TW202535352A - Compounds, compositions and methods thereof - Google Patents

Abstract

Among other things, the present disclosure provides compounds of formula I or salts thereof. In some embodiments, provided compounds are useful as Nav1.8 antagonists. In some embodiments, the present disclosure provides methods for preventing or treating Nav1.8-associated conditions, disorders or diseases.

Description

Compounds, Compositions and Methods Thereof

In some embodiments, this disclosure provides compounds and combinations thereof that can be used to modulate the activity of voltage-gated sodium channels 1.8 (Nav1.8). In some embodiments, the provided compounds and combinations thereof help prevent or treat conditions, disorders, or diseases related to Nav1.8, such as migraines, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, postoperative pain, and neuropathic pain. In some embodiments, this disclosure provides techniques for preparing the compounds and combinations thereof.

According to literature, pain is a way for the body to perceive stimuli. It is an important warning signal that alerts the body to the presence of tissue damage or injury and triggers an appropriate response.

According to several studies, painful stimuli involve electrical impulses transmitted from noxious dorsal root ganglion neurons through ascending pathways in the spinal cord, ultimately reaching the central nervous system (CNS). Pain receptors are thought to express voltage-gated sodium channels (VGSCs), which selectively mediate the influx of sodium ions and play a crucial role in initiating and conducting action potentials (APs) (Yu et al., *Genomics* 4:207, 2003). VGSCs are reported to consist of nine α subunits encoded by genes SCN1A to SCN11A and form complexes with β subunits that regulate channel properties. The fourth transmembrane segment (S4) in the α subunit acts as a voltage sensor, mediating the different electrophysiological characteristics of nine Nav channel subtypes (Nav1.1-Nav1.9), resulting in distinct voltage dependence and dynamic properties. Tetrodotoxin (TTX) has been reported to bind to Nav channels on nerve cell membranes, inhibiting the release of neuronal action potentials. Based on their response to tetrodotoxin, Nav channels can be divided into two categories: TTX-sensitive channels (TTXs) such as Nav1.1-1.4, Nav1.6, and Nav1.7, and TTX-resistant channels (TTXr) such as Nav1.5, Nav1.8, and Nav1.9. Furthermore, the expression patterns of Nav channels are reported to exhibit organization specificity, with Nav1.1 and Nav1.6 primarily located in the central nervous system, while Nav1.7, Nav1.8, and Nav1.9 are mainly found in neurons of the peripheral nervous system (PNS).

Nav1.8, encoded by the SCN10A gene, is reportedly selectively expressed in specific pain receptors, with expression concentrated in small-diameter neurons of the dorsal root ganglia (DRG) in the peripheral nervous system. These neurons are typically less than 30 μm in diameter. These DRG neurons reportedly play a crucial role in pain perception as primary sensory neurons. They receive and process injury-related signals from peripheral nerve endings and transmit this information to the spinal cord for further processing and integration. Increased DRG neuron excitability is reportedly important in various types of peripheral pain. Nav1.8 is reportedly involved in the initial stages of motor potential generation in pain receptors. Mutations or deletions of the Nav1.8 gene have been reported to be frequently associated with neuropathic pain. For example, excitatory mutations of Nav1.8 have been found in patients diagnosed with painful microfibroneuropathy. On the other hand, Nav1.8 gene knockout leads to a reduced pain phenotype, particularly in inflammation-induced pain (A.N. Akopian et al., Nature Neuroscience, 1999; 2; 541-548). Furthermore, Nav1.8 gene knockout can reduce pain-related behaviors, including in neuropathic pain (J. Lai et al., Pain, 2002; 95(1-2): 143-152). Furthermore, according to some literature, a natural mutant, A1073V, can induce a shift in the activation voltage of the channel towards a more depolarized direction, and to some extent improve pain symptoms.

Among other things, this disclosure contains the recognition that the effectiveness of existing pain management medications is limited, often providing only partial relief, and in some cases, no relief at all. Furthermore, some existing treatments may be accompanied by significant adverse reactions. In certain implementation schemes, this disclosure provides superior pain management techniques to address this pressing medical need.

In some embodiments, this disclosure provides techniques for targeting Nav1.8 voltage-gated sodium ion channels, such as using modulators, like inhibitors, to provide therapeutic methods for treating or preventing various conditions, disorders, or diseases related to Nav1.8. In some embodiments, the provided techniques, such as compounds having the structure of Formula I or salts thereof, can selectively inhibit Nav1.8 channels. In some embodiments, the provided techniques selectively inhibit peripheral Nav1.8 channels, representing a strategy for non-addictive analgesics. In some embodiments, this disclosure provides non-addictive analgesics. In some implementations, the condition, disorder, or disease is migraine, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, postoperative pain, neuropathic pain, chronic pruritus, or pruritus.

In some embodiments, this disclosure provides various compounds, such as compounds having the structure of Formula I or salts thereof, as well as combinations thereof and methods. In some embodiments, this disclosure provides a compound having the structure of general formula I:

or its salt, wherein:

^R1 is a substituted group selected from 6-10 aryl groups; 5-10 heteroaryl groups containing 1-4 heteroatoms, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur; 3-10 heterocyclic groups containing 1-4 heteroatoms, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur; and a bicyclic structure wherein the first ring is attached to a nitrogen atom and is a benzene ring or a 5-6 heteroaryl ring containing 1-4 heteroatoms, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur, and the second ring is a benzene ring, or a 5-10 heteroaryl ring containing 1-4 heteroatoms, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur, or a 3-10 heterocyclic ring containing 1-4 heteroatoms, wherein the heteroatoms are independently nitrogen, oxygen, or sulfur; or R ¹ is

R1 ^' is R', or ^R1 and R1 ^' together with the nitrogen atom to which they are attached form a optionally substituted 3-6 membered ring, which has 0-3 heteroatoms in addition to the nitrogen atom.

^R2 is a substituted group, selected from phenyl and 5-6 membered heteroaryl groups having 1-4 independent heteroatoms selected from nitrogen, oxygen and sulfur; or ^R2 is ;

^R3 and ^R4 are each independently hydrogen, -CN, or R;

X is -O-, -S-, -S(O)-, -S(O) _2- or -C( ^Rx ) _2- , where each ^Rx is independently hydrogen or alternatively substituted _C1 - _C6 aliphatic, OR or -N(R) ₂ ;

W is N, C, or C(R ^w ), where R ^w is hydrogen or alternatively substituted _C1 - _C6 aliphatic, OR, or -N(R) ₂ , where Z is C when W is C;

Z is N, C, or C( ^Rz ), where ^Rz is hydrogen or alternatively substituted C1 _{- C6} aliphatic, OR, or -N(R) ₂ , where W is C or Y is -C( ^Ry ) when Z is C;

Y is -O-, -S-, -N( ^Ry )-, -C( ^Ry ) _2- or -C( ^Ry )=, where each ^Ry is independently hydrogen or alternatively substituted C1 _{- C6} aliphatic, OR or -N(R) ₂ , where Z is C when Y is -C( ^Ry )=;

Ring A and ring B are independently substituted 5-6 membered aromatic rings, said rings containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Each R s1 is an independent halogen, -CN,Rs11 , -OR s11  , -NR  s11R s12 , -C(O)R s11 , -C(O)NR s11 R s12  , -S(O)2 NRs11Rs12, -S(O)2NRs11Rs12  , or -OS ( O) 2  NR  s11Rs12 ;

Each R s2 is an independent halogen, -CN,Rs21 , -OR s21 , -NR  s21 Rs22, -C(O)R s21 , -C(O)NR  s21 Rs22 , -S(O)2NR s21  , -S(O)Rs21 , -S(O)(NRs22)Rs21  , -S(O)NR s21 R s22 , or -OS(O)  2 NR s21 R s22 ;

s1 and s2 are each independently 0, 1, 2, 3, 4, or 5;

Each of ^Rs11 , ^Rs12 , ^Rs21 and ^Rs22 is independently R';

Each They are all independent single or double keys;

Each R' is independently R, -OR, -C(O)R, -C(O)OR, -S(O)R, or -S(O) _2R ;

Each R is independently a hydrogen or optionally substituted group, said group being selected from C1-C6 aliphatic groups, _C1 - _C6 heteroaliphatic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-10 membered cyclic aliphatic groups, 3-10 membered heterocyclic groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 membered aryl groups, 5-10 membered heteroaryl groups having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 membered aryl- _C1 - _C6 aliphatic groups, and 5-10 membered heteroaryl- _C1 - _C6 aliphatic groups having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

Two R groups on the same atom are arbitrarily selected and independently form a substituted 3-10 membered ring with the atom, the ring containing, in addition to the atom, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

The two R groups can optionally and independently form substituted 3-10-membered rings with the atoms between them, and have 0-4 heteroatoms in addition to the atoms between them; and

Where X is -O-, W is not -CH- or Z is not -CH- or Y is not -C(R ^y ) ₂ -.

In some embodiments, this disclosure provides a pharmaceutical composition of the said compound. In some embodiments, this disclosure provides a pharmaceutical composition comprising the said compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, this disclosure provides a pharmaceutical composition for delivering the provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The provided techniques have a variety of applications. In some embodiments, the compound can be used as a sodium channel modulator. In some embodiments, the compound is a Nav1.8 modulator. In some embodiments, the provided techniques (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 Nav1.8. In some embodiments, the condition, disorder, or disease is or includes migraine, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, postoperative pain, neuropathic pain, chronic pruritus, and pruritus. In some embodiments, the condition, disorder, or disease is related to the administration of another treatment.

In some embodiments, this disclosure provides a method for preventing a condition, disorder, or disease, comprising administering or delivering an effective amount of said compound, such as a compound of formula I or a salt thereof, to a susceptible individual. In some embodiments, this disclosure provides a method for treating a condition, disorder, or disease, comprising administering or delivering an effective amount of said compound, such as a compound of formula I or a salt thereof, to an individual suffering from said condition, disorder, or disease. In some embodiments, said condition, disorder, or disease is a condition, disorder, or disease associated with Nav1.8. In some embodiments, said condition, disorder, or disease is associated with the activation of Nav1.8. In some embodiments, the condition, disorder, or disease includes or relates to migraine, post-ischemic neurodegeneration, epilepsy, inflammatory pain, spontaneous pain, acute pain, preoperative pain, perioperative pain, postoperative pain, neuropathic pain, chronic pruritus, and pruritus.

In some embodiments, this disclosure provides a method for preventing a condition, disorder, or disease, comprising administering or delivering an effective amount of said compound and another agent to a subject susceptible to the condition, disorder, or disease. In some embodiments, this disclosure provides a method for treating a condition, disorder, or disease, comprising administering or delivering an effective amount of said compound and another agent to a subject suffering from the condition, disorder, or disease.

In some embodiments, this disclosure provides techniques, such as methods, reagents, etc., for preparing compounds of general formula I or pharmaceutically acceptable salts thereof.

Specific implementation methods

The present disclosure can be more easily understood by referring to the following detailed description of certain embodiments.

Definition

Unless otherwise stated, the definitions used herein are as follows. For the purposes of this disclosure, chemical elements are identified according to the CAS version of the periodic table, Handbook of Chemistry and Physics, 75th edition. Furthermore, 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, Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

According to this disclosure, in the absence of clear context, the following terms shall have the following meanings: (i) the term “a” may be understood as at least one; (ii) the term “or” may be understood as “and/or”; (iii) the terms “comprising,” “including” (whether or not used with “not limited to”) and “including” (whether or not used with “not limited to”) may be understood as including the listed elements or steps, whether presented alone or with one or more additional elements or steps; (iv) the term “another” may be understood as at least one additional/second or more; (v) the terms “about” and “generally” may be understood as allowing for standard variations as understood by a person of ordinary skill; (vi) if a scope is provided, the endpoint is included. Isomers of the compound are also included unless the context clearly indicates otherwise. Those skilled in the art will know that compounds can be provided, administered, or delivered in various forms, such as salts (e.g., pharmaceutically acceptable salts), solvents, hydrates, esters, prodrugs, tautomers, etc.

In this article, the initial "rac-" refers to a racemic combination or preparation of a chiral compound. With the initial "rac-", (R)- and (S) in the chemical name indicate relative stereochemistry.

In this article, the prefix "rel-" refers to a single enantiomer with an unknown or unspecified absolute configuration when associated with chiral compounds. In compounds with the prefix "rel-", the (R)- and (S)- symbols in the chemical name reflect the relative stereochemical structure of the compound, but not necessarily its absolute stereochemical structure. If the relative stereochemical properties of a given stereocenter are unknown, no stereochemical designation is provided. In some cases, the absolute configuration of some stereocenters is known, while the relative configuration of others is unknown.

Aliphatic: As used herein, "aliphatic" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain containing one or more unsaturated units (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic or polycyclic hydrocarbon ring, or combination thereof, containing one or more unsaturated units (but not aromatic). 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.

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

Alkyl: As used herein, the term "alkyl" has the common meaning in the art and can include saturated aliphatic groups, including linear alkyl, branched alkyl, cycloalkyl (alicyclic), alkyl-substituted cycloalkyl, and cycloalkyl-substituted alkyl. In some embodiments, the alkyl group has 1-100 carbon atoms. In some embodiments, the backbone of a linear or branched alkyl group contains about 1-20 carbon atoms (e.g., _C1 - _C20 for linear and _C2 - _C20 for branched), or about 1-10 carbon atoms. In some embodiments, the cycloalkyl ring has about 3-10 carbon atoms in its cyclic structure, wherein such rings are monocyclic, bicyclic, or polycyclic, and the number of carbon atoms in the cyclic structure is about 5, 6, or 7. In some embodiments, the alkyl group may be a lower alkyl group, wherein the lower alkyl group comprises 1-4 carbon atoms (e.g., straight-chain lower alkyl groups are _C1 - _C4 ).

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

Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In some embodiments, non-human animals are mammals (such as rodents, rats, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, and/or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and/or worms. In some embodiments, animals may be transgenic animals, genetically engineered animals, and/or cloned animals.

Aryl: As used herein, the term "aryl," whether used alone or as part of a larger molecule, such as "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or polycyclic cyclic system having a total of five to thirty cyclic components, wherein at least one ring in the system is aromatic. In some embodiments, aryl refers to a monocyclic, bicyclic, or polycyclic cyclic system having 5 to 14 cyclic components, wherein at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 cyclic components. In some embodiments, each monocyclic unit is aromatic. In some embodiments, aryl is diaryl. The term "aryl" is used interchangeably with the term "aryl ring." In certain embodiments of this disclosure, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, binaphthyl, anthracene, etc., which may have one or more substituents. The scope of the term "aryl" as used herein also includes groups fused to an aromatic ring with one or more non-aromatic rings, such as indene, phthalimino, naphthylimino, or tetrahydronaphthyl.

Comparability: As used herein, "comparable" means that two sets (or more) of conditions or environments are sufficiently similar to each other that the results obtained or the phenomena observed can be compared. In some embodiments, comparable conditions or environments have several substantially identical features and one or a few different features. Those skilled in the art will understand that sets of conditions are comparable when they have a sufficient number and type of substantially identical features, thus reasonably leading to the conclusion that the differences in results obtained or observed under different conditions or environments are caused by, or indicate, changes in, these changing features.

The terms "cycloaliphatic,""carbocyclic,""carbonchain,""carbocyclicgroup," and "carbocyclic" are used interchangeably as described herein to refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic systems, unless otherwise stated, containing 3 to 30 cyclic 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 to 6 carbon atoms. In some embodiments, the cycloaliphatic group is a saturated cycloalkyl group. The term "cycloaliphatic" may also include an alicyclic ring fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl. 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 a C3 _{- C6} monocyclic hydrocarbon, or a _C8 - _C10 bicyclic or polycyclic hydrocarbon, which is fully saturated or contains one or more unsaturated units but is not aromatic, or a _C9 - _C16 polycyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, and has a single-point connection to the rest of the molecule.

Heteroaliphatic: As used herein, the term "heteroaliphatic" has its common meaning in the art, referring to the aliphatic group described herein, in which one or more carbon atoms are independently substituted by one or more heteroatoms (such as oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). In some embodiments, one or more units selected from C, CH, _CH2 , and _CH3 are independently substituted by one or more heteroatoms (including their oxidized and/or substituted forms). In some embodiments, the heteroaliphatic group is a heteroalkyl group. In some embodiments, the heteroaliphatic group is a heteroalkenyl group.

Heteroalkyl: As used herein, the term "heteroalkyl" has its common meaning in this field, referring to an alkyl group in which one or more carbon atoms are independently substituted by one or more heteroatoms (such as oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). Examples of heteroalkyl groups include, but are not limited to, alkoxy, polyethylene glycol, alkyl-substituted amino, tetrahydrofuranyl, piriminyl, morpholinyl, etc.

Heteroaryl: The terms "heteroaryl" and "heteroaryl-" as used herein may be used alone or as part of a larger molecule (such as "heteroalkyl" or "heteroalkoxy"), referring to a monocyclic, bicyclic, or polycyclic system having 5 to 30 ring members, wherein at least one ring in the system is an aromatic ring and at least one aromatic ring atom is a heteroatom. In some embodiments, a heteroaryl is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic, or polycyclic), and in some embodiments, a heteroaryl is a group having 5, 6, 9, or 10 ring atoms. In some embodiments, each monocyclic unit is aromatic. In some embodiments, the heteroaryl group has 6, 10, or 14 shared π electrons arranged in a ring; in addition to the carbon atom, it also has 1 to 5 heteroatoms. The heteroaryl group includes, but is not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, darazinyl, pyrimidinyl, pyrazinyl, indoleazinyl, purinyl, naphridinyl, and pteridinyl. In some embodiments, the heteroaryl group is a heterodiaryl group, such as bispyridinyl. The terms "hybrid aryl" and "hybrid-" used in this article also include groups in which a heteroaryl ring is fused with one or more aryl rings, cycloalicyclic rings or heterocyclic rings, wherein the groups or connecting sites are located on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, 4H-quinoxolinyl, 4H-quinoxolinyl, zozolyl, acridineyl, terazinyl, phenothiazinyl, phenothiazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic, or polycyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaromatic," where any of these terms includes an optional substituted ring. The term "heteroaryl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently and optionally substituted.

Superatom: As used herein, "superatom" refers to an atom that is not carbon or hydrogen. In some embodiments, the superatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (such as quaternary ammonium forms, forms in ammonium groups, etc.), phosphorus, sulfur, oxygen, etc.). In some embodiments, the superatom is silicon, phosphorus, oxygen, sulfur, or nitrogen. In some embodiments, the superatom is silicon, oxygen, sulfur, or nitrogen. In some embodiments, the superatom is oxygen, sulfur, or nitrogen.

Heterocyclic: The terms "heterocyclic,""heterocyclicgroup,""heterocyclicgroup," and "heterocyclic" are used interchangeably herein to refer to monocyclic, bicyclic, or polycyclic molecules (e.g., 3-30 molecules) that are saturated or partially unsaturated and have one or more heteroatom ring atoms. In some embodiments, the heterocyclic group is a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic molecule that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms in addition to a carbon atom, as defined above. When referring to the ring atom 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 (e.g., 3,4-dihydro-2H-pyrrole), NH (e.g., pyrrolidinyl), or ⁺ NR (e.g., N-substituted pyrrolidinyl). The heterocycle can be attached to its dangling ring group on any heteroatom or carbon atom to form a stable structure, and any atom on the ring can be selectively substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, piridyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolyl, pirazine, dioxoheterocyclic, dioxoheterocyclic pentyl, diazaheterocyclic heptyl, oxonitrileheterocyclic heptyl, thionitrileheterocyclic heptyl, morpholinyl, and quinolinyl. The terms "heterocyclic", "heterocyclic group", "heterocyclic ring", "heterocyclic molecule", and "heterocyclic group" are used interchangeably herein and also include groups fused with one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3H-indololinyl, chromyl, phenanthridine, or tetrahydroquinolinyl. Heterocyclic groups can be monocyclic, bicyclic, or polycyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic alkyl group, wherein the alkyl group and the heterocyclic alkyl group are each optionally substituted independently.

Optional Substitution: As described herein, the disclosed compounds may comprise substituted, substituted, and/or unsubstituted molecules. Generally, the term "substitution" means that one or more hydrogen atoms in a given molecule are independently substituted by a substituent. Unless otherwise stated, an "optionally substituted" group may independently have one substituent at each substituted position of that group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted by two or more substituents. In some embodiments, the optionally substituted group is unsubstituted. In some embodiments, the optionally substituted group is substituted. Various substituents are described below.

The monovalent substituents are independently ^halogens ; -( _CH2 ) _0-4RO ; ^- (CH _{(2) ) 0-4ORO ;} -O(CH2 ⁾ _0-4RO , -O-( _CH2 ) _0-4C (O)ORO; -(CH2)0-4CH(ORO) _{2 ;} - ⁽ _CH2 ) _0-4Ph , which can be substituted ^{by Ro} ; -( _CH2 ) _0-4O ( _CH2 ) _0-1Ph , which can be substituted by ^Ro ; -CH=CHPh, which can be substituted by ^Ro ; -( _CH2 ) _0-4O ( _CH2 ) _0-1 -pyridyl, which can be substituted by ^Ro ; _-NO2 ; -CN; _-N3 ; -( _CH2 ) _0-4N ( ^RO ) ₂ ; -( _CH2 ) _0-4N (RO ⁾ _{) C} ^{( O ) RO ​} _​ ^{​ ​} _{​ ​ ​} ^{​ ​ ​ ​ ​ ​} )N(R ^O )C(O)N(R ^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)OSi(R ^O ) ₃ ;-(CH ₂ ) _0-4 OC(O)R ^O ;-OC(O)(CH ₂ ) _0-4 SR ^o ,-SC(S)SR ^o ;-(CH ₂ ) _0-4 SC(O)R ^O ;-(CH ₂ ) _0-4 C(O)N(R ^O ) ₂ ;-C(S)N(R ^O ) ₂ ;-C(S)SR ^o ;-SC(S)SR ^o ,-(CH ₂ ) _0-4 OC(O)N(R ^O ) ₂ ;-C(O)N(OR ^O )R ^O ;-C(O)C(O)R ^O ;-C(O)CH ₂ C(O)R ^O ;-C(NOR ^O )R ^O ;-(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 N(R ^O ) ₂ ;-(CH ₂ ) _0-4 S(O)R ^O ;-N(R ^O )S(O) ₂ N(R ^O ) ₂ ;-N(R ^O )S(O) ₂ R ^O ; -N(OR ^O )R ^O ; -C(NH)N(R ^O ) ₂ ; -Si(R ^O ) ₃ ; -OSi(R ^O ) ₃ ; -P(R ^O ) ₂ ; -P(OR ^O ) ₂ ; -OP(R ^O ) ₂ ; -OP(OR ^O ) ₂ ; -N(R ^O )P(R ^O ) ₂ ;-B( ^RO ) ₂ ;-OB( ^RO ) ₂ ;-P(O)( ^RO ) ₂ ;-OP(O)( ^RO ) ₂ ;-N( ^RO )P(O)( ^RO ) ₂ ;-( _C1-4 straight-chain or branched-chain alkyl)ON( ^RO ) ₂ ; or-( _C1-4 straight-chain or branched-chain alkyl)C(O)ON( ^RO ) ₂ , wherein each ^RO can be independently substituted by the following, and is independently hydrogen, _C1-10 (e.g., _C1-6 , _C1-4 , etc.) aliphatic, _C1-10 (e.g., _C1-6 , _C1-4 , etc.) heteroaliphatic, having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, _C6-10 (e.g., C6 _... Aryl groups (e.g., _C10 , etc.), 5-10 (e.g., 5-9, 5-6, 5, 6, ₉ , _{10, etc.) heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -CH2-(C6-10 (e.g., C6, C10 , etc. ) aryl} ), -O(CH2) _0-1 (C6-10 (e.g., C6, _C10 , etc.) aryl), _-CH2- (5-10 ( _e.g. , 5-9, 5-6, 5, 6, ₉ , 10, etc.) member heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -O( _CH2 ) _0-1 (5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) members of heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) members of monocyclic, bicyclic, or polycyclic, saturated or partially unsaturated rings having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus, or, despite the above definitions, two independently occurring R groups. ^O, together with the atoms between them, forms a heteroaryl group with 3-10 members (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.), or a heteroaryl group with 3-10 members (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.), having 0-4 independent heteroatoms selected from nitrogen, oxygen, sulfur, silicon, and phosphorus, 3-6, 5- Monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated, or aromatic rings (for aromatic rings, members 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.)) have 0-5 heteroatoms selected independently from nitrogen, oxygen, sulfur, silicon, and phosphorus, in addition to the intermediate atom. These heteroatoms can be substituted as defined below.

The monovalent substituents on ^RO (or a ring formed by two independently occurring ^RO atoms together) are independently halogens: -( _CH₂ ) _O₻₂R˙ ^, -(halogen ^R˙ ), -( _CH₂ )O₻₂OH, -(CH₂) ^O₻₂OR˙ , -(CH₂ _{) O₻₂CH} ( ^OR˙ ) _₂ ; -O(halogen ^R˙ ) _, -CN, _-N³ , -( _CH₂ ) _O₻₂C (O ⁾ R˙, _{- ( CH₂} ) _O₻₂C (O)OH ^, -( _CH₂ ) _O₻₂C (O)OR˙, -( _CH₂ )O₻₂SR˙, -( _CH₂ ) _O₻₂SH ^, -( _{CH₂ ) O₻₂ NH₂} , -( _CH₂ ) _₀- ^2NHR˙ , - _{( CH₂} ) _{₀ -} ^2NR˙₂ , _{-NO₂ ,} ^-SiR˙₃ , -OSiR˙₃, -C( ^O ) ^SR˙ , -(C₁ _-4 straight-chain or branched-chain alkylene)C(O) ^OR˙ , or -SSR˙ ^, wherein each ^R˙ is unsubstituted, or, in the case of a "halogen" prefix, is substituted by only one or more halogens, and is independently selected from C₁ _-4 aliphatic, _-CH₂Ph , -O( _CH₂ ) _₀-1 Ph or 3-6 (e.g., 3-5, 5-6, etc.) saturated rings, partially unsaturated rings, or aromatic rings (aromatic rings are 5 or 6-membered rings), having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The divalent substituents on the ^{R O} saturated carbon atoms are independently =O or =S.

The divalent substituents are independently of the following types: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) ₂ R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3 O- or -S(C(R ^* ₂ )) _2-3 S-, wherein each independently occurring R ^* is selected from hydrogen, C _1-6 aliphatic (which may be substituted as defined below) or unsubstituted 3-6 (e.g., 3-5, 5-6 etc.) saturated ring, partially unsaturated ring or aromatic ring (aromatic ring is 5 or 6-membered ring), which has 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The divalent substituents attached to the adjacent substituted carbon of the "optionally substituted" group are independently -O(CR ^* ₂ ) _2-3O- , wherein each independently occurring R ^* is selected from hydrogen, and can be defined as a substituted _C1-6 aliphatic or unsubstituted 3-6 (e.g., 3-5, 5-6, etc.) saturated ring, a partially unsaturated ring, or an aromatic ring (aromatic rings are 5 or 6-membered rings) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

The substituents on the R ^* aliphatic group are independently halogens, -R˙, -(halogen ^R˙ ), -OH, -OR˙, ^{-O (} halogen ^R˙ ), -CN, -C(O)OH, -C ⁽ O) ^OR˙ , -NH2 _, -NHR˙, _-NR˙2 , or _-NO2 , where each ^R˙ is unsubstituted, or, if preceded by "halogen", is substituted by only one or more halogens ^, and is independently _C1-4 aliphatic, _-CH2Ph , -O( _CH2 ) _O-1 Ph or 3-6 (e.g., 3-5, 5-6, etc.) saturated rings, partially unsaturated rings, or aromatic rings (aromatic rings are 5 or 6-membered rings) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

The substituents on the substituted nitrogen are independently -R ^† , -NR ^† ₂ , -C(O)R ^† , -C(O)OR ^† , -C(O)C(O)R ^{† ,} -C(O)CH2C(O)R _† , -S(O) _2R ^† , -S(O) _2NR ^† ₂ , -C(S)NR ^† ₂ , -C(NH)NR ^† ₂ , or -N(R ^† )S(O) _2R ^† ; wherein each R ^† is independently hydrogen, C _1-6 aliphatic (substituted as defined below), unsubstituted -OPh, or unsubstituted 3-6 (e.g., 3-5, 5-6, etc.) saturated, partially unsaturated, or aromatic rings (aromatic rings are 5 or 6-membered rings) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or, notwithstanding the foregoing definition, two independently occurring R ^† together with the atoms between them form an unsubstituted 3-12 (e.g., 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

The substituents on the aliphatic group R ^† are independently halogens, -R ^˙ , -(halogenated R ^˙ ), -OH, -OR ^˙ , -O(halogenated R ^˙ ), -CN, -C(O)OH, -C(O)OR ^˙ , -NH _2, -NHR ^˙ , -NR ^˙ ₂ , or -NO ₂ , wherein each R ^˙ is unsubstituted, or, in the case of a preceding "halogen", is substituted by only one or more halogens, and is independently C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _O-1 Ph or 3-6 (e.g., 3-5, 5-6, etc.) saturated rings, partially unsaturated rings, or aromatic rings (aromatic rings are 5 or 6-membered rings) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

Partially unsaturated: As used herein, "partially unsaturated" refers to a ring molecule containing at least one double or triple bond. The term "partially unsaturated" is intended to include rings with multiple unsaturated sites, but excludes aryl or heteroaryl groups as defined herein.

Drug Combinations: As used herein, "drug combination" refers to an active pharmaceutical ingredient formulated together with one or more pharmaceutically acceptable carriers. In certain regimens, the unit dose of the active pharmaceutical ingredient is suitable for administration in a treatment regimen that, when administered to the relevant population, has a statistically significant probability of achieving the intended therapeutic effect. In certain regimens, drug combinations may be specifically formulated into solid or liquid forms for administration, including combinations suitable for: oral administration, e.g., infusions (aqueous or non-aqueous or suspensions); tablets, e.g., tablets, suppositories, powders, granules, and tongue pastes for oral, sublingual, and systemic absorption; and parenteral administration, such as subcutaneous injection, intramuscular injection, etc. Injection into the flesh, via intravenous injection, or via epidural injection, such as sterile solutions, suspensions, or sustained-release formulations; topical application, for example, as creams, ointments, controlled-release patches, or sprays to the skin, lungs, or mouth; vaginal or rectal administration, for example, as suppositories, creams, or foams; sublingual administration; ophthalmic administration; transdermal administration; or administration to the nasal cavity, lungs, and other mucosal surfaces.

Pharmaceutically acceptable: As used herein, "pharmaceutically acceptable" means, to a reasonable degree of medical judgment, a compound, material, composition, and/or dosage form that is suitable for use in human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers: As used in this article, "pharmaceutically acceptable carriers" refers to pharmaceutically acceptable materials, compositions, or delivery systems, such as liquid or solid fillers, thinners, excipients, or solvent encapsulation materials, used to carry or deliver a test compound from one organ or site of the body to another. Each carrier must be "acceptable," meaning it is compatible with other components in the formulation and will not cause harm to the patient. Materials that can serve 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; sea buckthorn powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; and oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and... Soybean oil; ethylene glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginate; pyrogen-free water; isotonic brine; Ringer's solution; ethanol; pH-buffered solutions; polyesters, polycarbonates, and/or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical preparations.

Pharmaceutically Acceptable Salts: As used herein, “pharmaceutically acceptable salts” refers to salts of compounds suitable for use in pharmaceutical environments, meaning salts that, within reasonable medical judgment, are suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in this field. For example, SMBerge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some implementation schemes, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts of amino groups 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 by means of other methods used in the art such as ion exchange. In some implementation schemes, pharmaceutically acceptable salts include, but are not limited to, adipic acid salts, alginate salts, ascorbic acid salts, aspartate salts, benzenesulfonate salts, benzoate salts, hydrogen sulfate salts, borate salts, butyrate salts, camphorate salts, camphorsulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, glucohepate salts, glycerophosphate salts, gluconate salts, hemisulfate salts, heptaate salts, hydrogen iodide salts, and 2-hydroxyethane salts. Sulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonic acids, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitic acids, dihydroxynaphthalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. In some embodiments, the provided compound comprises one or more acidic groups, and the pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium salt (e.g., an ammonium salt of N(R) _₃ , wherein each R is independently defined and described in this disclosure). Representative alkali 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, pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations that counteract ion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl groups having 1-6 carbon atoms, sulfonates, and aryl sulfonates. In some embodiments, the provided compounds contain two or more acid groups. In some embodiments, the pharmaceutically acceptable salt or common salt of such compounds contains two or more cations, which may be the same or different. In some embodiments, in pharmaceutically acceptable salts (or common salts), all ionizable hydrogen atoms in the acidic groups (e.g., in aqueous solutions with pKa not greater than about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, pKa not greater than about 7; in some embodiments, pKa not greater than about 6; in some embodiments, pKa not greater than about 5; in some embodiments, pKa not greater than about 4; in some embodiments, pKa not greater than about 3) are cation-substituted.

