiments, each R is independently selected from C 1-6 aliphatic and phenyl optional substituents. In some embodiments, the compound having the C-4 structure or a salt thereof has a structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the C-3 structure or a salt thereof has a structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the C-2 structure or a salt thereof has A structure or its salt, wherein each variable is independently as described herein. In some embodiments, the reaction is carried out under desilication conditions. In some embodiments, the reaction is carried out in the presence of a fluorinating agent. In some embodiments, the fluorinating agent is TBAF.

[0309] In some embodiments, the present disclosure provides a method comprising: Reacting a compound having the formula C-1 structure: or its salt to provide a compound having the formula C-2 structure: or its salt, wherein Hal is a halogen and Rsi is -Si(R) 3 , and each variable is independently as described herein.

[0310] 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 , wherein each R is independently as described herein and is not -H. In some embodiments, each R is independently an optionally substituted group selected from C 1-6 aliphatic and C 6-10 aryl. In some embodiments, each R is independently an optionally substituted group selected from C 1-6 aliphatic and phenyl. In some embodiments, the compound having the C-2 structure or its salt has a structure or its salt, 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 in the presence of a silylating agent, such as a compound having the formula Rsi-LG structure or its salt, wherein LG is a leaving group such as Cl, OTf, etc. In some embodiments, the reaction is carried out at a lower temperature, such as -100 °C.

[0311] In some embodiments, a method is described by taking Scheme 4 as an example: Scheme 4

[0312] Taking Scheme 4 as an example, a method for preparing the provided compounds (such as compounds of Formula I or their salts, such as compounds of Formula C or their salts) is illustrated, where each variable is independently as described herein. In some embodiments, the compound or its salt having the structure of Formula C-1 is silylated under conditions such as LDA / TMSCl / THF to obtain the compound or its salt having the structure of Formula C-2. In some embodiments, the compound or its salt having the structure of Formula C-2 and the aldehyde compound or its salt having the structure of Formula C-3 are treated under desilylation conditions such as TBAF / THF to obtain the alcohol compound or its salt having the structure of Formula C-4. In some embodiments, under the conditions of transition metal-catalyzed intramolecular C-O coupling (such as NaH / CuCl / PhMe or Pd(OAc) 2 / TrixiePhos / Cs 2 CO 3 ), the compound or its salt having the structure of Formula C-4 undergoes cyclization to obtain the compound or its salt having the structure of Formula C-5. Placing the compound or its salt having the structure of Formula C-5 under hydrolysis conditions (such as LiOH / THF / H 2 O) gives the compound or its salt having the structure of Formula I, such as the compound or its salt having the structure of Formula C.

[0313] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of Formula D-7: or its salt to provide a compound or its salt having the structure of Formula I, where each variable is independently as described herein.

[0314] In some embodiments, the compound or its salt having the structure of Formula D-7 has the structure or its salt, where each variable is independently as described herein. In some embodiments, the compound or its salt having the structure of Formula I has the structure or its salt, where each variable is independently as described herein. In some embodiments, the reaction is carried out under oxidative conditions (e.g., Pinnick oxidation conditions). According to the present disclosure, various techniques can be used to convert aldehydes to carboxylic acids.

[0315] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of Formula D-6: or its salt to provide a compound having the structure of Formula D-7: or its salt, where R d6 is -CH(OR)2 and each variable is independently as described herein.

[0316] In some embodiments, a compound having the structure of formula D-6 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, a compound having the structure of formula D-7 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein.

[0317] 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 1-6 aliphatic. In some embodiments, two Rs together with their intervening atom form an optionally substituted 4-10 (e.g., 5-10, 5-6, 4, 5, 6, 7, 8, 9, or 10) membered ring having 0-3 heteroatoms in addition to the intervening atom. In some embodiments, there are no heteroatoms other than the intervening atom. 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 6-membered. In some embodiments, the ring is substituted. In some embodiments, the ring is unsubstituted. In some embodiments, the ring is a saturated ring. In some embodiments, the ring is monocyclic. In some embodiments, R d6 is optionally substituted In some embodiments, R d6 is

[0318] A compound having the structure of formula D-6 or a salt thereof can be converted to a compound having the structure of formula D-7 or a salt thereof using various techniques 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.

[0319] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of formula D-5: or a salt thereof to provide a compound having the structure of formula D-6: or a salt thereof, wherein Hal 1 is Hal as described herein and the other variables are independently as described herein.

[0320] In some embodiments, a compound having the structure of formula D-5 or a salt thereof has A structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of D-6 or a salt thereof has A structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, Hal 1 is Cl. In some embodiments, Hal 1 is Br. In some embodiments, Hal 1 is I.

[0321] In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is present in a metal complex. In some embodiments, the metal is palladium. In some embodiments, palladium is a complex. In some embodiments, the palladium complex is Pd(OAc) 2 . In some embodiments, the reaction is carried out in the presence of a phosphine compound, for example, a phosphine compound having the structure of P(R) 3 or a salt thereof, wherein each R is independently as described herein and is not H. In some embodiments, the compound is 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 Cs 2 CO 3 . In some embodiments, the base is NaH.

[0322] In some embodiments, the present disclosure provides a method, comprising: Reacting a compound having the structure of D-4: or a salt thereof to provide a compound having the structure of D-5: or a salt thereof, wherein each variable is independently as described herein.

[0323] In some embodiments, the compound having the structure of D-5 or a salt thereof has A structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of D-4 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein.

[0324] In some embodiments, useful reaction conditions are reducing conditions. According to the present disclosure, various techniques can be utilized to reduce a ketone to an alcohol. 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 NaBH 4 .

[0325] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of Formula D-2: or a salt thereof with a compound having the structure of Formula D-3: or a salt thereof to provide a compound having the structure of Formula D-4: or a salt thereof, wherein each Hal 2 is Hal as described herein, each R d21 and R d22 is independently R as described herein, and each other variable is independently R as described herein.

[0326] In some embodiments, R d21 is optionally substituted C 1-6 aliphatic. In some embodiments, R d21 is optionally substituted C 1-6 alkyl. In some embodiments, R d21 is methyl. In some embodiments, R d22 is optionally substituted C 1-6 aliphatic. In some embodiments, R d22 is optionally substituted C 1-6 alkyl. In some embodiments, R d22 is methyl.

[0327] In some embodiments, the compound having the structure of Formula D-2 or a salt thereof has the structure 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 structure 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 structure or a salt thereof, wherein each variable is independently as described herein.

[0328] In some embodiments, Hal 2 is Cl. In some embodiments, Hal 2is Br. In some embodiments, Hal 2 is I.

[0329] In some embodiments, the reaction is carried out in the presence of an organometallic preparation. In some embodiments, the preparation is a lithium preparation such as n-BuLi. In some embodiments, the preparation is a magnesium preparation such as i-PrMgBr. In some embodiments, a compound having the structure of formula D-3 or a salt thereof is contacted with an organometallic preparation, and the resulting preparation is contacted with a compound having the structure of formula D-2 or a salt thereof.

[0330] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of formula D-1: or a salt thereof with a compound having the structure of formula NH(R d21 )OR d22 or a salt thereof to obtain a compound having the structure of formula D-2: or a salt thereof, wherein each variable is independently as described herein.

[0331] In some embodiments, the compound having the structure of formula D-2 or a salt thereof has a structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of formula NH(R d21 )OR d22 or a salt thereof is MeNHOMe or a salt thereof, such as MeNHOMe-HCl.

[0332] In some embodiments, the reaction is carried out under coupling conditions. According to the present disclosure, various coupling techniques can be used.

[0333] In some embodiments, a method is described by taking Scheme 5 as an example: Scheme 5

[0334] The preparation method of the provided compound, such as the compound of formula I or a salt thereof, such as the compound of formula D or a salt thereof, is illustrated by taking Scheme 5 as an example, wherein each variable is independently as described herein. In some embodiments, under amide coupling conditions (such as HATU / DIPEA), the acidic compound of formula D-1 or a salt thereof (in some embodiments, Hal 1(wherein Hal is Cl, Br or I), to obtain a compound of formula D-2 or a salt thereof. In some embodiments, an organometallic reagent (such as n-BuLi or i-PrMgBr) is used to react a compound of formula D-3 or a salt thereof with a protected aldehyde (in some embodiments, Hal 2 is Br or I) for halometal exchange, and the resulting arylmetal intermediate is added to a compound of formula D-2 or a salt thereof to obtain a ketone compound of formula D-4 or a salt thereof. In some embodiments, a reducing reagent such as NaBH 4 is used to reduce the ketone of formula D-4 or a salt thereof to obtain an alcohol compound of formula D-5 as described herein. In some embodiments, under transition metal-catalyzed intramolecular C-O coupling conditions, such as NaH / CuCl / PhMe or Pd(OAc) 2 / TrixiePhos / Cs 2 CO 3 , cyclizing the compound of formula D-5 as described herein to obtain a compound of formula D-6 or a salt thereof. In some embodiments, the compound of formula D-6 or a salt thereof is subjected to acid hydrolysis conditions (such as HCl), and then the resulting aldehyde compound of formula D-7 or a salt thereof is oxidized under Pinnick oxidation conditions, etc., to obtain a compound of formula I or a salt thereof, such as a compound of formula D or a salt thereof.

[0335] In some embodiments, the present disclosure provides a method comprising: reacting a compound or a salt thereof having the structure of formula D'-5: to provide a compound having the structure of formula D'-6: or a salt thereof, wherein each variable is independently as described herein.

[0336] In some embodiments, the compound or a salt thereof having the structure of formula D'-5 has a structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound or a salt thereof having the structure of formula D'-6 has a structure or a salt thereof, wherein each variable is independently as described herein.

[0337] The compound or a salt thereof having the structure of formula D'-5 can be converted into the compound or a salt thereof having the structure of formula D-6 by various techniques. In some embodiments, the condition is Mitsunobu condition. 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 azodicarboxylic acid compound. In some embodiments, the phosphine compound has P(R) 3The structure, wherein each R is independently as described herein and is not -H. In some embodiments, each R is independently an optionally substituted phenyl group. In some embodiments, the phosphine compound is PPh 3 . In some embodiments, the azodicarboxylic acid compound has R a1 O 2 C-N=N-CO 2 R a2 structure or a salt thereof, wherein each R a1 and R a2 is independently R. In some embodiments, neither R a1 nor R a2 is -H. In some embodiments, R a1 is C 1-6 aliphatic. In some embodiments, R a1 is ethyl. In some embodiments, R a1 is isopropyl. In some embodiments, R a2 is C 1-6 aliphatic. In some embodiments, R a2 is ethyl. In some embodiments, R a2 is isopropyl. In some embodiments, the azodicarboxylic acid compound is DIAD. In some embodiments, the azodicarboxylic acid compound is DEAD.