Protecting Groups: The term "protecting group" as used in this article is well-known in the field, including the protecting groups described in detail in the book *Protecting Groups in Organic Synthesis*, by T.W. Greene and P.G.M. Wuts, 3rd edition, John Willie & Son, 1999, which is incorporated herein by reference in its entirety. Additionally, it includes the protecting groups specifically used for nucleoside and nucleotide chemistry described in *Current Protocols in Nucleic Acid Chemistry*, edited by Serge L. Beaucage et al. Suitable amino protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfonyl)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-[9-(10,10-dioxo-10,10,10,10-tetrahydrothionanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenylacetocarbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), and 1,1-dimethyl-2-halogenated ethyl carbamate. 1,1-Dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-Dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-Methyl-1-(4-biphenyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), ethyl 2-(2'- and 4'-pyridyl)carbamate (Pyoc), ethyl 2-(N,N-dicyclohexylmethylamino)carbamate, tert-butyl carbamate (BOC), ethyl 1-adamantylcarbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (1-isopropylallyl) carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate Carbamate (Noc), 8-quinolinyl carbamate, N-hydroxyguanidine carbamate, 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-anthraylmethyl carbamate, 2-methylthioethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithiazolyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,2-phosphonitroethyl carbamate (Peoc), 2-triphenylphosphonitroisopropyl 1,1-Dimethyl-2-cyanoethyl carbamate, m-chloro-p-acetoxybenzyl carbamate, p-(dihydroxybenzyl)carbamate, 5-benzoxazole methyl carbamate, 2-(trifluoromethyl)-6-bromomethyl carbamate (Tcroc), m-nitrocarbamate, 3,5-dimethoxycarbamate, ortho-nitrocarbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(ortho-nitrophenyl)methyl carbamate, benzothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonic acid aminocarbonyl derivative, N'-phenylaminothiocarbonyl derivative, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate Cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridine) 2-Furfuryl methyl carbamate, 2-Iodoethyl carbamate, Isobutyl carbamate, Isobutyl carbamate, Isocyanate carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, ethyl 1-methylcyclohexyl carbamate, ethyl 1-methyl-1-cyclopropylmethyl carbamate, ethyl 1-methyl-1-(3,5-dimethoxyphenyl) carbamate, ethyl 1-methyl-1-(p-phenylazophenyl) carbamate, ethyl 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-phenylazobenzyl carbamate, 2,4,6-tributylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate Ester, 2,4-methylamine, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridinamide, 3-pyridinamide, N-benzoylphenylacetamide derivative, benzoylamine, p-phenylbenzoylamine, angionitrobenzylacetamide, angionitrobenzylacetamide, acetylacetamide, (N'-dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenyl)acetamide 3-(ann-nitrophenyl)propionamide, 2-methyl-2-(ann-nitrophenoxy)propionamide, 2-methyl-2-(ann-phenylazophenyloxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, ann-nitrocinnamylamine, N-acetymethionine derivatives, ann-nitrobenzylamine, ann-benzyloxymethylbenzylamine, 4,5-diphenyl-3-acezoline -2-one, N-phenylenediamine, N-dithiobutadieneimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldiazidoxane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl- 1,3,5-Triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-ethoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxybenzene) N-[(4-methoxyphenyl)diphenylmethylamine]amine, N-5-dibenzofuranylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluoreneamine (PhF), N-2,7-dichloro-9-fluorenemethylamine, N-ferrocenemethylamine (Fcm), N-2-cyclopentanamine N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N- (N',N'-Dimethylaminomethylene)amine, N,N'-isopropyldiamine, N-p-nitrobenzylamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentacarbonylchromium or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitrosamine, N-nitrosoamine, amine N-oxygen Compounds, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkylphosphamide, dibenzylphosphamide, diphenylphosphamide, benzylsulfonamide, anisonitrobenzenesulfonamide (Nps), 2,2,3,6,-triphenylmethylsulfonamide, 3-nitropyridinesulfonamide (Npys), p-toluenesulfonamide (Ts), benzylsulfonamide, 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-trimethylsilyl ethanesulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzylsulfonamide.

Suitable protected carboxylic acids include, but are not limited to, silicone, alkyl, alkenyl, aryl, and aralkyl-protected carboxylic acids. Suitable silicones include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, etc. Suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, tributyl, tetrabutyl, tetrahydropyran-2-yl, etc. Suitable alkenyl groups include allyl. Suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl groups. Examples of suitable aralkyl groups include optionally substituted benzyl groups (such as p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, orthonitrobenzyl, p-nitrobenzyl, p-halogenated benzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), as well as 2- and 4-cortolyl groups.

Suitable hydroxyl protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), t-butoxymethyl, 4-pentenoxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), and tetrahydrogen. Pyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiaranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiaranyl, 4-methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxyguanidin-4-yl (CTMP), 1,4-dioxanecyclopentan-2-yl, tetrahydrofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-tolyzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1 -Methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, orthonitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl-p-cyanobenzyl, p-phenylbenzyl, 2-pyridyl, 4-pyridyl, 3-methyl-2-pyridin N-oxo, diphenylmethyl, p,p'-dinitrophenyl, 5-dibenzofuranyl, triphenylmethyl, α-naphthyldiphenylmethyl 4,4',4"-tris(4,5-dichlorobenzylaminophenyl)methyl, 4,4',4"-tris(levo-benzoxylphenyl)methyl, 4,4',4"-tris(benzoxylphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xanthrayl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiol-2-yl, benzoisothiazolyl S,S-dioxo,trimethyl Silyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), dimethylisopropylsilyl group (IPDMS), diethylisopropylsilyl group (DEIPS), dimethylhexylsilyl group, tert-butyldimethylsilyl group (TBDMS), tert-butyldiphenylsilyl group (TBDPS), tribenzylsilyl group, tri-p-oxysilyl group, triphenylsilyl group, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxygen Levovallate, 4,4-(ethylidene dithio)vallate (levovallate dithioacetaldehyde), pteropenolate, adamantyl ester, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (formamidinate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethylalkyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(benzenesulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), isobutyl carbonate Alkyl carbonate, vinyl alkyl carbonate, allyl alkyl carbonate, p-nitrophenyl alkyl carbonate, benzyl alkyl carbonate, p-methoxybenzyl alkyl carbonate, 3,4-dimethoxybenzyl alkyl carbonate, ortho-nitrobenzyl alkyl carbonate, p-nitrobenzyl alkyl carbonate, thiocarbonate S-benzyl alkyl, 4-ethoxy-1-naphthyl carbonate, dithiocarbonate methyl, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, ortho-(dibromomethyl)benzoate, 2-methylbenzenesulfonate, 2-(meththiomethoxy)ethyl, 4-(meththiomethoxy)butyrate, 2-(meththiomethoxymethyl)benzoic acid Esters, 2,6-dichloro-4-methylphenoxyacetic acid ester, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid ester, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid ester, dichlorophenylacetic acid ester, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, orthomethoxycarbonylbenzoate, α-naphthaleneate, nitrate, N,N,N',N'-tetramethylphosphodiamine alkyl ester, N-phenylcarbamate alkyl ester, borate, dimethyl thiophosphate, alkyl 2,4-dinitrobenzenesulfonate, sulfate, methanesulfonate (methanesulfonates), benzyl sulfonate and p-sulfonate (Ts). Protecting groups used to protect 1,2- or 1,3-diols include methylene acetal, ethyl acetal, 1-t-butyl ethyl acetal, 1-phenyl ethyl acetal, (4-methoxyphenyl)ethyl acetal, 2,2,2-trichloroethyl acetal, acetone, cyclopentyl acetal, cyclohexyl acetal, cycloheptyl acetal, benzyl acetal, p-methoxybenzyl acetal, 2,4-dimethoxybenzyl acetal, 3,4-dimethoxybenzyl acetal, 2-nitrobenzyl acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ester, 1-methoxy Ethylene, 1-ethoxyethylene, 1,2-dimethoxyethylene, α-methoxybenzylene, 1-(N,N-dimethylamino)ethylene derivative, α-(N,N'-dimethylamino)benzylene derivative, 2-oxocyclopentylene, di-tert-butylsilyl group (DTBS), 1,3-(1,1,3,3-tetraisopropyldisiloxanemethylene) derivative (TIPDS), tetra-tert-butoxydisiloxane-1,3-dimethylene derivative (TBDS), cyclic carbonates, cyclic borates, ethyl borate, and phenyl borate.

In some embodiments, the hydroxyl protecting group includes 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-dichlorophenyl, diphenylmethyl, p-nitrophenylmethyl, triphenylmethyl (triphenylmethyl), 4,4'-dimethyl Oxytriphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoic acid ester, chloroacetyl, trichloroacetyl, trifluoroacetyl, tert-pentaylyl, 9-fluorenemethyl carbonate, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, triphenylmethyl, monomethoxytriphenylmethyl (MMTr), 4,4'-dimethoxytriphenylmethyl (DMTr) and 4, 4',4"-Trimethoxytriphenylmethyl (TMTr), 2-cyanoethyl (CE or Cne), 2-(trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl, 2-(4-nitrophenyl)ethyl (NPE), 2-(4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4, 6-Trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4"-tris(benzoyloxy)trimethylmethyl, diphenylaminomethyl, vinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenyloxanthracene-9-yl (pixyl), or 9-(p-methoxyphenyl)xanthine-9-yl (MOX). In some embodiments, the hydroxyl protecting group is independently selected from acetyl, benzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 4,4'-dimethoxytriphenylmethyl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of triphenylmethyl, monomethoxytriphenylmethyl, and 4,4'-dimethoxytriphenylmethyl. In some embodiments, the protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonyluylethyl, methyl, benzyl, orthonitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxyamino)-1-propyl, 4-oxopentyl, 4-methylphenylethyl, 4-methylphenylethyl, 4-methylphenylethyl, 4-methylphenylethyl, 4-methylphenylethyl, 4-methylphenylethyl 4-Methylphenethyl, 4-methylphenethyl, 4-methylphenethyl, 4-methylphenethyl, 4-methylphenethyl, 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-methoxy,N-methyl)aminoethyl, or 4-[N-methyl-N-(2,2,2-trifluoroacetyl)amino]butyl.

Test subject: As used herein, the terms "subject" or "test object" refer to any organism to which a compound or combination of substances is administered, for example, for experimental, diagnostic, preventative, and/or therapeutic purposes, in accordance with this disclosure. 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 implementation protocols, the test object is a human. In some implementation protocols, the test subject may have and/or be susceptible to a disease, disorder, and/or condition.

Substantively: As used herein, the term "substantively" refers to a qualitative condition encompassing all or nearly all of the characteristics or attributes of concern. Those of ordinary skill in the fields of biology and/or chemistry will understand that biological and chemical phenomena rarely (if at all) achieve completeness and/or wholeness, or reach or avoid absolute results. Therefore, this article uses the term "substantively" to encompass the inherent potential incompleteness of many biological and/or chemical phenomena.

Susceptible Population: A "susceptible person" for a disease, disorder, and/or condition is someone who has a higher risk of developing a disease, disorder, and/or condition than the general public. In some embodiments, individuals susceptible to a disease, disorder, and/or condition have a predisposition to develop that disease, disorder, and/or condition. In some embodiments, individuals susceptible to a disease, disorder, and/or condition may not yet be diagnosed with that disease, disorder, and/or condition. In some embodiments, individuals susceptible to a disease, disorder, and/or condition may exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, individuals susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, individuals susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some implementations, individuals susceptible to disease, disorder, and/or condition may not develop the disease, disorder, and/or condition.

Therapeutic agent: As used herein, the term "therapeutic agent" refers to any drug that, when administered to subjects, produces the expected effect (such as the expected biological, clinical, or pharmacological effect). In some protocols, a formulation is considered a therapeutic agent if it demonstrates a statistically significant effect in an appropriate population. In some protocols, an appropriate population refers to a group of subjects who have and/or are susceptible to a disease, disorder, or condition. In some protocols, an appropriate population is a model organism population. In some protocols, an appropriate population can be defined by one or more criteria, such as age group, sex, genetic background, prior clinical condition, prior treatment, etc. In some embodiments, a treatment is a substance that, when administered to a subject in an effective amount, can reduce, improve, alleviate, inhibit, prevent, delay the onset, reduce the severity, and/or decrease the incidence of one or more symptoms or features of a disease, disorder, and/or condition. In some embodiments, a "treatment" means a formulation that has been or requires approval from a government agency before being marketed for human use. In some embodiments, a "treatment" is a formulation that requires a medical prescription for use in the human body. In some embodiments, a treatment is a provided compound.

Therapeutic effective amount: As used herein, the term "therapeutic effective amount" refers to the amount of a substance (such as a treatment agent, combination, and/or formulation) that, when administered as part of a treatment regimen, elicits the expected biological response. In some implementations, the therapeutically effective amount of a substance refers to the amount sufficient to treat, diagnose, prevent, and/or delay the onset of a disease, disorder, and/or condition when administered to a subject who has or is susceptible to such a disease, disorder, and/or condition. As will be understood by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance to be delivered, and the target cells or tissues. For example, the effective amount of a compound in a formulation for treating diseases, disorders, and/or conditions refers to the amount that can reduce, improve, alleviate, inhibit, prevent, delay the onset, reduce the severity, and/or decrease the incidence of one or more symptoms or features of the disease, disorder, and/or condition. In some regimens, the effective therapeutic amount is administered as a single dose; in others, multiple unit doses are required to achieve the effective therapeutic amount.

Treatment: As used herein, the term "treatment" refers to any method used to partially or completely alleviate, improve, relieve, suppress, prevent, delay the onset of, reduce the severity of, and/or decrease the incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to subjects who do not present with disease, disorder, and/or symptoms. In some implementation protocols, treatment may be administered to subjects who only present with early symptoms of a disease, disorder, and/or condition, for example, to reduce the risk of pathological progression associated with the disease, disorder, and/or condition.

Unsaturated: The term "unsaturated" as used here refers to a molecule having one or more unsaturated units.

As will be understood by those skilled in the art, the methods and compositions described herein relating to the provided compounds are generally also applicable to pharmaceutically acceptable salts of this class of compounds.

Among other things, this disclosure provides compounds with a variety of uses. In some embodiments, the provided compounds are those represented by Formula I:

Or its salts, wherein each variable is independent as described in this disclosure.

In some embodiments, the provided compound is the compound represented by general formula II:

Or its salts, wherein each variable is independent as described in this disclosure.

Examples of various variables in various general formulas (such as General Formula I, General Formula II, etc.) are described in this disclosure. Those skilled in the art who read this disclosure will be able to select embodiments for each variable and combine them; such combinations are within the scope of this disclosure. Those skilled in the art will also understand that embodiments described for a variable (e.g., R) can be used for other variables that can be that variable (e.g., R', ^Rs11 , ^Rs12 , ^Rs21 , ^Rs22 , ^Rs31 , ^Rs32 , ^Rs41 , ^Rs42 , etc. can be variables of R).

R ¹

In some embodiments, ^R1 is an optional substituted group selected from 6-10 aryl groups, 5-10 heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-10 heterocyclic groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and bicyclic systems, wherein the first ring is attached to a nitrogen atom and is a phenyl ring or a 5-6 heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the second ring is a phenyl ring, a 5-10 heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-10 heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is .

In some embodiments, ^R1 is an optional 6-10 aryl group. In some embodiments, ^R1 is an optional phenyl group. In some embodiments, ^R1 is a phenyl group. In some embodiments, ^R1 is an optional naphthyl group. In some embodiments, ^R1 is a naphthyl group.

In some embodiments, ^R1 is a substituted 5-10 heteroaryl group having 1-4 heteroatoms. In some embodiments, ^R1 is a substituted 5-10 heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^R1 is a substituted 5-6 membered heteroaryl group having 1-4 heteroatoms. In some embodiments, ^R1 is a substituted 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having 1-4 heteroatoms. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having 1-3 heteroatoms. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having 1-2 heteroatoms. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having two heteroatoms. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having one heteroatom. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having one oxygen atom. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having one nitrogen atom. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having one sulfur atom. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 5-membered heteroaromatic ring having two heteroatoms, one of which is nitrogen. In some embodiments, ^R1 is a substituted 5-membered heteroaryl ring having two heteroatoms independently selected from N and S. In some embodiments, ^R1 is a substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen and oxygen. In some embodiments, ^R1 is a substituted 5-membered heteroaryl ring having two heteroatoms independently selected from oxygen and sulfur. In some embodiments, ^R1 is ^a substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the ring has a single heteroatom. In some embodiments, the ring has two or more heteroatoms, at least one of which is nitrogen. In some embodiments, each heteroatom is nitrogen. In some embodiments, all heteroatoms are identical. In some embodiments, at least one heteroatom differs from the others.

In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having 1-4 heteroatoms. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having 1-3 heteroatoms. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having 1-2 heteroatoms. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having two heteroatoms. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having one nitrogen atom. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having two independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having two heteroatoms, wherein each heteroatom is nitrogen. In some embodiments, ^R1 is a substituted 6-membered heteroaromatic ring having three heteroatoms. In some embodiments, ^R1 is a substituted six-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted six-membered heteroaryl ring having three heteroatoms, one of which is nitrogen.

In some embodiments, ^R1 is a substituted 9-membered heteroaryl group having 1-4 heteroatoms. In some embodiments, ^R1 is a substituted 9-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 9-membered heteroaryl group having 1-2 heteroatoms. In some embodiments, ^R1 is a substituted 9-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^R1 is a substituted 10-membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, ^R1 is a substituted 10-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 10-membered heteroaryl ring having 1-2 heteroatoms. In some embodiments, ^R1 is a substituted 10-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^R1 is a substituted 3-10 membered heterocyclic group having 1-4 heteroatoms. In some embodiments, ^R1 is a substituted 3-10 membered heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1 is a substituted 3-10 membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a substituted 3-7 membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is ^a substituted 3 membered heterocyclic group having 1 heteroatomium independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a optionally substituted 4-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a optionally substituted 5-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is a optionally substituted 6-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 is an optionally substituted 7-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^R1 is an optional substituted bicyclic system, wherein the first ring is attached to a nitrogen atom and is a benzene ring or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; the second ring is a benzene ring, a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-10 membered heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the first ring is an optional substituted benzene ring. In some embodiments, the first ring is a benzene ring. In some embodiments, the first ring is an optional substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the first ring is a 5-6 membered heteroaryl ring with 1-2 independently selected heteroatoms of nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a substituted benzene ring. In some embodiments, the second ring is a benzene ring. In some embodiments, the second ring is a 5-6 membered heteroaryl ring with 1-4 independently selected heteroatoms of nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a 5-6 membered heteroaryl ring with 1-2 independently selected heteroatoms of nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a 3-10 membered heterocyclic group with 1-4 independently selected heteroatoms of nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a 3-10 membered heterocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a 5-6 membered heterocyclic group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a 5-6 membered heterocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a 5 membered heterocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the second ring is a 6 membered heterocyclic group with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some implementation schemes, the first and second rings are fused.

In some embodiments ^{, R1} is an optional pyridinyl group ^. In some implementation schemes,

^R1 is In some implementations, ^R1 is an alternative. In some implementation schemes, ^R1 is... In some implementations, ^R1 is an alternative. In some implementation schemes, ^R1 is... In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. .

In some implementation schemes, ^R1 is Each variable is independent as described in this disclosure.

In some embodiments, ring A is an optional substituted phenyl group. In some embodiments, ring A is a benzene ring.

In some embodiments, ring A is a substituted 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted benzene ring. In some embodiments, ring A is a substituted 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5-membered heteroaryl ring having 1-2 heteroatoms, where one heteroatom is nitrogen and the other heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5-membered heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 6-membered heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 6-membered heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 6-membered heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 6-membered heteroaromatic ring having 1 nitrogen atom. In some embodiments, ring A is a 6-membered heteroaromatic ring having 1 nitrogen atom. In some embodiments, ring A is optionally substituted with a pyridinyl group.

^{In some embodiments, each substituent of R1 is independently Rs1', wherein each Rs1 is independently selected from halogens, -CN, Rs11, -ORs11, -NRs11Rs12, -C(O)Rs11 , -C ( O ) NRs11Rs12 , -S} (O)2NRs11Rs12, -S(O) ^2Rs11 , -S ₍ O ^{)Rs11 ,} -S(O) ⁽ _NRs12 ) ^Rs11 , -S(O) ^NRs11Rs12 , ^or -OS(O) ^2NRs11Rs12 , wherein _each ^{Rs11 and Rs12 is} independently -H or an optional substituted group ^selected from _C1 -C _6. An aliphatic group or a 5-6 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the group is optionally substituted by one or more substituents (e.g. 1-3), wherein the substituents are independently selected from halogen, -OH or =O. ^{In some embodiments, each substituent of R1 is independently Rs1', wherein each Rs1 is independently selected from halogens, -CN, Rs11, -ORs11, -NRs11Rs12, -C(O)Rs11 , -C ( O ) NRs11Rs12 , -S} (O)2NRs11Rs12, -S(O) ^2Rs11 , -S ₍ O) ^Rs11 , -S(O) ⁽ _NRs12 ) ^Rs11 , ^{-S(O)NRs11Rs12, and -OS(O)2NRs11Rs12, wherein each Rs11 and Rs12 is independently -H} _or ^{an optional substituted group selected} from _C1 -C _6. An aliphatic group or a 5-6 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the group is optionally substituted by one or more substituents (e.g. 1-3), wherein the substituents are independently selected from halogen, -OH or =O. In some embodiments, each substituent of ^R1 is independently Rs1 ^' , wherein each ^Rs1 is independently selected ^{from halogens, -CN, Rs11, -ORs11, -NRs11Rs12, -C(O)Rs11 , -C ( O} ) ^NRs11Rs12 , -S(O)2NRs11Rs12, -S(O)2Rs11, -S ₍ O ^{) Rs11} , -S(O) ⁽ _NRs12 ) ^Rs11 , ^-S (O ^{)NRs11Rs12 ,} and -OS(O) ^2NRs11Rs12 , wherein _each ^Rs11 and ^{Rs12 is} independently -H ^or an optional substituted group ^selected from _C1 -C _6. An aliphatic group or a 5-6 membered saturated ring having 0-4 nitrogen atoms, wherein the group is optionally substituted by one or more substituents (e.g., 1-3), the substituents being independently selected from halogens, -OH or =O. In some embodiments, each substituent of ^R1 is independently Rs1 ^' , wherein each ^Rs1 is independently selected from halogens, -CN, ^Rs11 , ^-ORs11 , ^{-NRs11 Rs12} , -C(O) ^Rs11 , -C(O) ^{NRs11 Rs12} , -S(O) _2NRs11 ^Rs12 , -S(O) ^2Rs11 , -S(O) ^Rs11 , -S(O) ₍ ^NRs12 ) ^Rs11 , -S(O) ^{NRs11 Rs12 ,} and -OS(O) _2NRs11 ^Rs12 , wherein each ^Rs11 and ^{Rs12 is} independently -H or an optional substituted group ^selected from _C1 -C _6. An aliphatic group or a 5-6 membered saturated ring having 1-2 nitrogen atoms, wherein the group is optionally substituted by one or more substituents (e.g., 1-3), the substituents being independently selected from halogens, -OH, or =O. In some embodiments, each halogen is -F.

In some embodiments, ^Rs1 is a halogen. In some embodiments, ^Rs1 is F. In some embodiments, ^Rs1 is Br.

In some implementation schemes, R ^s1 is CN.

In some embodiments, Rs1 is Rs11 , where Rs11 is as described in this disclosure. In some embodiments, Rs1 is -ORs11 , where Rs11 is as described in this disclosure. In some embodiments, Rs1 is -NRs11Rs12 , where each variable is independent as described in this disclosure. In some embodiments, Rs1 is -NHRs11 , where Rs11 is as described in this disclosure. In some embodiments, Rs1 is -NHRs11 , where Rs11 is an optionally substituted C1-6 aliphatic compound. In some embodiments, Rs1 is -C(O) Rs11 , where Rs11 is as described in this disclosure. In some embodiments, Rs1 is -C(O) Rs11 , where Rs11 is an optional C1-6 aliphatic compound. In some embodiments, Rs1 is -C(O) NRs11Rs12 , where each variable is independent as described in this disclosure. In some embodiments, Rs1 is -C(O) NHRs11 , where Rs11 is as described in this disclosure. In some embodiments, Rs1 is -C(O) NHRs11 , where Rs11 is an optional C1-6 aliphatic compound. In some embodiments, Rs1 is -S(O) 2NRs11Rs12 , where each variable is independent as described in this disclosure. In some embodiments, R s1 is -S(O) 2 NHR s11 , where R s11  is as described in this disclosure. In some embodiments, R s1 is -S(O) 2 NHRs11 , where R s11  is an optionally substituted C 1-6  aliphatic compound. In some embodiments, R s1 is -S(O)R s11  , where each variable is independent as described in this disclosure. In some embodiments, R s1  is -S(O)(NRs12 )R s11 , where each variable is independent as described in this disclosure. In some embodiments, R s1 is -S(O)(NH)R s11 , where R s11 is as described in this disclosure. In some embodiments, R s1 is -S(O)NRs11 R s12 , where each variable is independent as described in this disclosure. In some embodiments, R  s1  is -S(O)NHR s11  , where R  s11 is as described in this disclosure. In some embodiments, Rs1 is -S(O) 2 NRs11 R s12 , where each variable is independent as described in this disclosure. In some embodiments, R  s1  is -OS(O) 2 NHRs11 , where R s11 is as described in this disclosure. In some implementation schemes, R s1 is -OS(O) 2 NHR s11 , where R s11 is C 1-6 aliphatic.

In some embodiments, ^Rs11 is R', where R' is as described in this disclosure. In some embodiments, ^Rs11 is an optionally substituted C1-6 aliphatic compound. In some embodiments, ^Rs11 is an optionally substituted _C1-6 alkyl compound. In some embodiments, ^Rs11 is a _{C1 - C6} aliphatic compound selectively substituted with one or more (e.g., 1-3) halogens, -OH, or =O. In some embodiments, ^Rs11 is a _C1 - _C6 alkyl compound selectively substituted with one or more (e.g., 1-3) halogens or -OH. In some embodiments, ^Rs11 is a _C1 - _{C4 alkyl} compound selectively substituted with one or more (e.g., 1-3) halogens, -OH, or =O. In some embodiments, ^Rs11 is a _C1 - _C6 alkyl. In some embodiments, ^Rs11 is a _C1 - _C3 alkyl. In some embodiments, ^Rs11 is methyl. In some embodiments, ^Rs11 is -CH₂OH. In some embodiments, ^Rs11 is _-CHF₂ . In some embodiments, ^Rs11 is -CH( _OH ) _CH₂OH . In some embodiments, ^Rs11 is -C(OH)(Me) _₂ .

In some embodiments, R ^s11 is a substituted five-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^Rs11 is an optional substituted 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs11 is optional.

In some embodiments, R s11  is a 3-10 (e.g., 3-8, 3-6, 3-5, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heterocyclic group with 1-4 (e.g., 1-2, 1, 2, 3, 4, etc.) independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rs11 is a 5-membered heterocyclic group with 1-4 independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R s11  is a 6-membered heterocyclic group with 1-4 independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R s11 is an optionally substituted... In some implementation schemes, R s11 is In some implementations, R s11 is an optional alternative. .

In some implementation schemes, R ^s11 is H.

In some embodiments, ^Rs12 is R', where R' is as described in this disclosure. In some embodiments, ^Rs12 is an optionally substituted C1-6 aliphatic compound. In some embodiments, ^Rs12 is an optionally substituted _C1-6 alkyl compound. In some embodiments, ^Rs12 is a _C1 - _C6 aliphatic compound selectively substituted with one or more (e.g., 1-3) substituents independently selected from halogens, -OH, or =O. In some embodiments, ^Rs12 is a C1-C ₍₆ ) alkyl compound selectively substituted with one or more (e.g., 1-3) substituents independently selected from halogens, -OH, or =O. In some embodiments, ^Rs12 is a ^C1 -C4 _alkyl compound selectively substituted with one or more (e.g., 1-3) substituents independently selected from halogens, -OH, or =O. In some embodiments, ^Rs12 is a _C1 - _C6 alkyl. In some embodiments, ^Rs12 is a _C1 - _C3 alkyl. In some embodiments, ^Rs12 is methyl. In some embodiments, ^Rs12 is -CH₂OH. In some embodiments, ^Rs12 is _-CHF₂ . In some embodiments, ^Rs12 is -CH( _OH ) _CH₂OH . In some embodiments, ^Rs12 is -C(OH)(Me) _₂ .

In some embodiments, ^Rs12 is a substituted 5-membered heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs12 is a substituted 6-membered heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs12 is optionally substituted. .

In some embodiments, Rs12 is a 3-10 (e.g., 3-8, 3-6, 3-5, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heterocyclic group with 1-4 (e.g., 1-2, 1, 2, 3, 4, etc.) independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rs12 is a 5-membered heterocyclic group with 1-4 independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R s12  is a 6-membered heterocyclic group with 1-4 independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rs12 is an optionally substituted... In some implementation schemes, R s12 is... In some implementations, R s12 is an optional alternative. .

In some implementation schemes, R ^s12 is H.

In some embodiments, ^Rs1 is -C(O) _NH2 . In some embodiments, ^Rs1 is -C(O) _NHCH3 . In some embodiments, ^Rs1 is _-CH2OH . In some embodiments, ^Rs1 is _-CHF2 . In some embodiments, ^Rs1 is -S(O) _2NH2 . In some embodiments, ^Rs1 is a _halogen . In some embodiments, ^Rs1 is -F. In some embodiments, ^Rs1 is -Cl. In some embodiments, ^Rs1 is -S(O) _2Me . In some embodiments, ^Rs1 is -S(O)Me. In some embodiments, ^Rs1 is -CH(OH) _CH2 (OH). In some embodiments, ^Rs1 is optionally substituted. In some implementation schemes, ^Rs1 is... In some implementation schemes, ^Rs1 is... In some embodiments, ^Rs1 is -S(NH)(O)Me. In some embodiments, ^Rs1 is -S(NMe)(O)Me. In some embodiments, ^Rs1 is -CHO. In some embodiments, ^Rs1 is -C( _CH3 ) _2OH . In some embodiments, ^Rs1 is an optionally substituted _C1-6 aliphatic group. In some embodiments, ^Rs1 is an optionally substituted _C1-6 alkyl group. In some embodiments, ^Rs1 is a C1-6 alkyl group. In some embodiments, ^Rs1 is methyl. In some embodiments, ^Rs1 is _-NH2 . In some embodiments, ^Rs1 is an optionally substituted _5-6 heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs1 is... In some embodiments, ^Rs1 is -OR, where R is as described in this disclosure. In some embodiments, ^Rs1 is -OH. In some embodiments, ^Rs1 is -OR, where R is an optional _C1-6 aliphatic compound. In some embodiments, ^Rs1 is -OR, where R is an optional _C1-6 alkyl compound. In some embodiments, ^Rs1 is -OMe. In some embodiments, ^Rs1 is _-NH2 . In some embodiments, ^Rs1 is _-OCH2CH (OH) _CH2 (OH). In some embodiments, ^Rs1 is ( S ) _-OCH2CH (OH) _CH2 (OH). In some embodiments, ^Rs1 is ( R ) _-OCH2CH (OH) _CH2 (OH). In some embodiments, ^Rs1 is -H.

In some embodiments, the two ^Rs1 groups, together with the intervening atom, form a selectively substituted ring as described herein. In some embodiments, the two ^Rs1 groups, together with the intervening atom, form a selectively substituted 5-6 membered ring, which, in addition to the intervening atoms, has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the two ^Rs1 groups, together with the intervening atom, form a selectively substituted 5 membered ring, which, in addition to the intervening atoms, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the two Rs1 groups, together with the intervening atom, form a selectively substituted 6 membered ring, which, in addition to the intervening atoms, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, s1 is 0, 1, 2, 3, 4, or 5. In some embodiments, s1 is 0. In some embodiments, s1 is 1. In some embodiments, s1 is 2. In some embodiments, s1 is 3. In some embodiments, s1 is 4. In some embodiments, s1 is 5. In some embodiments, s1 is 1 or 2.

In some implementation schemes, ^R1 was not replaced.

In some embodiments, ^R1 is a phenyl group optionally substituted by 1-5 Rs1 ^groups . In some embodiments, ^R1 is a phenyl group optionally substituted by 1 or 2 ^{Rs1 groups} . In some embodiments, ^R1 is a phenyl group substituted by 2 or more ^Rs1 groups. In some embodiments, ^R1 is a phenyl group substituted by one Rs1 ^group .

In some embodiments, ^R1 is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is optionally substituted by 1-4 Rs1 atoms. In some embodiments, ^R1 is a 5-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is optionally substituted by 1-4 ^{Rs1 atoms} . In some embodiments, ^R1 is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is substituted by two or more ^{Rs1 atoms} . In some embodiments, ^R1 is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is substituted by one ^{Rs1 atom} .

In some embodiments, ^R1 is a 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is optionally substituted by 1-5 Rs1 atoms. In some embodiments, ^R1 is a 6-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is optionally substituted by 1-5 ^{Rs1 atoms} . In some embodiments, ^R1 is a 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is substituted by two or more Rs1 ^atoms . In some embodiments, ^R1 is a 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is substituted by one ^{Rs1 atom} .

In some embodiments, ^R1 is a 2-pyridyl group substituted with ^Rs1 . In some embodiments, R1 is a 3-pyridyl group substituted with one ^Rs1 . In some embodiments, ^R1 is a 4-pyridyl group substituted with one ^Rs1 . In some embodiments, ^R1 is a 2-pyridyl group substituted with two ^Rs1 groups. In some embodiments, ^R1 is a 3-pyridyl group substituted with two Rs1 ^groups . In some embodiments, ^R1 is a 4-pyridyl group substituted with two Rs1 ^groups . In some embodiments, ^R1 is ^a 2-pyridyl group substituted with two or more Rs1 ^groups . In some embodiments, ^R1 is a 3-pyridyl group substituted with two or more Rs1 ^groups . In some embodiments, ^R1 is a 4-pyridyl group substituted with two or more Rs1 ^groups .

In some embodiments, R1 is the substituted group. In some embodiments, R1 has one substituent. In some embodiments, R1 has two substituents. In some embodiments, R1 has three or more substituents. In some embodiments, the substituent is located at position 2 (the atom of R1 bonded to the nitrogen atom is at position 1). In some embodiments, the substituent is located at position 3 (the atom of R1 bonded to the nitrogen atom is at position 1). In some embodiments, the substituent is located at position 4 (the atom of R1 bonded to the nitrogen atom is at position 1). In some embodiments, the substituent is located at position 2 and position 3, wherein R1 is bonded to the nitrogen atom at position 1. In some embodiments, one substituent is located at position 3 and one substituent is located at position 4, wherein R1 is bonded to the nitrogen atom at position 1. In some embodiments, each substituent is independently R s1 as described in this disclosure. In some embodiments, R 1  has one substituent. In some embodiments, R 1  has two substituents. In some embodiments, R 1  has three or more substituents. In some embodiments, the substituent is located at position 2 (R 1  is attached to the nitrogen atom at position 1). In some embodiments, the substituent is located at position 3 (R 1  is attached to the nitrogen atom at position 1). In some embodiments, the substituent is located at position 4 (R 1  is attached to the nitrogen atom at position 1). In some embodiments, the substituent is located at both positions 2 and 3, with R 1  attached to the nitrogen atom at position 1. In some embodiments, the substituent is located at both positions 3 and 4, with R 1  attached to the nitrogen atom at position 1. In some embodiments, each substituent is independently R s1 as described herein.

In some implementation schemes, ^R1 is Each of ^Ra1 , ^Rb1 , ^Rc1 , ^Rd1 , and ^Re1 is independently ^Rs1 . In some embodiments, ^Ra1 , ^Rb1 , ^Rc1 , ^{Rd1 ,} and ^Re1 are each independently selected from halogens, -CN, ^-ORs11 , ^-NRs11Rs12 , -C(O) ^NRs11Rs12 , -S( _O ^{)2NRs11Rs12 , and} Each ^Rs11 and ^Rs12 is independently -H or optionally substituted _C1 - _C6 aliphatic. In some embodiments, ^Ra1 , ^Rb1 , ^Rc1 , ^Rd1 , and ^Re1 are each independently selected from halogens, -CN, ^{-ORs11 , -NRs11Rs12} , ^{-CONRs11Rs12 ,} _{-SO2NRs11Rs12} ^{, and} , wherein R ^s11 and R ^s12 are each independently -H or optionally substituted C ₁ -C ₆ aliphatic.

In some implementation schemes, R1 is Each variable is independent as described in this disclosure. In some embodiments, R1 is... Each variable is independent as described in this disclosure. In some embodiments, R1 is... R b1 is -CONR s11 R s12 , -SO 2 NR s11 R s12, or Where Rs11 is -H or optionally substituted C1 - C6 aliphatic, and Rs12 is as described in this disclosure. In some embodiments, R1 is Rb1 is -CONH2 , -SO2NH2 , or In some implementation schemes, R1 is... Each variable is independent as described in this disclosure. In some embodiments, R1 is... Each variable is independent as described in this disclosure. In some embodiments, R1 is... Where R e1 is -OR s11 , and each of the other variables is independent as described in this disclosure. In some embodiments, R 1 is Rb1 is as described in this disclosure. In some embodiments, Rb1 is selected from halogens, -CN, -OMe, -CONH2 , and -SO2NH2 . In some embodiments, R1 is ... Each variable is independent as described in this disclosure. In some embodiments, R1 is... And each of Rb1 and Rc1 is independently selected from halogens, -CN, -OMe, -C(O) NH2 , and -SO2NH2 . In some embodiments, R1 is Rb1 is selected from halogens, -CN, -OMe, -C(O) NH2 and -SO2NH2 , and Rc1 is selected from -F and -CN.

In some implementations, ^R1 is chosen from the following structure:

In some implementation schemes, R1 is Each of Rf1 , Rg1 , Rh1 , and Ri1 is independently Rs1 , where each variable is independently as described in this disclosure. In some embodiments, R1 is And each of Rf1 , Rg1 , Rh1 , and Ri1 is independently Rs1 , wherein each Rs1 is independently selected from halogens, -CN, -ORs11 , -NRs11Rs12 , -C(O) NRs11Rs12 , -SO2NRs11Rs12 , and Each Rs11 is independently -H or optionally substituted C 1 -C 6  aliphatic. In some embodiments, R 1  is... Each variable is independent as described in this disclosure. In some embodiments, R1 is... Each variable is independent as described in this disclosure. In some embodiments, Rg1 is a halogen, -CN, -OR s11 , -NR s11 R s12 , or Each of Rs11 and Rs12 is independently -H or optionally substituted C1 - C6 aliphatic, Rs12 as described in this disclosure. In some embodiments, Rg1 is a halogen, -CN, -ORs11 , -NRs11 , or Rs12 . Each Rs11 and Rs12 is independently a C1 - C6 aliphatic group with -H or optional halogen or -OH substitution, and Rs12 is as described in this disclosure. In some embodiments, Rg1 is -C(O)N( Rs1 ) 2 , -S(O) 2N ( Rs1 ) 2 , -S(O) Rs1, -S(O)2Rs1 , -S (O)(= NRs1 ) Rs2 , or -OS(O) 2N ( Rs1 ) 2 , wherein each Rs1 is independently a C1 - C6 aliphatic group with -H or optional substituted substitution. In some embodiments, Rg1 is an optional substituted 3-10 membered heterocyclic group having 1-4 heteroatoms. In some embodiments, Rg1 is a substituted 3-6 membered heterocyclic group with 1-3 heteroatoms. In some embodiments, Rg1 is a substituted 6 membered heterocyclic group with 1-3 heteroatoms. In some embodiments, Ri1 is a halogen, -CN, -OR s11 , -C(O)NR s11 R s12 , -S(O) 2 NR s11 R s12 , or... R s11 is -H or optionally substituted C 1 -C6 aliphatic, and R s12 is independently as described in this disclosure. In some embodiments, R i1  is a halogen. In some embodiments, R i1 is F.

In some implementation schemes, ^R1 is selected from , , , ,

In some implementation schemes, R1 is And each of Rj1 , Rk1 , Rl1 , and Rm1 is independently Rs1 , wherein each variable is independently as described in this disclosure. In some embodiments, R1 is Each of Rj1 , Rk1 , Rl1 , and Rm1 is independently Rs1 , wherein each Rs1 is independently selected from halogens, -CN, -ORs11 , -NRs11Rs12 , -C(O) NRs11Rs12 , -S (O) 2NRs11Rs12 , and Each of Rs11 and Rs12 is independently -H or optionally substituted C1 - C6 aliphatic, and Rs12 is as described in this disclosure. In some embodiments, R1 is Each variable is independent as described in this disclosure. In some embodiments, Rk1 is a halogen, -CN, -ORs1 , -N( Rs1 ) 2 , -C(O)N( Rs1 ) 2, -S(O) 2N ( Rs1 ) 2 , or Each R s1 is independently -H or optionally substituted C <sub>1 -C 6  aliphatic. In some embodiments, R k1  is halogen, -CN, -OH, -C(O)NH 2 , -S(O) 2 NH2 , or... .

In some implementation schemes, ^R1 is In some implementation schemes, ^R1 is...

In some embodiments, ^R1 is an optional substituted pyridine ^N -oxide. In some implementation schemes, ^R1 is... In some implementations, ^R1 is an alternative. In some implementation schemes, ^R1 is... In some implementations, ^R1 is an alternative. In some implementation schemes, ^R1 is... In some implementation schemes, ^R1 is... .

In some implementation schemes, ^R1 is an alternative. , , , , , , , ,and In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. ,

and The substituents are selected from halogens, -CN, -OR s1 , -N(R s1 ) 2 , -C(O)N(R s1 ) 2 , -S(O) 2N ( R s1 ) 2 and Each Rs1 is independently -H or optionally substituted C 1 -C 6  aliphatic. In some embodiments, R 1 is optionally substituted. , , , , , , , ,and The substituents are selected from halogens, -CN, -OR s1 , -N(R s1 ) 2 , -C(O)N(R s1 ) 2 , -S(O) 2N ( R s1 ) 2 and Each Rs1 is independently -H or optionally substituted C 1 -C 6  aliphatic. In some embodiments, R 1  is In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... .

In some implementation schemes, ^R1 is an alternative. , ,

and In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. In some implementations, ^R1 is an alternative. , ,

and The substituents are selected from halogens, -CN, -ORs1 , -N( Rs1 ) 2 , -C(O)N( Rs1 ) 2 , -S(O) 2N ( Rs1 ) 2 , and... Each Rs1 is independently -H or optionally substituted C 1 -C 6  aliphatic. In some embodiments, R 1 is optionally substituted. , , , , ,

, , ,and The substituents are selected from halogens, -CN, -OR s1 , -N(R s1 ) 2 , -C(O)N(R s1 ) 2 , -S(O) 2N (R s1 ) 2 and Each Rs1 is independently -H or optionally substituted C 1 -C 6  aliphatic. In some embodiments, R 1  is In some implementation schemes, R1 may be alternatively replaced. In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is...

In some implementation schemes, R1 is an alternative. , , , ,and In some implementations, R1 is an alternative. In some implementations, R1 is an alternative. In some embodiments, R1 is an alternative. In some implementations, R1 is an alternative. In some implementations, R1 is an alternative. In some implementations, R1 is an alternative. ,, , ,and Each substituent is independently Rs1 , and Rs1 is as described in this disclosure. In some embodiments, R1 is optional. , , ,,,, ,and Each substituent is independently selected from halogens, -CN, -OR s11 , -NR s11 R s12 , -C(O)NR s11 R s12 , -S(O) 2NR s11 R s12 , and R s11 and R s12 are each independently -H or optionally substituted C 1 -C 6  aliphatic compounds. In some embodiments, R 1  is optionally substituted. , , , ,and And each substituent is independently selected from halogens, -CN, -OR s11 , -NR s11 R s12 , -C(O)NR s11 R s12 , -S(O) 2NR s11 R s12 and R s11 and R s12 are each independently -H or optionally substituted C 1 -C( 6) aliphatic. In some embodiments, R 1  is In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is... In some implementation schemes, R1 is...

R ^1'

In some embodiments, R1 ^' is the R' described in this disclosure. In some embodiments, R1 ^' is the R described in this disclosure. In some embodiments, R1 ^' is hydrogen. In some embodiments, ^R1 and R1 ^' together with the nitrogen atom to which they are attached form an optional substituted 3-6 membered ring, said ring having 0-3 heteroatoms in addition to the nitrogen atom.

In some implementation schemes, R1 ^' is hydrogen.

In some embodiments, ^R1 and R1 ^', together with the nitrogen atom to which they are attached, form a selectively substituted 3-6 membered ring, which, in addition to the nitrogen atom, contains 0-3 heteroatoms. In some embodiments, R1 and ^{R1 '} , together with the nitrogen atom to which they are attached, form a selectively substituted 5-6 membered heterocycle, which has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R1 and R1 ^', together with the nitrogen atom to which they are attached, form a selectively substituted... In some embodiments, ^R1 and R1 ^' together with the nitrogen atoms they are bonded to form In some embodiments, ^R1 and R1 ^' together with the nitrogen atoms they are bonded to form

R ²

In some embodiments, ^R2 is an optional substituent group selected from a phenyl group and having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or ^R2 is Each variable is independent as described in this disclosure.

In some embodiments, ^R2 is an optional substituted phenyl group. In some embodiments, ^R2 is a phenyl group.

In some embodiments, ^R2 is a substituted 5-6 membered heteroaryl group having 1-4 heteroatoms. In some embodiments, ^R2 is a substituted 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^R2 is a substituted 5-membered heteroaryl group having 1-4 heteroatoms. In some embodiments, ^R2 is a substituted 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a substituted 5-membered heteroaryl group having 1-3 heteroatoms. In some embodiments, ^R2 is a substituted 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a substituted 5-membered heteroaryl group having 1-2 heteroatoms. In some embodiments, ^R2 is a substituted 5-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a selectively substituted 5-membered heteroaryl group having two heteroatoms. In some embodiments, ^R2 is a selectively substituted 5-membered heteroaryl group having one heteroatom. In some embodiments, ^R2 is a selectively substituted 5-membered heteroaryl group having one oxygen atom. In some embodiments, ^R2 is a selectively substituted 5-membered heteroaryl group having one nitrogen atom. In some embodiments, ^R2 is a selectively substituted 5-membered heteroaryl group having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a selectively substituted 5 ^- membered heteroaryl group, wherein the ring has two heteroatoms, one of which is a nitrogen atom. In some embodiments, _R2 is a optionally substituted 5-membered heteroaryl group, the ring having two heteroatoms independently selected from N and S. In some embodiments, R2 is a optionally substituted 5-membered heteroaryl group, the ring having two heteroatoms independently selected from oxygen and sulfur. In some embodiments, ^R2 is a optionally substituted 5-membered heteroaryl group having three heteroatoms. In some embodiments, ^R2 is ^a optionally substituted 5-membered heteroaryl group, the ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 identical. In some implementations, at least one heteroatom is different from the other heteroatoms.

In some embodiments, ^R2 is a substituted 6-membered heteroaryl group having 1-4 heteroatoms. In some embodiments, ^R2 is a substituted 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a substituted 6-membered heteroaryl group having 1-3 heteroatoms. In some embodiments, ^R2 is a substituted 6-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a substituted 6-membered heteroaryl group having 1-2 heteroatoms. In some embodiments, ^R2 is a substituted 6-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a selectively substituted 6-membered heteroaryl group having two heteroatoms. In some embodiments, _R2 is a selectively substituted 6-membered heteroaryl group having one heteroatom selected from O, N, and S. In some embodiments, R2 is a selectively substituted 6-membered heteroaryl group, wherein the ring has two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a selectively substituted 6-membered heteroaryl group, wherein the ring has two heteroatoms, each of which is nitrogen. In some embodiments, ^R2 is a selectively substituted 6-membered heteroaryl group having three heteroatoms. In some embodiments, ^R2 is ^a selectively substituted 6-membered heteroaryl group having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is an optional substituted 6-membered heteroaryl group with 3 heteroatoms, one of which is nitrogen.

In some implementation schemes, ^R2 is Each variable is independent as described in this disclosure.

In some embodiments, ring B is a optionally substituted 5-6-membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is an optionally substituted benzene ring. In some embodiments, ring B is an optionally substituted 5-6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is an optionally substituted 5-6-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is an optionally substituted 5-6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, cyclob is a substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, cyclob is a 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, cyclob is a substituted 6-membered heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, cyclob is a 6-membered heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, each substituent of ^R2 is independently ^Rs2 as described herein. In some embodiments, each substituent of ^R2 is ^Rs2 , wherein each ^Rs2 is independently selected from halogens, -CN, ^Rs21 , ^-ORs21 , ^{-NRs21 Rs22} , -C(O) ^Rs21 , -C(O) ^{NRs21 Rs22} , -S(O)2NRs21 ^Rs22 , -S(O) ^2Rs21 , -S(O) ^Rs21 , -S(O)( _NRs22 ) ^Rs21 , -S(O) ^{NRs21 Rs22 , and -OS(O)2NRs21 Rs22} _, ^wherein _each ^Rs21 and ^{Rs22 is} independently -H or an optional substituted group selected from _C1 -C2. _6. An aliphatic group or a 5-6 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the group is optionally substituted by one or more substituents (e.g. 1-3), the substituents being independently selected from halogen, -OH or =O, wherein each other variable is independently as described herein. In some embodiments, each substituent of ^R2 is ^Rs2 , wherein each ^Rs2 is independently selected ^from halogen, -CN, ^Rs21 , ^-ORs21 , ^-NRs21Rs22 , -C(O) ^Rs21 , -C(O) ^NRs21Rs22 , -S(O) ^2NRs21Rs22 , -S(O) ^2Rs21 , -S(O) ^Rs21 , -S(O)( ^NRs22 ) ^Rs21 , -S(O) ^{NRs21Rs22 ,} _and ^-OS (O) ^2NRs21Rs22 , wherein each ^Rs21 and ^Rs22 is independently -H or ^an optional substituted group ^selected from _C1 -C _6. An aliphatic group or a 5-6 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the group is optionally substituted by one or more substituents (e.g. 1-3), the substituents being independently selected from halogen, -OH or =O, wherein each other variable is independently as described herein. In some embodiments, each substituent of ^R2 is ^Rs2 , wherein each ^Rs2 is independently selected ^from halogen, -CN, ^Rs21 , ^-ORs21 , ^-NRs21Rs22 , -C(O) ^Rs21 , -C(O) ^NRs21Rs22 , -S(O) ^2NRs21Rs22 , -S(O) ^2Rs21 , -S(O) ^Rs21 , -S(O)( _{NRs22 )} ^Rs21 , -S(O) ^NRs21Rs22 , ^{and -OS} (O) _2NRs21Rs22 , wherein ^{each Rs21} and ^Rs22 is independently -H ^{or an} optional substituted group ^selected from _C1 -C _6. An aliphatic group or a 5-6 membered saturated ring having 0-4 nitrogen atoms, wherein the group is optionally substituted by one or more substituents (e.g., 1-3), the substituents being independently selected from halogens, -OH or =O, wherein each other variable is independently as described herein. In some embodiments, each substituent of ^R2 is ^Rs2 , wherein each ^Rs2 is independently selected ^from halogen, -CN, ^Rs21 , ^-ORs21 , ^-NRs21Rs22 , -C(O) ^Rs21 , -C(O) ^NRs21Rs22 , -S(O) ^2NRs21Rs22 , -S(O) ^2Rs21 , -S(O) ^Rs21 , -S(O)( _{NRs22 )} ^Rs21 , -S(O) ^NRs21Rs22 , ^{and -OS} (O) _2NRs21Rs22 , wherein ^{each Rs21} and ^Rs22 is independently -H ^{or an} optional substituted group ^selected from _C1 -C A _6- aliphatic group or a 5-6 membered saturated ring having 1-2 nitrogen atoms, wherein said group is optionally substituted by one or more substituents (e.g., 1-3), said substituents being independently selected from halogens, -OH, or =O, wherein each other variable is ^{independently} as described herein. In some embodiments, each ^Rs2 is independently a halogen and ^{-ORs21 ,} wherein ^Rs21 is ^an optionally substituted _C1-6 aliphatic group. In some embodiments, each ^Rs2 is independently a halogen and ^-ORs21 , wherein ^Rs21 is an optionally substituted _C1-6 aliphatic group, wherein the _C1-6 aliphatic group is optionally substituted with a halogen, -OH, or ⁼ O. In some embodiments, each ^Rs2 is independently a halogen and ^-ORs21 , wherein ^Rs21 is a _C1-6 aliphatic group. In some embodiments, each ^Rs2 is independently a halogen and -OMe. In some embodiments, each ^halogen is independently -F or -Cl. In some embodiments, each halogen ^is -F. In some implementations, each ^{Rs2 is} independently -F, -Cl, or -OMe.

In some embodiments, ^Rs2 is a halogen. In some embodiments, ^Rs2 is F. In some embodiments, ^Rs2 is Br.

In some implementation schemes, R ^s2 is CN.

In some embodiments, R s2 is R s21 , where Rs21 is as described in this disclosure. In some embodiments, Rs2 is -OR s21  , where R s21  is as described in this disclosure. In some embodiments, R  s2  is -NRs21Rs22 , where R s21  is as described in this disclosure. In some embodiments, R s2  is -C(O)NRs21 R s22 , where each variable is as described in this disclosure. In some embodiments, R s2 is -S(O) 2 NR s21 Rs22 , where each variable is as described in this disclosure. In some embodiments, R s2 is -S(O) 2 Rs21 , where each variable is independent as described in this disclosure. In some embodiments, R s2  is -S(O)Rs21 , where each variable is independent as described in this disclosure. In some embodiments, R s2 is -S(O)NR s21  R s22  , where each variable is independent as described in this disclosure. In some embodiments, R s2 is -OS(O) 2 NRs21 R s22 , where each variable is independent as described in this disclosure.

In some embodiments, ^Rs21 is R', where R' is as described in this disclosure. In some embodiments, ^Rs21 is an optionally substituted C1-6 aliphatic compound. In some embodiments, ^Rs21 is an optionally substituted _{C1-6 alkyl compound. In some embodiments, Rs21 is a C1-C6 aliphatic compound selectively substituted with one or more substituents (e.g., 1-3) independently selected from halogens, -OH, or =O. In some embodiments, Rs21 is a C1-C6} ^alkyl _{compound selectively substituted} ^with _one or more substituents (e.g., 1-3) independently selected from halogens, -OH, or =O. In some embodiments, ^Rs21 is a C1 _{- C4 alkyl} compound selectively substituted with one or more substituents (e.g., 1-3) independently selected from halogens, -OH, or =O. In some embodiments, ^Rs21 is a _C1 - _C6 alkyl. In some embodiments, ^Rs21 is a _C1 - _C3 alkyl. In some embodiments, ^Rs21 is methyl. In some embodiments, ^Rs21 is -CH2OH. In some embodiments, ^Rs21 is _-CHF2 . In some embodiments, ^Rs21 is -CH( _OH ) _CH2OH . In some embodiments, ^Rs21 is -C(OH)(Me) ₂ .

In some embodiments, ^Rs21 is a substituted 5-membered heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs21 is a substituted 6-membered heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs21 is substituted... .

In some embodiments, ^Rs21 is a substituted 5-membered heterocyclic group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs21 is a substituted 6-membered heterocyclic group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs21 is optionally substituted. In some implementation schemes, R ^s21 is In some implementations, R ^s21 is an alternative. .

In some implementation schemes, R ^s21 is H.

In some embodiments, ^Rs22 is R', where R' is as described in this disclosure. In some embodiments, ^Rs22 is an optionally substituted C1-6 aliphatic compound. In some embodiments, ^Rs22 is an optionally substituted _{C1-6 alkyl compound. In some embodiments, Rs22 is a C1-C6 aliphatic compound selectively substituted with one or more substituents (e.g., 1-3) independently selected from halogens, -OH, or =O. In some embodiments, Rs22 is a C1-C6} ^alkyl _{compound selectively substituted} ^with _one or more substituents (e.g., 1-3) independently selected from halogens, -OH, or =O. In some embodiments, ^Rs22 is a C1 _{- C4 alkyl} compound selectively substituted with one or more substituents (e.g., 1-3) independently selected from halogens, -OH, or =O. In some embodiments, ^Rs22 is a _C1 - _C6 alkyl. In some embodiments, ^Rs22 is a _C1 - _C3 alkyl. In some embodiments, ^Rs22 is methyl. In some embodiments, ^Rs22 is -CH2OH. In some embodiments, ^Rs22 is _-CHF2 . In some embodiments, ^Rs22 is -CH( _OH ) _CH2OH . In some embodiments, ^Rs22 is -C(OH)(Me) ₂ .

In some embodiments, ^Rs22 is a substituted 5-membered heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs22 is a substituted 6-membered heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^Rs22 is substituted... .

In some embodiments, R s22  is a substituted 5-membered heterocyclic group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R s22  is a substituted 6-membered heterocyclic group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R s22  is substituted... In some implementation schemes, R s22 is... In some implementations, R s22 is an alternative. .

In some implementation schemes, R ^s22 is H.

In some embodiments, ^Rs2 is _-CONH2 . In some embodiments, ^Rs2 is _-CONHCH3 . In some embodiments, ^Rs2 is -S(O) _2NH2 . In some embodiments, ^Rs2 is -S(O) _2Me . In some embodiments, ^Rs2 is -S(O)Me. In some embodiments, ^Rs2 is -S(NH)(O)Me. In some embodiments, ^Rs2 _is -S(NMe)(O)Me. In some embodiments, ^Rs2 is -OH. In some embodiments, ^Rs2 is -OMe. In some embodiments, ^Rs2 is _-NH2 . In some embodiments, ^Rs2 is _-OCH2CH (OH) _CH2 (OH).

In some embodiments, the two ^Rs2 groups and their spacer atoms together form a optionally substituted 5-6 membered ring, wherein the ring, in addition to the spacer atom, has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the two ^Rs2 groups and their spacer atoms together form a optionally substituted 5-membered ring, wherein the ring, in addition to the spacer atom, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the two ^Rs2 groups and their spacer atoms together form a optionally substituted 6-membered ring, wherein the ring, in addition to the spacer atom, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some implementations, s² is 0, 1, 2, 3, 4, or 5. In some implementations, s² is 0. In some implementations, s² is 1. In some implementations, s² is 2. In some implementations, s² is 3. In some implementations, s² is 4. In some implementations, s² is 5. In some implementations, s² is 1 or 2.

In some implementation schemes, ^R2 is not replaced.

In some embodiments, ^R2 is a phenyl group optionally substituted with 1 to 5 Rs2 ^groups . In some embodiments, _R2 is a phenyl group optionally substituted with 1 or 2 ^{Rs2 groups} . In some embodiments, _R2 is a phenyl group substituted with 2 or more ^{Rs2 groups} . In some embodiments, _R2 is a phenyl group substituted with three Rs2 ^groups , each ^Rs2 group being independent as described in this disclosure.

In some embodiments, ^R2 is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said heteroaryl group being optionally substituted by 1-5 ^Rs2 , as described in this disclosure. In some embodiments, R2 is a 5 ^- membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said heteroaryl group being optionally substituted by 1-5 ^Rs2 , as described in this disclosure. In some embodiments, ^R2 is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen ^, oxygen, and ^sulfur , said heteroaryl group being substituted by 2 or more ^Rs2 , as described ⁱⁿ this disclosure.

In some embodiments, ^R2 is a 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said heteroaryl group being optionally substituted by 1-5 ^Rs2 , as described in this disclosure. In some embodiments, R2 is a 6 ^- membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said heteroaryl group being optionally substituted by 1-5 ^Rs2 , as described in this disclosure. In some embodiments, ^R2 is a 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and ^sulfur , wherein said heteroaryl group is substituted by 2 or more ^Rs2 , and ^Rs2 is as described ⁱⁿ this disclosure.

In some embodiments, ^R2 is a 2-pyridyl group substituted with two or more Rs2 ^groups , wherein ^Rs2 is as described in this disclosure. In some embodiments, ^R2 is a 3-pyridyl group substituted with two or more ^Rs2 groups, wherein ^Rs2 is as described in this disclosure. In some embodiments, ^R2 is a 4-pyridyl group substituted with two or more Rs2 ^groups , wherein ^Rs2 is as described in this disclosure.

In some embodiments, ^R2 is substituted. In some embodiments, the substituent is located at position 2 ( ^R2 is attached to the nitrogen atom at position 1). In some embodiments, the substituent is located at position 3 ( ^R2 is attached to the nitrogen atom at position 1). In some embodiments, the substituent is located at position 4 ( ^R2 is attached to the nitrogen atom at position 1). In some embodiments, an ^Rs2 group is located at position 2 and an ^Rs2 group is located at position 3, wherein ^R2 is attached to the nitrogen atom at position 1. In some embodiments, an ^Rs2 group is located at position 3 and an ^Rs2 group is located at position 4, wherein ^R2 is attached to the nitrogen atom at position 1.

In some implementation schemes, ^R2 is Each of Ra2, ^Rb2 , ^Rc2 , ^Rd2 , and ^Re2 is independently ^Rs2 , and ^{Rs2 is} as described in this disclosure. In some embodiments, ^R2 is ^Rs2 , ^Rb2 , and ^Rc2 are each independently ^Rs2 , and ^Rs2 is as described in this disclosure. In some embodiments, each ^Rs2 is independently selected from halogen, -CN, ^-ORs21 , ^-NRs21Rs22 , ^-C (O) ^Rs21 , -C(O) ^NRs21Rs22 , or -S(O) ^2NRs21Rs22 , wherein each _variable is independently as described in this disclosure. In some embodiments, each of ^Rs21 and ^Rs22 is independently -H or an optional substituted _C1-6 ^aliphatic group. In some embodiments, ^Rs21 and ^Rs22 are each independently -H or an optional substituted _C1-6 aliphatic group. In some embodiments, ^Rs22 is ^-H .

In some embodiments, ^Ra2 is -OR ^s21 , where R ^s21 is an optional substituted _C1-6 alkyl group. In some embodiments, ^Ra2 _is -OMe.

In some embodiments, ^Rb2 is a halogen. In some embodiments, ^Rb2 is F. In some embodiments, ^Rb2 is Br.

In some embodiments, ^Rc2 is a halogen. In some embodiments, ^Rc2 is F. In some embodiments, ^Rc2 is Br.

In some implementation schemes, ^R2 is In some implementation schemes, ^R2 is...

In some embodiments, ^R3 and ^R4 are each independently a hydrogen, -CN, or an alternatively substituted group selected from _C1 - _C6 aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-10 membered heterocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or ^R3 and ^R4 together with the carbon atom to which they are attached form an alternatively substituted 3-6 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^R3 is a hydrogen, -CN, or an alternatively substituted group selected from _C1 - _C6 aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-10 membered heterocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or ^R3 and ^R4 together with the carbon atom to which they are attached form an alternatively substituted 3-6 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some implementation schemes, ^R3 is hydrogen.

In some implementations, ^R3 is -CN.

In some embodiments, ^R3 is an optional substituted _C1 - _C6 aliphatic compound. In some embodiments, ^R3 is an optional substituted _C1 - _C6 alkyl compound. In some embodiments, ^R3 is an optional substituted _C1 - _C3 alkyl compound. In some embodiments, ^R3 is a _C1 -C3 alkyl compound substituted with a halogen. In some embodiments, ^R3 is a _C1 - _{C3 alkyl} compound substituted with a halogen. In some embodiments, ^R3 is a _C1 - _{C3 alkyl} compound. In some embodiments, ^R3 is an optional substituted methyl compound. In some embodiments, ^R3 is methyl. In some embodiments, ^R3 is a methyl compound substituted with a halogen. In some embodiments, _R3 is _-CF3 . In some embodiments, ^R3 is _-CHF2 . In some embodiments, ^R3 is an optional substituted ethyl group. In some embodiments, ^R3 is a halogen-substituted ethyl group. In some embodiments, R ⁽³ ₎ is _-CH2CF3 . In some embodiments, ^R3 is an optional substituted n-propyl group. In some embodiments, ^R3 is a halogen-substituted n-propyl group. In some embodiments, _R3 is an optional substituted isopropyl group. In some embodiments ^{, R3} is a halogen-substituted isopropyl group. In some embodiments, ^R3 is isopropyl.

In some embodiments, ^R3 is an optionally substituted phenyl group. In some embodiments, ^R3 is a phenyl group. In some embodiments, ^R3 is 2-trifluoromethylphenyl. In some embodiments, ^R3 is 3-trifluoromethylphenyl. In some embodiments, ^R3 is 4-trifluoromethylphenyl.

Those skilled in the art will understand upon reading this disclosure that, in certain implementations, ^R3 may have... The structural groups are substituted, and each of ^Ra3 , ^Rb3 , ^Rc3 , ^Rd3 , and ^Re3 is independently ^Rs3 , where ^Rs3 is the substituent described in this disclosure. In some embodiments, ^R3 is And each of ^Ra3 , ^Rb3 , Rc3, ^Rd3 , and ^Re3 is independently ^Rs3 , ^{wherein Rs3} is ^Rs31 _, halogen, -CN, ^-ORs31 , ^-NRs31Rs32 , -C(O) ^{NRs31Rs32 ,} and -S(O) ^2Rs31Rs32 , wherein each ^Rs31 and ^Rs32 is independently -H or optionally halogen-substituted _C1 - ^{C6 aliphatic} . In some embodiments _, ^R3 is ^Ra3 is ^Rs3 , where ^Rs3 is ^Rs31 , halogen, -CN, ^-ORs31 , ^-NRs31Rs32 , -C(O) ^{NRs31Rs32 ,} and -S(O) ^2Rs31Rs32 , wherein each ^Rs31 and ^{Rs32 is} independently -H or optionally halogen-substituted _C1 - _{C6 aliphatic} . In some embodiments, ^{R3 is Rb3} is ^Rs3 , where ^Rs3 is ^Rs31 , halogen, -CN, ^-ORs31 , ^-NRs31Rs32 , -C(O) ^{NRs31Rs32 ,} and -S(O) ^2Rs31Rs32 , wherein each ^Rs31 and ^{Rs32 is} independently -H or optionally halogen-substituted _C1 - _{C6 aliphatic} . In some embodiments, ^{R3 is Rc3} is ^Rs3 , where ^Rs3 is ^Rs31 , halogen, -CN, ^-ORs31 , ^-NRs31Rs32 , -C(O) ^{NRs31Rs32 ,} and -S(O) ^2Rs31Rs32 , wherein each ^Rs31 and ^{Rs32 is} independently -H or ^optionally halogenated _C1 - _{C6 aliphatic} .

In some embodiments, ^Ra3 is a optionally substituted _C1 - _C6 aliphatic compound. In some embodiments, ^Ra3 is a optionally substituted _C1 - _C6 alkyl compound. In some embodiments, ^Ra3 is a optionally substituted _C1 - _C3 alkyl compound. In some embodiments, ^Ra3 is a _C1 - _C3 alkyl compound. In some embodiments, ^Ra3 is an optionally substituted methyl compound. In some embodiments, ^Ra3 is methyl. In some embodiments, ^Ra3 is _-CF3 . In some embodiments, ^Ra3 is _-CHF2 . In some embodiments, ^{Ra3 is a halogen. In some embodiments, Ra3 is} F. In some embodiments, ^Ra3 is Br. In some embodiments, ^Ra3 is I. In some embodiments, ^Ra3 is ^-ORs31 , wherein ^Rs31 is as described in this disclosure. In some embodiments, ^Ra3 is -OR ^s31 , where R ^s31 is -H or an optional substituted C1- _C6 alkyl group. In some embodiments, ^Ra3 is -OH. In some embodiments, ^Ra3 is -OR ^s31 , where R ^s31 is an optional substituted _{C1 - C6} alkyl group. In some embodiments, ^Ra3 is -OMe.

In some embodiments, ^Rb3 is an optional _C1 - _C6 aliphatic compound. In some embodiments, ^Rb3 is an optional _C1 - _C6 alkyl compound. In some embodiments, ^Rb3 is an optional _C1 - _C3 alkyl compound. In some embodiments, ^Rb3 is a _C1 - _C3 alkyl compound. In some embodiments, ^Rb3 is an optional methyl compound. In some embodiments, ^Rb3 is methyl. In some embodiments, ^Rb3 is _-CF3 . In some embodiments, ^Rb3 is _-CHF2 . In some embodiments, ^Rb3 is a halogen. In some embodiments, ^Rb3 is F. In some embodiments, ^Rb3 is Br. In some embodiments, ^Rb3 is I. In some embodiments, ^Rb3 is -OR ^s31 , where R ^s31 is -H or an optional substituted C1- _C6 alkyl group. In some embodiments, ^Rb3 is -OH. In some embodiments, ^Rb3 is -OR ^s31 , where R ^s31 is an optional substituted _{C1 - C6} alkyl group. In some embodiments, ^Rb3 is -OMe.

In some embodiments, ^Rc3 is an optional _C1 - _C6 aliphatic compound. In some embodiments, ^Rc3 is an optional _C1 - _C6 alkyl compound. In some embodiments, ^Rc3 is an optional _C1 - _C3 alkyl compound. In some embodiments, ^Rc3 is a _C1 - _C3 alkyl compound. In some embodiments, ^Rc3 is an optional methyl compound. In some embodiments, ^Rc3 is methyl. In some embodiments, ^Rc3 is _-CF3 . In some embodiments, ^Rc3 is _-CHF2 . In some embodiments, ^Rc3 is a halogen. In some embodiments, ^Rc3 is F. In some embodiments, ^Rc3 is Br. In some embodiments, ^Rc3 is I. In some embodiments, ^Rc3 is -OR ^s31 , where R ^s31 is -H or an optional substituted C1- _C6 alkyl group. In some embodiments, ^Rc3 is -OH. In some embodiments, ^Rc3 is -OR ^s31 , where R ^s31 is an optional substituted _{C1 - C6} alkyl group. In some embodiments, ^Rc3 is -OMe.

In some embodiments, ^R3 is a optionally substituted 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is a optionally substituted 5 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is a optionally substituted 5 membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is a optionally substituted 6 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is a optionally substituted 6 membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments ^{, R3} is an optional pyridinyl group ^. In some implementation schemes, ^R3 is... In some implementation schemes, ^R3 is an alternative. In some implementation schemes, ^R3 is... In some implementation schemes, ^R3 is an alternative. In some implementation schemes, ^R3 is... .