[0338] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the formula D'-4 structure or a salt thereof: to provide a compound having the formula D'-5 structure: or a salt thereof, wherein PG is a protecting group and the other variables are independently as described herein.

[0339] In some embodiments, the compound having the formula D'-4 structure or a salt thereof has structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the formula D'-5 structure or a salt thereof has structure or a salt thereof, wherein each variable is independently as described herein. Those skilled in the art will appreciate that there are many techniques available for protecting and deprotecting phenolic 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, allyl, etc.

[0340] In some embodiments, the present disclosure provides a method comprising: React a compound having the structure of D'-3 or a salt thereof: to provide a compound having the structure of D'-4: or a salt thereof, wherein each variable is independently as described herein.

[0341] In some embodiments, the compound having the structure of D'-3 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of D'-4 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein.

[0342] In some embodiments, useful reaction conditions are reducing conditions. According to the present disclosure, various techniques can be utilized to reduce a ketone to an alcohol.

[0343] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of D'-1 or a salt thereof: with a compound having the structure of D'-2 or a salt thereof: to provide a compound having the structure of D'-3: or a salt thereof, wherein each Hal 3 is Hal as described herein, and each other variable is independently as described herein.

[0344] In some embodiments, the compound having the structure of D'-1 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of D'-2 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein. In some embodiments, the compound having the structure of D'-3 or a salt thereof has the structure or a salt thereof, wherein each variable is independently as described herein.

[0345] In some embodiments, Hal 3 is Cl. In some embodiments, Hal 3 is Br. In some embodiments, Hal 3 is I.

[0346] In some embodiments, the reaction is carried out in the presence of a metal. In some embodiments, the metal is present in a metal complex. In some embodiments, the metal complex is a palladium complex. In some embodiments, the metal complex is XPhos Pd G3. In some embodiments, a suitable solvent is dioxane. In some embodiments, the reaction is carried out in the presence of a base. In some embodiments, the base is Cs 2 CO 3 .

[0347] In some embodiments, the present disclosure provides a method comprising: reacting a compound having the structure of formula D'-0: or a salt thereof with a compound having the structure of formula D-3 or a salt thereof: to provide a compound having the structure of formula D'-1: or a salt thereof, wherein each variable is independently as described herein.

[0348] In some embodiments, the compound having the structure of formula D'-0 and its salts have a structure. In some embodiments, the compound having the structure of formula D-3 or its salts have a structure 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 its salts have a structure or a salt thereof, wherein each variable is independently as described herein.

[0349] In some embodiments, the reaction is carried out in the presence of an organometallic preparation. In some embodiments, the preparation is a lithium preparation such as n-BuLi. In some embodiments, the preparation is a magnesium preparation such as i-PrMgBr. In some embodiments, the compound having the structure of formula D-3 or its salts is contacted with the organometallic preparation, and the resulting preparation is contacted with the compound having the structure of formula D'-0 or its salts.

[0350] In some embodiments, a method is described by taking Scheme 6 as an example: Scheme 6

[0351] The method for preparing the provided compounds, such as the compound of formula I or its salt, such as the compound of formula D' or its salt, is illustrated by Scheme 6, wherein each variable is independently as described herein. In some embodiments, the compound of formula D-3 or its salt is subjected to halogen-metal exchange using an organometallic reagent (such as n-BuLi or i-PrMgBr), and the resulting arylmetal intermediate is added to N-methoxy-N-methylacetamide to obtain the ketone compound of formula D'-1 or its salt. In some embodiments, under appropriate conditions, such as under Pd-catalyzed ketone α-arylation conditions (such as XPhos Pd G3 / Cs 2 CO 3 / dioxane), the compound of formula D'-1 or its salt and the aryl halide of formula D'-2 or its salt are treated to obtain the α-aryl ketone of formula D'-3 or its salt. In some embodiments, the ketone of formula D'-3 or its salt is reduced with a reducing reagent (such as NaBH 4 ) to obtain the alcohol compound of formula D'-4 or its salt. In some embodiments, removing the protecting group of phenol gives the compound of formula D'-5 or its salt. In some embodiments, under suitable conditions, such as under Mitsunobu conditions (such as DIAD / PPh 3 ), cyclizing the compound of formula D'-5 or its salt gives the compound of formula D'-6 or its salt. In some embodiments, the compound of formula D'-6 or its salt is subjected to acid hydrolysis conditions (such as HCl), and the resulting aldehyde compound of formula D'-7 or its salt is oxidized (such as Pinnick oxidation) to obtain the compound of formula I or its salt, such as the compound of formula D' or its salt.

[0352] In some embodiments, a method is described by taking Scheme 7 as an example: Scheme 7

[0353] The method for preparing the provided compounds, such as the compound of formula I or its salt, such as the compound of formula E (such as formula E-8) or its salt, is illustrated by taking Scheme 7 as an example, wherein each variable is independently as described herein. In some embodiments, the provided method includes subjecting the compound of formula E-1 or its salt to halogen-metal exchange using an organometallic reagent (such as n-BuLi or i-PrMgBr) to provide an arylmetal compound. In some embodiments, the provided method includes adding the arylmetal compound to N-methoxy-N-methylacetamide to provide the ketone compound of formula E-2 or its salt. In some embodiments, the method includes under suitable conditions, such as under Pd-catalyzed ketone α-arylation conditions (such as XPhos Pd G3 / Cs 2 CO 3 / dioxane), treating a compound of formula E-2 or a salt thereof and an aryl halide of formula E-3 or a salt thereof to provide an α-aryl ketone of formula E-4 or a salt thereof. In some embodiments, the method includes using a reducing agent such as NaBH 4 reducing the ketone of formula E-4 or a salt thereof to provide an alcohol compound of formula E-5 or a salt thereof. In some embodiments, the method includes removing the protecting group of phenol to provide 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 suitable conditions, such as under Mitsunobu conditions (e.g., DIAD / PPh 3 ) to provide 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., TMSN 3 ) to provide a compound of formula I or a salt thereof, such as a compound of formula E-8 or a salt thereof.

[0354] In some embodiments, a method is described by taking Scheme 8 as an example: Scheme 8

[0355] A method for preparing the provided compounds, such as a compound of formula I or a salt thereof, such as a compound of formula F-7, formula F-8, formula F-9 or a compound of formula F or a salt thereof, is illustrated by taking Scheme 8 as an example, wherein each variable is independently as described herein. In some embodiments, Hal 1 、Hal 2 and Hal 3 each independently is F, Cl, Br or I. In some embodiments, Hal 1 is -Br. In some embodiments, Hal 2 is -Br. In some embodiments, Hal 3 is -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 zinc reagent to provide a compound of formula F-2 or a salt thereof. In some embodiments, the zinc reagent is zinc or contains zinc. In some embodiments, the reaction is carried out in the presence of a salt, such as a lithium salt, such as LiCl. In some embodiments, the method includes under suitable conditions, such as using SOCl 2, reacting a compound of formula F-3 or a salt thereof to produce a compound of formula F-4 or a salt thereof. In some embodiments, the 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 (such as a transition coupling) to form a compound of formula F-5 or a salt thereof. In some embodiments, the coupling of the compound of formula F-2 or a salt thereof with the compound of formula F-4 or a salt thereof utilizes a metal agent, such as CuCN. In some embodiments, such reaction is carried out in the presence of a salt, such as a lithium salt, such as LiCl. In some embodiments, the method includes reducing a compound of formula F-5 or a salt thereof to provide a compound of formula F-6 or a salt thereof. In some embodiments, the reduction is hydrogenation or includes hydrogenation. In some embodiments, the hydrogenation utilizes H 2 . In some embodiments, the hydrogenation is in-situ trans-hydrogenation. In some embodiments, the hydrogenation utilizes a metal catalyst. In some embodiments, the hydrogenation utilizes 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, it is RuCl(p-cymene)[(S,S)-Ts-DPEN]. In some embodiments, the hydrogenation utilizes RuCl(p-cymene)[(S,S)-Ts-DPEN]. and HCOOH. According to the present disclosure, various reduction techniques can be used. In some embodiments, a method includes reacting a compound of formula F-6 or a salt thereof under appropriate conditions, such as using a base, to provide a compound of formula F-7 or a salt thereof. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is t-BuONa. In some embodiments, the base is a metal alkoxide. In some embodiments, a method includes reacting a compound of formula F-7 or a salt thereof with a cyanide reagent to provide a compound of formula F-8 or a salt thereof. In some embodiments, the cyanide reagent is CuCN. In some embodiments, a method includes reacting a compound of formula F-8 or a salt thereof with an azide reagent to provide a compound of formula F-9 or a salt thereof. In some embodiments, the azide reagent is TMSN 3 . In some embodiments, the azide reagent is NaN 3 . In some embodiments, the reaction is carried out in the presence of a catalyst. In some embodiments, the catalyst is Bu 2 SnO. In some embodiments, a method includes reacting a compound of formula F-8 or a salt thereof with TMSN 3 and Bu 2The SnO reaction is carried out to provide the compound of formula F-9 or its salt. In some embodiments, the reaction is carried out in the presence of a base and / or a salt of a base (such as TEA-HCl). In some embodiments, the base is an amine base. In some embodiments, a method includes reacting a compound of formula F-8 or its salt with NaN 3 , TEA-HCl and NMP to provide the compound of formula F-9 or its salt. In some embodiments, a method includes reacting a compound of formula F-8 or its salt with an azide reagent to provide the compound of formula F-9 or its salt, and the reaction amount is greater than or equal to 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 method includes reacting a compound of formula F-8 or its salt with an azide reagent to provide the compound of formula F-9 or its salt, and the reaction amount is 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 method includes reacting a compound of formula F-9 or its salt with a base to provide the compound of formula F or its salt. In some embodiments, the base is NaOH. In some embodiments, the base is KOH.

[0356] In some embodiments, the present disclosure provides a method that includes contacting a compound of formula I or its salt with a base to prepare a salt of the compound of formula I, where R 1 is -C(O)OR 11 , -P(O)(OR 12 )(OR 13 ) or or where R 11 is hydrogen, and at least one of R 12 and R 13 is hydrogen. 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. Various bases can be used to prepare salts, including pharmaceutically acceptable salts, and can be used according to the present disclosure.

[0357] Those skilled in the art who read the present disclosure will understand that in some embodiments, the compound of formula F-1 or its salt can be replaced by the compound of formula F-1' , where each variable is as described herein. In some embodiments, Hal 3 is F. In some embodiments, Hal 2is Br. In some embodiments, the compound of formula F-1 or F-1' is In some embodiments, the compound of formula F-2 or a salt thereof can be replaced with a compound of formula F-2' or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of F-2 or F-2' is In some embodiments, the compound of F-2 or F-2' is In some embodiments, the compound of formula F-3 is In some embodiments, the compound of formula F-4 is In some embodiments, the compound of formula F-5 or a salt thereof can be replaced by a compound of formula F-5' or a salt thereof, wherein 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' is In some embodiments, the compound of formula F-6 or a salt thereof can be replaced with a compound of formula F-6' or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F-6 or F-6' is In some embodiments, the compound of formula F-6 or F-6' is In some embodiments, the compound of formula F-7 or a salt thereof can be replaced with a compound of formula F-7' or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F-7 or F-7' is In some embodiments, the compound of formula F-7 or F-7' is In some embodiments, the compound of formula F-8 or a salt thereof can be replaced with a compound of formula F-8' or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound of formula F-8 or F-8' is In some embodiments, the compound of formula F-8 or F-8' is In some embodiments, the compound of formula F-9 or a salt thereof can be replaced by a compound of formula F-9' or a salt thereof, wherein each variable is as described herein. In some embodiments, the compound or a salt of formula F-9 or F-9' is or a salt thereof. In some embodiments, the compound or a salt of formula F-9 or F-9' is or a salt thereof. In some embodiments, the compound or a salt of formula F is a compound or a salt of formula F' wherein each variable is as described herein. In some embodiments, the compound or a salt of formula F or F' is In some embodiments, a compound of formula F or F' or a salt thereof is 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 optionally substituted 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 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 optionally substituted 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 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

[0358] In some embodiments, the present disclosure provides a method comprising reacting a compound having the structure of formula I (wherein R 1 is -CN) or a salt thereof to provide a compound having the structure of formula I (wherein R 1 is ) or a salt thereof. According to the present disclosure, such reactions can be carried out using various techniques. For example, in some embodiments, a method comprises contacting a compound having the structure of formula I (wherein R 1 is -CN) or a salt thereof with an azide and a tin oxide. In some embodiments, the azide is TMSN 3 . In some embodiments, the tin oxide has the structure of R 2 Sn(O) or a salt thereof. In some embodiments, each R is an optionally substituted C 1-6 aliphatic. In some embodiments, each R is independently a C 1-6 alkyl. In some embodiments, each R is independently a C 1-6 alkyl. In some embodiments, two Rs are the same. In some embodiments, the tin oxide is dibutyltin oxide. In some embodiments, the reaction is carried out at a temperature above ambient temperature, such as about 100 °C, 110 °C or higher. In some embodiments, the reaction is carried out in a solvent (such as toluene). In some embodiments, the reaction time is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours or longer.

[0359] In some embodiments, the present disclosure provides a method comprising reacting a compound having the structure of formula I (wherein R 1 is -C(O)NH 2) or its salt to provide a compound having the structure of formula I, wherein R 1 is -CN). According to the present disclosure, various techniques can be used for such reactions. For example, in some embodiments, a compound having the structure of formula I, wherein R 1 is -C(O)NH 2 ) or its salt is contacted with an acid anhydride. In some embodiments, a compound having the structure of formula I, wherein R 1 is -C(O)NH 2 ) or its salt is contacted with TFAA. In some embodiments, the contacting is carried out in the presence of a base such as Et 3 N. In some embodiments, the reaction is carried out in a suitable solvent such as dichloromethane. In some embodiments, the reaction is carried out at a temperature below ambient temperature, for example about 0 °C.

[0360] In some embodiments, the present disclosure provides a method comprising reacting a compound having the structure of formula I, wherein R 1 is -C(O)OH) or its salt to provide a compound having the structure of formula I, wherein R 1 is -C(O)NH 2 ). Various techniques such as amidation techniques can be used for such reactions and can be utilized according to the present disclosure. For example, in some embodiments, a compound having the structure of formula I (wherein R 1 is -C(O)OH) or its salt is activated. In some embodiments, a compound having the structure of formula I, wherein R 1 is -C(O)OH) or its salt is contacted with SOCl 2 . In some embodiments, a compound having the structure of formula I, wherein R 1 is -C(O)OH) or its salt or its activated form is contacted with NH3 (such as NH 3 in MeOH). In some embodiments, the present disclosure provides a method comprising reacting a compound having the structure of formula I, wherein R 1 is -C(O)OH) or its salt to provide a compound having the structure of formula I, wherein R 1 is -CN).

[0361] In some embodiments, the formulation or composition is rich in stereoisomers. In some embodiments, the formulation or composition is rich in diastereomers. In some embodiments, the formulation or composition is rich in enantiomers. In some embodiments, the formulation or composition is diastereomerically pure. In some embodiments, the formulation or composition is enantiomerically pure. According to the present disclosure, various stereoselective techniques, such as chiral auxiliaries, stereoselective reactions, stereoselective catalysis, etc., can be utilized to prepare formulations and compositions with high stereochemical enrichment or purity. For example, in some embodiments, the compound of formula F-5 or F-5' or a salt thereof can be stereoselectively reduced to provide the compound of formula F-6 or F-6' or a salt thereof. In some embodiments, the stereogenic carbon formed upon reduction is R. In some embodiments, it is S. In some embodiments, the reduction is carried out in the presence of a chiral metal catalyst (such as RuCl(p-cymene)[(S,S)-Ts-DPEN]).

[0362] Certain preparation techniques of the provided compounds are illustrated in the Examples. Use

[0363] In some embodiments, the present disclosure provides a method of modulating the activity of MRGPRX4 by contacting MRGPRX4 with an effective amount of a compound or pharmaceutical composition described herein.

[0364] In some embodiments, the present disclosure provides a method of modulating the activity of MRGPRX4 in a system comprising MRGPRX4, comprising administering or delivering to the system an effective amount of a compound or pharmaceutical composition as described herein. In some embodiments, the system is a cell or comprises a cell. In some embodiments, the system is a tissue or comprises a tissue. In some embodiments, the system is an organ or comprises an organ. In some embodiments, the system is an organism 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, compared to not using the provided compound, a method can reduce the level of MRGPRX4 activity. In some embodiments, the reduction amount is about or at least about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%.

[0365] In some embodiments, the present disclosure provides a method of preventing a disorder, condition or disease, comprising administering to a susceptible subject an effective amount of the provided compound or composition. In certain embodiments, the present disclosure provides a method of treating a disorder, condition or disease, comprising administering to a subject having the disorder, condition or disease an effective amount of the provided compound or composition. In certain embodiments, the present disclosure provides a method of preventing a disorder, condition or disease, comprising delivering to a susceptible subject an effective amount of the provided compound or composition. In certain embodiments, the present disclosure provides a method of treating a disorder, condition or disease, comprising delivering to a subject having the disorder, condition or disease an effective amount of the provided compound or composition. 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, the free drug may be administered for delivery of the provided compound.

[0366] In some embodiments, the compound is used 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 used in the stereochemically pure form described herein. In some embodiments, the compound is used in enantiomerically pure form. In some embodiments, as described herein, the composition is enriched in one or more stereoisomers. In some embodiments, as described herein, the composition is enriched in the enantiomers described herein. In some embodiments, the composition is stereochemically pure. In some embodiments, the composition is enantiomerically pure.

[0367] In some embodiments, the disorder, condition or disease is itch or includes itch. In some embodiments, the disorder, condition or disease is itch. In some embodiments, the disorder, condition or disease is an MRGPRX4-related disorder, condition or disease. In some embodiments, the disorder, condition or disease is associated with MRGPRX4 activation.

[0368] In some embodiments, the disorder, condition 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, eczematous dermatitis, atopic eczema, eczema, lupus erythematosus, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iron deficiency anemia, kidney disease, leukemia, liver disease, lymphoma, malignancy, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia vera, pruritus ani, pseudorabies, psoriasis, rectal prolapse, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus or urticaria.

[0369] In some embodiments, the disorder, condition or disease is MRGPRX4-related pruritus. In some embodiments, the disorder, condition or disease is acute or chronic pruritus associated with MRGPRX4 and is related to a liver disorder, condition or disease.

[0370] In some embodiments, the MRGPRX4-related pruritus is acute or chronic pruritus associated with a hepatobiliary disorder, condition or disease. In some embodiments, the hepatobiliary disorder, condition or disease is intrahepatic cholestasis of pregnancy (ICP), estrogen-, progesterone-, testosterone-induced cholestasis, toxin- or other drug-induced cholestasis of hepatocytes, benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC), chronic hepatitis C virus, 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 small duct cholangiopathy, cholelithiasis, IgG4-related cholangitis, biliary atresia, cholangiocarcinoma, benign cholangioma or other obstructive cholestasis.

[0371] In some embodiments, the disorder, condition or disease is a liver disorder, condition or disease. In some embodiments, the liver disorder, condition or disease is non-alcoholic steatohepatitis (NASH). In some embodiments, the liver disorder, condition or disease is non-alcoholic fatty liver disease (NAFLD). In some embodiments, the liver disorder, condition or disease is ICP. In some embodiments, the liver disorder, condition or disease is primary biliary cholangitis (PBC). In some embodiments, the liver disorder, condition or disease is progressive familial intrahepatic cholestasis (PFIC). In some embodiments, the liver disorder, condition or disease is PSC. In some embodiments, the liver disorder, condition or disease is BRIC. In some embodiments, the liver disorder, condition or disease is chronic hepatitis B.