In some embodiments, ^R3 is a substituted 3-10-membered heterocycloalkyl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is a substituted 3-6-membered heterocycloalkyl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is a substituted 5-6-membered heterocycloalkyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is a substituted 3-6-membered cycloalkyl group. In some embodiments, ^R3 is substituted. In some implementation schemes, ^R3 is... In some implementation schemes, ^R3 is an alternative. In some implementation schemes, ^R3 is... In some implementation schemes, ^R3 is an alternative. In some implementation schemes, ^R3 is... In some implementation schemes, ^R3 is an alternative. In some implementation schemes, ^R3 is... .

In some embodiments, ^R3 is the R described in this disclosure. For example, in some embodiments, ^R3 is R, where R is an optional substituted 6-10 aryl- _C1 - _C6 aliphatic group. In some embodiments, ^R3 is R, where R is an optional substituted -CH2 _- Ph group. In some embodiments, ^R3 is R, where R is an optional substituted 5-10 heteroaryl group having 1-6 heteroatoms of a _-C1 - _C6 aliphatic group, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is R, where R is an optional substituted 5-10 heteroaryl group having 1-6 heteroatoms of _-CH2- , where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.

R ⁴

In some embodiments, ^R4 is a hydrogen, -CN, or alternatively substituted group selected from _C1 - _C6 aliphatic, phenyl, 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-10 membered heterocyclic with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or ^R3 and ^R4 together with the carbon atom to which they are attached form an alternatively substituted 3-6 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some implementation schemes, ^R4 is hydrogen.

In some implementations, R ⁴ is -CN.

In some embodiments, ^R4 is an optional substituted _C1 - _C6 aliphatic compound. In some embodiments, ^R4 is an optional substituted _C1 - _C6 alkyl compound. In some embodiments, ^R4 is an optional substituted _C1 - _C3 alkyl compound. In some embodiments, ^R4 is a _C1 -C3 alkyl compound substituted with a halogen. In some embodiments, ^R4 is a _C1 - _C3 alkyl compound substituted with a halogen. In some embodiments, ^R4 is a _C1 - _{C3 alkyl} compound. In some embodiments, ^R4 is an optional substituted methyl compound. In some embodiments, ^R4 is methyl. In some embodiments, ^R4 is a methyl compound substituted with a halogen. In some embodiments, ^R4 is _-CF3 . In some embodiments, ^R4 is _-CHF2 . In some embodiments, ^R4 is an optional substituted ethyl group. In some embodiments, ^R4 is _a halogen-substituted ethyl group. In some embodiments, ^R4 is _-CH₂CF₃ . In some embodiments, ^R4 is an optional substituted n-propyl group. In some embodiments, ^R4 is a halogen-substituted n-propyl group. In some embodiments, ^R4 is an optional substituted isopropyl group. In some embodiments, ^R4 is an isopropyl group. In some embodiments, ^R4 is isopropyl.

In some embodiments, ^R4 is an optional substituted phenyl group. In some embodiments, ^R4 is a phenyl group.

Those skilled in the art will understand upon reading this disclosure that, in certain implementations, ^R4 may have... The structural groups are substituted, and each of ^Ra4 , ^Rb4 , ^Rc4 , ^Rd4 , and ^Re4 is independently ^Rs4 , wherein ^Rs4 is the substituent described in this disclosure. In some embodiments, ^R4 is And each of ^Ra4 , ^Rb4 , ^Rc4 , ^Rd4 , and ^Re4 is independently ^Rs4 , wherein ^Rs4 is ^Rs41 _, halogen, -CN, ^-ORs41 , ^-NRs41Rs42 , -C(O) ^{NRs41Rs42 ,} and -S(O) ^2Rs41Rs42 , wherein each ^Rs41 and ^Rs42 is independently -H or optionally halogen-substituted _C1 - ^{C6 aliphatic} . In some embodiments _, ^R4 is ^Ra4 is ^Rs4 , where ^Rs4 is ^Rs41 , halogen, -CN, ^-ORs41 , ^-NRs41Rs42 , -C(O) ^NRs41Rs42 , and -S(O) ^2Rs41Rs42 , wherein each ^Rs41 and ^{Rs42 is} independently -H or ^optionally halogenated _C1 - _{C6 aliphatic} . In some embodiments, ^{R4 is Rb4} is ^Rs4 , where ^Rs4 is ^Rs41 , halogen, -CN, ^-ORs41 , ^-NRs41Rs42 , -C(O) ^{NRs41Rs42 ,} and -S(O) ^2Rs41Rs42 , wherein each ^Rs41 and ^{Rs42 is} independently -H or optionally halogenated _C1 - _{C6 aliphatic} . In some embodiments, ^{R4 is Rc4} is ^Rs4 , where ^Rs4 is ^Rs41 , halogen, -CN, ^-ORs41 , ^-NRs41Rs42 , -C(O) ^{NRs41Rs42 ,} and -S(O) ^2Rs41Rs42 , wherein each ^Rs41 and ^Rs42 is independently -H or an optional halogen ^- substituted ^C1 _{- C6 aliphatic} .

In some embodiments, ^Ra4 is an optionally substituted _C1 - _C6 aliphatic compound. In some embodiments, ^Ra4 is an optionally substituted _C1 - _C6 alkyl compound. In some embodiments, ^Ra4 is an optionally substituted _C1 - _C3 alkyl compound. In some embodiments, ^Ra4 is a _C1 - _C3 alkyl compound. In some embodiments, ^Ra4 is an optionally substituted methyl compound. In some embodiments, ^Ra4 is methyl. In some embodiments, ^Ra4 is _-CF3 . In some embodiments, ^Ra4 is _-CHF2 . In some embodiments, ^Ra4 is a halogen. In some embodiments, ^Ra4 is F. In some embodiments, ^Ra4 is ^-ORs41 , wherein ^Rs41 is as described in this disclosure. In some embodiments, ^Ra4 is -OR ^s41 , where R ^s41 is -H or an optional substituted C1- _C6 alkyl group. In some embodiments, ^Ra4 is -OH. In some embodiments, ^Ra4 is -OR ^s41 , where R ^s41 is an optional substituted _{C1 - C6} alkyl group. In some embodiments, ^Ra4 is -OMe.

In some embodiments, ^Rb4 is an optional _C1 - _C6 aliphatic compound. In some embodiments, ^Rb4 is an optional _C1 - _C6 alkyl compound. In some embodiments, ^Rb4 is an optional _C1 - _C3 alkyl compound. In some embodiments, ^Rb4 is a _C1 - _C3 alkyl compound. In some embodiments, ^Rb4 is an optional methyl compound. In some embodiments, ^Rb4 is methyl. In some embodiments, ^Rb4 is _-CF3 . In some embodiments, ^Rb4 is _-CHF2 . In some embodiments, ^Rb4 is a halogen. In some embodiments, ^Rb4 is F. In some embodiments, ^Rb4 is Cl. In some embodiments, ^Rb4 is Br. In some embodiments, ^Rb4 is I. In some embodiments, ^Rb4 is -OR ^s41 , wherein ^Rs41 is as described in this disclosure. In some embodiments, ^Rb4 is -OR ^s41 , wherein ^Rs41 is -H or an optional substituted _C1 - _C6 alkyl group. In some embodiments, ^Rb4 is -OH. In some embodiments, ^Rb4 is -OR ^s41 , wherein ^Rs41 is an optional substituted _C1 - _C6 alkyl group. In some embodiments, ^Rb4 is -OMe.

In some embodiments, ^Rc4 is an optional _C1 - _C6 aliphatic compound. In some embodiments, ^Rc4 is an optional _C1 - _C6 alkyl compound. In some embodiments, ^Rc4 is an optional _C1 - _C3 alkyl compound. In some embodiments, ^Rc4 is a _C1 - _C3 alkyl compound. In some embodiments, ^Rc4 is an optional methyl compound. In some embodiments, ^Rc4 is methyl. In some embodiments, ^Rc4 is _-CF3 . In some embodiments, ^Rc4 is _-CHF2 . In some embodiments, ^Rc4 is a halogen. In some embodiments, ^Rc4 is F. In some embodiments, ^Rc4 is Br. In some embodiments, ^Rc4 is I. In some embodiments, ^Rc4 is -OR ^s41 , where R ^s41 is -H or an optional substituted C1- _C6 alkyl group. In some embodiments, ^Rc4 is -OH. In some embodiments, ^Rc4 is -OR ^s41 , where R ^s41 is an optional substituted _{C1 - C6} alkyl group. In some embodiments, ^Rc4 is -OMe.

In some embodiments, ^R4 is a 5-6 membered heteroaryl group with 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is a 5 membered heteroaryl group with 1-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is a 5 membered heteroaryl group with 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is a 6 membered heteroaryl group with 1-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is a 6 membered heteroaryl group with 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur.

In some embodiments ^{, R4} is an optional pyridinyl group ^. In some implementation schemes, ^R4 is... In some implementations, ^R4 is an alternative. In some implementation schemes, ^R4 is... In some implementations, ^R4 is an alternative. In some implementation schemes, ^R4 is... .

In some embodiments, ^R4 is a substituted 3-10-membered heterocyclic group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is a substituted 3-6-membered heterocyclic group having 1-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is a substituted 5-6-membered heterocyclic group having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is a substituted 3-6-membered cycloalkyl group. In some embodiments, ^R4 is a substituted... In some implementation schemes, ^R4 is... In some implementations, ^R4 is an alternative. In some implementation schemes, ^R4 is... In some implementations, ^R4 is an alternative. In some implementation schemes, ^R4 is... In some implementations, ^R4 is an alternative. In some implementation schemes, ^R4 is... .

In some embodiments, ^R4 is the R described in this disclosure. For example, in some embodiments, ^R4 is R, where R is an optional substituted 6-10-membered aryl- _C1 - _C6 aliphatic. In some embodiments, ^R4 is R, where R is an optional substituted -CH2 _- Ph. In some embodiments, ^R4 is R, where R is an optional substituted 5-10-membered heteroaryl- _C1 - _C6 aliphatic-cyclic ring having 1-6 heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R4 is R, where R is an optional substituted 5-10-membered heteroaryl- _CH2- having 1-6 heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^R3 and ^R4 are both optionally substituted _C1 - _C3 alkyl groups. In some embodiments, ^R3 and ^R4 are both optionally substituted C1- _{C3 alkyl} groups by halogenation. In some embodiments, ^R3 and ^R4 are both _C1 - _{C3 alkyl} groups. In some embodiments, ^R3 and ^R4 are both methyl groups.

In some embodiments, ^R3 is a halogen-substituted _C1 -C3 _alkyl group, and ^R4 is not a halogen-substituted _C1 - _C3 alkyl group. In some embodiments, ^R3 is a halogen-substituted _C1 - _C3 alkyl group, and ^R4 is a _C1 - _C3 alkyl group. In some embodiments, ^R3 is a halogen-substituted C1 _{- C3} alkyl group, and ^R4 is hydrogen. In some embodiments, each of ^R3 and ^R4 is independently a halogen-substituted C1- _{C3 alkyl} group. In some embodiments, one of ^R3 and ^R4 is _-CF3 , and the other is _-CH3 . In some embodiments, ^R3 is _-CF3 .

In some embodiments, one of ^R3 and ^R4 is a optionally substituted _C1-6 aliphatic phenyl group (such as _-CH3 , _-CF3, etc.), and the other is an optionally substituted phenyl group (such as 2-, 3-, or 4-trifluoromethylphenyl). In some embodiments, one of ^R3 and ^R4 is hydrogen, and the other is an optionally substituted phenyl group (such as 2-, 3-, or 4-trifluoromethylphenyl). In some embodiments, ^R3 is an optionally substituted _C1-6 aliphatic phenyl group (such as _-CH3 , _-CF3, etc.). In some embodiments, ^R3 is -H.

In some embodiments, one of ^R3 and ^R4 is a selectively substituted _C1-6 aliphatic group (e.g., _-CH3 , _-CF3 , etc.), and the other is a selectively substituted 5-6 heteroaryl group (e.g., 2-, 3-, or 4-pyridyl) having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one of ^R3 and ^R4 is hydrogen, and the other is a selectively substituted phenyl group (e.g., 2-, 3-, or 4-trifluoromethylphenyl). In some embodiments, ^R3 is a selectively substituted _C1-6 aliphatic group (e.g., _-CH3 , _-CF3 , etc.). In some embodiments, ^R3 is -H.

In some embodiments, ^R3 and ^R4 are both R, which together with the attached carbon atom form a substituted 3-10 membered ring, which has 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the attached atom.

In some embodiments, ^R3 and ^R4 , together with the carbon atoms to which they are attached, form optional substituted 3-6-membered rings having 0-3 heteroatoms. In some embodiments, ^R3 and ^R4, together with the carbon atoms to which they are attached, form optional substituted 3-6-membered rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 and ^R4, together with the carbon atoms to which they are attached, form optional substituted 5-6-membered rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^R3 and ^R4 , together with the carbon atoms to which they are attached, form an optional substituted 3-6-membered cycloaliphatic group. In some embodiments, ^R3 and ^R4 , together with the carbon atoms to which they are attached, form an optional substituted 3-6-membered cycloalkyl group. In some embodiments, ^R3 and ^R4, together with the carbon atoms to which they are attached, form a 3-6-membered cycloalkyl group. In some embodiments, ^R3 and ^R4 , together with the carbon atoms to which they are attached, form a halogen-substituted 3-6-membered cycloalkyl group. In some embodiments, ^R3 and ^{R4 ,} together with the carbon atoms to which they are attached, form an optional substituted cycloalkyl group ^. In some embodiments, ^R3 and ^R4, together with the carbon atoms they are attached to, form optional substitutions. In some embodiments, ^R3 and ^R4 form optional substitutions with the carbon atoms they are attached to. In some embodiments, ^R3 and ^R4, together with the carbon atoms they are attached to, form optional substitutions. .

In some embodiments, ^R3 and ^R4 , together with the carbon atoms they are attached to, form halogen-substituted compounds. In some embodiments, ^R3 and ^R4, together with the carbon atoms they are attached to, form -F-substituted compounds. In some embodiments, ^R3 and ^R4 together with the carbon atoms they are bonded to form .

In some embodiments, the carbons connecting ^R3 and ^R4 are achiral. In some embodiments, the carbons connected to ^R3 and ^R4 are chiral with the configuration R. In some embodiments, the carbons connected to ^R3 and ^R4 are chiral with the configuration S. In some embodiments, ^R3 is cis-C(O)N( ^R1 )( ^R1 '). In some embodiments, ^R3 is a optionally substituted _C1-6 aliphatic carbon, cis-C(O)N( ^R1 )( ^R1 '), and ^R4 is not an optionally substituted _C1-6 aliphatic carbon. In some embodiments, _R3 is _-CF3 , cis-C(O)N( ^R1 )( ^R1 '), and ^R4 is not _-CF3 . In some implementation schemes, -CR ³ R ⁴ - is Where ^x represents a connection to X, and ^y represents a connection to Y. In some implementations, -CR ³ R ⁴ - is Where ^x represents a connection to X, and ^y represents a connection to Y. In some implementations, -CR ³ R ⁴ - is Where ^x represents a connection to X, and ^y represents a connection to Y. In some implementations, -CR ³ R ⁴ - is , where ^x represents a connection to X and ^y represents a connection to Y.

In some implementation schemes, -CR ³ R ⁴ - are selected from , , ,

, , , ,and , where (X) represents the connection to X, and (Y) represents the connection to Y.

X

In some implementations, X is -O-. In some implementations, X is -S-. In some implementations, X is -S(O)-. In some implementations, X is -S(O) _2- .

In some embodiments, X is -C( ^Rx ) _²- , where each ^Rx is independent as defined herein. In some embodiments, X is -C( ^Rx ) _²- , and each ^Rx is independent as defined herein. In some embodiments, X is -C( ^Rx ) _²- , and each ^Rx is independently -OR, where R is independent as defined herein. In some embodiments, X is -C(Rx) _²- , and each ^Rx is independently -N(R) _² , where each R is independent as defined herein. In some embodiments, X is -C( ^Rx ) _²- , and each ^Rx is independently -N(R) _² , where each R is independent as defined herein. In some embodiments, each R is independently -H or _C1 - _C6 aliphatic groups. In some implementation schemes, X is -CH ₂ .

W

In some implementations, the key between W and Z is a single key. In other implementations, it is a two-key key.

In some implementation schemes, W is N.

In some implementations, W is C and Z is C. In other implementations, W is C and Z is C, and the key between W and Z is a double key.

In some embodiments, W is C( ^Rw ), where ^Rw is hydrogen or an alternatively substituted _C1 - _C6 aliphatic, OR, or -N(R) ₂ , and each other variable is independent as described in this disclosure. In some embodiments, W is CH. In some embodiments, W is C( ^Rw ), where ^Rw is an alternatively substituted _C1 - _C6 aliphatic. In some embodiments, W is C( ^Rw ), where ^Rw is an alternatively substituted _C1 - _C6 alkyl. In some embodiments, W is C( ^Rw ), where ^Rw is an alternatively substituted _C1 - _C3 alkyl. In some embodiments, W is C( ^Rw ), where ^Rw is an alternatively substituted methyl. In some embodiments, W is C( ^Rw ), where ^Rw is methyl. In some embodiments, W is C( ^Rw ), where ^Rw is a halogen-substituted methyl group. In some embodiments, W is C( ^Rw ), where ^Rw is _-CF3 . In some embodiments, W is C( ^Rw ), where ^Rw is _-CHF2 .

In some embodiments, W is C(R ^w ), where R ^w is an optional substituted -OR, and R is as described in this disclosure. In some embodiments, W is C(R ^w ), where R ^w is -OR, and R is H or an optional substituted _C1 - _C6 aliphatic compound. In some embodiments, W is C(R ^w ), where R ^w is an optional substituted -N(R) ₂ , and each R exists independently as described in this disclosure. In some embodiments, W is C(R ^w ), where R ^w is -N(R) ₂ , and each R is independently H or an optional substituted _C1 - _C6 aliphatic compound. In some embodiments, R ^w and R ³ are trans. In some embodiments, R ^w and R ³ are cis.

Z

In some implementations, the key between Y and Z is a single key. In other implementations, it is a two-key key.

In some implementation schemes, Z is N.

In some embodiments, Z is C, W is C, or Y is -C( ^Ry ) = , where ^{Ry is} as described in this disclosure. In some embodiments, Z is C and W is C. In some embodiments, Z is C and Y is -C( ^Ry ) = , where ^{Ry is} as described in this disclosure.

In some embodiments, Z is C, W is C, and the key between Z and W is a double key. In some embodiments, Z is C, Y is -C(R ^y )=, where R ^y is as described in this disclosure.

In some embodiments, Z is C( ^Rz ), where ^Rz is hydrogen or an alternatively substituted _C1 - _C6 aliphatic, -R', -OR, or -N(R) ₂ . In some embodiments, Z is -CH-. In some embodiments, Z is C( ^Rz ), where ^Rz is an alternatively substituted _C1 - _C6 aliphatic. In some embodiments, Z is C( ^Rz ), where ^Rz is an alternatively substituted _C1 - _C6 alkyl. In some embodiments, Z is C( ^Rz ), where ^Rz is an alternatively substituted _C1 - _C3 alkyl. In some embodiments, Z is C( ^Rz ), where ^Rz is an alternatively substituted methyl. In some embodiments, Z is C( ^Rz ), where ^Rz is methyl. In some embodiments, Z is C ^{( Rz} ), where ^Rz is _-CF3 . In some implementations, Z is C(R ^z ), where R ^z is -CHF ₂ .

In some embodiments, Z is C(Rz ), where R z is an optionally substituted -OR, and R is as described in this disclosure. In some embodiments, W is C(Rz ), where R z is -OR, and R is H or an optionally substituted C 1 -C 6  aliphatic. In some embodiments, W is C(R z ) , where R z  is -N(R) 2  , and each R is H or an optionally substituted C 1 -C 6  aliphatic. In some embodiments, R z and R3 are trans. In some embodiments, R z and R3 are cis.

Y

In some embodiments, Y is -O-, -S-, -N( ^Ry )-, -C( ^Ry ) _2- , or -C( ^Ry )=, wherein each ^Ry is independently hydrogen, an optional _C1 - _C6 aliphatic group, OR, or -N(R) ₂ ; wherein when Y is -C(Ry ⁾ =, Z is C. In some embodiments, Y is -O-. In some embodiments, Y is -S-. In some embodiments, Y is -N( ^Ry )- and ^Ry is independently hydrogen or an optional _C1 - _C6 aliphatic group. In some embodiments, Y is -N( ^Ry )- and ^Ry is hydrogen. In some embodiments, Y is -N( ^Ry )- and ^Ry is an optional _C1 - _C6 aliphatic group. In some embodiments, Y is -N( ^Ry )- and ^Ry is an optional _C1 - _C6 alkyl group. In some embodiments, Y is -N( ^Ry )- and ^Ry is an optional _C1 - _C3 alkyl group. In some embodiments, Y is -N( ^Ry )- and ^Ry is methyl.

In some embodiments, Y is -C( ^Ry ) _₂- , where each ^Ry is independently hydrogen or an alternatively substituted C₁ _{- C₆} aliphatic, -OR, or -N(R) _₂ . In some embodiments, Y is _-CH₂- . In some embodiments, Y is -CH( ^Ry )-, where ^Ry is an alternatively substituted _C₁ - _C₆ aliphatic. In some embodiments, Y is -CH( ^Ry )-, where ^Ry is an alternatively substituted _{C₁ - C₃} alkyl. In some embodiments, Y is -CH( ^Ry )-, ^{where Ry} is _a ^methyl group. In some embodiments, Y is -C( ^Ry ) _2- , and each ^Ry is independently -OR, where R is as described in this disclosure. In some embodiments, Y is -C( ^Ry ) _2- , and each ^Ry is independently -OR, where R is hydrogen or an alternatively substituted _C1 - _C6 aliphatic compound. In some embodiments, Y is ^-CHRy- , and ^Ry is independently -OR, where R is an alternatively substituted _C1 - _C6 aliphatic compound. In some embodiments, Y is ^-CHRy- , and ^Ry is -OMe. In some embodiments, Y is -C( ^Ry ) _2- , and each ^Ry is independently -N(R) ₂ , where each R is independently as described in this disclosure. In some embodiments, Y is -C( ^Ry ) _₂- , and each ^Ry is independently -N(R) _₂ , where each R is independently hydrogen or an alternatively substituted _C₁ - _C₆ aliphatic compound. In some embodiments, ^R₃ and ^Ry are trans. In some embodiments, ^R₃ and ^Ry are cis.

In some embodiments, Y is -C( ^Ry )=, Z is C, and the bond between Y and Z is a double bond, wherein ^Ry is hydrogen or an optional substituted _C1 - _C6 aliphatic compound. In some embodiments, Y is -CH=, Z is C, and the bond between Y and Z is a double bond. In some embodiments, Y is -C( ^Ry )=, Z is C, and the bond between Y and Z is a double bond, wherein ^Ry is an optional substituted _C1 - _C6 aliphatic compound. In some embodiments, Y is -C( ^Ry )=, Z is C, and the bond between Y and Z is a double bond, wherein ^Ry is an optional substituted _C1 - _C6 alkyl compound. In some embodiments, Y is -C( ^Ry )=, Z is C, and the bond between Y and Z is a double bond, wherein ^Ry is an optional substituted _C1 - _C3 alkyl group.

In some implementation schemes, Selected from:

R'

R' can be any of the variables described in this disclosure. In some embodiments, R' is hydrogen.

In some embodiments, R' is the R described in this disclosure. In some embodiments, R' is -OR, where R is as described in this disclosure. In some embodiments, R' is -C(O)R, where R is as described in this disclosure. In some embodiments, R' is -C(O)OR, where R is as described in this disclosure. In some embodiments, R' is -S(O)R, where R is as described in this disclosure. In some embodiments, R' is -S(O) _2R , where R is as described in this disclosure.

R

R can be any of the variables described in this disclosure. This disclosure extensively describes various implementations of R, including parts applicable to other variables that can be R (such as R ^' , ^Rs1 , ^Rs2 , Rs11, ^Rs12 , ^Rs21 , ^Rs22 , ^Rs31 , ^Rs32 , ^Rs41 , ^{Rs42 ,} etc.).

In some implementations, R is -H. In other implementations, R is not -H.

In some embodiments, each R is independently hydrogen or a optionally substituted _C1 - _C6 aliphatic group, a _C1 - _C6 heteroaliphatic group with 1-3 heteroatoms, a 3-10 membered cycloaliphatic group, a 3-10 membered heterocycloaliphatic group with 1-4 heteroatoms, a 6-10 membered aryl group, a 5-10 membered heteroaryl group with 1-6 heteroatoms, a 6-10 membered aryl- _C1 - _C6 aliphatic group, and a 5-10 membered heteroaryl- _C1 - _C6 aliphatic group with 1-6 heteroatoms.

In some embodiments, R is an optional _C1-6 aliphatic compound. In some embodiments, R is an optional _C1-6 alkyl compound. In some embodiments, R is an optional methyl compound. In some embodiments, R is an optional ethyl compound. In some embodiments, R is an optional n-propyl compound. In some embodiments, R is an optional isopropyl compound. 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.

In some embodiments, R is a _C1-6 heteroaliphatic group having 1-3 (e.g., 1, 2, or 3) independently selected _heteroatoms of oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

In some embodiments, R is an optionally substituted _C3-10 (e.g., _C4-10 , _C3-9 , _C3-7 , or 3, 4, 5, 6, 7, 8, 9, or 10-membered) cyclic aliphatic group. In some embodiments, the cyclic aliphatic group is cycloalkyl. In some embodiments, the cyclic aliphatic group is monocyclic. In some embodiments, the cyclic aliphatic group is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., _C4-10 , _C3-9 , _C3-7 , or 3, 4, 5, 6, 7, 8, 9, or 10-membered) cyclic aliphatic ring. In some embodiments, the cyclic aliphatic group is saturated. In some embodiments, the cycloaliphatic group is partially unsaturated. In some embodiments, R is a optionally substituted cyclopropyl group. In some embodiments, R is a optionally substituted cyclobutyl group. In some embodiments, R is a optionally substituted cyclopentyl group. In some embodiments, R is a optionally substituted cyclohexyl group. In some embodiments, R is a optionally substituted cycloheptyl group. In some embodiments, R is a cyclopropyl group. In some embodiments, R is a cyclobutyl group. In some embodiments, R is a cyclopentyl group. In some embodiments, R is a cyclohexyl group. In some embodiments, R is a cycloheptyl group.

In some embodiments, R is a heterocyclic ring of 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10) members, each independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a heterocyclic ring of 3-10 (e.g., 3-9, 3-6, 3-5, or 3, 4, 5, 6, 7, 8, 9, or 10) members, each independently selected from oxygen, nitrogen, and sulfur. In some embodiments, the heterocyclic group is monocyclic. In some embodiments, the heterocyclic group is bicyclic. In some embodiments, the heterocyclic group is multicyclic. In some embodiments, each monocyclic unit is an independent 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) heterocycle having 1-4 (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, the heterocyclic group 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.

In some embodiments, R is a optionally substituted _C6-10 (e.g., _C6 , _C10 , etc.) aryl group. 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 an independent 6-membered aromatic ring. In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is a phenyl group. In some embodiments, R is an optionally substituted 10-membered aryl group. In some embodiments, R is an optionally substituted naphthyl group. In some embodiments, R is a naphthyl group.

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

In some embodiments, R is an optional substituted _C6-10 (e.g., _C6 , _C10 , etc.) aryl- _C1-6 aliphatic group, wherein the aryl and aliphatic groups are independently as described in this disclosure. In some embodiments, R is an optional substituted _C6-10 aryl- _C1-6 alkyl group.

In some embodiments, R is a 5-10 (e.g., 5-9, or 5, 6, 7, 8, 9, or 10, etc.) heteroaryl- _C1-6 aliphatic compound with 1-6 heteroatoms (e.g., 1, 2, 3, 4, 5, or 6), wherein the heteroaryl group and aliphatic group are independently as described in this disclosure. In some embodiments, R is a 5-10 heteroaryl- _C1-6 aliphatic compound with 1-5 heteroatoms. In some embodiments, R is a 5-6 heteroaryl- _C1-6 aliphatic compound with 1-4 heteroatoms. In some embodiments, R is a 5-10 membered heteroaryl- _C1-6 alkyl group having 1-6 heteroatoms (e.g., 1, 2, 3, 4, 5, or 6), wherein the heteroaryl and alkyl groups are independently as described in this disclosure. In some embodiments, R is a 5-10 membered heteroaryl- _C1-6 alkyl group having 1-5 heteroatoms. In some embodiments, R is a 5-6 membered heteroaryl- _C1-6 alkyl group having 1-4 heteroatoms. Various suitable heteroaryl and aliphatic groups are described in this disclosure.

In some embodiments, two R groups on the same atom are optionally and independently formed with the atom to form a substituted 3-10 ternary (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 ternary) ring, the ring having 0-4 (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 formed with the intervening atom to form a substituted 3-10 ternary (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 ternary) ring, the ring having 0-4 (e.g., 0, 1, 2, 3, or 4) heteroatoms in addition to the intervening atom.

As described herein, in various cases, two R groups, or two groups that are or may be R (e.g., R', ^R2 , ^R3, etc.), can form alternatively substituted rings as described herein, together with the atoms between them. In some embodiments, the formed ring is substituted (except for the groups attached to the atoms between them). In some embodiments, the formed ring is not substituted. In some embodiments, the formed ring is a 3-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 a bicyclic ring. In some embodiments, it is a multicyclic ring. In some embodiments, each monocyclic unit is independently a 3-10 ternary ring (e.g., 3-8 ternary, 3-6 ternary, 5-6 ternary or 3, 4, 5, 6, 7, 8, 9 or 10 ternary rings, etc.), said ring being independently a saturated, partially unsaturated or aromatic ring, and having 0-4 heteroatoms (e.g. 0, 1, 2, 3 or 4). In some embodiments, each monocyclic unit is independently a 3-10 member (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10 member rings, etc.), said ring being independently a saturated, partially unsaturated, or aromatic ring, and having 0-4 (e.g., 0, 1, 2, 3, or 4 heteroatoms, etc.) independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently a 3-7 member ring. In some embodiments, each monocyclic unit is independently a 3-6 member ring. In some embodiments, each monocyclic unit is independently a 5-7 member ring. In some embodiments, each monocyclic unit is independently a saturated or partially unsaturated ring. In some embodiments, at least one monocyclic unit is a saturated ring. In some embodiments, at least one monocyclic unit is a partially unsaturated ring. In some embodiments, at least one monocyclic unit is an aromatic ring. In some embodiments, the formed ring, in addition to the atoms therein, has 0-4 (e.g., 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 two additional heteroatoms. In some embodiments, there are three additional heteroatoms. In some embodiments, there are four additional heteroatoms. In some embodiments, there are five additional heteroatoms. In some embodiments, there are six or more additional heteroatoms. In some embodiments, the additional heteroatoms are nitrogen. In some embodiments, the additional heteroatoms are oxygen. In some embodiments, the additional heteroatoms are sulfur.

As described in this disclosure, various groups may be optionally substituted. Substitution is widely used in the chemical field, including in the development of various pharmaceuticals. According to this disclosure, various substituents may be used. In some embodiments, the optionally substituted groups are unsubstituted. In some embodiments, the optionally substituted groups are substituted. As described in this disclosure, preferred substituents are those that can form compounds having the desired properties, activities, uses, etc. In some embodiments, the compound is stable for the therapeutic uses described in this disclosure. The term "stable" as used in this disclosure means that the compound does not undergo substantial change when subjected to conditions permissible for its production, detection, and (in some embodiments) its recovery, purification, and use for one or more purposes disclosed in this disclosure. In some embodiments, the substituent is an 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 nonhalogen heteroatoms in the substituents is about or no more than about 1; in some embodiments, no more than about 2; in some embodiments, no more than about 3; in some embodiments, no more than about 4; in some embodiments, no more than about 5; in some embodiments, no more than about 6; in some embodiments, no more than about 7; in some embodiments, no more than about 8; in some embodiments, no more than about 9; in some embodiments, no more than about 10; in some embodiments, no more than about 11; in some embodiments, no more than about 12; in some embodiments, no more than about 13; in some embodiments, no more than about 14; in some embodiments, no more than about 15; and in some embodiments, no more than about 20. In some embodiments, the total number of carbon and nonhalogenated heteroatoms in each substituent independently does not exceed about 20. In some embodiments, the total number of carbon and nonhalogenated heteroatoms in each substituent independently does not exceed about 15. In some embodiments, the total number of carbon and nonhalogenated heteroatoms in each substituent independently does not exceed about 10. In some embodiments, the total number of carbon and nonhalogenated heteroatoms in each substituent independently does not exceed about 6. In some embodiments, each optional substituent on the substituted group (e.g., ring A, ring B, R, etc.) is independently a halogen, _C1-4 alkyl, -OH, -CN, _-NO2 , _C1-4 halogenated alkyl (e.g., _-CF3 ), ^-ORSB , -N( ^RSB ) ₂ , -C(O) ^ORSB , -C(O)N( ^RSB ) ₂ , or -S(O) _2N ( ^RSB ) ₂ , wherein each ^RSB is independently -H, _C1-4 alkyl, or optionally substituted _C1-4 halogenated alkyl. In some embodiments, each optional substituent on the substituted group (e.g., ring A, ring B, R, etc.) is independently a halogen, _C1-4 alkyl, _C1-4 halogenated alkyl, or -OH. In some embodiments, each optional substituent on the substituent group (such as ring A, ring B, R, etc.) is independently a halogen or an optional substituted _C1-4 alkyl group. As embodiments, many substituents are illustrated in the compounds described herein, such as those in Table 1.

In some embodiments, this disclosure provides compounds having the structures listed in Table 1 (or salts thereof). In some embodiments, this disclosure provides stereoisomers of compounds having the structures listed in Table 1 (or salts thereof). In some embodiments, this disclosure provides enantiomers of compounds having the structures listed in Table 1 (or salts thereof). In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the compound may optionally be present in a solution form. As will be understood by those skilled in the art upon reading this disclosure, the compounds described herein may exist in various forms, such as acids, alkalis, salts, solutions (e.g., solutions in the form of various acids, alkalis, or salts), etc.

Preparation method

In some embodiments, this disclosure provides various techniques, such as reagents, intermediates, conditions, etc., for the preparation of compounds and compositions as described herein. Those skilled in the art will understand that many of these techniques are available and can be used according to this disclosure.