[0372] In some embodiments, the liver disorder, condition or disease is non-alcoholic steatohepatitis (NASH). In some embodiments, the disorder, condition or disease is a bile acid synthesis disorder, condition or disease. In some embodiments, the bile acid synthesis disorder, condition or disease is caused by a single enzyme defect (SED). In some embodiments, the disorder, condition or disease is a peroxisomal disorder, condition or disease such as Zellweger spectrum disorder. In some embodiments, the disorder, condition or disease is a liver disorder, condition or disease, or steatorrhea or a complication caused by reduced absorption of fat-soluble vitamins.

[0373] In some embodiments, the condition, disorder or disease is a cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic liver disease, gastrointestinal disease, kidney disease, metabolic disease, cancer (such as colorectal cancer) or a neurological disease such as stroke. In certain embodiments, the condition, disorder or disease is primary biliary cholangitis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral 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), graft-versus-host disease associated with liver transplantation, 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 kidney disease is diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic allograft glomerulopathy, chronic interstitial nephritis or polycystic kidney. In some embodiments, the cardiovascular disease is atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia. In some 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 inflammation, disorder or disease such as allergy, osteoarthritis, appendicitis, bronchial asthma, pancreatitis, allergic rash, psoriasis, etc. In certain 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 I 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 colorectal cancer, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, kidney cancer, gastric cancer, pancreatic cancer, prostate cancer or insulinoma. In some embodiments, the condition, disorder or disease is FXR-mediated. In some embodiments, the condition, disorder or disease is TGR 5 mediated. In some embodiments, susceptible and / or diseased subjects may benefit from FXR and / or TGR 5Benefit from the increased activity level. In some embodiments, the disorder, condition or disease is chronic kidney disease. In some embodiments, the disorder, condition or disease is uremic pruritus.

[0374] In some embodiments, the disorder, condition or disease is related to the administration or delivery of an agent that can activate MRGPRX4. Many techniques for evaluating MRGPRX4 activation, such as in vivo, in vitro, etc., can be used to evaluate whether an agent can activate MRGPRX4. Certain useful techniques have been described in the study by Meixiong et al. MRGPRX4 is a G protein-coupled receptor activated by bile acids or their analogs or derivatives, which may lead to cholestatic pruritus, PNAS, 2019, 116(21), 10525-10530; Yu et al. MRGPRX4 is the bile acid receptor for human cholestatic pruritus, eLife, 2019, 8, e48431.

[0375] In some embodiments, a disorder, condition, or disease is associated with the administration or delivery of an agent that can activate MRGPRX4 but also provides another activity, and the agent may be used as a therapeutic agent for treating a condition, disorder, or disease. In some embodiments, the present disclosure provides methods for preventing or treating a disorder, condition, or disease associated with the administration of an agent, including administering or delivering to a subject an effective amount of the provided compound or composition. In some embodiments, the present disclosure provides a method for preventing a disorder, condition, or disease associated with the administration of an agent, including administering to a subject an effective amount of the provided compound or composition. In some embodiments, the present disclosure provides a method for preventing a disorder, condition, or disease associated with the administration of an agent, including delivering to a subject an effective amount of the provided compound or composition. In some embodiments, the present disclosure provides a method for treating a disorder, condition, or disease associated with the administration of an agent, including administering to a subject an effective amount of the provided compound or composition. In some embodiments, the present disclosure provides a method for treating a disorder, condition, or disease associated with the administration of an agent, including delivering to a subject an effective amount of the provided compound or composition. In some embodiments, the agent can activate MRGPRX4. In some embodiments, the agent is a bile acid or a salt thereof (such as a pharmaceutically acceptable salt). In some embodiments, the agent is a bile acid analogue or a salt thereof (such as a pharmaceutically acceptable salt). In some embodiments, the agent is a bile acid derivative or a salt thereof (such as a pharmaceutically acceptable salt). In some embodiments, the agent is a bile acid conjugate, such as a taurine conjugate, or a salt thereof (such as 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 ursolic acid. In some embodiments, the bile acid is phenodeoxycholic acid. In some embodiments, the bile acid or its analogue or derivative is cis-cholic acid. In some embodiments, the bile acid or its analogue or derivative is tauroursodeoxycholic acid or a salt thereof (e.g., a pharmaceutically acceptable salt); in some embodiments, it is tauroursodeoxycholic acid; in some embodiments, it is sodium tauroursodeoxycholate. In some embodiments, the agent is an FXR agonist. In some embodiments, the agent is TGR 5Agonist. In some embodiments, the agent is a therapeutic agent. In some embodiments, the agent is an approved therapeutic agent, for example, a therapeutic agent approved by the US Food and Drug Administration (such as cholic acid, obeticholic acid, taurodihydrocholic acid, ursodeoxycholic acid, etc.), which can be used alone or in combination with another therapeutic agent. In some embodiments, the agent is obeticholic acid and is used in combination with ursodeoxycholic acid. In some embodiments, the agent is taurodihydrocholic acid and is used together with sodium phenylbutyrate. In some embodiments, the condition, disorder or disease associated with the administration of the formulation is or includes pruritus. In some embodiments, the provided method can improve the patient's compliance with the formulation. In some embodiments, the provided method can increase the single dose, total dose, dose frequency and / or the time of the dosing regimen of the agent. In some embodiments, the provided compound can reduce the severity of side effects, such as pruritus. In some embodiments, the provided compound is 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 the administration of the agent. In some embodiments, the provided compound is 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 the administration of the agent. In some embodiments, the provided compound is administered or delivered simultaneously with the administration of the agent.

[0376] In some embodiments, the compounds described herein can be used as combination therapy with another therapeutic agent to prevent or treat a certain condition, disorder or disease. In some embodiments, the condition, disorder or disease is related to MRGPRX4 activation. In some embodiments, the therapeutic agent administered or delivered to the subject can activate MRGPRX4. In some embodiments, the provided compound can alleviate the condition, disorder or disease associated with MRGPRX4 activation. In some embodiments, the condition, disorder or disease is or includes concurrent MRGPRX4-related pruritus. In some 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, BAR 7 04, BAR 502, EYP-001, RDX-023, AGN-242266, HPG-1860, AGN-242256, IOT-022, M-480, INV-33, etc. In some embodiments, the therapeutic agent is an ileal bile acid transporter (IBAT) inhibitor, such as odevixibat, maralixibat, etc. In some embodiments, the therapeutic agent is ursodeoxycholic acid. In some embodiments, a 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]-dioxaphospholane), etc. In some embodiments, the therapeutic agent is a peroxisome proliferator-activated receptor (PPAR) agonist, such as elafibranor, lanifibranor, saroglitazar, pioglitazone, rosiglitazone, etc. In some embodiments, the therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist, such as semaglutide, exenatide, dulaglutide, liraglutide, lixisenatide, danuglipron (PF-06882961), PF-07081532, etc. In some embodiments, the therapeutic agent is a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, such as tirzepatide. In some embodiments, the therapeutic agent is an acetyl-CoA carboxylase (ACC) inhibitor, such as firsocostat, PF-05221304, WZ66, etc. In some embodiments, the therapeutic agent is a diacylglycerol O-acyltransferase homolog 2 (DGAT2) inhibitor, such as PF-06865571. In some embodiments, another therapeutic agent is a ketohexokinase (KHK) inhibitor, such as PF-06835919. In some embodiments, the therapeutic agent is an approved formulation (such as approved by the US Food and Drug Administration), which can be used alone or in combination to treat a certain condition, disorder or disease. Various approved formulations and their uses are publicly available and can be used together with the provided compounds according to the present disclosure.For example, in some embodiments, obeticholic acid is approved for the treatment of adult patients with primary biliary cholangitis (PBC) without cirrhosis or with compensated cirrhosis and no evidence of portal hypertension, in combination with ursodeoxycholic acid (UDCA), but with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. In some embodiments, bile acid drugs are approved for the treatment of bile acid synthesis disorders caused by single enzyme defects (SED) or as adjuvant therapy for peroxisomal diseases (PD), including Zellweger spectrum disorders, in patients presenting with complications of liver disease, steatorrhea, or reduced absorption of fat-soluble vitamins. In some embodiments, tauroursodeoxycholic acid, in combination with sodium phenylbutyrate (Relyvrio), is approved for the treatment of amyotrophic lateral sclerosis (ALS).

[0377] In some embodiments, the provided compound is administered or delivered concurrently with another therapeutic agent. In some embodiments, the provided compound is administered or delivered in a single composition with another therapeutic agent. In some embodiments, the provided compound is administered or delivered concurrently with another therapeutic agent in different compositions. In some embodiments, the provided compound is administered or delivered prior to another 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 prior to another therapeutic agent). In some embodiments, the provided compound is administered or delivered subsequent to another 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 subsequent to another therapeutic agent). In some embodiments, the provided compound is administered or delivered while the subject is under the therapeutic effect of another therapeutic agent.

[0378] In some embodiments, Meixiong et al. reported bile acids or their analogs or derivatives. MRGPRX4 is a G protein-coupled receptor activated by bile acids and may cause cholestatic pruritus, PNAS, 2019, 116(21), 10525-10530; Yu et al. MRGPRX4 is the bile acid receptor for human cholestatic pruritus, eLife, 2019, 8, e48431. In some embodiments, a bile acid or its analog or derivative is reported in WO 2016086169, US10519191, WO 2016130809, US10246483, WO 2017147174, WO 2017147159, WO2017147137, US10364267, US10323061, US10323060, WO 2017189663, WO 2017189652, WO2017189651, US10080743, US10080742, US10080741, WO 2017201155, WO 2017201152, WO2017201150, US10144729, US10138228, WO 2018067704, US10450306, WO 2018081285, US10597391, WO 2018102418, US10584145, WO 2018152171, US10472386, WO 2018187804, US10676500, WO 2019118571, US10689391, WO 2020231917, WO 2016073767, US10266560, WO2016086134, US10208081, WO 2016086218, US10696713, US10968249, WO 2016086115, WO2016161003, US10457703, US11040998, US11034684, US10947264, US10961272, WO2019160813 or US10829486, each of which bile acid and its analog or derivative is incorporated herein by reference.In some embodiments, FXR agonists are reported in WO 2016086169, US10519191, WO 2016130809, US10246483, WO 2017147174, WO 2017147159, WO 2017147137, US10364267, US10323061, US10323060, WO 2017189663, WO 2017189652, WO 2017189651, US10080743, US10080742, US10080741, WO 2017201155, WO 2017201152, WO 2017201150, US 10144729, US10138228, WO 2018067704, US10450306, WO 2018081285, US10597391, WO 2018102418, US10584145, WO2018152171, US10472386, WO 2018187804, US10676500, WO 2019118571, US 10689391, WO2020231917, WO 2016073767, US10266560, WO 2016086134, US10208081, WO 2016086218, US10696713, US10968249, WO 2016086115, WO 2016161003, US10457703, US11040998, US11034684, US10947264, US10961272, WO 2019160813 or US10829486, each of which is incorporated herein by reference.