As those skilled in the art will understand, in chemical reactions, various groups (e.g., hydroxyl, amino, carboxyl, etc.) may be protected to prevent undesirable reactions. Many protection/deprotection techniques are available to those skilled in the art and can be used according to this disclosure. Some of these techniques are described herein, including examples in the embodiments.

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 a polar solvent. In some embodiments, the solvent is a nonpolar solvent. In some embodiments, the solvent is a protic solvent. In some embodiments, the solvent is an aprotic solvent. In some embodiments, the solvent is a polar but aprotic solvent. Solvents suitable for various reactions are available to those skilled in the art and can be used in accordance with this disclosure.

In some embodiments, the reaction is carried out under an inert atmosphere, such as _N₂ or Ar. In some embodiments, the reaction is carried out in air. In some embodiments, the reaction is carried out under anhydrous conditions, such as after reagents, solvents, containers, etc., have been properly dried. In some embodiments, the reaction is carried out in the presence of a large amount of water (e.g., about or more than about 0.1, 0.5, or 1 equivalent).

In some embodiments, the reaction is carried out or sustained at temperatures above, below, or close to the standard ambient temperature (25°C). In some embodiments, the reaction temperature is below the standard ambient temperature. In some embodiments, the temperature is approximately or does not exceed approximately -78, -60, -50, -40, -30, -20, -10, 0, or 10°C. In some embodiments, the temperature is approximately or does not exceed approximately 10°C. In some embodiments, the temperature is approximately or does not exceed approximately 15°C. In some embodiments, the temperature is approximately or does not exceed approximately 20°C. In some embodiments, the reaction temperature is approximately the standard ambient temperature. In some embodiments, the reaction temperature is above the standard ambient temperature. In some embodiments, the reaction temperature is about 35, 40, 50, 60, 70, 80, 90, 100, or 100 °C. In some embodiments, the reaction involves reflux in a boiling solvent system, such as in a system containing diethyl ether or toluene. In some embodiments, the temperature changes during the reaction, for example, from a lower temperature to a higher temperature, from a higher temperature to a lower temperature, or both.

In some embodiments, a particular product can be synthesized selectively relative to other potential products. In some embodiments, the production of a product has chemical selectivity, stereoselectivity, and/or regional selectivity. In some embodiments, selectivity is expressed as a ratio, such as the ratio of one product to another. In some implementation schemes, the ratio is approximately or at least approximately 1.5:1, 2:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 200:1, 500:1, or more.

The reaction can proceed over varying time durations. In some embodiments, the reaction is completed instantaneously. In others, the reaction time varies from minutes to hours to days, for example, 5, 10, 15, 20, 30, or 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 byproducts, etc.

In some embodiments, this 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 or greater than about 80%. In some embodiments, the purity of the compound is or greater than 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%.

In some embodiments, this disclosure provides compounds with high stereochemical purity. In some embodiments, the stereochemical purity of the compounds 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 compounds is or greater than about 80%. In some embodiments, the stereochemical purity of the compounds is or greater than about 85%. In some embodiments, the stereochemical purity of the compounds is or greater than about 90%. In some embodiments, the stereochemical purity of the compounds is or greater than about 95%. In some embodiments, the stereochemical purity of the compounds is or greater than about 96%. In some embodiments, the stereochemical purity of the compounds is or greater than about 97%. In some embodiments, the stereochemical purity of the compound is 98% or greater. 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%.

In some embodiments, this 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 or greater than about 80%. In some embodiments, the enantiomeric purity of the compound is or greater than about 85%. In some embodiments, the enantiomeric purity of the compound is or greater than about 90%. In some embodiments, the enantiomeric purity of the compound is or greater than about 95%. In some embodiments, the enantiomeric purity of the compound is or greater than about 96%. In some embodiments, the enantiomeric purity of the compound is or greater than about 97%. In some embodiments, the enantiomeric purity of the compound is or greater than about 98%. In some embodiments, the enantiomeric purity of the compound is or greater than about 99%. In some embodiments, the enantiomeric purity of the compound is or greater than 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%. In some embodiments, the configuration of the stereocenter is shown next to the stereocenter in the chemical structure, for example, shown as " R ", " S ", " (R) ", " (S) ", etc., and this configuration is usually determined by such software when describing chemical structures using business software such as ChemDraw. In some embodiments, the configuration of the stereocenter is not shown. Those skilled in the art can easily determine the configuration of the stereo center based on common practices in the field.

This disclosure provides various techniques for preparing compounds and compositions that are stereochemically pure (e.g., enantiomerically pure). For example, in some embodiments, they can be prepared by separation (including chiral separation); in other embodiments, they can be prepared by stereoselective synthesis.

In some embodiments, this disclosure describes a method comprising one or more steps as described below, wherein each variable is independent as described in this disclosure. In some embodiments, one of the methods described below is provided as an example. In some embodiments, this disclosure provides a compound having the following selected general formula structure or a salt thereof.

In some embodiments, this disclosure provides a method comprising: chemically reacting a compound having a general formula III-a structure or a salt thereof with a compound having an ^R3 -C(O) ^-R4 structure or a salt thereof.

To provide compounds having the general formula IV-a or salts thereof:

Where R ^m1 is R' as described in this disclosure, and the other variables are independent as described in this disclosure.

In some embodiments, this disclosure provides a method comprising: reacting a compound having the general formula III-b structure or a salt thereof with a compound having the ^R3 -C(O) ^-R4 structure or a salt thereof:

To provide compounds having the general formula IV-b or their salts:

Where R ^m1 is R' as described in this disclosure, and the other variables are independent as described in this disclosure.

In some embodiments, this disclosure provides a method comprising reacting a compound having the general formula III-c structure or a salt thereof with a compound having the ^R3 -C(O) ^-R4 structure or a salt thereof:

To provide compounds having the general formula IV-c or their salts:

Where R ^m1 is R' as described in this disclosure, and the other variables are independent as described in this disclosure.

In some embodiments, this disclosure provides a method comprising reacting a compound having a general formula III-d structure or a salt thereof, or a compound having an HC(O)C(O)OR ^m1 structure or a salt thereof:

R ₂ -NH-C(R ^y ) ₂ -C(R ³ )(R ⁴ )-OH, III-d

To provide compounds having the general formula IV-d or their salts:

Where R ^m1 is R' as described in this disclosure, and the other variables are independent as described in this disclosure.

In some embodiments, the method is carried out in the presence of _acid . In some embodiments, the method is carried out in the presence of _H₂SO₄ . In some embodiments, the method is carried out in the presence of concentrated _H₂SO₄ . In some embodiments, the method is carried out in the presence of TsOH, pyridinium p-toluenesulfonate (PPTS), and _{BF₃- Et₂O .} In some embodiments, the method is carried out in the presence of _{pyridine p-toluenesulfonate (PPTS). In some embodiments, the method is carried out in the presence of BF₃-Et₂O .} In some embodiments, the method is carried out in the presence of TsOH. In some embodiments, the method is carried out in the presence of TsOH. In some embodiments, the method is carried out in the presence of TsOH.

In some embodiments, this disclosure provides a method comprising reacting a compound having the general formula III-e structure or a salt thereof with a compound having the ^R3 -C(O) ^-R4 structure or a salt thereof:

III-e

To provide compounds having the general formula IV-a or salts thereof:

Where ^Rm1 is R', LG is a leaving group (such as -Br, -OTs, etc.), and the other variables are independent as described in this disclosure.

In some embodiments, this disclosure provides a method comprising reacting a compound having the general formula III-f or a salt thereof with a compound having the ^R3 -C(O) ^-R4 structure or a salt thereof:

To provide compounds having the general formula IV-a structure or salts thereof:

Where ^Rm1 is R', LG is a leaving group (such as -Br, -OTs, etc.), and the other variables are independent as described in this disclosure.

In some embodiments, this disclosure provides a method comprising reacting a compound having the general formula III-g structure or a salt thereof with a compound having the ^Rw- C(O)-C(O) ^ORm1 structure or a salt thereof:

To provide compounds having the general formula IV-g structure or salts thereof:

Where ^Rm1 is R', and the other variables are independent as described in this disclosure.

In some embodiments, this disclosure provides a method comprising reacting a compound having the general formula III-h structure or a salt thereof with a compound having the Rw ^- CH(SH)-C(O) ^ORm1 structure or a salt thereof:

C(R( ³ ))(R ⁴ )=C(R ^y )-C(O)-R ₂ , III-h

To provide compounds having the general formula IV-h or their salts:

IV-h

Converting compounds or salts having the general formula IV-h to compounds or salts having the general formula IV-h-2 or IV-h-3:

Converting compounds having the general formula IV-h-2 or their salts to compounds having the general formula IV-h-3 or their salts; and converting compounds having the general formula IV-h-2 or IV-h-3 or their salts to compounds having the general formula IV-h-4 or their salts:

Wherein, ^Rm1 is R', and the other variables are independent as described in this disclosure.

In some embodiments, this disclosure provides a method comprising conditions for converting a compound of formula IV-h or a salt thereof to a compound of formula IV-h-2 or a salt thereof. In some embodiments, this disclosure provides a method comprising conditions for converting a compound of formula IV-h or a salt thereof to a compound of formula IV-h-3 or a salt thereof. In some embodiments, this disclosure provides a method comprising conditions for converting a compound of formula IV-h-2 or a salt thereof to a compound of formula IV-h-3 or a salt thereof. In some embodiments, this disclosure provides a method comprising conditions for converting a compound of formula IV-h-2 or IV-h-3 or a salt thereof to a compound of formula IV-h-4 or a salt thereof. In some embodiments, this disclosure provides a method comprising conditions for converting a compound of formula IV-h-3 or a salt thereof to a compound of formula IV-h-4 or a salt thereof. In some embodiments, a compound of formula IV-h-3 or a salt thereof is converted to a compound of formula IV-h-4 or a salt thereof by hydrogenation, for example, in the presence of a metal catalyst as described herein (e.g., a catalyst containing a metal such as Pd). In some embodiments, a compound of formula IV-h-3 or a salt thereof is converted to a compound of formula IV-h-4 or a salt thereof in the presence of a metal (e.g., Mg) and an alcohol (e.g., a _C1-4 alcohol such as MeOH).

In some embodiments, this disclosure provides a method comprising reacting a compound having the general formula III-i structure or a salt thereof with a compound having the C(R( ³ )) ₍ ^R4 )=C( ^Ry ) ₂ structure:

O ^(- )-N ⁺ (PG)=C(R ^z )(R ² )、III-i

To provide compounds having the general formula IV-i structure:

IV-i

Or its salt;

Converting compounds of general formula IV-i or their salts into compounds of general formula IV-i-2:

or its salt;

To convert compounds of general formula IV-i-2 or their salts into (e.g., by reaction with compounds having an O=C=NR ¹ structure) compounds of general formula IV-i-3:

or its salts;

Wherein PG is R' or a suitable protecting group (such as _-CH2- (optionally substituted aromatic group (such as phenyl)), and other variables are independent as described in this disclosure.

In some implementations, the method is carried out in the presence of an _alkali . In some implementations, the method is carried out in the presence of _K₂CO₃ .

In some embodiments, the provided method includes contacting a compound having general formula I or a salt thereof, wherein X is S, with an oxidizing agent to provide a compound of general formula I or a salt thereof, wherein X is -S(O)-. According to this disclosure, various suitable oxidizing agents can be used. In some embodiments, the oxidizing agent is m-CPBA.

In some embodiments, the reaction is carried out below 0°C. In some embodiments, the reaction is carried out below -10°C. In some embodiments, the reaction is carried out at temperatures below -20°C. In some embodiments, the reaction is carried out at temperatures below -30°C. In some embodiments, the method is carried out below -40°C. In some embodiments, the reaction is carried out below -50°C. In some embodiments, the reaction is carried out below -60°C. In some embodiments, the reaction is carried out at temperatures below -70°C. In some embodiments, the reaction is carried out at temperatures around -78°C. In some embodiments, the reaction is carried out at temperatures between around -78°C and 0°C. In some embodiments, the reaction is carried out at temperatures between around -78°C and -10°C. In some embodiments, the reaction is carried out at temperatures between around -78°C and -20°C. In some embodiments, the experiment is conducted at temperatures ranging from approximately -78°C to -30°C. In some embodiments, the experiment is conducted at temperatures ranging from approximately -78°C to -40°C. In some embodiments, the experiment is conducted at temperatures ranging from approximately -40°C to 0°C. In some embodiments, the experiment is conducted at temperatures ranging from approximately -40°C to -10°C. In some embodiments, the experiment is conducted at temperatures ranging from approximately -40°C to -20°C. In some embodiments, the experiment is conducted at temperatures ranging from approximately -78°C to 120°C.

In some embodiments, the reaction takes approximately 1 hour. In some embodiments, the reaction takes approximately 50 minutes. In some embodiments, the reaction takes approximately 40 minutes. In some embodiments, the reaction takes approximately 30 minutes. In some embodiments, the reaction takes approximately 20 minutes. In some embodiments, the reaction takes approximately 10 minutes. In some embodiments, the reaction takes less than 2 hours. In some embodiments, the reaction takes less than 3 hours. In some embodiments, the reaction takes less than 4 hours. In some embodiments, the reaction takes less than 5 hours. In some embodiments, the reaction takes less than 6 hours. In some embodiments, the response takes less than 12 hours to complete. In some embodiments, the response takes less than 24 hours to complete.

In some embodiments, ^Rm1 is an optional _C1 - _C6 aliphatic compound. In some embodiments, ^Rm1 is an optional _C1 - _C6 alkyl compound. In some embodiments, ^Rm1 is ethyl. In some embodiments, ^Rm1 is methyl. In some embodiments, ^R3 is hydrogen. In some embodiments, ^R3 is an optional _C1 - _C6 aliphatic compound. In some embodiments, ^R3 is an optional _C1 - _C6 alkyl compound. In some embodiments, ^R3 is an optional _C1 - _C3 alkyl compound. In some embodiments, ^R3 is halogen-substituted _C1 - _C3 alkyl. In some embodiments, ^R3 is _C1 - _C3 alkyl. In some embodiments, ^R3 is methyl. In some embodiments, ^R3 is _-CF3 .

In some embodiments, ^R4 is hydrogen. In some embodiments, ^R4 is an optional _C1 - _{C6 aliphatic} alkyl group. In some embodiments, ^R4 is an optional _C1 - _C6 alkyl group. In some embodiments, ^R4 is an optional _C1 - _C3 alkyl group. In some embodiments, ^R4 is a halogen-substituted _C1 - _C3 alkyl group. In some embodiments, ^R4 is a _C1 - _C3 alkyl group. In some embodiments, ^R4 is methyl. In some embodiments, ^R4 is _-CF3 .

In some embodiments, this disclosure provides a method for converting -C(O)OR ^m1 to -COOH or a salt thereof to provide a compound of formula II or a salt thereof, wherein R ^m1 is as described in this disclosure. In some embodiments, this disclosure provides a method for reacting -C(O)OH or a salt thereof with NHR ¹ R ^1' or a salt thereof to provide a compound of formula I or a salt thereof, wherein each variable is independently as described in this disclosure. In some embodiments, this disclosure provides a method for reacting -C(O)OR ^m1 with NHR ¹ R ^1' or a salt thereof to provide a compound of formula I or a salt thereof, wherein each variable is independently as described in this disclosure.

Applications

According to several studies, painful stimuli involve electrical impulses transmitted from noxious dorsal root ganglion neurons through ascending pathways in the spinal cord, ultimately reaching the central nervous system (CNS). Pain receptors are thought to express voltage-gated sodium channels (VGSCs), which selectively mediate the influx of sodium ions and play a crucial role in initiating and conducting action potentials (APs) (Yu et al., *Genomics* 4:207, 2003). VGSCs are reported to consist of nine α subunits encoded by genes SCN1A to SCN11A, forming complexes with β subunits that regulate channel properties. The fourth transmembrane segment (S4) in the α subunit acts as a voltage sensor, mediating the different electrophysiological characteristics of the nine Nav channel subtypes (Nav1.1-Nav1.9), resulting in their varying voltage dependence and dynamic properties.

Nav1.8 is reported to selectively express in specific pain receptors, with expression concentrated in small-diameter neurons of the dorsal root ganglia (DRG) in the peripheral nervous system, playing a crucial role in peripheral pain mechanisms. Notably, excitation-promoting mutations of Nav1.8 have been found in patients diagnosed with painful microfibroneuropathy. Furthermore, Nav1.8 gene knockdown has been shown to alleviate pain-related behaviors, particularly in neuropathic pain (J. Lai et al., Pain, 2002; 95(1-2): 143-152). Additionally, according to some literature, a natural mutant, A1073V, can shift the activation voltage of the inducible channel towards a more depolarized direction, thus improving pain symptoms to some extent. In some embodiments, this disclosure provides techniques for pharmacologically modulating Nav1.8 for the treatment of Nav1.8-related diseases.

In some embodiments, this disclosure provides a method for modulating Nav1.8 activity in a system containing Nav1.8, the method comprising administering or delivering an effective dose of the compound or pharmaceutical composition described herein to the system. In some embodiments, the system is or comprises cells. In some embodiments, the system is or comprises tissue. In some embodiments, the system is or comprises an organ. In some embodiments, the system is or comprises an organism. In some embodiments, the system is a subject. In some embodiments, the system is an animal. In some embodiments, the system is a human. In some embodiments, the system expresses Nav1.8. In some embodiments, the system is or comprises skin. In some embodiments, the system is or comprises nonneuronal cells or tissues. In some embodiments, the system is or comprises epidermal keratinocytes. In some embodiments, the system is or comprises hair follicles. In some embodiments, this method reduces the activity level of Nav1.8 compared to the case where no compound is provided. In some embodiments, the reduction is about or at least about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

In some embodiments, the activity level of Nav1.8 is enhanced compared to not using the provided compound. In some embodiments, the increase is approximately or at least about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

In some embodiments, this disclosure provides a method for preventing a condition, disorder, or disease, including administering an effective amount of the provided compound or composition to a susceptible individual. In some embodiments, this disclosure provides a method for treating a condition, disorder, or disease, including administering an effective amount of the provided compound or composition to an individual suffering from the condition, disorder, or disease. In some embodiments, this disclosure provides a method for preventing a condition, disorder, or disease, including delivering an effective amount of the provided compound or composition to a susceptible individual. In some embodiments, this disclosure provides a method for treating a condition, disorder, or disease, including delivering an effective amount of the provided compound or composition to an individual suffering from the condition, disorder, or disease. In some embodiments, the compound is administered or delivered in the form of a pharmaceutically acceptable salt. In some embodiments, the composition is a pharmaceutical composition. In some implementations, a prodrug may be administered to deliver the provided compound.

In some embodiments, the compound is used in a racemic form other than the stated form. In some embodiments, the composition is a stereo-random mixture of multiple stereoisomers. For example, in some embodiments, the composition is a stereo-random mixture of two enantiomers. In some embodiments, the compound is used in a single stereochemically pure form as described herein. In some embodiments, the compound is used in a single enantiomer pure form. In some embodiments, the composition is rich in one or more stereoisomers, as described herein. In some embodiments, the composition is rich in enantiomers as described herein. In some embodiments, the composition is a single stereochemically pure form. In some embodiments, the composition is a single enantiomer pure form.

In some implementations, the symptom, disorder, or disease is a symptom, disorder, or disease related to Nav1.8. In some implementations, the symptom, disorder, or disease is related to Nav1.8 activation.

In some implementation protocols, the condition, disorder, or disease is or includes pain. In some implementation protocols, the condition, disorder, or disease is or includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, peroneal muscle atrophy syndrome, urinary or fecal incontinence, pathological cough, or arrhythmia. In some implementation protocols, the condition, disorder, or disease is or includes neuropathic pain, musculoskeletal pain, osteoarthritis pain, acute pain, acute postoperative pain, postoperative pain, hallux valgus pain, abdominoplasty pain, hernia pain, or visceral pain. In some implementation protocols, the condition, disorder, or disease is or includes postherpetic neuralgia, microfibroneuropathy, idiopathic microfibroneuropathy, diabetic neuropathy, or diabetic peripheral neuropathy.

In some implementations, the symptom, disorder, or disease is migraine, post-ischemic neurodegeneration, epilepsy, arthritis, cardiogenic pain due to ischemic myocarditis, acute pain, chronic pain, throbbing pain, neuropathic pain, postoperative pain, pain caused by neuralgia (e.g., postherpetic neuralgia, traumatic neuralgia, fibromyalgia, trigeminal neuralgia), pain caused by diabetic neuropathy, toothache, cancer pain, or inflammatory pain (e.g., arthritis and osteoarthritis). In some implementations, the symptom, disorder, or disease is or includes spontaneous pain, acute pain, preoperative pain, perioperative pain, or postoperative pain.

In some implementation schemes, symptoms, disorders, or diseases are or include neuropathic pain, pain, toothache, AIDS pain, chest pain due to ischemic myocarditis, pain due to migraines, joint pain, neurosis, neurodegeneration, retinopathy, neurodermatitis, stroke, bladder allergy, urinary incontinence, vulvitis, irritable bowel syndrome, gastroesophageal reflux disease, intestinal diseases, gastric ulcers, gastrointestinal diseases such as irritable bowel syndrome, gastroesophageal reflux disease, enteritis, ileitis, gastroduodenal ulcers, inflammatory bowel disease, Crohn's disease, celiac disease. Inflammatory diseases such as pancreatitis; respiratory diseases such as allergic and non-allergic rhinitis, asthma, or chronic obstructive pulmonary disease; skin, eye, or mucous membrane irritation; atopic dermatitis, eczema, pruritus, fever, muscle spasms, vomiting, movement disorders, depression, Huntington's disease, memory impairment, limited brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratoacanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis, anxiety, or benign prostatic hyperplasia. In some implementation schemes, the symptom, disorder, or disease is atopic dermatitis, eczema, seborrheic eczema, pruritus, dermatitis, or psoriasis, or includes atopic dermatitis, eczema, seborrheic eczema, pruritus, dermatitis, or psoriasis.

In some implementation protocols, idiopathic pain includes fibromyalgia.

In some implementation schemes, symptoms, disorders, or diseases are or include acute pain, subacute and chronic pain, hyperalgesia, neuropathic pain, inflammatory pain, neurospasmodic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuropathic pain, epilepsy, neurodegenerative diseases, mental illness, anxiety disorder, depression, bipolar disorder, dystonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, etc. Visceral pain, osteoarthritis, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, urinary and fecal incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, pain sensation, breakthrough pain, postoperative pain (such as pain after joint replacement surgery, soft tissue surgery, hernia removal, hallux valgus removal, or abdominoplasty), cancer. Pain (including chronic cancer pain and breakthrough cancer pain), stroke (such as post-stroke central neuropathic pain), whiplash-related diseases, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteoporosis, multiple rheumatoid arthritis, pustular dermatitis, chronic generalized pain, diffuse idiopathic osteoproliferative disease, intervertebral disc degeneration/disc herniation pain, radiculopathy, facial arthritis syndrome, back surgery failure syndrome, burns, carpal tunnel syndrome Symptoms, Parkinson's disease pain, spinal stenosis, spinal dysplasia, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcomatosis, spinolysis, spondylolysis, chemotherapy-induced stomatitis, Charcot neuromuscular disease, temporomandibular joint disorder, joint displacement pain, non-cardiac chest pain, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis (ALS), stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

In some implementation protocols, symptoms, disorders, or diseases are or include femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, irritable bowel syndrome pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie syndrome, etc. e-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radicular neuropathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent/chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom pain (lower limb, upper limb, post-mastectomy), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain. Skeletal pain, joint pain, mechanical back pain, neck pain, tendinitis, injury pain, exercise pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, angina pectoris, pelvic pain, renal colic, acute obstetric pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain Pain, leprosy pain, Behcet's disease pain, fatty degeneration, sore throat, Guillain-Barré pain, leg pain and toe movement pain, Haggard's syndrome, erythromelalgia pain, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, hyperbladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, generalized pain, paroxysmal extreme pain, pruritus, pain caused by tinnitus or angina.

In some implementation protocols, neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, HIV-associated sensorineural neuropathy pain, trigeminal neuralgia, oral burning syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus nerve avulsion, and complex regional pain syndrome. Neuropathic pain induced by medication, neuropathic pain induced by cancer chemotherapy, neuropathic pain induced by antiretroviral therapy, nerve avulsion, brachial plexus nerve avulsion, complex regional pain syndrome, neuropathic pain induced by medication, neuropathic pain induced by cancer chemotherapy, neuropathic pain induced by antiretroviral therapy, post-spinal cord injury pain, microfibrosis, idiopathic microfibrosis, idiopathic sensory neuropathy, or trigeminal neuralgia.

In some implementation protocols, musculoskeletal pain includes arthritis pain, back pain, cold pain, burn pain, or toothache.

In some implementation protocols, inflammatory pain includes pain associated with rheumatoid arthritis, rheumatoid arthritis, or vulvitis.

In some implementation protocols, the symptom, disorder, or disease is skin inflammation.

In some implementation schemes, symptoms, disorders, or diseases are or include acute pain, chronic pain, spontaneous pain, essential pain, neuropathic pain, peripheral neuropathy, migraine, post-ischemic neurodegeneration, multiple sclerosis, epilepsy, peroneal muscle atrophy syndrome, post-ischemic neurodegeneration, epilepsy, trigeminal neuralgia, trigeminal automatic headache, diabetic neuropathy, sciatica, Optic neuritis, AIDS-related sensory neuropathy, burning mouth syndrome, spinal stenosis, carpal tunnel syndrome, chemotherapy-related sensory neuropathy, diabetic neuropathy, sciatica, optic neuritis, AIDS-related sensory neuropathy, burning mouth syndrome, trigeminal neuralgia, diabetic neuropathy, sciatica, optic neuritis, AIDS-related sensory neuropathy, burning mouth syndrome Spinal stenosis, carpal tunnel syndrome, chemotherapy-induced peripheral neuropathy, radicular pain, nerve avulsion, brachial plexus nerve injury, neuropathic pain induced by antiretroviral therapy, spinal cord injury, primary small fibroneuropathy, primary sensory neuropathy, inflammatory pain, rheumatoid arthritis pain, cancer pain, intestinal pain, visceral pain, musculoskeletal pain, acute pain caused by fractures, musculoskeletal pain. Bone injury, chronic low back pain, phantom limb pain, chronic pelvic pain, intestinal pain, pancreatitis, renal colic, burn pain, preoperative pain, perioperative pain, postoperative pain, osteoarthritis, toothache, vulvar pain, fibromyalgia, urinary incontinence, pathological cough, arrhythmia, hereditary erythematosus urticaria, asthma, pruritus, allergic or contact dermatitis, renal failure, cholestasis, or arrhythmia.

In some embodiments, this disclosure provides a method for suppressing voltage-gated sodium ion channels in a subject, the method comprising administering or delivering an effective amount of a provided compound or composition to the subject. In some embodiments, the voltage-gated sodium ion channel is or includes Nav1.8.

In some embodiments, the compounds or combinations described in this disclosure may be used in conjunction with one or more additional therapeutic agents (e.g., Nav 1.7 inhibitors) as a comprehensive therapy for the prevention or treatment of a condition, disorder, or disease.

In some embodiments, the provided compound is administered or delivered concurrently with another treatment. In some embodiments, the provided compound is administered or delivered as a single combination with another treatment. In some embodiments, the provided compound is administered or delivered concurrently with another treatment, but in a different combination. In some embodiments, the provided compound is administered or delivered before another treatment (e.g., approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days in advance, or approximately 1, 2, 3, 4, or 5 weeks in advance, or approximately 1, 2, 3, 4, or 5 months in advance). In some embodiments, the compound is administered or delivered following another treatment (e.g., after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or after 1, 2, 3, 4, or 5 weeks, or after 1, 2, 3, 4, or 5 months). In some embodiments, the compound is administered or delivered while the subject is under the influence of another treatment.

In some embodiments, this disclosure provides a method for improving subject adherence to a dosage regimen, the method comprising administering or delivering an effective amount of the compound or drug combination described in this disclosure to a subject receiving the dosage regimen. In some embodiments, this disclosure provides a method for improving the single dose, total dose, frequency of administration, and/or duration of treatment of a drug, the method comprising administering or delivering an effective amount of the compound or drug combination described in this disclosure to a subject receiving the drug. In some embodiments, the single dose is increased. In some embodiments, the total dose over a period of time is increased. In some embodiments, the frequency of administration over a period of time is increased. In some implementation protocols, the treatment duration is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days; or approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks; or approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months; or approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In some implementation protocols, the treatment duration is extended.

In some implementation protocols, the subjects were adult patients. In other implementation protocols, the subjects were pediatric patients.

Drug Compositions

In some embodiments, this disclosure provides a pharmaceutical composition comprising the provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, this disclosure provides a pharmaceutical composition that can deliver the provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

According to this disclosure, various techniques, such as routes, modes, and dosage regimens, can be used to administer and/or deliver the provided compounds and compositions. In some embodiments, the route of administration and/or mode of administration can be varied according to the desired outcome. Those skilled in the art (e.g., physicians) know that dosage regimens can be adjusted to provide the desired response, such as a therapeutic response. Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intrathecal, intravaginal, transdermal, rectal, inhalation, or local administration, particularly to the ear, nose, eye, or skin. In some embodiments, the mode of administration is determined by the practitioner. For example, in some embodiments, the compound or composition is administered or delivered orally. In some implementation schemes, the compound or composition is administered topically or by delivery.

In some embodiments, compounds may be formulated as drug combinations and administered as such. These drug combinations are suitable for a variety of uses, including administration and delivery to subjects in vivo or in vitro. In some embodiments, the drug combination also includes a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is a drug that does not self-induce an immune response harmful to the individual receiving the combination and can be administered without excessive toxicity. Pharmaceutically acceptable carriers (or excipients) include, but are not limited to, liquids such as water, saline, glycerol, sugars, and ethanol. Furthermore, such carriers may contain excipients such as humectants or emulsifiers, pH buffers, etc.

The compounds in the pharmaceutical composition may be pharmaceutically acceptable salts. In some embodiments, the compounds in the pharmaceutical composition may form salts with acids such as hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and benzenesulfonic acid. In some embodiments, the compounds in the pharmaceutical composition may form salts with alkalis. In some embodiments, the salts are alkali metals, alkaline earth metals, or ammonium salts, such as sodium salts, calcium salts, diethanolamine salts, ethanolamine salts, trialkylamine salts, etc.

In some embodiments, the salt is more soluble in aqueous solutions or other proton solvents than the corresponding free acid or alkali form. In some embodiments, the pharmaceutical composition may be a lyophilized powder. In some embodiments, the pharmaceutical composition comprises the provided compound, such as a compound of general formula I or a pharmaceutically acceptable salt thereof, dissolved in a pharmaceutically acceptable buffer. In some embodiments, the buffer is a physiological saline buffer. In some embodiments, the pH of the buffer is around 7.4.

Pharmaceutical compositions may include solvents (aqueous or non-aqueous solutions), solutions (aqueous or non-aqueous solutions), emulsions (such as oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersants and suspension media, coatings, isointense agents, and absorption enhancers or delay agents that are compatible with drug administration or intravesical administration. Aqueous and non-aqueous solvents, solutions, and suspensions may contain suspending agents and thickeners. In some embodiments, pharmaceutical compositions or formulations are in the form of tablets (coated or uncoated), capsules (hard or soft capsules), microbeads, powders, granules, and/or crystals. Co-active compounds (such as preservatives, antibacterial agents, antiviral agents, and antifungal agents) may also be added to pharmaceutical compositions.

Pharmaceutical combinations can be formulated to be compatible with specific routes of administration or delivery described in this disclosure or known to those skilled in the art.

In some embodiments, the provided composition is suitable for parenteral administration. In some embodiments, such compositions include aqueous and non-aqueous solutions, suspensions, or emulsions of the active compound. These formulations are typically sterile and is isotropic to the blood of the intended recipient. Examples include water, buffered saline, Hanks' solution, Ringer's solution, glucose, fructose, ethanol, animal oil, vegetable oil, or synthetic oil. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Furthermore, suspensions of the active compound can also be prepared as suitable oily 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. In addition, the suspension may contain appropriate stabilizers or solubility-enhancing agents to prepare high-concentration solutions.

Solubilizers and adjuvants may be added to the compositions and formulations. Non-limiting examples of solubilizers include those containing hydroxyl or other polar groups, such as alcohols like isopropanol; ethylene glycols like propylene glycol, polyethylene glycol, polypropylene glycol, and glycol ethers; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Adjuvants include surfactants such as soybean lecithin and oleic acid; sorbitan esters, such as sorbitan trioleate; and polyvinylpyrrolidone.

After the drug combination is prepared, it can be placed in a suitable container and labeled for therapeutic use. This label may include dosage, frequency of administration, and method of administration.

Various pharmaceutical composition techniques and delivery systems applicable to the compositions, methods and uses described in this disclosure are available (see Remington: The Science and Practice of Pharmacy. ^23rd Edition., Academic Press, 2020) and can be used in accordance with this disclosure.

In some embodiments, this disclosure provides methods for delivering the provided compounds and compositions into cells, animals, or subjects. In some embodiments, such methods include contacting, administering, or delivering to a subject (e.g., the subject's cells or tissues) the provided compound, such as a compound of formula I, or a salt thereof, or a composition thereof.

The compounds or combinations described herein may be administered in adequate or effective amounts to a subject (or its cells, tissues, or organs) in need. Dosage may vary and may depend on the type, onset, progression, severity, frequency, duration, or probability of the condition, disorder, or disease being treated, the desired clinical endpoint, prior or concurrent treatments, the subject's overall health, age, sex, race, or immune capacity, and other factors that will be understood by those skilled in the art. Dosage, quantity, frequency, or duration may be increased or decreased proportionally based on efficacy, any adverse side effects, complications, or other risk factors, and the subject's condition. Those skilled in the art will understand the factors that may influence dosage and timing to provide an adequate amount to achieve a therapeutic or preventative effect.

The dosage required to achieve a therapeutic effect will vary depending on a number of factors, including the route of administration, the amount required to achieve the therapeutic effect, the specific condition, disorder, or disease being treated, the host's immune response to the administered compound or combination, and the stability of the administered compound or combination.

An effective or adequate dose may be provided in a single administration or may require multiple administrations, and may be administered alone or in combination with another formulation (e.g., containing or delivering another treatment). For example, the dosage may be increased proportionally based on the subject's needs, the condition being treated, the type, state, and severity of the disorder or disease, and any side effects of the treatment. Doses considered effective also include those that reduce the need for other treatments, regimens, or protocols.