[0379] In some embodiments, the disorder, condition or disease is primary biliary cholangitis (PBC). In some embodiments, the disorder, condition or disease is primary biliary cholangitis (PBC) without cirrhosis or compensated cirrhosis without evidence of portal hypertension. In some embodiments, the other therapeutic agent is or provides obeticholic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the other therapeutic agent is or provides ursodeoxycholic acid (UDCA) or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating primary biliary cholangitis (PBC), comprising administering or delivering to a subject suffering from the disease an effective amount of the provided compound, wherein the subject is receiving or exposed to or under the action of another therapeutic agent (e.g., UDCA or a salt thereof). In some embodiments, the other therapeutic agent is administered or delivered concomitantly with the provided compound. In some embodiments, the other therapeutic agent and the provided compound are administered or delivered via the same pharmaceutical composition. In some embodiments, one of the provided compounds is administered before or after the other therapeutic agent. In some embodiments, the subject is concomitantly exposed to therapeutically relevant levels of the provided compound and the other therapeutic agent. In some embodiments, the subject is concomitantly exposed to the therapeutically relevant effects of the provided compound and the other therapeutic agent.

[0380] In some embodiments, the disorder, condition or disease is a bile acid synthesis disorder. In some embodiments, the disorder, condition or disease is a bile acid synthesis disorder due to single enzyme defect (SED). In some embodiments, the disorder, condition or disease is a peroxisomal disorder (PD). In some embodiments, the disorder, condition or disease is a peroxisomal disorder (PD) including Zellweger spectrum disorder. In some embodiments, the subject exhibits liver disease, steatorrhea or complications. In some embodiments, the other therapeutic agent is cholic acid.

[0381] In some embodiments, the disorder, condition or disease is a neurodegenerative disorder, condition or disease. In some embodiments, the disorder, condition or disease is ALS. In some embodiments, the other therapeutic agent is taurursodiol in combination with sodium phenylbutyrate (Relyvrio).

[0382] In some embodiments, the subject is an adult patient. In some embodiments, the subject is a pediatric patient. Pharmaceutical Compositions and Administration

[0383] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the provided compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition that can provide the 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.

[0384] A variety of techniques, such as routes, modes, dosage regimens, etc. can be used to administer and / or deliver the compounds and compositions provided according to the present disclosure. In some embodiments, the route of administration and / or the mode of administration can be varied according to the desired result. Those skilled in the art (i.e., physicians) know that the dosage regimen can be adjusted to provide the desired response, such as 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, inhaled, or topical, particularly to the ear, nose, eyes, 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 mode of administration is at the discretion of the practitioner.

[0385] In some embodiments, the compound can be incorporated into a pharmaceutical composition and administered as a pharmaceutical composition. Such pharmaceutical compositions are mainly used for in vivo or in vitro administration. In some embodiments, the pharmaceutical composition further contains a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier is an agent that does not itself induce an immune response harmful to the individual receiving the composition and does not produce unnecessary toxicity when administered. Pharmaceutically acceptable carriers (or excipients) include, but are not limited to, liquids such as water, saline, glycerol, sugars, and ethanol. In addition, auxiliary substances such as wetting agents or emulsifying agents, pH buffering substances, etc. may also be contained in such carriers.

[0386] The compound in the pharmaceutical composition can be provided in the form of a pharmaceutically acceptable salt. In some embodiments, the salt can be formed from 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, the salt can be formed from a base. In some embodiments, the salt is an alkali metal, alkaline earth metal, or ammonium salt, such as sodium salt, calcium salt, diethanolamine salt, ethanolamine salt, trialkylamine salt, etc.

[0387] In some embodiments, the salts are more soluble in aqueous solutions or other protic solvents than the corresponding free acid or base forms. In some embodiments, the pharmaceutical composition can be a lyophilized powder. In some embodiments, the pharmaceutical composition comprises the provided compound, such as 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.

[0388] The pharmaceutical composition can include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (such as oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersing agents and suspending media, coatings, isotonic agents, and absorption promoters or retarders, which are compatible with drug administration or in vivo contact or administration. Aqueous and non-aqueous solvents, solutions, and suspensions can include suspending agents and thickening agents. In some embodiments, the pharmaceutical composition or formulation is a tablet (coated or uncoated), capsule (hard or soft capsule), microbead, powder, granule, and / or crystal. Supplementary active compounds, such as preservatives, antibacterial, antiviral, and antifungal agents, can also be added to the pharmaceutical composition.

[0389] The pharmaceutical composition can be formulated to be compatible with a specific mode of administration or route of administration described herein or known to those skilled in the art.

[0390] In some embodiments, the provided composition is suitable for parenteral administration. In certain embodiments, such compositions include aqueous and non-aqueous solutions, suspensions, or emulsions of the active compound, and these formulations are generally sterile and isotonic with the blood of the intended subject. Non-limiting examples include water, buffered saline, Hank's solution, Ringer's solution, glucose, 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. In addition, suspensions of the active compound can also be prepared as appropriate oil-injection suspensions. Suitable lipophilic solvents or carriers include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. The suspension may also optionally contain suitable stabilizers or agents that increase solubility in order to prepare highly concentrated solutions.

[0391] Cosolvents and adjuvants can be added to the compositions and formulations. Non-limiting examples of cosolvents include hydroxyl or other polar groups, such as alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethylene glycol, polypropylene glycol, ethylene glycol ethers; glycerol; polyoxyethylene alcohols, and polyoxyethylene fatty acid esters. Adjuvants include surfactants, such as soy lecithin and oleic acid; sorbitan esters, such as sorbitan trioleate; and polyvinylpyrrolidone.

[0392] After formulating the pharmaceutical composition, it can be placed in a suitable container and labeled for handling. Such labels can include dosage, frequency, and method of administration.

[0393] 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 used in accordance with the present disclosure.

[0394] In some embodiments, the present disclosure provides methods for delivering the provided compounds and compositions into cells, animals, or subjects. In some embodiments, such methods include contacting a subject (e.g., a cell or tissue of a subject) with the provided compound (e.g., a compound of Formula I or a salt thereof or a composition thereof), or administering or delivering the provided compound (e.g., a compound of Formula I or a salt thereof or a composition thereof) to a subject (e.g., a mammal or a human).

[0395] The compounds or compositions described herein can be administered to a subject in need thereof (or its cells, tissues, or organs) in a sufficient or effective amount. The dosage can vary and depends on the type of condition, disorder, or disease being treated, the onset, progression, severity, frequency, duration, or probability thereof, the desired clinical endpoint, previous or concurrent treatments, the general health of the subject, age, gender, race, or immunocompetence, and other factors understood by a skilled artisan. The dosage, number of doses, frequency, or duration can be increased or decreased proportionally based on efficacy, any adverse side effects, complications, or other risk factors of the treatment or therapy, and the condition of the subject. A skilled artisan will appreciate the factors that may affect dosage and timing to provide an amount sufficient to provide the benefits of treating or preventing a disease.

[0396] The dosage to achieve efficacy will vary depending on a variety of factors, including the route of administration, the amount to achieve efficacy, the specific condition, disorder, or disease being treated, the host's immune response to the administered compound or composition, the stability of the administered compound or composition, etc.

[0397] The effective or sufficient amount can be administered in a single dose, may require multiple doses, can be administered alone or in combination with another composition (e.g., containing or providing another therapeutic agent). For example, the dosage can be increased proportionally based on the needs of the subject, the type, status, and severity of the condition, disorder, or disease being treated, and / or the side effects (if any) of the treatment. A dose considered effective also includes a dose that results in a reduction in the use of another treatment method, treatment regimen, or protocol.

[0398] In some embodiments, the pharmaceutical composition comprises or provides an effective amount of an active ingredient, such as a compound of formula I or a pharmaceutically acceptable salt thereof, for achieving a desired purpose, such as a therapeutic purpose. According to the present disclosure, various techniques can be utilized to determine a therapeutically effective amount. Among other factors, the therapeutic dose also depends on the age and general condition of the subject, the severity of the condition, the disorder or disease, etc. In some embodiments, the therapeutically effective amount in humans can be within a relatively broad range and is determined by a medical practitioner based on the response of an individual patient.

[0399] In some embodiments, the methods and uses of the present disclosure include systemic, regional, or local administration or by any route, such as by injection or infusion or oral administration. In certain embodiments, administration of the pharmaceutical composition in vivo can generally be accomplished by injection using a conventional syringe, but other administration methods, such as convection enhanced delivery, can also be used. In certain embodiments, the compounds and compositions can be administered subcutaneously, epidermally, intradermally, intracutaneously, intraorbitally, intramucosally, intraperitoneally, intravenously, intrapleurally, intraarterially, orally, intrahepatically, via the portal vein, or intramuscularly. In certain embodiments, the administration methods include oral and pulmonary administration, suppositories, and transdermal applications. The optimal route of administration of the compounds and compositions described herein can be determined by a clinician treating a patient.