In some embodiments, the pharmaceutical composition contains or provides an effective amount of the active ingredient, such as a compound of general formula I or a pharmaceutically acceptable salt thereof, to achieve a intended purpose, such as a therapeutic purpose. According to this disclosure, various techniques can be used to determine the effective therapeutic amount. Among other factors, the therapeutic dosage also depends on the subject's age and general condition, disease status, severity of disorder or disease, etc. In some embodiments, the effective therapeutic amount for humans can be determined by a healthcare practitioner within a relatively broad range based on the individual patient's response.

In some embodiments, the methods and uses described in this disclosure include systemic, regional, or local delivery and administration, or administration via any route, such as injection, infusion, or oral administration. In some embodiments, the administration of the drug combination in vivo is generally achieved by injection using a conventional syringe, but in other embodiments, other methods of administration, such as convection-enhanced administration, may be used. The compounds and combinations can be administered subcutaneously, epidermally, intradermally, intracavitarily, intraorbitally, intramucosariformly, intraperitoneally, intravenously, intrapleurally, intraarterially, orally, intrahepatically, via portal vein, or intramuscularly. In some embodiments, the routes of administration include oral, pulmonary, suppository, and transdermal application. Clinicians can determine the optimal route of administration for the compounds and combinations described in this disclosure.

Specific implementation examples

This document describes certain examples of the provided techniques (such as compounds, compositions, methods (preparation, use, evaluation, etc.)). Those skilled in the art who read this disclosure will understand that various techniques, including those described below and their modifications, variations, and derivatives, can be used to manufacture, characterize, and/or evaluate the provided techniques in accordance with this disclosure.

Some abbreviations used in the following examples:

EA = Ethyl acetate;

DMF = N,N-dimethylformamide;

Dess-Martin periodinane = 1,1-dihydro-1,1,1-triethoxy-1,2-benzoiodocyanine-3(1H)-one;

DCM = Dichloromethane;

THF = Tetrahydrofuran

LAH = Lithium aluminum hydrogenate;

DME = 1,2-dimethoxyethane;

TEA = Triethylamine

EIPEA = N,N-diisopropylethylamine;

DEAD = Diethylazodicarbonate;

DIAD = Diisopropyl azodicarbonate;

HATU = 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate;

EDCI = (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride);

HOBt = 1-hydroxybenzotriazole;

DIBAL-H = Diisobutylaluminum hydrogenide;

Bn = benzyl; DMSO = dimethyl monoxide;

RT = Room temperature;

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene;

NCS = N-chlorobutylideneimide;

LiHMDS = Lithium bis(trimethylsilicon)amide;

DMAP = 4-Dimethylaminopyridine;

n-BuLi = n-Butyllithium;

ACN = Acetonitrile;

TCFH = Chloro-N,N,N',N'-Tetramethylformamidinium hexafluorophosphate;

NMI = 1-Methylimidazole;

Some useful materials and experiments: All reagents are reported and/or purchased from commercial suppliers (Sigma-Aldrich, Alfa, Across, etc.) and, unless otherwise specified, require no further purification before use. THF can be continuously refluxed under nitrogen and freshly distilled from sodium and benzophenone, and DCM can be continuously refluxed under nitrogen and freshly distilled from _CaH₂ . In some embodiments, the reaction is monitored by TLC (e.g., on a silicone 60HSGF254 filter plate (0.15–0.2 mm _SiO₂ )) and observed using UV light and/or staining with DNP solution (12 g 2,4-dinitrophenylhydrazine, 60 mL concentrated sulfuric acid, 80 mL _H₂O , 200 mL EtOH) followed by heating. In some implementation schemes, flow is carried out via LCMS (e.g., Chromolith SpeedROD, RP-18e, 50x4.6 mm, mobile phase: solvent A: _CH3CN / _H2O / _HCOOH =10/90/0.05, solvent B: CH3CN/ _H2O /HCOOH=90/10/0.05, 0.8 min @ 10% B, 2.7 min gradient (10%-95% B), then 0.8 min @ 95% B, flow rate: 3 mL/min, temperature: 40 °C); or Waters XBridge C18, 250x4.6 mm, mobile phase: solvent A: _H2O /TFA=100/0.05, solvent B: _CH3CN , 2 min @ 10% B, 12 min gradient (10-90% B), then 6 min @ 90% B). B, 2min gradient (90-10% B), flow rate: 1mL/min, temperature: 30℃). In some embodiments, separation is performed using preparative high-performance liquid chromatography (HPLC) (column: Xbridge BEH C18 OBD column, 5µm, 10mm*250mm; mobile phase: [water (0.05% FA)-ACN]; B%: 10%-90%, 20 min). In some embodiments, separation is performed by preparing thin-layer chromatography (using pre-coated silicone 60 F 254 plates provided by NuoTai®; observed under UV light (λ 254nm, λ 366nm)). In some embodiments, ^¹H spectra are recorded at JEOL® 400 MHz, and chemical shifts (δ) are reported in ppm relative to tetramethylsilane (δ = 0.000 ppm). The spectra are calibrated to the residual solvent signal of chloroform (δ = 7.26 for ¹H). Data packages for ^¹H NMR spectra are as follows: Chemical shifts (multiplicity, number of hydrogen atoms). Abbreviations: s (single), d (double), t (triple), q (tetraple), quant (quintet), m (multiple), br (broadness).

The following examples illustrate various formulations and compositions of various compounds. As will be understood by those skilled in the art upon reading this disclosure, for the context of such formulations and compositions, wavy lines connected to a stereoconformation center generally indicate that the formulation or composition is provided as a mixture of stereoisomers relative to that stereoconformation center (see, for example, compound 1, compound 76, etc.), while a stereoconformation center with all linear lines generally indicates that the formulation or composition is provided as a single diastereomeric isomer (see, for example, compound 4) or enantiomer (see, for example, compound 75) relative to that stereoconformation center, but in each case, neither the relative nor absolute configuration of the stereoconformation center is specified.

Example 1. Compounds 1-3, 559, 65-66, 87-92, and 147.

Compound 59.

Step 1: Add _K₃PO₄ (4.76 g, 22.42 mmol, 2.5 equivalents), dicyclohexyl(2',6' _- dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (736 mg, 1.79 mmol, 0.2 equivalents) and Pd(OAc) _₂ (201 mg, 0.89 mmol, 0.1 equivalents) to the reaction vessel. Purge the flask three times with argon gas, then add 1-bromo-3,4-difluoro-2-methoxybenzene (1.25 mL, 2 g, 8.97 mmol, 1 equivalent, in 20 mL DMF) and ( E) at room temperature. A solution of ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)acrylate (2.64 mL, 2.64 g, 11.66 mmol, 1.3 equivalents in 20 mL DMF) was added to the mixture. The reaction mixture was evacuated and re-purged with argon three times, and then stirred at 100 °C for 16 hours. After quenching with ice water (100 mL), the aqueous layer was extracted with EtOAc (100 mL × 2), the combined organic extracts were washed with brine ( ₁₀₀ mL × 2), dried with _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silicone chromatography (PE:EtOAc = 300:1 to 50:1) to give a white solid (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (1.7 g, 78.3%). ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.83 (d, J = 16.2 Hz, 1H), 7.27–7.15 (m, 1H), 6.88 (td, J = 9.2, 7.2 Hz, 1H), 6.44 (d, J = 16.2 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.02 (d, J = 2.4 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H).

Step 2: Add ethyl ( E )-3-(3,4-difluoro-2-methoxyphenyl)acrylate (1.8 g, 7.43 mmol, 1.0 equivalent), 2-methyl-2-propanol (18 mL), and _H₂O (18 mL) to the reaction vessel. At room temperature, add 2-hydroxypropane-1,2,3-tricarboxylic acid (2.86 g, 14.86 mmol, 2.0 equivalent), 4-methylmorpholine 4-oxide (957 mg, 8.17 mmol, 1.1 equivalent), and _{K₂O₅sO₄} · _2H₂O (273 _mg , 0.743 mmol, 0.1 equivalent) to the mixture sequentially. Stir the mixture at room temperature for 2 hours, reduce pressure, concentrate, and quench with ice water (50 mL). The aqueous layer was extracted with EtOAc (50 mL × 2), and the combined organic extracts were washed with brine (100 mL × 2 ₎ , dried with _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 10:1 to 3:1) to give a white solid -rac-ethyl (2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-2,3-dihydroxypropionate (1.7 g, 82.8%). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.26-7.14 (m, 1H), 6.89 (ddd, J =9.7, 8.9, 7.2Hz, 1H), 5.20 (d, J =4.6Hz, 1H), 4.40-4.25 (m, 3H), 4.02 (d, J =2.7Hz, 3H), 3.12 (d, J =5.7Hz, 1H), 2.96 (d, J =7.4Hz, 1H), 1.29 (t, J =7.1Hz, 3H).

Add rac-ethyl(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-2,3-dihydroxypropionate (50 mg, 0.18 mmol, 1 equivalent), 3-methoxybenzaldehyde (29.6 mg, 0.22 mmol, 1.2 equivalent), p-TsOH · _H₂O (3.3 mg, 0.018 mmol, 0.1 equivalent), and toluene (2 mL) to a reaction vessel. Stir the mixture at 50 °C for 2 hours, cool to room temperature, and concentrate under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=10:1) to give rac-ethyl (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-(3-methoxyphenyl)-1,3-dioxolane-4-carboxylic acid ester (30 mg, 42.0% yield), which was a colorless oil. ^¹H NMR (400MHz, _CDCl₃ , 3.5:1 mixture, reporting major isomer peaks) δ 7.38–7.34 (m, 1H), 7.27–7.23 (m, 1H), 7.21–7.13 (m, 2H), 7.02–6.96 (m, 1H), 6.93–6.86 (m, 1H), 6.22 (s, 1H), 5.54 (d, J = 6.0 Hz, 1H), 4.47 (d, J = 6.0 Hz, 1H), 4.34 (qd, J = 7.2, 2.7 Hz, 2H), 4.02 (d, J = 2.6 Hz, 3H), 3.86 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

Step 4: Add (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-(3-methoxyphenyl)-1,3-dioxolane-4-carboxylic acid rac-ethyl ester (30 mg, 0.076 mmol, 1 equivalent), LiOH (3.6 mg, 0.152 mmol, 2 equivalents), EtOH (2 mL), and water (0.1 mL) to the reaction vessel. Stir the reaction mixture at room temperature for 2 hours, adjust the pH to 3-4 with 1N HCl, and extract with EtOAc (20 mL × 2). The combined organic phase was dried _{with Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain crude rac- (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-(3-methoxyphenyl)-1,3-dioxolane-4-carboxylic acid (22 mg, 79.0% yield), which was used in subsequent steps without further purification.

Step 5: Add rac-(4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-(3-methoxyphenyl)-1,3-dioxolane-4-carboxylic acid (22 mg, 0.06 mmol, 1 equivalent), _CH3CN (2 mL), methyl 4-aminopyridine-2-carboxylate (10 mg, 0.066 mmol, 1.1 equivalent), NMI (6 mg, 0.96 mmol, 1.1 equivalent), and TCFH (23 mg, 0.096 mmol, 1.1 equivalent) to the reaction vessel. After stirring at 60°C for 12 hours, reduce the pressure to concentrate the mixture, and then quench it with ice water (10 mL). The mixture was extracted with DCM (20 mL × 2), and the combined organic extracts were washed with brine (20 mL × 2 ₎ , dried with _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (DCM: _CH₃OH = 15:1) to give rac- (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-N-(pyridin-4-yl)-2-(trifluoromethyl)-1,3-dioxolane-4-methylamine (15 mg, 49.9% yield). ESI-MS m/z = 501.10 [M+H] ^⁺ ; calculated molecular weight: 500.14.

Step 6: Add rac- (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-N-(pyridin-4-yl)-2-(trifluoromethyl)-1,3-dioxolane-4-methylamine (15 mg, 0.03 mmol, 1 equivalent) and _NH3 methanol solution (7 M, 2 mL) to the reaction vessel. After stirring at 50°C for 12 hours, the mixture was concentrated under reduced pressure and purified by thin-layer chromatography (DCM: _CH3OH = 15:1) to give rac-4- ((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-(3-methoxyphenyl)-1,3-dioxolane-4-methoxyamino)pyridinamide (8.5 mg, 58.7% yield, 2.2:1 mixture, 99.8% purity). ^¹H NMR (400 MHz, DMSO- d6 _, 2.2:1 mixture, major isomer peaks reported) δ 10.77 (s, 1H), 8.50 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 5.7 Hz, 1H), δ 8.34 (d, J = 5.7 Hz, 1H). =2.1Hz, 1H), 8.07(s, 1H), 7.88(dd, J =5.5, 2.1Hz, 1H), 7.63(s, 1H), 7.34(m, 2H), 7.21-7.12(m, 3H), 7.04-6.98(m, 1H), 6.16(s, 1H), 5.53(d, J =6.3Hz, 1H), 4.62(d, J =6.4Hz, 1H), 3.82(s, 3H), 3.76(s, 3H). ESI-MS m/z = 486.19 [M+H] ⁺ ; Calculated molecular weight: 485.14.

Unless otherwise stated, the preparation methods of the following compounds are similar to those described for compound 59. Compound 147 was prepared using ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)but-2-enoate as a starting material.

Example 2. Compounds 4-21, 23-26, 28, 34-56, 63-64, 67-77, 79-81, 85-86, 93-98, 103-108, 113-115, 117, 123-125, 128-132, 138-140, and 143.

Compounds 71 and 72

Step 1: Add ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (400.0 mg, 1.65 mmol, 1.00 equivalent), tert-butanol (10.0 mL), and _H₂O (10.0 mL) to the reaction vessel. At room temperature, add AD mixture α (2.32 g, 2.98 mmol, 1.80 equivalent) and _MeSO₂NH₂ (314 mg, 3.30 mmol, _2.00 equivalent) in portions. Wash the combined organic extract with brine (80 mL × 2), dry on _{anhydrous Na₂SO₄} , filter, and concentrate under reduced pressure. The residue was purified by silica column chromatography (PE:EtOAc=3:1) to give a white solid (2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-2,3-dihydroxypropionate ethyl ester (310 mg, yield 68%, ee value 99%). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.14 (ddd, J =8.8, 5.7, 2.1Hz, 1H), 6.89 (td, J =9.2, 7.3Hz, 1H), 5.20 (dd, J =7.5, 3.0Hz, 1H), 4.34-4.19 (m, 3H), 4.08-3.96 (m, 3H), 3.13 (d, J =5.7Hz, 1H), 2.97 (d, J =7.5Hz, 1H), 1.29 (td, J =7.1, 1.3Hz, 3H).

Step 2: Add con _{. H₂SO₄} (0.20 mL ₎ dropwise to a stirred solution of ethyl (2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-2,3-dihydroxypropionate (100.0 mg, 0.362 mmol, 1.00 equivalent) in trifluoroacetone (0.40 mL) at -40 °C. The resulting mixture is heated from -40 °C to -10 °C over 30 minutes, poured into ice water, and extracted with EtOAc (20 mL × 3). The combined organic extracts are washed with brine (10 mL × 2), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (PE:EtOAc=10:1) to obtain ethyl (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylic acid (56 mg, yield 41%, 1.3:1 mixture, major isomer peaks have been reported), which was a colorless oil. ^1H NMR (400MHz, _CDCl3 , peak values for major isomers reported) δ 7.14–7.10 (m, 1H), 6.95–6.86 (m, 1H), 5.55 (d, J = 7.7Hz, 1H), 4.52 (d, J = 7.7Hz, 1H), 4.28–4.21 (m, 2H), 3.99 (d, J = 2.7Hz, 3H), 1.68 (s, 3H), 1.27 (t, J = 7.2Hz, 3H).

Step 3: Add LiOH (31.0 mg, 0.743 mmol, 5.0 equivalent) in H₂O (0.70 mL) to the stirred (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylate in _MeOH (0.70 mL ₎ . Stir the resulting mixture at room temperature for 16 hours, adjust the pH to 5 with 1N HCl, and extract with EtOAc (20 mL × 3). Wash the combined organic extracts with brine (10 mL) and dry _with anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain crude (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylic acid (55 mg), which was used in subsequent steps without further purification. ESI-MS m/z = 341.01 [M+H] ⁺ ; calculated molecular weight: 342.05.

Step 4: At 0°C, pyridine (29.0 mg, 0.365 mmol, 5.00 equivalent) and POCl3 (12.0 mg in 0.2 mL DCM, 0.073 mmol, 1.10 equivalent) were added in portions to a stirred solution of (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylic acid (25.0 mg, 0.073 mmol, 1.00 equivalent) and methyl ₄ -amino-2-pyridinecarboxylate (12.0 mg, 0.08 mmol, 1.10 equivalent) in 1.00 mL DCM. The resulting mixture was stirred at room temperature under argon atmosphere for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc (20 mL × 3). The combined organic extracts were washed with brine (10 mL × 2), dried on _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure. The residues were purified by thin-layer chromatography (PE:EtOAc = 1:2) to give a white solid methyl 4-((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-1,3-dioxolane-4-methoxyamino)pyridinecarboxylate (30 mg, 0.063 mmol, yield 86%). ESI-MS m/z = 477.33 [M+H] ⁺ ; Calculated MW: 476.10; ^¹H NMR (400MHz, _CDCl₃ , 1.39:1 mixture, reporting major isomer peaks) δ 8.64 (d, J = 5.5Hz, 1H), 8.40 (s, 1H), 8.10 (dd, J = 2.2, 0.6Hz, 1H), 7.89 (dd, J = 5.5, 2.2Hz, 1H), 7.09 (ddd, J = 8.8, 5.7, 2.2Hz, 1H), 6.92 (tdd, J = 9.0, 7.1, 1.8Hz, 1H), 5.48 (d, J = 9.0Hz, 1H), 4.74 (d, J = 8.0Hz, 1H), 4.02 (d, J = 8.0Hz, 1H). =2.7Hz, 3H), 3.99 (s, 3H), 1.75 (s, 3H).

Step 5: In a 10 mL round-bottom flask, methyl 4-((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)-1,3-dioxolane-4-methoxyamino)pyridinecarboxylate (30.0 mg, 0.063 mmol, 1.00 equivalent) and _NH3 (1.00 mL, 7 M methanol solution) were added at 0 °C. The resulting mixture was stirred at room temperature for 16 hours, concentrated, and purified by thin-layer chromatography (PE:EtOAc = 1:2) to give a white solid compound 71 (first eluent, 8.0 mg, yield 27%, purity 99.6%). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.18 (s, ¹H), 8.51 (d, J = 5.5Hz, ¹H), 8.40–8.27 (m, ¹H), 8.15 (d, J = 2.2Hz, ¹H), 7.88 (d, J = 4.5Hz, ¹H), 7.22 (d, J = 7.6Hz, ¹H), 6.94 (q, J = 8.5Hz, ¹H), 5.65 (d, J = 4.5Hz, 1H), 5.54 (d, J = 8.7Hz, 1H), 4.66 (d, J = 8.7Hz, 1H), 3.91 (t, J = 2.1Hz, 3H), 1.78 (s, 3H). ESI-MS m/z = 462.15 [M+H] ^⁺ ; calculated molecular weight: 461.10. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.50 (d, J =5.5Hz, 1H), 8.46 (s, 1H), 8.10 (dd, J =5.6, 2.1Hz, 1H), 7.99 (d, J =2.2Hz, 1H), 7.90-7.78 (m, 1H), 7.10 (t, J =7.4Hz, 1H), 6.93 (q, J =8.5Hz, 1H), 5.71 (d, J =4.4Hz, 1H), 5.51 (d, J =8.1Hz, 1H), 4.74 (d, J =8.1Hz, 1H), 4.05-4.00 (m, 3H), 1.75 (s, 3H). ESI-MS m/z = 462.17[M+H] ⁺ ; Calculated MW: 461.10.

The preparation methods for the following compounds are similar to those described for compounds 71 and 72. In some embodiments, racemic compounds are prepared using racemic diols as starting materials, following a similar method to that described for compounds 71 and 72.

Example 3. Compounds 57-58, 99-102, 111-112.

Compound 57.

Step 1: Dissolve β-cyclodextrin (9.84 g, 8.67 mmol, 1.05 equivalents) in water (132 mL) and stir at 60 °C until a clear solution is formed. Add ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (2.0 g, 8.26 mmol, 1.0 equivalent) to acetone (8 mL) dropwise. After cooling to room temperature, add N-bromobutyldiimide (5.14 g, 28.90 mmol, 3.5 equivalents) and stir the mixture at 60 °C for 4 hours until the reaction is complete as monitored by TLC. Add appropriate amounts of sodium chloride and ethyl acetate to the suspension until the mixture separates into layers. Then filter the mixture, and wash the filter cake with methanol until the color fades. The filtrate was evaporated under vacuum to remove methanol, and the mixture was then extracted with ethyl acetate and the extract was filtered. The combined organic extracts were dried over _MgSO4 , concentrated under reduced pressure, and the residue was purified by column chromatography (0-20% EtOAc in PE) to give (2R,3R)-2-bromo-3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxypropionic acid rac- ethyl ester (2.77 g, 8.15 mmol, 98.7% yield) as an orange oily liquid. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.33 (ddd, J =8.5, 6.0, 2.1Hz, 1H), 7.19 (td, J =9.5, 7.4Hz, 1H), 6.33 (d, J =5.8Hz, 1H), 5.24 (dd, J =10.2, 4.0Hz, 1H), 4.58 (d, J =9.8Hz, 1H), 4.22 (q, J =7.1Hz, 2H), 3.96 (d, J =1.8Hz, 3H), 1.24 (t, J =7.1Hz, 3H).

Step 2: Add (2S,3S)-2-bromo-3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxypropionic acid rac-ethyl ester (300 mg, 0.89 mmol, _1.0 equivalent), 2,2,2-trifluoro-1-phenylethyl-1-one (199.4 mg, 1.78 mmol, 2.0 equivalent), _K₂CO₃ (245.6 mg, 1.78 mmol, 2.0 equivalent), and DMF (5 mL) to the reaction vessel. After stirring overnight, dilute the mixture with water and extract with ethyl acetate (25 mL × 2). The combined organic phases were washed with brine (25 mL × 3), dried _with anhydrous _Na₂SO₄ , concentrated, and purified by column chromatography to give rac-ethyl (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-phenyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylate (70 mg, 0.16 mmol, 18.2% yield). ^¹H NMR (400 MHz, DMSO- d₆ , major isomer peaks reported) δ 7.62–7.56 (m, 2H), 7.52–7.44 (m, 4H), 7.14–7.07 (m, 1H), 5.67 (d, J = 7.9 Hz, _1H ), 4.79 (d, J = 7.9 Hz, 1H), ...07 (m, 1H), δ 7.67 (d, J = 7.9 Hz, 1H), δ 7.67 (d, J = 7.9 Hz, 1H), δ 7.67 (d, J = 7.9 Hz, 1H), δ 7.67 (d, J = 7.9 Hz, 1H), δ 7.67 (d, J = 7.9 Hz, 1H), δ 7.67 (d, J = 7.9 Hz, 1H), δ 7.67 (d, J = 7.9 =7.9Hz, 1H), 4.18 (q, J =7.1 Hz, 2H), 3.72 (d, J =2.6Hz, 3H), 1.16 (t, J =7.1Hz, 3H).

Step 3: At room temperature, add LiOH (7.7 mg, 0.32 mmol, 2.0 equivalent) and water (0.1 mL) to a mixture of rac-ethyl (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-phenyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylate (70 mg, 0.16 mmol, 1.0 equivalent) in EtOH (1 mL). After stirring at room temperature for 2 hours, adjust the pH of the reaction mixture to 5 with 1.0% HCl and extract with ethyl acetate (5 mL × 2). The combined organic phases were washed with brine (5 mL × 1), dried _on anhydrous _Na₂SO₄ , and concentrated under vacuum to give crude rac-(4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-phenyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylic acid (60 mg), which was used in subsequent steps without further purification.

Step 4: Add rac- (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-phenyl-2-(trifluoromethyl)-1,3-dioxolane-4-carboxylic acid (60 mg, crude), methyl 4-aminopyridine-2-carboxylate (27.4 mg, 0.18 mmol, 1.2 equivalents), NMI (42.6 mg, 0.52 mmol, 3.5 equivalents), and MeCN (2 mL) to the reaction mixture. After cooling to 0°C, add TCFH (61.8 mg, 0.22 mmol, 1.5 equivalents) and stir overnight at 60°C under argon atmosphere. After cooling to room temperature, dilute the mixture with ethyl acetate (5 mL) and wash with brine. The organic phase was dried in anhydrous _{Na₂SO₄ ,} filtered, concentrated, and purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to give rac-methyl 4-((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-phenyl-2-(trifluoromethyl)-1,3-dioxolane-4-methoxyamino)pyridinecarboxylate (55 mg, 0.09 mmol, 56% yield). ^¹H NMR (400 MHz, DMSO- d₆ , 1.5:1 mixture, major isomer peaks reported) δ 10.91 (s, 1H), 8.63 (d, J = 5.5 Hz, 1H), 8.37 (d, J = 5.5 Hz, 1H), δ 10.91 (s _, 1H), 8.63 (d, J = 5.5 Hz, 1H), δ 8.37 ... =2.1Hz, 1H), 7.87(dd, J =5.5, 2.2Hz, 1H), 7.73-7.39(m, 2H), 7.59-7.49(m, 3H), 7.47-7.38(m, 1H), 7.24-7.19(m, 1H), 5.81(d, J =8.1Hz, 1H), 4.75 (d, J =8.0Hz, 1H), 3.89 (s, 3H), 3.68 (d, J =2.6Hz, 3H).

Step 5: Add rac-methyl 4-((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-phenyl-2-(trifluoromethyl)-1,3-dioxolane-4-methoxyamino)pyridinecarboxylate (50 mg, 0.09 mmol, 1.0 equivalent) and _NH3 methanol solution (7 M, 2 mL) to the reaction vessel. Then stir the mixture at 50 °C under argon atmosphere for 2 hours. After cooling to room temperature, the solution was concentrated and purified by thin-layer chromatography (DCM:MeOH = 50:1) to obtain rac - 4 -((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2-phenyl-2-(trifluoromethyl)-1,3-dioxolane-4-methoxyamino)pyridinamide (12.6 mg, 0.024 mmol, 26.8% yield, 1.5:1 mixture, purity 97.3%), a white solid. ^¹H NMR (400MHz, _DMSO-d⁶ , major isomer peaks reported) δ 10.82 (s, ¹H), 8.55–8.47 (m, ¹H), 8.24 (s, ¹H), 8.08 (s, ¹H), 7.87–7.80 (m, ¹H), 7.72–7.60 (m, ³H), 7.54–7.45 (m, ³H), 7.41–7.27 (m, ¹H), 7.18–7.10 (m, ¹H), 5.76 (d, J = 7.3Hz, ¹H), 4.69 (d, J = 7.5Hz, ¹H), 3.63 (s, ³H). ESI-MS m/z = 524.19 [M+H] ^⁺ ; calculated molecular weight: 523.42.

The preparation methods for the following compounds are similar to those described for compound 57.

Example 4. Compounds 61, 110, and 116.

Compound 61

Step 1: Add rac- ethyl 2-bromo-3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxypropionic acid (400.0 mg, 1.18 mmol, 1.0 equivalent), 15-crown ether-5 (28.6 mg, 0.130 mmol, 0.11 equivalent), and DMF (3 mL) to the reaction vessel. After cooling to -65°C, add a pre-cooled solution of 70% NaSH (127.5 mg, 1.59 mmol, 1.35 equivalent) in DMF (1.5 mL) dropwise at -65°C. Then stir the mixture at -40°C for 1 hour until the reaction is complete as monitored by TLC. Quench the reactants with ice water and then extract with ethyl acetate. The combined organic extract was washed with brine, dried with _MgSO4 , concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (PE:EtOAc=3:1) to give (2S,3R)-3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxy-2-hydroxypropionic acid rac- ethyl ester (225.6 mg, 0.77 mmol, 65.4% yield). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.25 (ddd, J =8.6, 6.2, 2.1Hz, 1H), 7.20-7.11 (m, 1H), 5.88 (d, J =5.7Hz, 1H), 5.14 (t, J =5.9Hz, 1H), 4.02 (qd, J =7.1, 1.4Hz, 2H), 3.93 (d, J =2.1Hz, 3H), 3.85 (d, J =6.1Hz, 1H), 2.76 (s, 1H), 1.07 (t, J =7.1Hz, 3H).

Step 2: Slowly add _H₂SO₄ (0.069 mL, 125.8 mg, 43.4 mmol, 5.0 equivalent) in acetone (0.2 mL) to a solution of (2S,3R)-3-( _3,4 -difluoro-2-methoxyphenyl)-3-hydroxy-2-hydroxypropionic acid rac- ethyl ester (75 mg, 0.257 mmol, 1.0 equivalent) in acetone (0.8 mL) at -40 °C. After stirring at -40 °C for 1 hour, slowly pour the mixture into ice water (30 mL) and extract with EtOAc. The combined organic extract was washed with saturated _NaHCO₃ solution (20 mL × 2), dried over _MgSO₄ , filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (PE:EtOAc=20:1) to give rac-ethyl (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-4-carboxylic acid ethyl ester (23.7 mg, 0.071 mmol, 27.8% yield), which was a colorless oil. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.33 (ddd, J =8.6, 6.0, 2.1Hz, 1H), 7.19 (td, J =9.5, 7.4Hz, 1H), 5.65 (d, J =7.6Hz, 1H), 4.22 (d, J =7.6Hz, 1H), 4.13 (t, J =7.1Hz, 2H), 3.89 (d, J =2.1Hz, 3H), 1.77 (s, 3H), 1.73 (s, 3H), 1.18 (t, J =7.1Hz, 3H).

Step 3: Add (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-4-carboxylic acid rac- ethyl ester (23.7 mg, 0.071 mmol, 1.0 equivalent), ethanol (1 mL), LiOH (3.42 mg, 0.143 mmol, 2.0 equivalent), and water (0.1 mL) to the reaction vessel. Stir the resulting white suspension at room temperature for 2 hours until the reaction is complete as monitored by TLC. Partition the mixture between EtOAc and 1N HCl aqueous solution, and check the pH of the aqueous phase to be 5–6. The combined organic extract was dried over _MgSO4 and concentrated under reduced pressure to obtain crude rac- (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiocyclopentane-4-carboxylic acid (24.1 mg), which could be used in the next step without further purification.

Step 4: In a reaction vessel, add methyl 4-amino-2-pyridinecarboxylate (14.5 mg, 0.095 mmol, 1.2 equivalents), rac- (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-4-carboxylic acid, NMI (0.022 mL, 22.8 mg, 0.277 mmol, 3.5 equivalents), and acetonitrile (0.8 mL). After cooling to -10°C, add TCFH (33.3 mg, 0.119 mmol, 1.5 equivalents) to acetonitrile (0.2 mL), heat the reaction mixture to rt, and stir overnight at rt. Quench the reaction with _H₂O and extract with ethyl acetate. The combined organic extract was washed with brine, dried on anhydrous _MgSO4 , concentrated, and purified by preparative thin-layer chromatography (PE:EtOAc = 1:1) to give rac-methyl 4-((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-4-methamino)pyridinecarboxylate (21.5 mg, 0.049 mmol, 61.9% yield), as a white powder. ¹ H NMR(400MHz, DMSO- d ₆ δ 10.73(s,1H),8.58(d, J =5.5Hz,1H),8.31(d, J =2.1Hz,1H),7.73(dd, J =5.4, 2.1Hz, 1H), 7.36-7.28 (m, 1H), 7.26-7.20 (m, 1H), 5.76 (d, J =7.3Hz, 1H), 4.30 (d, J =7.2Hz, 1H), 3.88 (s, 3H), 3.81 (d, J =2.0Hz, 3H), 1.85 (s, 3H), 1.77 (s, 3H).

Step 5: Add rac-methyl 4-((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-4-methoxyamino)pyridinecarboxylate (21.5 mg, 0.049 mmol, 1.0 equivalent) and ammonia (0.490 mL, 3.43 mmol, 7.0 M MeOH solution) to the reaction vessel. After stirring at room temperature for 16 hours, the reaction mixture was concentrated and purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain rac - 4 -((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-4-methamido)pyridinamide (8.4 mg, 0.02 mmol, 40.5% yield), as a white powder. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.67 (s, 1H), 8.50 (d, J =5.5Hz, 1H), 8.23 (d, J =2.2Hz, 1H), 8.07 (d, J =2.7Hz, 1H), 7.74 (dd, J =5.5, 2.2Hz, 1H), 7.64 (s, 1H), 7.32 (t, J =7.9Hz, 1H), 7.26-7.18 (m, 1H), 5.77 (d, J =7.2Hz, 1H), 4.30 (d, J =7.2Hz, 1H), 3.81 (d, J =2.0Hz, 3H), 1.85 (s, 3H), 1.77 (s, 3H). ESI-MS m/z = 424.10 [M+H] ⁺ ; Calculated molecular weight: 423.11

The preparation methods for the following compounds are similar to those described for compound 61.

Examples 5. Compounds 27, 33, 118, 120-121, 133-134, and 145.

Compound 118.

Step 1: Add ethyl (2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-2,3-dihydroxypropionate (100 mg, 0.362 mmol, 1 equivalent, 99% ee), _CH₂Cl₂ (1 mL), 4-methylbenzenesulfonic acid hydrate (6.9 _mg , 0.036 mmol, 0.1 equivalent), and 1,1,1-trimethoxyethane (0.065 mL, 62.2 mg, 0.517 mmol, 1.3 equivalent) to the reaction vessel. After stirring at room temperature for 3 hours, concentrate the reaction mixture, redissolve _it in _CH₂Cl₂ (1 mL), and cool to -15°C. Then add acetyl bromide (0.032 mL, 53.9 mg, 0.438 mmol, 1.2 equivalent). The mixture was stirred at -15°C for 3 hours. Then the cooling tank was removed, and the reaction mixture was heated to room temperature and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (PE:EtOAc=10:1) to give ethyl (2S,3R)-2-acetoxy-3-bromo-3-( ^3,4 -difluoro-2-methoxyphenyl)propionate (63 mg, 0.165 mmol, 45.7% yield), which was a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.37 (ddd, J =9.0, 5.6, 2.3Hz, 1H), 6.87 (td, J =9.3, 7.3Hz, 1H), 5.76 (d, J =6.3Hz, 1H), 5.60 (d, J =6.4Hz, 1H), 4.14 (q, J =7.1Hz, 2H), 4.04 (d, J =2.4Hz, 3H), 2.13 (s, 3H), 1.18 (t, J =7.1Hz, 3H).

Step 2: Acetyl chloride (0.011 mL, 13.0 mg, 0.165 mmol, 1 equivalent) was added to a solution of (2S,3R)-2-acetoxy-3-bromo-3-(3,4-difluoro-2-methoxyphenyl)propionate (63 mg, 0.165 mmol, 1 equivalent) in dry EtOH (1 mL). After stirring at 80 °C for 3 hours, the solvent was removed, and the residue was purified by thin-layer chromatography (PE:EtOAc = 5:1) to obtain a yellow oily ethyl (2S,3R)-3-bromo-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxypropionate (25 mg, 0.073 mmol, 44.6% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.44 (ddd, J =9.1, 5.8, 2.4Hz, 1H), 6.86 (td, J =9.2, 7.4Hz, 1H), 5.62 (d, J =5.0Hz, 1H), 4.66 (t, J =5.5Hz, 1H), 4.17 (q, J =7.1Hz, 2H), 4.04 (d, J =2.4Hz, 3H), 3.18 (d, J =6.9Hz, 1H), 1.21 (t, J =7.1Hz, 3H).

Step 3: Add ethyl (2S,3R)-3-bromo-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxypropionate (100 mg, 0.295 mmol, 1 equivalent) and tetrabutylammonium iodide (32.7 mg, 0.088 mmol, 0.3 equivalent) to a sealed tube. Purge the tube three times with argon. Add 1,2-dimethoxyethane (2 mL) to the mixture and cool the reaction to -60°C. At -60°C, add 1,1,1,3,3,3-hexafluoropropane-2-one (489.6 mg, 2.95 mmol, 10 equivalents) to the mixture. Seal the tube and heat at 120°C for 16 hours. Cool the mixture to -78°C and then quench it with ice water (5 mL). The aqueous layer was extracted with EtOAc (10 mL × 2). The combined organic extracts were washed with brine (20 mL ₎ , dried with _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by prepared thin-layer chromatography (PE:EtOAc = 20:1) to give ethyl (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-bis(trifluoromethyl)-1,3-dioxolane-4-carboxylate (117 mg, 0.276 mmol, 93.6% yield), as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.18 (dddd, J =8.7, 5.6, 2.3, 0.6Hz, 1H), 6.94 (td, J =9.1, 7.1Hz, 1H), 5.66 (d, J =8.8Hz, 1H), 4.54 (d, J =8.8Hz, 1H), 4.34-4.23 (m, 2H), 3.97 (d, J =3.0Hz, 3H), 1.28 (t, J =7.1Hz, 3H).

Step 4: Add ethyl (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-bis(trifluoromethyl)-1,3-dioxolane-4-carboxylate (117 mg, 0.276 mmol, 1 equivalent) and THF (2 mL) to the reaction vessel. After cooling to 0°C, add LiOH (19.8 mg, 0.827 mmol, 3 equivalent) from _H₂O (1 mL), raise the reaction mixture to room temperature, and stir at room temperature for 16 hours. Adjust the pH of the mixture to pH=6 with 1N HCl, and then extract the aqueous layer with EtOAc (10 mL × 2). The combined organic extracts were washed with brine (20 mL × 2), dried _{on Na₂SO₄} , filtered, and concentrated under reduced pressure to give crude (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-bis(trifluoromethyl)-1,3-dioxolane-4-carboxylic acid (100 mg, 0.252 mmol, 91.5% yield), which was used for the next step without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.20-7.11 (m, 1H), 7.00-6.89 (m, 1H), 5.63 (d, J =9.0Hz, 1H), 4.60 (d, J =8.9Hz, 1H), 3.94 (d, J =2.8Hz, 3H).

Step 5: Add (4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-bis(trifluoromethyl)-1,3-dioxolane-4-carboxylic acid (20 mg, 0.050 mmol, 1 equivalent), 4-aminopyridine-2-acetylamine (10.4 mg, 0.075 mmol, 1.5 equivalent), 1-methyl-1H-imidazole (10.4 mg, 0.126 mmol, 2.5 equivalent), and _CH3CN (0.7 mL) to the reaction vessel. After cooling to 0°C, add TCFH (21.3 mg, 0.075 mmol, 1.5 equivalent) to _CH3CN (0.1 mL). The mixture was heated to room temperature and stirred at room temperature for 16 hours. It was then quenched with ice water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic extract was washed with brine (20 mL × 2), dried _{with Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography ( _CH₂Cl₂ : _MeOH = 10:1) to obtain 15 mg of product with a purity less than 90%. Further purification by preparation-high performance liquid chromatography (0.1% FA, _CH3CN : _H2O = 20% to 90%, 30 min) yielded 4-((4R,5S)-5-(3,4-difluoro-2-methoxyphenyl)-2,2-bis(trifluoromethyl)-1,3-dioxolane-4-carboxyamino)pyridinamide (7.2 mg, 0.013 mmol, 27.7% yield, 99.8% purity), as a white solid. ^¹H NMR (400MHz, _CDCl₃ ) δ 8.58–8.50 (m, 2H), 8.12 (dd, J = 5.5, 2.2Hz, 1H), 8.04 (d, J = 0.6Hz, 1H), 7.86 (s, 1H), 7.17 (ddd, J = 8.9, 5.5, 2.2Hz, 1H), 6.97 (td, J = 9.1, 7.1Hz, 1H), 5.71 (d, J = 9.1Hz, 1H), 5.63 (s, 1H), 4.86 (d, J = 9.0Hz, 1H), 3.98 (d, J = 2.8Hz, 3H). ESI-MS m/z = 516.68 [M+H] ^⁺ ; calculated molecular weight: 515.32.

The following compounds were prepared using a similar method to that described for compound 118. Compound 33 was prepared using 2,2,2-trifluoro-1-phenylethyl-1-one as a starting material.

Example 6. Compounds 119 and 122.

Compound 119.

Step 1: Add ethyl (2S,3R)-3-bromo-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxypropionate (200.0 mg, 0.589 mmol, 1.0 equivalent), 15-crown ether-5 (14.3 mg, 0.0649 mmol, 0.11 equivalent), and DMF (1.5 mL) to the reaction vessel. After cooling to -65°C, add a pre-cooled solution of 70% NaSH (63.8 mg, 1.59 mmol, 1.35 equivalent) in DMF (0.75 mL) dropwise at -65°C. Then stir the mixture at -40°C for 1 hour until the reaction is complete as monitored by TLC. Quench with ice water and extract with ethyl acetate. The combined organic extract was washed with brine, dried with _MgSO4 , concentrated, and purified by preparative thin-layer chromatography (PE:EtOAc=5:1) to obtain ethyl (2S,3S)-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-3-phenylpropionate (130 mg, 0.444 mmol, 75.4% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.36-7.29 (m, 1H), 6.88-6.81 (m, 1H), 4.72 (dd, J =10.0, 3.1Hz, 1H), 4.48 (dd, J =5.1, 3.1Hz, 1H), 4.36-4.24 (m, 2H), 4.04 (d, J =2.4Hz, 3H), 3.36 (d, J =5.5Hz, 1H), 2.20 (d, J =10.0Hz, 1H), 1.31 (t, J =7.1Hz, 3H).

Step 2: Slowly add _H₂SO₄ (0.6 mL, 11.26 mmol, 25.3 equivalences) to a solution of ethyl (2S,3S)-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-3-ylpropionate (130 mg, 0.444 mmol, 1.0 equivalence ₎ in acetone (2.0 mL) at -40 °C. After stirring at -40 °C for 2 hours, slowly pour the mixture into ice water (30 mL) and extract with ethyl acetate. Wash the combined organic extract with saturated _NaHCO₃ solution (20 mL × 2), dry on _MgSO₄ , filter, and concentrate under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=10:1) to give (4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiocyclopentane-5-carboxylic acid ethyl ester (80 mg, 54.1% yield), which is a yellow oily liquid. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.31-7.26 (m, 1H), 6.89-6.85 (m, 1H), 5.22 (d, J =8.1Hz, 1H), 4.70 (d, J =8.1Hz, 1H), 4.15 (q, J =7.1Hz, 2H), 3.96 (d, J =2.2Hz, 3H), 1.78 (d, J =10.7Hz, 6H), 1.18 (t, J =7.1Hz, 3H).

Step 3: Add ethyl (4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-5-carboxylate (80 mg, 0.240 mmol, 1.0 equivalent), THF (1.6 mL), and LiOH (17.3 mg, 0.722 mmol, 3.0 equivalent) in _H₂O (0.8 mL) to the reaction vessel. The resulting white suspension was stirred at room temperature for 2 hours, then partitioned between EtOAc and 1M HCl aqueous solution, and the pH of the aqueous phase was measured to be 5–6. The combined organic extracts were dried in _MgSO4 and concentrated under reduced pressure to give crude (4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-5-carboxylic acid (70 mg, 0.229 mmol, 95.6% yield), a pale yellow oil that could be used in the next step without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.18 (s, 1H), 7.28-7.25 (m, 1H), 6.89-6.85 (m, 1H), 5.23 (d, J =7.9Hz, 1H), 4.78 (d, J =7.9Hz, 1H), 3.95 (d, J =2.4Hz, 3H), 1.76 (d, J =9.1Hz, 6H).

Step 4: In a reaction vessel, methyl 4-amino-2-pyridinecarboxylate (52.5 mg, 0.345 mmol, 1.5 equivalents), (4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-5-carboxylic acid (70 mg, 0.230 mmol, 1.0 equivalent), NMI (0.044 mL, 47.22 mg, 0.575 mmol, 2.5 equivalent), and acetonitrile (0.8 mL) were added. After cooling to -10 °C, TCFH (96.8 mg, 0.345 mmol, 1.5 equivalent) was added to acetonitrile (0.2 mL). The mixture was heated to rt and stirred overnight at rt. After removing the acetonitrile under vacuum, the mixture was washed with _H₂O and extracted with ethyl acetate. The combined organic extract was washed with brine, dried on anhydrous _MgSO4 , concentrated, and purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to give a white solid methyl 4-((4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-5-methamino)pyridinecarboxylate (83 mg, 0.189 mmol, 82.3% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.63 (d, J =5.5Hz, 1H), 8.45 (s, 1H), 8.05 (d, J =2.1Hz, 1H), 7.96 (dd, J =5.5, 2.2Hz, 1H), 7.28 (dt, J =5.6, 2.6Hz, 1H), 6.90 (td, J =9.2, 7.3Hz, 1H), 5.21 (d, J =9.0Hz, 1H), 4.83 (d, J =9.0Hz, 1H), 4.00 (s, 3H), 3.94 (d, J =2.4Hz, 3H), 1.85 (d, J =8.8Hz, 6H).

Step 5: Add methyl 4-((4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-5-methoxyamino)pyridinecarboxylate (80 mg, 0.182 mmol, 1.0 equivalent) and ammonia (1.6 mL, 7 MMeOH solution, 11.2 mmol, 61.4 equivalent) to the reaction vessel. After stirring at room temperature for 4 hours, the reaction mixture was evaporated in a vacuum and purified by thin-layer chromatography (DCM:MeOH=20:1) to give 4-((4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-2,2-dimethyl-1,3-oxothiacyclopentane-5-methamino)pyridinamide (35 mg, 0.082 mmol, 45.3% yield), a white solid. ¹ H NMR (400MHz, DMSO- d ₆ δ 10.55-10.34(m,1H),8.46(d, J =5.4Hz,1H),8.25(d, J =2.1 Hz,1H),7.96(s,1H),7.80(dd, J =5.6, 2.2Hz, 1H), 7.50 (s, 1H), 7.43-7.39 (m, 1H), 7.17 (td, J =9.5, 7.6Hz, 1H), 5.29 (d, J =8.2Hz, 1H), 4.90 (d, J =8.1Hz, 1H), 3.81 (d, J =1.9Hz, 3H), 1.75 (d, J =11.6Hz, 6H). ESI-MS m/z=424.27[M+H] ⁺ Calculated MW: 423.43.

The preparation method of compound 122 is similar to that of compound 119.

Example 7. Compounds 78 and 82-84.

Compound 83.

Step 1: Dissolve sodium hydroxide (496.0 mg, 12.39 mmol, 3.00 equivalents) in water (25.0 mL), then transfer 3.1 mL of _NaOH solution to a vial containing _K₂O₅O₂ (OH) _₄ (64.0 mg, 0.206 mmol, 0.05 equivalents). Add benzyl carbamate (1.93 g, 12.8 mmol, 3.10 equivalents) and i-PrOH (14.0 mL) to the remaining NaOH solution. Stir the mixture for 2 minutes and place it in an ice-water bath, then slowly add t-BuOCl (1.34 g, 12.39 mmol, 3.0 equivalents) with vigorous stirring. Then, the mixture was prepared sequentially with (DHQD) _2PHAL (dihydroquinine-1,4-phthalazine diether) (161.0 mg, 0.206 mmol, 0.05 equivalent, 1 mL), (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (1.00 g, 4.13 mmol, 1.00 equivalent), _the previously prepared _K2OsO2 (OH) ₄ solution, and i-PrOH (10 mL). The resulting mixture was stirred at room temperature under argon atmosphere for 16 hours, quenched with saturated sodium sulfite aqueous solution (25.0 mL), cooled in an ice-water bath, and then stirred for another 30 minutes. The separated aqueous phase was extracted with EtOAc (50 mL × 3), and the combined organic extract was washed with water (30 mL) and then with brine (50 mL). The _extract was dried with _Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. After purification by column chromatography (PE:EtOAc = 4:1), ethyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxypropionate (1.2 g, 2.93 mmol, 71% yield) was obtained as a colorless oil. ESI-MS m/z=410.19[M+H] ⁺ ; Calculated MW: 409.13; ¹ H NMR (400MHz, CDCl ₃ )δ 7.40-7.29(m,5H),7.01-6.92(m,1H),6.84(td, J =9.2,7.1Hz,1H),5.71(d, J =9.6Hz, 1H), 5.48(d, J =8.9Hz, 1H), 5.13-4.97(m, 2H), 4.38(s, 1H), 4.31-4.18(m, 2H), 4.06(s, 3H), 3.14(d, J =4.0Hz, 1H), 1.25(t, J =7.0Hz, 3H).

Step 2: At room temperature, Pd/C (400.0 mg) was added in portions to a stirred solution of ethyl (2R,3S)-3-(((benzyloxy)carbonyl)amino)-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxypropionate (800.0 mg, 1.955 mmol, 1.00 equivalent) toluene (7.00 mL). The resulting mixture was stirred at 60 °C and 1 atm hydrogen for 2 hours, cooled to room temperature, and filtered. After washing the filter cake with MeOH (30 mL × 3), the combined filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EtOAc = 2:1) to obtain ethyl (2R,3S)-3-amino-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxypropionate (440 mg, 1.58 mmol, 81% yield), which was a white solid. ^¹H NMR (400MHz, _CDCl₃ ) δ 7.11 (ddd, J = 8.3, 5.8, 2.2Hz, 1H), 6.86 (td, J = 9.2, 7.3Hz, 1H), 4.49 (d, J = 3.7Hz, 1H), 4.29 (d, J = 3.7Hz, 1H), 4.24 (qd, J = 7.2, 1.3Hz, 2H), 4.03 (d, J = 2.6Hz, 3H), 1.26 (t, J = 7.1Hz, 3H). ESI-MS m/z = 276.20 [M+H] ^⁺ ; calculated molecular weight: 275.10.

Step 3: At room temperature, add TFK (1.0 mL) and PPTS (270.0 mg, 1.09 mmol, 1.00 equivalent) to a stirred solution of ethyl (2R,3S)-3-amino-3-(3,4-difluoro-2-methoxyphenyl)-2-hydroxypropionate (300.0 mg, 1.09 mmol, 1.0 equivalent) in toluene (3.0 mL). Stir the resulting mixture at 100 °C for 16 hours, cool to room temperature, dilute with water, and extract with EtOAc (30 mL x 3). The combined organic extracts were washed with brine, dried on anhydrous _Na₂SO₄ , filtered, concentrated, and purified by thin-layer chromatography (PE:EtOAc=5 _: 1) to obtain (4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)oxazolidine-5-carboxylic acid ethyl ester (330 mg, 0.893 mmol, yield 82%, 1:1 mixture), which was a colorless oil. ^¹H NMR (400MHz, _CDCl₃ , 1:1 mixture, two peaks reported) δ 7.34 (t, J = 7.6Hz, 1H), 7.04–6.95 (m, 1H), 6.92–6.80 (m, 2H), 4.96 (d, J = 7.4Hz, 1H), 4.62 (d, J = 8.1Hz, 1H), 4.48 (d, J = 8.0Hz, 1H), 4.42 (d, J = 7.4Hz, 1H), 4.29–4.15 (m, 4H), 4.09 (d, J = 3.2Hz, 3H), 3.94 (d, J = 2.9Hz, 3H), 1.68 (s, 3H), 1.66 (s, 3H), 1.28 (t, J = 7.6Hz, 1H), δ 7.34 (t, J = 7.6Hz, 1H), 7.04–6.95 (m, 1H), 6.92–6.80 (m, 2H), 4.96 (d, J = 7.4Hz, 1 ...δ 1.28 (t, =7.1Hz, 3H), 1.23 (t, J =7.1Hz, 3H).

Step 4: Add ethyl (4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2-methyl-2-(trifluoromethyl)oxazolidine-5-carboxylate (100.0 mg, 0.271 mmol, 1.00 equivalent), AcOH (1.6 mg, 0.027 mmol, 0.10 equivalent), DCE (3.0 mL), and ( _CH₂O ) _ₙ powder (12.0 mg, 0.407 mmol, 1.50 equivalent) to the reaction vessel. Stir the resulting mixture at 70 °C for 1 hour, then cool to 0 °C. At 0 °C, add NaBH(OAc) _₃ (115.0 mg, 0.542 mmol, 2.00 equivalent) and react at 70 °C with stirring for 16 hours. After cooling to room temperature, the reaction was quenched with saturated _NH₄Cl (solution) and extracted with EtOAc (20 mL × 3). The combined organic extracts were washed with brine (10 mL × 2), dried _on anhydrous _Na₂SO₄ , filtered, concentrated under reduced pressure, and purified by preparation of thin-layer chromatography (PE.EtOAc = 6:1): (4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-carboxylic acid ethyl ester (first eluent, 29 mg, 0.075 mmol, 28% yield) was a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.14 (ddd, J =8.5, 5.8, 2.3Hz, 1H), 6.92 (td, J =9.1, 7.2Hz, 1H), 4.70-4.56 (m, 1H), 4.38 (d, J =8.1Hz, 1H), 4.29-4.07 (m, 2H), 3.93 (d, J =2.1Hz, 3H), 2.27 (q, J =2.3Hz, 3H), 1.57 (d, J =1.4Hz, 3H), 1.23 (t, J =7.1 Hz, 3H); and (4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-carboxylic acid ethyl ester (second eluent, 21 mg, 0.054 mmol, 20% yield) as colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.31 (ddd, J =8.6, 5.9, 2.3Hz, 1H), 6.92 (td, J =9.2, 7.2Hz, 1H), 4.29 (s, 2H), 4.23-4.07 (m, 2H), 3.89 (d, J =2.4Hz, 3H), 2.29 (s, 3H), 1.56 (d, J =1.4Hz, 3H), 1.19 (t, J =7.1Hz, 3H).

Step 5: Add LiOH (11.0 mg, 0.261 mmol, 5.0 equivalent) to a stirred THF (0.50 mL) solution of ethyl (4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-carboxylate (second eluent fraction, 20.0 mg, 0.052 mmol, 1.0 equivalent). Add the LiOH (11.0 mg, 0.261 mmol, 5.0 equivalent) from the THF ( _0.50 mL) to H₂O (0.30 mL). After stirring at room temperature for 16 hours, adjust the pH of the reaction mixture to 5 with 1 N HCl and extract with EtOAc (20 mL × 3). The combined organic extracts were washed with brine (10 mL × 2), dried on anhydrous _{Na₂SO₄ ,} and filtered. Concentration yielded crude (4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-carboxylic acid (25 mg), which was used in the next step without further purification. ESI-MS m/z = 356.19 [M+H] ^⁺ ; calculated molecular weight: 355.08.

Step 6: Add (4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-carboxylic acid (18.0 mg, 0.051 mmol, 1.0 equivalent), methyl 4-aminopicolinate (9.0 mg, 0.061 mmol, 1.2 equivalent), pyridine (40.0 mg, 0.51 mmol, 10.0 equivalent), and DCM (1.0 mL) to the reaction vessel. After cooling to 0°C, add _POCl3 (8.0 mg, 0.053 mmol, 1.05 equivalent) in DCM (0.2 mL) in portions at 0°C. Stir the resulting mixture at room temperature under argon atmosphere for 3 hours. Quench the reaction with water and extract with EtOAc (20 mL × 3). The combined organic extracts were washed with brine (10 mL × 2), dried _on anhydrous _Na₂SO₄ , filtered, concentrated, and purified by thin-layer chromatography (PE:EtOAc = 1:1) to give methyl 4-((4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-carboxylic acid ester (20 mg, 0.041 mmol, yield 80%), a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.63 (d, J =5.5Hz, 1H), 8.45 (s, 1H), 8.08 (d, J =2.1Hz, 1H), 7.89 (dd, J =5.4, 2.2Hz, 1H), 7.13 (ddd, J =8.4, 5.8, 2.2Hz, 1H), 6.93 (td, J =9.1, 7.1Hz, 1H), 4.65 (d, J =6.0Hz, 1H), 4.54 (d, J =6.7Hz, 1H), 3.99 (s, 3H), 3.96 (d, J =1.9Hz, 3H), 2.27 (d, J =2.3Hz, 3H), 1.64 (s, 3H).

Step 7: Add methyl 4-((4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-methamido)pyridinecarboxylate (20.0 mg, 0.041 mmol, 1.0 equivalent) and _NH3 (1.00 mL, 7 M MeOH) to the reaction vessel. After stirring at room temperature for 16 hours, the mixture was concentrated and purified by thin-layer chromatography (PE:EtOAc = 1:2) to obtain (4S,5R)-N-(2-aminomethoxypyridin-4-yl)-4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)oxazolidine-5-carboxamide (15 mg, 0.031 mmol, yield 77%, purity 99.1%) as a white solid; ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.50–8.44 (m, 2H), 8.10 (dd, J = 5.5, 2.2 Hz, 1H), 7.94 (d ... =2.1Hz, 1H), 7.84(s, 1H), 7.14(ddd, J =8.5, 5.8, 2.2Hz, 1H), 6.94(td, J =9.2, 7.2Hz, 1H), 5.64(s, 1H), 4.65(d, J =8.3Hz, 1H), 4.53(d, J =6.7Hz, 1H), 3.96(d, J =2.0Hz, 3H), 2.27(d, J =2.2Hz, 3H), 1.64(d, J =1.3Hz, 3H). ESI-MS m/z = 475.60 [M+H] ⁺ ; calculated molecular weight: 474.13.

Using the intermediate obtained in step 3 of the preparation of compound 83, compounds 78 and 82 were prepared according to a similar scheme described for compound 83. Compound 84 was prepared from the second elution fraction of step 4 according to a similar scheme described for the preparation of compound 83.

Example 8. Compounds 60 and 62.

Compound 62.

Step 1: Under room temperature and argon atmosphere, add 1,2-difluoro-3-methoxy-4-nitrobenzene (1.0 g, 5.29 mmol, 1.0 equivalent), ammonium formate (6.6 g, 105.80 mmol, 20.0 equivalent), Pd/C (200.0 mg), and EtOH (10 mL) to the reaction vessel. After stirring at 50 °C for 3 hours, adjust the mixture to pH 7-8 with saturated _NaHCO3 solution, extract with ethyl acetate (25 mL × 2), and wash with brine (25 mL × 3). The combined organic extracts were dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under vacuum to obtain crude 3,4-difluoro-2-methoxyaniline (800 mg, 95.1% yield), which could be used in the next step without further purification. ESI-MS m/z = 160.10 [M+H] ^⁺ ; calculated molecular weight: 159.14.

Step 2: In a reaction vessel, add ( R )-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1.2 g, 7.55 mmol, 1.2 equivalents, 97% ee (enantiomer excess 97%)), 3,4-difluoro-2-methoxyaniline (1.0 g, 6.29 mmol, 1.0 equivalent), NMI (1.8 g, 22.02 mmol, 3.5 equivalents), and MeCN (10 mL). Cool the mixture to 0 °C, add TCFH (2.6 g, 9.44 mmol, 1.5 equivalents), and stir overnight at 60 °C under argon atmosphere. After removing MeCN, quench the residue with _H₂O and extract with ethyl acetate (15 mL × 3). The combined organic extracts were washed with brine, dried on anhydrous _Na₂SO₄ , filtered, concentrated, and purified by column chromatography (PE:EtOAc = 50:1) to give _a white solid ( R )-N-(3,4-difluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1.3 g, 4.3 mmol, 69% yield). ESI-MS m/z = 300.09 [M+H] ^⁺ ; calculated molecular weight: 299.20.

Step 3: Add borane-tetrahydrofuran complex (11.7 mL, 11.70 mmol, 5.0 equivalent) to a solution of (R)-N-(3,4-difluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (700 mg, 2.34 mmol, 1.0 equivalent) in 7 mL of THF at 0 °C. Stir the mixture overnight at 60 °C under argon atmosphere, cool to room temperature, quench with ice water, and dilute with ethyl acetate (2 mL). Extract the residue with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous _{Na₂SO₄ ,} filtered, concentrated, and purified by column chromatography (PE/EtOAc = 10:1) to give ( R )-3-((3,4-difluoro-2-methoxyphenyl)amino)-1,1,1-trifluoro-2-methyl-2-propanol (500 mg, 1.76 mmol, 75.0% yield), as a colorless oil. ESI-MS m/z = 286.00 [M+H] ^⁺ ; calculated molecular weight: 285.21. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.91-6.65 (m, 1H), 6.44 (ddd, J =9.2, 4.7, 2.3Hz, 1H), 4.01 (d, J =1.9Hz, 3H), 3.51 (d, J =13.9Hz, 1H), 3.26 (d, J =13.9Hz, 1H), 2.98(br s, 1H), 1.48(s, 3H).

Step 4: Add 4A molecular sieve, (R)-3-((3,4-difluoro-2-methoxyphenyl)amino)-1,1,1-trifluoro-2-methylprop-2-ol (300 mg, 1.05 mmol, 1.0 equivalent), ethyl 2-oxoacetate (214.2 mg, 2.10 mmol, 2.0 equivalent), and PPTS (27.6 mg, 0.11 mmol, 0.1 equivalent) to the reaction vessel. After stirring at room temperature under argon atmosphere for 2 hours, filter the mixture, wash with _H₂O , and extract with ethyl acetate (10 mL × 3). The combined organic extract was washed with brine, dried on anhydrous _Na₂SO₄ , filtered, concentrated under vacuum, and purified by thin-layer chromatography (PE:EtOAc=20 _: 1) to obtain ethyl (2R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-carboxylate (60.0 mg, first eluent fraction). ¹ H NMR (400MHz, CDCl ₃ ) δ 6.85 (td, J =9.4, 8.1Hz, 1H), 6.50 (ddd, J =9.3, 4.9, 2.4Hz, 1H), 5.91 (s, 1H), 4.15 (qd, J =7.2, 1.9Hz, 2H), 3.99 (d, J =9.3Hz, 1H), 3.93 (d, J =1.7Hz, 3H), 3.42 (d, J =9.3Hz, 1H), 1.28 (s, 3H), 1.22 (t, J =7.1Hz, 3H). And (2S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-carboxylic acid ethyl ester (36.0 mg, second elution fraction). ^1H NMR (400MHz, DMSO- d6 , major isomer peaks reported) δ 7.11 (q, J = 9.3Hz, 1H), 6.74 (ddd, J = 9.4 _, 5.1, 2.3Hz, 1H), 5.84 (s, 1H), 4.14–3.98 (m, 2H), 3.93 (d, J = 11.0Hz, 1H), 3.82 (d, J = 1.4Hz, 3H), 3.64 (d, J = 11.0Hz, 1H), 1.59 (s, 3H), 1.04 (t, J = 7.1Hz, 3H).

Step 5: Add ethyl (2S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-carboxylate (second eluent fraction from Step 4, 36 mg, 0.09 mmol, 1.0 equivalent), EtOH (1 mL), LiOH (4.8 mg, 0.20 mmol, 2.2 equivalent), and water (1 mL) to the reaction vessel. After stirring at room temperature for 2 hours, adjust the reaction mixture to pH 5 with 10% HCl solution and extract with ethyl acetate (5 mL × 2). The combined organic extract was washed with brine, dried and concentrated on _{anhydrous Na₂SO₄} to give crude (5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-carboxylic acid (40 mg), which was used for the next step without further purification.

Step 6: Add (2S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-carboxylic acid (40 mg, 0.12 mmol, 1.0 equivalent), methyl 4-aminopyridine-2-carboxylate (21.3 mg, 0.14 mmol, 1.2 equivalent), NMI (16.4 mg, 0.42 mmol, 3.5 equivalent), and MeCN (2 mL) to the reaction vessel. After cooling to 0°C, add TCFH (50.6 mg, 0.18 mmol, 1.5 equivalent), and stir the mixture at 60°C under argon for 2 hours. After cooling to room temperature and removing acetonitrile under vacuum, wash the mixture with _H₂O and extract with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous _MgSO₄ , concentrated, and purified by column chromatography (DCM/MeOH = 20:1) to give methyl 4-((2S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-carboxylic acid (10 mg, 0.021 mmol, 17.5% yield) as a colorless oil. ESI-MS m/z = 476.10 [M+H] ⁺ ; calculated molecular weight: 475.37.

Step 7: Add methyl 4-((2S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-methamido)pyridinecarboxylate (10 mg, 0.02 mmol, 1.0 equivalent) and _NH3 (in 7M MeOH, 2 mL) to the reaction vessel. After stirring at 50°C for 2 hours, the mixture was concentrated and purified by thin-layer chromatography (DCM:MeOH=20:1) to obtain (2S,5R)-N-(2-aminomethoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2-methoxyphenylamine (4.0 mg, 0.008 mmol, 43.5% yield, purity 92.6%), a white solid. ¹ H NMR (400MHz, DMSO- d ₆ δ 10.99 (s, 1H), 8.50 (d, J =5.5Hz, 1H), 8.25 (d, J = 2.2Hz, 1H), 8.08 (s, 1H), 7.73 (dd, J =5.5, 2.2Hz, 1H), 7.63 (s, 1H), 7.12 (q, J =9.3Hz, 1H), 6.80-6.70 (m, 1H), 5.94 (s, 1H), 4.05 (d, J =10.7Hz, 1H), 3.81 (d, J =10.8Hz, 1H), 3.77 (d, J =1.1Hz, 3H), 1.58(s, 3H). ESI-MS m/z=461.10[M+H] ⁺ Calculated molecular weight: 460.36.

Compound 60 was prepared using the first elution fraction from step 4, following a similar process to that described for compound 62.

Example 9. Compounds 141 and 142.

Compounds 141 and 142

Step 1: Add D-alanine methyl hydrochloride (10 g, 71.04 mmol, 1.0 equivalent) to a flame-dried three-necked flask. Purge the flask three times with argon, then add _CH3CN (200 mL). After cooling to 0°C, add _K2CO3 (49.51 g, 358.2 mmol, 5.0 equivalent) to the mixture at 0°C, then add (bromomethyl)benzene (60.89 g, 358.2 mmol, 5.0 equivalent) dropwise from 0 to ₁₀ °C. Stir the reaction mixture at 60°C for 16 hours, cool to room temperature, filter, and concentrate under reduced pressure. The residue was purified by silicone chromatography (PE:EtOAc = 200:1 to 4:1) to give a colorless oily dibenzyl-D-alanine methyl ester (20 g , 70.58 mmol, 98.5% yield). 37 (d, J = 7.2 Hz, 4H), 7.32–7.27 (m, 4H), 7.24–7.18 (m, 2H), 3.82 (d, J = 14.1 Hz, 2H), 3.73 (s, 3H), 3.62 (d, J = 14.1 Hz, 2H), 3.50 (q, J = 7.1 Hz, 1H), 1.32 (d, J = 7.1 Hz, 3H).

Step 2: Add dibenzyl-D-alanine methyl ester (10 g, 35.29 mmol, 1.0 equivalent) and toluene (13.5 mL) to the reaction vessel. After cooling to 0°C, add trimethyl(trifluoromethyl)silane (7.82 mL, 52.93 mmol, 1.5 equivalent) and tetrabutylammonium acetate (532 mg, 1.76 mmol, 0.05 equivalent). Stir at room temperature for 2 hours, then quench at 0°C with saturated _NH₄Cl aqueous solution (50 mL). Extract the aqueous phase with EtOAc (50 mL x 2), wash the combined organic layers with brine (20 mL x 2), dry with _MgSO₄ , filter, and concentrate under reduced pressure. The residue was dissolved in THF (50 mL) and then cooled to 0 °C. Hydrochloric acid (1 mmol/mL, 12.7 mL, 12.7 mmol, 0.36 equivalence) was added to the mixture at 0 °C, and the mixture was stirred at room temperature for 2 hours. After quenching with a saturated _NaHCO3 aqueous solution (50 mL) at 0 °C, the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 200:1 to 20:1) to give a yellow oil (R)-3-(dibenzylamino)-1,1,1-trifluorobut-2-one (5.0 g, 15.56 mmol, 44.1% yield). ESI-MS m/z = 322.25 [M+H] ⁺ ; calculated molecular weight: 321.13.

Step 3: Add (R)-3-(dibenzylamino)-1,1,1-trifluorobutane-2-one (3.5 g, 10.89 mmol, 1.0 equivalent) and ethoxyethane (140 mL) to the reaction vessel. Cool the mixture to -5 °C and then purge it three times with argon. Add magnesium bromide (7.26 mL, 21.78 mmol, 2.0 equivalent) dropwise to the mixture at -5 °C, and stir the mixture at -5 °C for 2 hours. After cooling to 0 °C, quench the mixture with saturated _NH₄Cl aqueous solution (50 mL) and extract with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL × 2), dried on _MgSO₄ , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 300:1 to 100:1) to give a yellow oil (2R,3R)-3-(dibenzylamino)-1,1,1-trifluoro-2-methylbut-2-ol (1.3 g, 13.85 mmol, 35.4% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.36-7.25 (m, 10H), 5.82 (s, 1H), 3.84 (d, J =13.2Hz, 2H), 3.39 (d, J =13.2Hz, 2H), 3.24 (q, J =7.1Hz, 1H), 1.37 (q, J =1.1Hz, 3H), 1.21 (dd, J =7.2, 0.9Hz, 3H).