[0400] Among other things, the present disclosure also provides the following embodiments: 1. A compound having the structure of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is -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, R 2 and R 3 are each independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring A is wherein ring A' is an optionally substituted 5- to 10-membered aromatic ring having 0 to 4 heteroatoms; L ra is optionally substituted -(CH 2 )n-; n is 1, 2 or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH 2 -; Z is -N= or -C(R 9 )=; R 4 , R 5 , R 6 , R 7 and R 9 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring B is an optionally substituted ring selected from 5-10 membered heteroaryl rings having 1-6 heteroatoms and 6-10 membered aryl rings; R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 each independently is R'; Each R' is independently R, -OR, -C(O)R, -C(O)OR or -S(O)2R; Each R is independently hydrogen or an optionally substituted group selected from C 1 -C 6 -aliphatic, C 1 - having 1-3 heteroatoms 6 -heteroaliphatic, 3-10 membered cycloaliphatic, 3-10 membered heterocyclic group having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 -aliphatic and 5-10 membered heteroaryl-C 1 -C 6 -aliphatic; or Two R groups on the same atom may optionally and independently together with that atom form an optionally substituted 3-10 membered ring which, in addition to that atom, has 0-4 heteroatoms; or Two R groups on two atoms may optionally and independently together with their intervening atom form an optionally substituted 3-10 membered ring which, in addition to the intervening atom, has 0-4 heteroatoms. 2. A compound having the structure of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is -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, halogen, or R 2 and R 3 are each independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring A is wherein ring A' is an optionally substituted 5- to 10-membered aromatic ring having 0 to 4 heteroatoms; L ra is optionally substituted -(CH 2 )n-; n is 1, 2 or 3; X is -O-, -S-, -N(R 8 ), or optionally substituted -CH 2 -; Z is -N= or -C(R 9 )=; R 4 , R 5 , R 6 , R 7 and R 9 are each independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring B is an optionally substituted ring selected from 5- to 10-membered heteroaromatic rings having 1 to 6 heteroatoms and 6- to 10-membered aromatic rings; 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 an optionally substituted group selected from C 1 -C 6 aliphatic, C with 1 - 3 heteroatoms 1 -C 6 heteroaliphatic, 3 - 10 - membered cycloaliphatic, 3 - 10 - membered heterocyclic group with 1 - 4 heteroatoms, 6 - 10 - membered aryl, 5 - 10 - membered heteroaryl with 1 - 6 heteroatoms, 6 - 10 - membered aryl - C 1 -C 6 aliphatic and 5 - 10 - membered heteroaryl - C with 1 - 6 heteroatoms 1 -C 6 aliphatic; or two R groups on the same atom may optionally and independently together with the atom form an optionally substituted 3 - 10 - membered ring which, in addition to the atom, has 0 - 4 heteroatoms; or two R groups on two atoms may optionally and independently together with their intervening atom form an optionally substituted 3 - 10 - membered ring which, in addition to the intervening atom, has 0 - 4 heteroatoms. 3. A compound having the structure of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OH or its bioisostere, optionally protected -CHO or R d6 ; R d6 is -CH(OR) 2 ; R 2 and R 3 are each independently R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring A is wherein ring A' is an optionally substituted 5 - 10 - membered aromatic ring having 0 - 4 heteroatoms; L ra is optionally substituted -(CH 2 )n-; n is 1, 2 or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH 2 -; Z is -N= or -C(R 9 )=; R 4 、R 5 、R 6 、R 7and R 9 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring B is an optionally substituted ring selected from 5- to 10-membered heteroaryl rings having 1-6 heteroatoms and 6- to 10-membered aryl rings; R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 each independently is R'; Each R' independently is R, -OR, -C(O)R, -C(O)OR or -S(O) 2 R; Each R independently is hydrogen or an optionally substituted group selected from C1-C6 aliphatic, C1-C6 heteroaliphatic having 1-3 heteroatoms, 3- to 10-membered cycloaliphatic, 3- to 10-membered heterocyclic group having 1-4 heteroatoms, 6- to 10-membered aryl, 5- to 10-membered heteroaryl having 1-6 heteroatoms, 6- to 10-membered aryl-C1-C6 aliphatic and 5- to 10-membered heteroaryl-C1-C6 aliphatic having 1-6 heteroatoms; or Two R groups on the same atom may optionally and independently together with the atom form an optionally substituted 3- to 10-membered ring which, in addition to the atom, has 0-4 heteroatoms; or Two R groups on two atoms may optionally and independently together with their intervening atom form an optionally substituted 3- to 10-membered ring which, in addition to the intervening atom, has 0-4 heteroatoms. 4. A compound according to any one of the foregoing embodiments, wherein ring A' is an optionally substituted 5- to 6-membered aromatic ring having 0-4 heteroatoms. 5. A compound according to any one of embodiments 1-3, wherein ring A is 6. A compound according to any one of embodiments 1-4, wherein ring A is 7. A compound according to embodiment 6, wherein ring A' is an optionally substituted 5- to 6-membered aromatic ring having 1, 2, 3 or 4 heteroatoms. 8. A compound according to embodiment 6, wherein ring A' is an optionally substituted 5- to 6-membered aromatic ring having 1 or 2 heteroatoms. 9. A compound according to embodiment 6, wherein ring A' is an optionally substituted phenyl ring. 10. The compound of 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 of Embodiment 6, wherein ring A' is an optionally substituted 9-membered aromatic ring having 1 or 2 heteroatoms. 13. The compound of Embodiment 6, wherein ring A' is an optionally substituted 10-membered aromatic ring having 1, 2, 3 or 4 heteroatoms. 14. The compound of Embodiment 6, wherein ring A' is an optionally substituted 10-membered aromatic ring having 1 or 2 heteroatoms. 15. The compound of Embodiment 6, wherein ring A' is an optionally substituted divalent naphthalene ring. 16. The compound of Embodiment 6, wherein ring A' is optionally substituted 17. The compound of Embodiment 6, wherein ring A' is 18. The compound of any one of the foregoing embodiments, wherein Z is -C(R 9 )=. 19. The compound of any one of Embodiments 1-11, wherein R 9 is H. 20. The compound of any one of Embodiments 1-11, wherein R 9 is a halogen. 21. The compound of any one of Embodiments 1-11, wherein R 9 is F. 22. The compound of any one of Embodiments 1-11, wherein R 9 is an optionally substituted C 1 -C 6 aliphatic. 23. The compound of any one of Embodiments 1-11, wherein R 9 is an optionally substituted C 1 -C 6 alkyl. 24. The compound of any one of Embodiments 1-11, wherein R 9 is methyl. 25. The compound of any one of Embodiments 1-4, wherein ring A is 26. The compound of any one of Embodiments 1-4, wherein ring A is 27. The compound of any one of Embodiments 1-4, wherein ring A is 28. The compound according to any one of Embodiments 1-4, wherein Ring A is 29. The compound according to any one of Embodiments 1-4, wherein Ring A is 30. The compound according to any one of Embodiments 1-4, wherein Ring A is 31. The compound according to any one of Embodiments 25-30, wherein Ring A' is an optionally substituted 5- or 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 naphthalene ring. 40. The compound according to any one of Embodiments 25-30, wherein Ring A' is optionally substituted 41. The compound according to any one of Embodiments 25-30, wherein Ring A' is 42. The compound according to Embodiment 1 or 2, wherein Ring A is 43. The compound according to Embodiment 1 or 2, wherein Ring A is 44. The compound according to Embodiment 1 or 2, wherein Ring A is 45. The compound according to Embodiment 1 or 2, wherein Ring A is 46. The compound of Embodiment 1 or 2, wherein Ring A is 47. The compound of Embodiment 1 or 2, wherein Ring A is 48. The compound of any one of Embodiments 25 - 197, wherein n is 1. 49. The compound of any one of Embodiments 25 - 197, wherein n is 2. 50. The compound of any one of Embodiments 25 - 197, wherein n is 3. 51. The compound of any one of Embodiments 25 - 50, wherein R 10 is H. 52. The compound of any one of the foregoing embodiments, wherein X is -N(R 8 ). 53. A compound, wherein the compound has the structure of Formula B - 5: or a salt thereof, wherein each variable is independently as described in Embodiment 1 or 2. 54. The compound of any one of the foregoing embodiments, wherein R 8 is H. 55. The compound of any one of Embodiments 1 - 53, wherein R 8 is not H. 56. The compound of any one of Embodiments 1 - 53, wherein R 8 is optionally substituted C 1 -C 6 alkyl. 57. The compound of Embodiment 56, wherein R 8 is methyl. 58. The compound of Embodiment 56, wherein R 8 is propyl. 59. The compound of Embodiment 56, wherein R 8 is isopropyl. 60. The compound of Embodiment 56, wherein R 8 is isobutyl. 61. The compound of any one of Embodiments 1 - 53, wherein R 8 is optionally substituted C 3 -C 8 cycloalkyl. 62. The compound of Embodiment 61, wherein R 8 is 63. The compound of Embodiment 61, wherein R 8 is The compound of Embodiment 61, wherein R 8 is The compound of any one of Embodiments 1-53, wherein R 8 is an optionally substituted 6- to 10-membered aryl group. The compound of Embodiment 65, wherein R 8 is phenyl. The compound of any one of Embodiments 1-53, wherein R 8 is an optionally substituted 6- to 10-membered aryl-C 1 -C 6 alkyl. The compound of Embodiment 67, wherein R 8 is The compound of any one of Embodiments 1-51, wherein X is -O-. The compound of any one of Embodiments 1-51, wherein X is an optionally substituted -CH 2 -. The compound of any one of Embodiments 1-51, wherein X is -CH 2 -. The compound of any one of Embodiments 1-51, wherein X is -S-. The compound of any one of Embodiments 1-10 and 53-72, wherein Z is -N═. A compound, wherein the compound has the structure of Formula B-1: or a salt thereof, wherein Hal is a halogen, and each other variable is independently as described in Embodiment 1 or 2. A compound, wherein the compound has the structure of Formula C-1: or a salt thereof, wherein Hal is a halogen, and each other variable is independently as described in Embodiment 1 or 2. A compound, wherein the compound has the structure of Formula C-2: or a salt thereof, wherein Hal is a halogen, R si is -Si(R) 3 , and each other variable is independently as described in Embodiment 1 or 2. The compound of Embodiment 76, wherein R si is -Si(R) 3, wherein each R is independently not -H. 78. The compound of embodiment 76, wherein R si is -Si(R) 3 wherein each R is independently optionally substituted and selected from C 1-6 aliphatic and C 6-10 aryl. 79. The compound of embodiment 76, wherein R si is -Si(R) 3 wherein each R is independently optionally substituted and selected from C 1-6 aliphatic and phenyl. 80. The compound of embodiment 76, wherein R si is -Si(R) 3 wherein each R is independently optionally substituted C 1-6 aliphatic. 81. The compound of embodiment 76, wherein R si is -Si(Me) 3 . 82. A compound, wherein the compound has a formula C-4 structure: or a salt thereof, wherein Hal is a halogen, and each other variable is independently as described in embodiment 1 or 2. 83. The compound of any one of embodiments 74 - 82, wherein Hal is Cl. 84. The compound of any one of embodiments 74 - 82, wherein Hal is Br. 85. The compound of any one of embodiments 74 - 82, wherein Hal is I. 86. A compound, wherein the compound has a formula D-2 structure: or a salt thereof, wherein Hal is a halogen, and each other variable is independently as described in embodiment 1 or 2. 87. The compound of embodiment 86, wherein R d21 is optionally substituted C 1-6 aliphatic. 88. The compound of embodiment 86, wherein R d21 is methyl. 89. The compound of any one of embodiments 86 - 88, wherein R d22 is optionally substituted C 1-6 aliphatic. 90. The compound of any one of embodiments 86 - 88, wherein R d22 is methyl. 91. A compound, wherein the compound has the structure of formula D-2: or a salt thereof, wherein Hal 1 is a halogen, and each other variable is independently as described in Embodiment 1 or 2. 92. A compound, wherein the compound has the structure of formula D-4: or a salt thereof, wherein Hal 1 is a halogen, and each other variable is independently as described in Embodiment 1 or 2. 93. A compound, wherein the compound has the structure of formula D-5: or a salt thereof, wherein Hal 1 is a halogen, and each other variable is independently as described in Embodiment 1 or 2. 94. The compound according to any one of Embodiments 86-93, wherein Hal 1 is Cl. 95. The compound according to any one of Embodiments 86-93, wherein Hal 1 is Br. 96. The compound according to any one of Embodiments 86-93, wherein Hal 1 is Br. 97. The compound according to any one of Embodiments 86-96, wherein n is 1. 98. The compound according to any one of Embodiments 86-96, wherein n is 2. 99. The compound according to any one of Embodiments 86-96, wherein n is 3. 100. A compound, wherein the compound has the structure of formula D'-2: or a salt thereof, wherein Hal 3 is a halogen, PG is R' or a protecting group, and each other variable is independently as described in Embodiment 1 or 2. 101. The compound according to Embodiment 100, wherein Hal 3 is Cl. 102. The compound according to Embodiment 100, wherein Hal 3 is Br. 103. The compound according to Embodiment 100, wherein Hal 3 is I. 104. A compound, wherein the compound has the structure of formula D'-3: or a salt thereof, wherein PG is R' or a protecting group, and each other variable is independently as described in Embodiment 1 or 2. 105. A compound, wherein the compound has the structure of Formula D'-4: or a salt thereof, wherein PG is R' or a protecting group, and each other variable is independently as described in Embodiment 1 or 2. 106. The compound of any one of Embodiments 100 - 105, wherein PG is R', and R' is not H. 107. The compound of any one of Embodiments 100 - 105, wherein PG is a protecting group. 108. The compound of any one of Embodiments 100 - 105, wherein PG is selected from Bn, MEM, and allyl. 109. A compound, wherein the compound has the structure of Formula D'-5: or a salt thereof, wherein each variable is independently as described in Embodiment 1 or 2. 110. A compound, wherein the compound has the structure of Formula B-3: 111. or a salt thereof, wherein each variable is independently as described in Embodiment 1 or 2. The compound of any one of the foregoing embodiments, wherein R 4 is R. 112. The compound of any one of the foregoing embodiments, wherein R 4 is optionally substituted C 1 -C 6 alkyl. 113. The compound of any one of the foregoing embodiments, wherein R 4 is -CF3. 114. The compound of any one of Embodiments 1 - 110, wherein R 4 is -H. 115. The compound of any one of Embodiments 1 - 110, wherein R 4 is a halogen. 116. The compound of any one of Embodiments 1 - 110, wherein R 4 is -F. 117. The compound of any one of Embodiments 1 - 110, wherein R 4 is -Cl. 118. The compound of any one of Embodiments 1 - 110, wherein R 4 is R. The compound according to any one of Embodiments 1-110, wherein R 4 is an optionally substituted phenyl group. 120. The compound according to any one of Embodiments 1-110, wherein R 4 is a phenyl group. 121. The compound according to any one of the foregoing embodiments, wherein R 5 is -H. 122. The compound according to any one of Embodiments 1-120, wherein R 5 is an optionally substituted C 1-6 aliphatic. 123. The compound according to any one of Embodiments 1-120, wherein R 5 is an optionally substituted C 1-6 alkyl. 124. The compound according to any one of Embodiments 1-120, wherein R 5 is -CF 3 . 125. The compound according to any one of Embodiments 1-120, wherein R 5 is a halogen. 126. The compound according to any one of Embodiments 1-120, wherein R 5 is -F. 127. The compound according to any one of Embodiments 1-120, wherein R 5 is -Cl. 128. The compound according to any one of Embodiments 1-120, wherein R 5 is -CN. 129. The compound according to Embodiment 1 or 2, wherein Ring A is 130. The compound according to any one of the foregoing embodiments, wherein R 6 is -H. 131. The compound according to any one of Embodiments 1-128, wherein R 6 is R. 132. The compound according to any one of Embodiments 1-128, wherein R 6 is a halogen, -CN, an optionally substituted C 1 -C 6 alkyl, -OR wherein R is an optionally substituted C 1 -C 6 alkyl, an optionally substituted 6-10 membered aryl group, -C(O)OR wherein R is H or an optionally substituted C 1 -C 6 alkyl, or -S(O) 2 R wherein R is H or an optionally substituted C 1 -C6 Alkyl The compound according to any one of Embodiments 1 - 128, wherein R 6 is optionally substituted C 1-6 Aliphatic The compound according to any one of Embodiments 1 - 128, wherein R 6 is optionally substituted C 1-6 Alkyl The compound according to any one of Embodiments 1 - 128, wherein R 6 is -CF 3 The compound according to any one of Embodiments 1 - 128, wherein R 6 is optionally substituted phenyl The compound according to any one of Embodiments 1 - 128, wherein R 6 is -OR The compound according to any one of Embodiments 1 - 128, wherein R 6 is -OR, wherein R is optionally substituted C 1-6 Aliphatic The compound according to any one of Embodiments 1 - 128, wherein R 6 is -OMe The compound according to any one of Embodiments 1 - 128, wherein R 6 is -OCF 3 The compound according to any one of Embodiments 1 - 128, wherein R 6 is halogen The compound according to any one of Embodiments 1 - 128, wherein R 6 is -F The compound according to any one of Embodiments 1 - 128, wherein R 6 is -Cl The compound according to any one of Embodiments 1 - 128, wherein R 6 is -CN The compound according to any one of Embodiments 1 - 128, wherein R 6 is -C(O)OR The compound according to any one of Embodiments 1 - 128, wherein R 6 is -C(O)OH The compound according to any one of Embodiments 1 - 128, wherein R 6 is -S(O) 2 R ​​The compound according to any one of Embodiments 1-128, wherein R 6 is -S(O) 2 R, where R is C 1-6 aliphatic. The compound according to any one of Embodiments 1-128, wherein R 6 is -S(O) 2 Me. The compound according to any one of the foregoing embodiments, wherein R 7 is -H. The compound according to any one of Embodiments 1-149, wherein R 7 is R. The compound according to any one of Embodiments 1-149, wherein R 7 is optionally substituted C 1-6 aliphatic. The compound according to any one of Embodiments 1-149, wherein R 7 is a halogen. The compound according to any one of Embodiments 1-149, wherein R 7 is -F. The compound according to any one of Embodiments 1-149, wherein R 7 is -Cl. The compound according to Embodiment 1 or 2, wherein ring A is The compound according to Embodiment 1 or 2, wherein ring A is The compound according to Embodiment 157, wherein R 6 is -CF 3 . The compound according to Embodiment 157 or 158, wherein R 8 is H or methyl. The compound according to Embodiment 1 or 2, wherein ring A is The compound according to Embodiment 160, wherein ring A is The compound according to any one of Embodiments 160-162, wherein X is O or S. The compound according to any one of Embodiments 160-162, wherein R 5 is optionally substituted C 1 -C 6 alkyl. The compound according to any one of Embodiments 160-163, wherein R5 is -CF 3 . 165. A compound according to any one of embodiments 160 - 164, wherein R 6 is a halogen. 166. A compound according to any one of embodiments 160 - 165, wherein R 6 is Cl. 167. A compound according to embodiment 1 or 2, wherein ring A is 168. A compound according to embodiment 167, wherein R 4 is optionally substituted C 1 -C 6 alkyl. 169. A compound according to embodiment 167 or 168, wherein R 4 is -CF 3 . 170. A compound according to any one of embodiments 167 - 169, wherein R 5 is a halogen. 171. A compound according to any one of embodiments 167 - 170, wherein R 5 is F or Cl. 172. A compound according to embodiment 1 or 2, wherein ring A is 173. A compound according to embodiment 172, wherein R 5 is optionally substituted C 1 -C 6 alkyl. 174. A compound according to embodiment 172 or 173, wherein R 5 is -CF 3 . 175. A compound according to any one of embodiments 172 - 174, wherein R 7 is a halogen. 176. A compound according to any one of embodiments 172 - 175, wherein R 7 is Cl. 177. A compound according to embodiment 1 or 2, wherein ring A is 178. A compound according to embodiment 177, wherein ring A is 179. A compound according to embodiment 177 or 178, wherein ring A is 180. A compound according to any one of embodiments 177 - 179, wherein R 5 is a halogen or optionally substituted C 1 -C 6Alkyl 181. The compound according to any one of Embodiments 177 - 180, wherein R 5 is Cl 182. The compound according to any one of Embodiments 177 - 180, wherein R 5 is -CF 3 183. The compound according to any one of Embodiments 177 - 179, wherein Ring A is 184. The compound according to Embodiment 1 or 2, wherein Ring A is 185. The compound according to Embodiment 184, wherein Ring A is 186. The compound according to Embodiment 184 or 185, wherein R 5 is optionally substituted C 1 -C 6 alkyl 187. The compound according to any one of Embodiments 184 - 186, wherein R 5 is -CF 3 188. The compound according to Embodiment 1 or 2, wherein Ring A is 189. The compound according to Embodiment 188, wherein Ring A is 190. The compound according to Embodiment 188 or 189, wherein R 5 is optionally substituted C 1 -C 6 alkyl 191. The compound according to any one of Embodiments 188 - 190, wherein R 5 is -CF 3 192. The compound according to Embodiment 188, wherein Ring A is 193. The compound according to Embodiment 192, wherein R 6 is optionally substituted C 1 -C 6 alkyl 194. The compound according to Embodiment 192 or 193, wherein R 6 is -CF 3 195. The compound according to any one of the foregoing embodiments, wherein R 4 and R 5 together with their intervening atoms form an optionally substituted 5 - or 6 - membered aromatic ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur​​​​ 196. A compound according to any one of the foregoing embodiments, wherein R 4 and R 5 , together with their intervening atoms, form an optionally substituted phenyl ring. 197. A compound according to any one of the foregoing embodiments, wherein the formed ring is unsubstituted. 198. A compound, wherein the compound has the structure of formula B-2: or a salt thereof, wherein each variable is independently as described in Embodiment 1 or 2. 199. A compound, wherein the compound has the structure of formula C-3: or a salt thereof, wherein each variable is independently as described in Embodiment 1 or 2. 200. A compound, wherein the compound has the structure of formula D'-1: or a salt thereof, wherein each variable is independently as described in Embodiment 1 or 2. 201. A compound, wherein the compound has the structure of formula D-3: or a salt thereof, wherein Hal 2 is a halogen, and each other variable is independently as described in Embodiment 1 or 2. 202. The compound of Embodiment 201, wherein Hal 2 is Cl. 203. The compound of Embodiment 201, wherein Hal 2 is Br. 204. The compound of Embodiment 201, wherein Hal 2 is I. 205. A compound, wherein the compound has the structure of formula B-2: or a salt thereof, wherein each variable is independently as described in Embodiment 1 or 2. 206. A compound according to any one of the foregoing embodiments, wherein ring B is an optionally substituted phenyl ring. 207. A compound according to any one of the foregoing embodiments, wherein ring B is 208. The compound according to any one of Embodiments 206-207, wherein R 1 is located at the o-position (relative to the carbon bonded to ring A). The compound of Embodiment 208, wherein R 2 is at the ortho position. 210. The compound of Embodiment 209, wherein R 3 is at the meta position adjacent to R 2 . 211. The compound of Embodiment 209, wherein R 3 is at the meta position adjacent to R 1 . 212. The compound of Embodiment 209, wherein R 3 is at the para position. 213. The compound of Embodiment 208, wherein R 2 is at the meta position adjacent to R 1 . 214. The compound of Embodiment 213, wherein R 3 is at the ortho position. 215. The compound of Embodiment 213, wherein R 3 is at the meta position. 216. The compound of Embodiment 213, wherein R 3 is at the para position. 217. The compound of Embodiment 208, wherein R 3 is at the meta position adjacent to R 1 . 218. The compound of Embodiment 217, wherein R 2 is at the ortho position. 219. The compound of Embodiment 217, wherein R 2 is at the meta position. 220. The compound of Embodiment 217, wherein R 2 is at the para position. 221. The compound of Embodiment 208, wherein R 2 is at the para position. 222. The compound of Embodiment 221, wherein R 3 is at the ortho position. 223. The compound of Embodiment 221, wherein R 3 is at the meta position. 224. The compound of any one of Embodiments 206 - 207, wherein R 1 is at the meta position (relative to the carbon bonded to Ring A). 225. The compound of Embodiment 224, wherein R 2 is at the ortho position adjacent to R 1 . 226. The compound of Embodiment 225, wherein R 3 is at the ortho position. The compou...

Claims

1. A compound having the structure of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is R 2 and R 3 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring A is wherein ring A' is an optionally substituted 5- to 10-membered aromatic ring having 0 to 4 heteroatoms; L ra is optionally substituted -(CH 2 ) n -; n is 1, 2 or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH 2 -; Z is -N= or -C(R 9 )=; R 4 、R 5 、R 6 、R 7 and R 9 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring B is an optionally substituted ring selected from 5- to 10-membered heteroaryl rings having 1 to 6 heteroatoms and 6- to 10-membered aryl rings; R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 each independently is R'; Each R’ is independently R, -OR, -C(O)R, -C(O)OR or -S(O) 2 R; Each R is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, C with 1 - 3 heteroatoms 1 -C 6 heteroaliphatic, 3 - 10 membered cycloaliphatic, 3 - 10 membered heterocyclic group with 1 - 4 heteroatoms, 6 - 10 membered aryl, 5 - 10 membered heteroaryl with 1 - 6 heteroatoms, 6 - 10 membered aryl - C 1 -C 6 aliphatic and 5 - 10 membered heteroaryl - C1 - C6 aliphatic with 1 - 6 heteroatoms; or Two R groups on the same atom may optionally and independently together with the atom form an optionally substituted 3- to 10-membered ring which, in addition to the atom, has 0 to 4 heteroatoms; or Two R groups on two atoms may optionally and independently together with their intervening atom form an optionally substituted 3- to 10-membered ring which, in addition to the intervening atom, has 0 to 4 heteroatoms.

2. A compound having the structure of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)OH or its bioisostere, 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 )SO 2 R 15 , -C(O)NR 16 R 17 , -CN, halogen, or R d6 is -CH(OR) 2 ; R 2 and R 3 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring A is wherein ring A' is an optionally substituted 5- to 10-membered aromatic ring having 0 to 4 heteroatoms; L ra is optionally substituted -(CH 2 ) n -; n is 1, 2 or 3; X is -O-, -S-, -N(R 8 )- or optionally substituted -CH 2 -; Z is -N= or -C(R 9 )=; R 4 、R 5 、R 6 、R 7 and R 9 each independently is R', -OR', halogen, -CN, -NO 2 or -N(R') 2 ; Ring B is an optionally substituted ring selected from 5- to 10-membered heteroaryl rings having 1 to 6 heteroatoms and 6- to 10-membered aryl rings; 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 an optionally substituted group selected from C 1 -C 6 aliphatic, C having 1-3 heteroatoms 1 -C 6 heteroaliphatic, 3-10 membered cycloaliphatic, 3-10 membered heterocyclic group having 1-4 heteroatoms, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms, 6-10 membered aryl-C 1 -C 6 aliphatic and 5-10 membered heteroaryl-C having 1-6 heteroatoms 1 -C 6 aliphatic; or Two R groups on the same atom may optionally and independently together with the atom form an optionally substituted 3- to 10-membered ring which, in addition to the atom, has 0 to 4 heteroatoms; or Two R groups on two atoms may optionally and independently together with their intervening atom form an optionally substituted 3- to 10-membered ring which, in addition to the intervening atom, has 0 to 4 heteroatoms.

3. The compound of claim 1, wherein ring A is 4. The compound of claim 1, wherein ring A is 5. The compound of any one of claims 1-4, wherein L ra is -CH 2 -.

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

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

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

10. The compound of claim 1, wherein ring A is 11. The compound of claim 10, wherein R 5 is halogen or optionally substituted C 1 -C 6 alkyl.

12. The compound of claim 11, wherein R 5 is -CF 3 .

13. The compound according to any one of claims 10 - 12, wherein ring B is 14. A compound according to any one of claims 10 - 12, wherein ring B is 15. The compound of claim 14, wherein R 2 is a halogen.

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

17. A compound according to any one of claims 1-14, wherein R 2 is R.

18. A compound according to any one of claims 1-14, wherein R 2 is H.

19. A compound according to any one of claims 1-14, wherein R 2 is -C(O)OR, wherein R is H or optionally substituted C 1-6 aliphatic. The compound of any one of claims 1-14, wherein R 2 is -OR, wherein R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

21. A compound according to any one of claims 1-12, wherein R 3 is a halogen.

22. A compound according to any one of claims 1-12, wherein R 3 is R.

23. A compound according to any one of claims 1-12, wherein R 3 is H.

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

25. A compound according to any one of claims 1-12, wherein R 3 is -OR, wherein R is optionally substituted C 1 -C 6 alkyl, optionally substituted 6-10 membered aryl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted 5-10 membered heteroaryl having 1-6 heteroatoms.

26. A compound, wherein the compound is a compound selected from Table 1 or a salt thereof.

27. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

28. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

29. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

30. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

31. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

32. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

33. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

34. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

35. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

36. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

37. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

38. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

39. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

40. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

41. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

42. The compound of any one of the preceding claims, wherein the compound is a pharmaceutically acceptable salt.

43. The compound of any one of the preceding claims, wherein the compound is a sodium salt.

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

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

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

47. A method of treating a disorder, condition or disease, comprising administering to a subject suffering from the disorder, condition or disease an effective amount of the compound or pharmaceutical composition of any one of claims 1-45.

48. A method of treating a disorder, condition or disease, comprising delivering to a subject suffering from the disorder, condition or disease an effective amount of the compound or pharmaceutical composition of any one of claims 1-45.

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

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

51. A method according to any one of claims 47 - 48, wherein the disorder, condition or disease is or comprises pruritus.

52. A method according to any one of claims 47 - 48, wherein the disorder, condition or disease is or comprises chronic itch, 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, eczematous dermatitis, atopic eczema, eczema, lupus erythematosus, folliculitis, fungal skin infection, hemorrhoids, herpes, HIV infection, Hodgkin's disease, hyperthyroidism, iron - deficiency anemia, kidney disease, leukemia, liver disease, lymphoma, malignancy, multiple myeloma, neurodermatitis, onchocerciasis, Paget's disease, pediculosis, polycythemia vera, pruritus ani, pseudorabies, psoriasis, rectal prolapse, scabies, schistosomiasis, scleroderma, severe stress, stasis dermatitis, swimmer's itch, thyroid disease, tinea cruris, uremic pruritus or urticaria.

53. A method according to claim 51, wherein the pruritus is acute or chronic pruritus associated with a liver disorder, condition or disease.

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

55. A method according to claim 53 or 54, wherein the liver disorder, condition or disease is intrahepatic cholestasis of pregnancy (ICP), estrogen -, progesterone - or testosterone - induced cholestasis, toxin - or other drug - induced cholestasis of hepatocytes, benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC), chronic hepatitis C virus, 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 small - duct cholangiopathy, cholelithiasis, IgG4 - related cholangitis, biliary atresia, cholangiocarcinoma, benign cholangioma or other obstructive cholestasis.

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

57. A method according to any one of claims 47 - 56, wherein the compound or composition is used in combination with an additional therapeutic agent.

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

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

60. A compound, composition or method as described in this specification or in any one of embodiments 1 - 1178.

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