Step 4: Add (2R,3R)-3-(dibenzylamino)-1,1,1-trifluoro-2-methylbut-2-ol (1.3 g, 3.85 mmol, 1.0 equivalent) and MeOH (13 mL) to the reaction vessel. After adding Pd(OH) _₂ /C (20 wt%, 411 mg), cool the mixture to -5°C and purge it three times with hydrogen. Stir the reaction mixture at room temperature for 16 hours. Filter the mixture, and wash the residue with MeOH (10 mL × 2). Then, add dioxane hydrochloride (4 mmol/mL, 1.93 mL, 7.71 mmol) to the filtrate at room temperature and stir the mixture at room temperature for 30 minutes. The solvent was concentrated under reduced pressure, and the mixture was then freeze-dried under reduced pressure to give crude (2R,3R)-3-amino-1,1,1-trifluoro-2-methylbut-2-ol hydrochloride (700 mg, 3.62 mmol, 93.8% yield) as a yellow solid. ^¹H NMR (400 MHz, DMSO- d ₆ δ 8.17 (s, 3H), 3.36 (p, J = 6.3 Hz, 1H), 1.30 (s, 3H), 1.19 (d, J = 6.8 Hz, 3H).

Step 5: Add (2R,3R)-3-amino-1,1,1-trifluoro-2-methylbut-2-ol hydrochloride (300 mg, 1.55 mmol, 1.0 equivalent), DCM (3 mL), and 1H-imidazole (474.7 mg, 6.97 mmol, 4.5 equivalent) to the reaction vessel. After cooling to 0°C, add dropwise tert-butyldiphenylchlorosilane (0.604 mL, 2.32 mmol, 1.5 equivalent) from DCM (1 mL) to the mixture at 0°C. Stir the reaction mixture at rt for 16 hours and quench it at 0°C with ice water (10 mL). The aqueous layer was extracted with DCM (10 mL x 2), and the combined organic layer was washed with brine (20 mL x 2), dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 100:1 to 10:1) to give (2R,3R)-3-((tert-butyldiphenylsilyl)oxy)-4,4,4-trifluoro-3-methylbut-2-amine (336 mg, 0.849 mmol, 54.8% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.76-7.61 (m, 4H), 7.47-7.32 (m, 6H), 3.14 (t, J =6.8Hz, 1H), 1.19-1.07 (m, 6H), 1.05 (d, J =1.5Hz, 9H).

Step 6: Add (3,4-difluoro-2-methoxyphenyl)boric acid (295 mg, 1.57 mmol, 2.0 equivalent), boric acid (97 mg, 1.57 mmol, 2.0 equivalent), Cu(OAc) _₂ (142 mg, 0.783 mmol, 1.0 equivalent), and 4A molecular sieve (150 mg) to a flame-dried test tube. Purge the test tube three times with oxygen. (2R,3R)-3-((tert-butyldiphenylsilyl)oxy)-4,4,4-trifluoro-3-methylbut-2-amine (310 mg, 0.783 mmol, 1.0 equivalent) was dissolved in _CH3CN (6 mL) and then added to the mixture at room temperature. The mixture was quenched with saturated _NH4Cl aqueous solution (10 mL), and the aqueous phase was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (20 mL × 2) and purified in MgSO4. The _product was dried, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 200:1 to 5:1) to give N-((2R,3R)-3-((tert-butyldiphenylsilyl)oxy)-4,4,4-trifluoro-3-methylbut-2-yl)-3,4-difluoro-2-methoxyaniline (30 mg, 0.055 mmol, 7.1% yield), a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.83–7.78 (m, 2H), 7.76–7.72 (m, 2H), 7.52–7.38 (m, 6H), 6.53 (ddd, J) =10.2, 9.2, 8.2Hz, 1H), 5.50 (ddd, J =9.4, 4.6, 2.2Hz, 1H), 3.84 (d, J =1.5Hz, 3H), 3.38 (q, J =5.2Hz, 1H), 1.24-1.20 (m, 6H), 1.09 (s, 9H).

Step 7: Add N-((2R,3R)-3-((tert-butyldiphenylsiloxy)-4,4,4-trifluoro-3-methylbut-2-yl)-3,4-difluoro-2-methoxyaniline (40 mg, 0.0744 mmol, 1.0 equivalent) and tetrabutylammonium fluoride (1 mmol/mL THF solution, 1 mL, 13.4 equivalent) to the reaction vessel. Purge the reaction mixture three times with argon and then stir at 60 °C for 2 hours. Quench the mixture at 0 °C with ice water (10 mL). Extract the aqueous solution with EtOAc (10 mL × 2). Wash the combined organic layers with brine (20 mL × 2) in MgSO₄. _4. Dry, filter, and concentrate under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc = 5:1) to give (2R,3R)-3-((3,4-difluoro-2-methoxyphenyl)amino)-1,1,1-trifluoro-2-methylbut-2-ol (20 mg, 0.0668 mmol, 89.8% yield), a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 6.76 (ddd, J = 9.9, 9.2, 8.2 Hz, 1H), 6.48 (ddd, J = 9.3, 4.7, 2.2 Hz, 1H), 3.96 (d, J = 1.8 Hz, 3H), 3.67 (q, J = 6.7 Hz, 1H), 1.37 (d, J = 6.7 Hz, 1H), 1.37 (d, J = 6.7 Hz, 1H). J =1.1Hz, 3H), 1.23 (dd, J =6.7, 1.0Hz, 3H).

Step 8: Add 4A molecular sieve (40 mg), pyridine-1-onthium-4-methylbenzenesulfonate (1.68 mg, 0.0066 mmol, 0.1 equivalent), and (2R,3R)-3-((3,4-difluoro-2-methoxyphenyl)amino)-1,1,1-trifluoro-2-methylbut-2-ol (20 mg, 0.066 mmol, 1.0 equivalent) to the reaction vessel. Add ethyl 2-oxoacetate (50% toluene, 1.0 mL) to the mixture, and stir the mixture at 80 °C for 16 hours. Quench the mixture with ice water (5 mL), and extract the aqueous layer with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried on anhydrous _MgSO₄ , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=20:1) to give ethyl (4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxazolidine-2-carboxylate (first eluent, 9.4 mg, 0.024 mmol, 36.7% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 6.83 (q, J =9.1Hz, 1H), 6.64 (ddd, J =9.1, 5.1, 2.3Hz, 1H), 5.63 (s, 1H), 4.36 (q, J =6.2Hz, 1H), 3.98 (q, J =7.2Hz, 2H), 3.94 (d, J =1.5Hz, 3H), 1.44 (s, 3H), 1.13 (d, J =6.2Hz, 3H), 1.07 (t, J =7.1Hz, 3H). ⁽ 4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxazolidine-2-carboxylic acid ethyl ester (second eluent, 9.7 mg, 0.025 mmol, 37.8% yield) was a yellow solid. ¹H NMR (400 MHz, _CDCl₃ ) δ 6.80 (td, J = 9.3, 8.1 Hz, 1H), 6.67 (ddd, J = 9.3, 5.2, 2.3 Hz, 1H), 4.23–4.11 (m, 3H), 3.88 (d, J = 2.1 Hz, 3H), 1.49 (d, J = 1.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H).

Step 9: Add ethyl (4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxazolidine-2-carboxylate (first eluent fraction from Step 8, 9.4 mg, 0.024 mmol, 1.0 equivalent), THF (0.5 mL), and LiOH (1.76 mg, dissolved in 0.25 mL _H₂O , 0.073 mmol, 3 equivalent) to the reaction vessel. Stir the reaction mixture at room temperature for 1 hour. Cool the mixture with ice water (5 mL) and acidify with hydrochloric acid (1 mmol/mL) to pH 6. Extract the aqueous layer with EtOAc (10 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried _{on Na₂SO₄} , filtered, and concentrated under reduced pressure to give crude (4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxazolidine-2-carboxylic acid (8.7 mg, 0.024 mmol, 99.8% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ 6.82 (td, J =9.3, 8.0Hz, 1H), 6.69-6.60 (m, 1H), 5.62 (s, 1H), 4.35 (q, J =6.3Hz, 1H), 3.94 (d, J =1.7Hz, 3H), 1.32(s, 3H), 1.10(d, J =6.3Hz, 3H).

Step 10: Add (4R,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxazolidine-2-carboxylic acid (9 mg, 0.025 mmol, 1 equivalent), 4-aminopyridinecarboxamide (4.52 mg, 0.032 mmol, 1.3 equivalent), and _CH3CN (0.4 mL) to the reaction vessel. After cooling to 0 °C, add 1-methyl-1H-imidazole (5.2 mg, dissolved in 0.1 mL MeCN, 0.063 mmol, 2.5 equivalent) and TCFH (10.7 mg, dissolved in 0.1 mL MeCN, 0.038 mmol, 1.5 equivalent). Stir the mixture at room temperature for 16 hours, quench with ice water (10 mL), and extract with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried _{with Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography and eluted with (PE:EtOAc = 1:1) to give (4R,5R)-N-(2-aminomethoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxazolidine-2-carboxamide (compound 141, 1.0 mg, 0.0021 mmol, 8.3% yield, purity 99.6%), as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.51 (s, 1H), 8.43 (d, J =5.5Hz, 1H), 8.02 (dd, J =5.5, 1.9Hz, 1H), 7.87 (s, 1H), 7.83 (d, J =2.1Hz, 1H), 6.81 (q, J =9.0Hz, 1H), 6.66-6.59(m, 1H), 5.60(s, 1H), 5.50(s, 1H), 4.43(q, J =6.7Hz, 1H), 3.98(d, J =1.9Hz, 3H), 1.49(s, 3H), 1.03(d, J =6.6Hz, 3H). ESI-MS m/z = 475.28 [M+H] ⁺ ; Calculated MW: 474.39.

Similar to Preparation Example 141, Compound 142 was prepared from the second elution fraction of Step 8. White solid (3.8 mg, 0.008 mmol, 31.6% yield, purity 97.8%). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.06 (s, ¹H), 8.47 (d, J = 5.6Hz, ¹H), 8.20 (dd, J = 5.6, 2.2Hz, ¹H), 7.98–7.88 (m, 2H), 6.97–6.82 (m, 2H), 5.66 (s, ¹H), 5.21 (s, ¹H), 4.08 (d, J = 2.9Hz, 3H), 3.92 (q, J = 6.4Hz, 1H), 1.52 (s, 3H), 1.12 (d, J = 6.4Hz, 3H). ESI-MS m/z = 475.25 [M+H] ^⁺ ; calculated molecular weight: 474.39.

The preparation methods for the following compounds are similar to those described for compounds 141 and 142.

Examples 10. Compounds 29, 126-127, 135-137, 146, and 148-150.

Compounds 127 and 135

Step 1: At room temperature, add 1-bromo-3,4-difluoro-2-methoxybenzene (5.0 g, 22.4 mmol, 1.0 equivalent), DMF (45.0 mL), _H₂O (4.5 mL), 1-(ethoxy)butane (6.73 g, 67.3 mmol, 3.0 equivalent), dppp (923.0 mg, 2.24 mmol, 0.10 equivalent), _K₂CO₃ (4.64 _g , 33.6 mmol, 1.5 equivalent), and Pd(OAc) _₂ (254.0 mg, 1.12 mmol, 0.05 equivalent) to a 100 mL round-bottom flask. The resulting mixture is stirred at 95 °C under argon atmosphere for 16 hours, and the reaction is monitored by TLC. After the reaction was complete, the reactants were cooled to room temperature, and 2M HCl (78.0 mL, 157 mmol, 7.0 equivalence) was added _dropwise at 0 °C. The resulting mixture was stirred at room temperature for another 2 hours, then diluted with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 20:1) to give 1-(3,4-difluoro-2-methoxyphenyl)ethyl-1-one (2.9 g, yield 69%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.49 (ddd, J =9.0, 6.1, 2.3Hz, 1H), 6.91 (td, J =9.0, 6.8Hz, 1H), 4.07 (d, J = 2.6Hz, 3H), 2.59 (s, 3H)

Step 2: At 0°C, pyrrolidine (382.0 mg, 5.38 mmol, 2.0 equivalent) was added in portions to a stirred solution of 1-(3,4-difluoro-2-methoxyphenyl)ethyl-1-one (500.0 mg, 2.69 mmol, 1.0 equivalent) and 1,1,1-trifluoropropane-2-one (1.5 g, 13.44 mmol, 5.0 equivalent) in methanol (5.0 mL). The resulting mixture was stirred at room temperature under argon atmosphere for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried _over anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (PE/EtOAc = 10:1) to give 1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbut-1-one (420 mg, yield 52%), a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.45 (ddd, J = 9.0, 6.0, 2.3 Hz, 1H), 6.94 (td, J = 9.0, 6.8 Hz, 1H), 5.12 (s, 1H), 4.10 (d, J = 3.2 Hz, 3H), 3.54 (d, J = 17.3 Hz, 1H), 3.05 (d, J = 17.2 Hz, 1H), 1.45 (s, 3H).

Step 3: To a stirred solution of 1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbut-1-one (850.0 mg, 2.85 mmol, 1.0 equivalent) and pyridine (6760 mg, 8.56 mmol, 3.0 equivalent) in DCM (10.0 mL), add _SOCl2 (679.0 mg, 5.70 mmol, 2.0 equivalent) in DCM (5.0 mL) at 0 °C. The resulting mixture is stirred at room temperature under argon atmosphere for 16 hours, diluted with _DCM , washed with _H2O (2 × 30 mL) and 1 M HCl (aq.) (1 × 30 mL), and dried with anhydrous _Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (PE/EtOAc = 10:1) to give a yellow oil (E)-1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-3-methylbut-2-en-1-one (660 mg, yield 82%). ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.50 (ddd, J = 8.9, 6.0, 2.3 Hz, 1H), 7.12 (p, J = 1.5 Hz, 1H), 6.96 (tdd, J = 9.0, 6.8, 1.6 Hz, 1H), 4.03 (d, J = 2.7 Hz, 3H), 2.16 (d, J = 1.5 Hz, 3H).

Step 4: To a THF (8.0 mL) solution of (E)-1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-3-methylbut-2-en-1-one (660.0 mg, 2.38 mmol, 1.0 equivalent) and ethyl 2-methylbutyrate (314.0 mg, 2.62 mmol, 1.1 equivalent), TEA (480.0 mg, 4.76 mmol, 2.0 equivalent) was added dropwise at room temperature. The resulting mixture was stirred at 60 °C under argon atmosphere for 16 hours. After the reaction was complete, the mixture was diluted with water and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried _over anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc=10:1) to give ethyl 3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxy-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (830 mg, yield 87%), which was a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.49-7.41 (m, 1H), 6.87 (td, J =9.2, 7.3Hz, 1H), 5.10 (s, 1H), 5.02 (d, J =1.9Hz, 1H), 4.10-4.02 (m, 5H), 2.97 (dd, J =13.7, 2.0Hz, 1H), 2.02 (d, J =13.7Hz, 1H), 1.78 (s, 3H), 1.11 (t, J =7.1Hz, 3H).

Step 5: Add a solution of SOCl₂ (238.0 mg, 4.00 mmol, 2.0 equivalent) in DCM (3.0 mL) to a stirred mixture of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxy-5-methyl-5-(trifluoromethyl)tetrahydrothiophene- ₂ -carboxylate (800.0 mg, 2.0 mmol, 1.0 equivalent) at °C. Stir the resulting mixture at room temperature under argon atmosphere for 2 hours. After the reaction is complete, dilute with DCM, wash with _H₂O (2 × 30 mL) and 1 M HCl (aq.) (1 × 30 mL), and dry _with anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain crude ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-2,5-dihydrothiophene-2-carboxylate (800 mg), which is a yellow oily substance that can be used in subsequent steps without further purification.

Step 6: Add DBU (636.0 mg, 4.19 mmol, 2.0 equivalent) to a stirred solution of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-2,5-dihydrothiophene-2-carboxylate (800.0 mg, 2.09 mmol, 1.0 equivalent) in THF (10.0 mL) at 0 °C. The resulting mixture was stirred at room temperature under argon atmosphere for 4 hours. After the reaction was complete, the mixture was diluted with water and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried _over anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc=10:1) to give ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrothiophen-2-carboxylate (760 mg, 95% yield, containing about 10% ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-2,5-dihydrothiophen-2-carboxylate), which was a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.92-6.76 (m, 2H), 4.09 (q, J =7.5Hz, 2H), 3.91 (d, J =2.2Hz, 3H), 3.51 (d, J = 18.2Hz, 1H), 3.08 (d, J =18.2Hz, 1H), 1.72(s, 3H), 1.14(t, J =7.1Hz, 3H).

Step 7: Add ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrothiophene-2-carboxylate (12.0 mg, 0.031 mmol, 1.0 equivalent) to a 10 mL round-bottom flask, and add EtOH (2.0 mL) and 10% Pd(OH) _₂ /C (20.0 mg) at room temperature. Stir the resulting mixture at 60 °C for 16 hours under hydrogen atmosphere (1 atmosphere). Filter the resulting mixture, and wash the filter cake with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure and purified by preparative liquid chromatography (PE/EtOAc=10:1) to obtain rac-ethyl (3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (10 mg, yield 82%), which was a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.93 (ddd, J =8.3, 5.6, 2.2Hz, 1H), 6.78 (td, J =9.2, 7.3Hz, 1H), 4.29 (d, J =6.6Hz, 1H), 4.08 (d, J =3.0Hz, 3H), 4.05-3.96 (m, 1H), 3.87 (qd, J =7.1, 1.3Hz, 2H), 3.34-3.24 (m, 1H), 2.01 (dd, J =12.1, 5.1Hz, 1H), 1.70 (s, 3H), 1.00 (t, J =7.1Hz, 3H).

Step 8: To a stirred solution of (2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid rac- ethyl ester (10.0 mg, 0.026 mmol, 1.00 equivalent) in ethanol (0.50 mL), LiOH (5.0 mg, 0.182 mmol, 5.0 equivalent) dissolved in water (0.20 mL) was added at 0 °C. The resulting mixture was stirred at room temperature under argon atmosphere for 16 hours. The reaction mixture was adjusted to pH 5 with HCl (1 M) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried _with anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain rac- (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (10 mg, crude product), which is a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.91 (ddd, J =8.0, 5.6, 2.1Hz, 1H), 6.83 (td, J =9.1, 7.1Hz, 1H), 4.40 (d, J =10.8Hz, 1H), 4.15-4.05 (m, 1H), 3.99 (d, J =2.6Hz, 3H), 2.50 (t, J =13.1Hz, 1H), 2.17 (dd, J =12.9, 6.1Hz, 1H), 1.72 (s, 3H).

Step 9: To a stirred solution of rac- (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-tetrahydrothiophene-2-carboxylic acid (9.0 mg, 0.025 mmol, 1.0 equivalent) and methyl 4-aminopyridinecarboxylate (5.0 mg, 0.030 mmol, 1.2 equivalent) in DCM (0.2 mL), pyridine (22.0 mg, 0.25 mmol, 10.0 equivalent) and _POCl3 (5.0 mg, 0.03 mmol, 1.05 equivalent) in DCM (0.2 mL) were added in portions at 0 °C. The resulting mixture was stirred at room temperature under argon atmosphere for 4 hours, then diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried with anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (PE/EtOAc = 2: ₁ ) to give rac-methyl 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-methoxyamino)pyridinecarboxylate (6 mg, yield 46%), a pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.56 (d, J =5.6Hz, 1H), 8.08 (s, 1H), 7.85 (d, J =5.6Hz, 1H), 6.94 (d, J =7.0Hz, 1H), 6.82 (q, J =8.5Hz, 1H), 4.44 (d, J =10.7Hz, 1H), 4.15 (dp, J =19.7, 6.9, 6.4Hz, 1H), 3.96 (s, 6H), 2.55 (t, J =12.9Hz, 1H), 2.21 (dd, J =12.9, 6.2Hz, 1H), 1.78 (s, 3H).

Step 10: In a 10 mL round-bottom flask, add methyl 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-methamidoamino)pyridinecarboxylate (6.0 mg, 0.012 mmol, 1.0 equivalent) and _NH₃ (1.0 mL, 7 M methanol solution) at 0 °C. The resulting mixture is stirred at room temperature under argon atmosphere for 3 days. After the reaction is complete, the MeOH is removed by reduced pressure concentration. The residue was purified by thin-layer chromatography (PE/EtOAc=2:1) to give rac-4 -((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-methoxyamino)pyridinamide (2.8 mg, 0.006 mmol, 48% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 9.66 (s, 1H), 8.48-8.40 (m, 1H), 8.29 (dd, J =5.6, 2.1Hz, 1H), 8.09 (d, J = 2.1Hz, 1H), 7.98 (d, J = 4.4Hz, 1H), 6.99 (t, J =6.4Hz, 1H), 6.89-6.77 (m, 1H), 5.98 (s, 1H), 4.68 (d, J =10.8Hz, 1H), 4.34-4.19 (m, 1H), 4.03 (d, J =2.4Hz, 3H), 2.59 (t, J =13.1Hz, 1H), 2.29-2.24 (m, 1H), 1.78 (s, 3H). ESI-MS m/z = 476.27 [M+H] ⁺ ; Calculated MW: 475.10.

Step 11: Use chiral HPLC to separate rac-4 -((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-methacinyl)pyridinylamine was isolated into single enantiomers to give compounds 4-((2S,3R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-methacinyl)pyridinylamine (compound 149, first elution peak) and 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-methacinyl)pyridinylamine (compound 150, second elution peak). Chiral HPLC separation conditions - Instrument: YMC K-Prep; Column: CHIRALPAK IK, 2.5 × 10 cm, 10 μm; Mobile phase: 20% iPrOH/80% hexane; Flow conditions: 30 mL/min, 38 °C; Detector wavelength: 254 nm; Injection details: 10 mL of 7.8 mg/mL 20% iPrOH/80% hexane. Chiral analysis chromatographic conditions - Instrument: Shimadzu LC-20AT; Column: CHIRALPAK IK 0.46×25cm; Mobile phase: 20% iPtOH/80% hexane; Flow conditions: 1mL/min, 35℃; Detector wavelength: 254nm; Injection details: 1μL concentrated fraction. Peak 1 (compound 149), 99.01% ee; RT = 5.341 min; Peak 2 (compound 150), 99.72% ee, RT = 6.273 min.

Step 12: To a mixture of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrothiophene-2-carboxylate (30.0 mg, 0.078 mmol, 1.0 equivalent) and Mg (38.0 mg, 1.57 mmol, 20.0 equivalent) in MeOH (2.00 mL), 1,2-dibromoethane (1.5 mg, 0.0078 mmol, 0.10 equivalent) was added in portions at room temperature. The resulting mixture was stirred at 50 °C for 3 hours under argon atmosphere. The reaction was cooled to room temperature and quenched with hydrochloric acid (1 M) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried on _{anhydrous Na₂SO₄} , filtered, and concentrated. The residues were purified by thin-layer chromatography (PE/EtOAc (10:1)) to give a mixture of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (26 mg, 86% yield).

Step 13: At 0°C, add 0.5 mL of LiOH dissolved in water to a stirred ethanol solution of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (26.0 mg, 0.068 mmol, 1.0 equivalent). Stir the resulting mixture at room temperature under argon atmosphere for 16 hours. Adjust the pH of the reaction mixture to 5 with HCl (1 M) and extract with EtOAc (3 × 20 mL). Wash the combined organic layers with brine (2 × 10 mL), dry _with anhydrous _Na₂SO₄ , and filter. Concentration yielded (2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (28 mg, crude), a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ , 1:1 mixture, two peaks reported): δ 6.96–6.89 (m, 2H), 6.86–6.79 (m, 2H), 4.46–4.38 (m, 2H), 4.05–4.02 (m, 2H), 4.01–3.98 (m, 6H), 2.71–2.64 (m, 2H), 2.22–2.15 (m, 2H), 1.73 (s, 3H), 1.61 (s, 3H).

Unless otherwise stated, the preparation methods of the following compounds are similar to those described for compound 127. Compounds 29, 126, and 135 were prepared from Int 135 using a similar method to that described for compound 127. Compounds 136 and 137 were prepared from the intermediate obtained in step 6. Compound 146 was prepared from 1,1,1,3,3,3-hexafluoropropane-2-one using a similar method to that described for compound 127.

Example 11. Compound 144.

Compound 144.

Step 1: Add 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propionic acid (1.0 g, 4.72 mmol, 1.0 equivalent), DMF (4.86 mL), tert-butyldimethylchlorosilane (1.78 g, 11.79 mmol, 2.5 equivalent), and imidazole (1.44 g, 21.22 mmol, 4.5 equivalent) to the reaction vessel. Purge the reaction mixture three times with argon, stir at room temperature for 16 hours, and then extract with isohexane (3 × 50 mL). The combined organic layers were washed with saturated _NaHCO3 (50 mL) and brine (50 mL), _dried over MgSO4, filtered, and concentrated under reduced pressure to give crude tert-butyldimethylsilyl)oxy)-3,3,3-trifluoro-2-(trifluoromethyl)propionate (1.6 g, 3.63 mmol, 77.1% yield) as a colorless oil. ^¹H NMR (400 MHz, _CDCl3 ) δ 0.85 (s, 18H), 0.00 (s, 12H).

Step 2: Add tert-butyldimethylsilyl)oxy)-3,3,3-trifluoro-2-(trifluoromethyl)propionate (1.6 g, 3.63 mmol, 1.0 equivalent) and DCM (dichloromethane) (13 mL) to the reaction vessel. After cooling to 0°C, add oxalichlor (0.353 mL, 4.18 mmol, 1.15 equivalent), followed by DMF (26.55 mg in 1 mL DCM, 0.028 mL, 0.363 mmol, 0.1 equivalent). Stir the solution at 0°C to rt for 16 hours. At 0°C, the reaction mixture was slowly added to a solution of 3,4-difluoro-2-methoxyaniline (576 mg, 3.63 mmol, 1.0 equivalent) and pyridine (329 mg, 0.337 mmol, 4.18 mmol, 1.15 equivalent) in DCM (7.61 mL). The reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and quenched with ice water (10 mL). The aqueous layer was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 100:1 to 50:1) to give 2-((tert-butyldimethylsilyl)oxy)-N-(3,4-difluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-(trifluoromethyl)propionic acid (1.02 g, 2.18 mmol, 60.2% yield) as a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.81 (s, 1H), 8.10–8.03 (m, 1H), 6.88 (td, J = 9.6, 8.0 Hz, 1H), 4.04 (d, J = 2.7 Hz, 3H), 0.99 (s, 9H), 0.28 (s, 6H).

Step 3: Tetrabutylammonium fluoride (2.62 mL, 2.62 mmol, 1.2 equivalents) was added to a solution of 2-((tert-butyldimethylsilyl)oxy)-N-(3,4-difluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-(trifluoromethyl)propionic acid (1.02 g, 2.18 mmol, 1.0 equivalent) in tetrahydrofuran (20 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, then rapidly cooled with ice water (10 mL), and the aqueous layer was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried over anhydrous _MgSO₄ , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 100:1 to 10:1) to give N-(3,4-difluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propionic acid (750 mg, 2.12 mmol, 97.3% yield) as a white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.56 (s, 1H), 8.02–7.95 (m, 1H), 6.92 (td, J = 9.5, 7.9 Hz, 1H), 5.31 (s, 1H), 4.08 (d, J = 2.5 Hz, 3H).

Step 4: Add _NaBH₄ (48.2 mg, 1.27 mmol, 4.5 equivalents) and THF (0.3 mL) to the reaction vessel. After cooling to 0°C, add N-(3,4-difluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propionic acid (100 mg, 0.283 mmol, 1.0 equivalent in 0.2 mL THF) dropwise to the mixture at 0°C. After stirring at 0°C for 30 minutes, add _BF₃ · _Et₂O (0.174 mL, 1.42 mmol, 5.0 equivalents) dropwise to the mixture at 0°C. Stir the mixture at room temperature for 3 hours, then at 50°C for 16 hours. The reaction was quenched at 0°C with saturated _NH₄Cl (5 mL), extracted with EtOAc (10 mL × 2), and the combined organic layers were washed with brine, dried with anhydrous _MgSO₄ , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc = 5:1) to give 2-(((3,4-difluoro-2-methoxyphenyl)amino)methyl)-1,1,1,3,3,3-hexafluoropropane-2-ol (14 mg, 0.041 mmol, 14.6% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.85-6.74 (m, 1H), 6.49-6.43 (m, 1H), 4.52 (s, 1H), 4.01 (d, J =2.3Hz, 3H), 3.64 (s, 2H).

Step 5: Add 4A molecular sieve (20 mg), pyridine-1-onthium-4-methylbenzenesulfonate (0.74 mg, 0.0029 mmol, 0.1 equivalent), 2-(((3,4-difluoro-2-methoxyphenyl)amino)methyl)-1,1,1,3,3,3-hexafluoropropane-2-ol (14 mg, 0.029 mmol, 1.0 equivalent), and ethyl 2-oxoacetate (50% toluene, 0.3 mL) to the reaction vessel. After stirring at 80 °C for 16 hours, the mixture was quenched with ice water (5 mL) at 0 °C, and the aqueous layer was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried on anhydrous _MgSO4 , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=20:1) to give ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5,5-bis(trifluoromethyl)oxazolidine-2-carboxylate (8 mg, 0.018 mmol, 45.8% yield), which was a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.84 (td, J =9.3, 8.1Hz, 1H), 6.50 (ddd, J =9.3, 4.8, 2.4Hz, 1H), 5.94 (s, 1H), 4.21-4.10 (m, 3H), 3.97 (d, J =11.0Hz, 1H), 3.87 (d, J =1.6Hz, 3H), 1.22 (t, J =7.2Hz, 3H).

Step 6: Add ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5,5-bis(trifluoromethyl)oxazolidine-2-carboxylate (8.0 mg, 0.018 mmol, 1 equivalent), THF (0.5 mL), and LiOH (1.36 mg in 0.25 mL _H₂O , 0.056 mmol, 3 equivalents) to the reaction vessel. Stir the reaction mixture at room temperature for 1 hour, quench with ice water (5 mL), and acidify with HCl (1 mmol/mL) to pH 6. Extract the aqueous layer with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried _{on Na₂SO₄} , filtered, and concentrated under reduced pressure to give 3-(3,4-difluoro-2-methoxyphenyl)-5,5-bis(trifluoromethyl)oxazolidine-2-carboxylic acid (8 mg, crude), as a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 6.84 (td, J = 9.3, 8.1 Hz, 1H), 6.61–6.39 (m, 1H), 5.94 (t, J = 0.9 Hz, 1H), 4.12 (d, J = 11.2 Hz, 1H), 4.03–3.95 (m, 1H), 3.88 (dd, J = 1.8, 1.0 Hz, 3H).

Step 7: Add 3-(3,4-difluoro-2-methoxyphenyl)-5,5-bis(trifluoromethyl)oxazolidine-2-carboxylic acid (8 mg, 0.02 mmol, 1 equivalent), 4-aminopyridinamide (3.61 mg, 0.026 mmol, 1.3 equivalent), and _CH3CN (0.4 mL) to the reaction vessel. After cooling to 0 °C, add 1-methyl-1H-imidazole (4.16 mg, dissolved in 0.1 mL MeCN, 0.05 mmol, 2.5 equivalent), followed by TCFH (8.52 mg, dissolved in 0.1 mL MeCN, 0.030 mmol, 1.5 equivalent). Stir the mixture at room temperature for 16 hours, quench with ice water (10 mL), and then extract with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried _{with Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography and eluted with (PE:EtOAc = 1:1) to give N-(2-aminomethoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5,5-bis(trifluoromethyl)oxazolidine-2-carboxamide (1.2 mg, 0.0023 mmol, 11.5% yield, 99.5% purity) as a white solid. ^¹H NMR (400MHz, _CDCl₃ ) δ 8.61 (s, ¹H), 8.48 (d, J = 5.5Hz, ¹H), 8.10 (dd, J = 5.6, 2.2Hz, ¹H), 7.91 (d, J = 2.2Hz, ¹H), 7.83 (s, ¹H), 6.90–6.80 (m, ¹H), 6.75–6.70 (m, ¹H), 5.71 (s, ¹H), 5.60 (s, ¹H), 4.29 (d, J = 11.1Hz, ¹H), 4.02 (d, J = 2.3Hz, ³H), 3.77 (d, J = 11.1Hz, ¹H). ESI-MS m/z = 515.24 [M+H] ^⁺ ; calculated molecular weight: 514.33.

Example 12. Compound 22.

Compound 22.

Step 1: At 0°C, 3,4-difluoro-2-methoxybenzaldehyde (70 mg, 0.407 mmol, 1.0 equivalent), N-(2,4-dimethoxybenzyl)hydroxylamine (89 mg, 0.488 mmol, 1.2 equivalent), THF (1.5 mL), and _MgSO₄ (244 mg, 2.035 mmol, 5.0 equivalent) were added to a reaction vessel. The mixture was stirred overnight at room temperature and filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography (PE:EtOAc = 1:1) to give a white solid (E)-1-(3,4-difluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)methylimine oxide (130 mg, 0.386 mmol, 94.7% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 9.05 (ddd, J =8.9, 6.3, 2.3Hz, 1H), 7.70 (s, 1H), 7.35 (d, J =8.2Hz, 1H), 6.89 (td, J =9.4, 7.5Hz, 1H), 6.56-6.45(m, 2H), 5.01(s, 2H), 3.92(d, J =2.1Hz, 3H), 3.82(s, 3H), 3.81(s, 3H).

Step 2: Add (E)-1-(3,4-difluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)methylimine oxide (50 mg, 0.148 mmol, 1.0 equivalent), toluene (0.1 mL), and (3,3,3-trifluoropropyl-1-en-2-yl)benzene (0.5 mL) to the reaction vessel. Stir at 100°C for 7 hours, then cool the mixture to room temperature and concentrate under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc = 10:1) to give 3-(3,4-difluoro-2-methoxyphenyl)-2-(2,4-dimethoxybenzyl)-5-phenyl-5-(trifluoromethyl)-isooxazolidine (57 mg, 0.112 mmol, 75.6% yield), as a white foam. ^¹H NMR (400 MHz, _CDCl₃ , 1:0.38 stereoisomer mixture, major isomer peaks reported) ESI-MS m/z = 510.35 [M+H] ^⁺ ; calculated MW: 509.16. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.59-7.49 (m, 1H), 7.44-7.40 (m, 2H), 7.41-7.33 (m, 1H), 7.36-7.28 (m, 2H), 7.04 (ddd, J =8.6, 6.0, 2.3Hz, 1H), 6.71 (td, J =9.2, 7.2Hz, 1H), 6.49 (dd, J =8.4, 2.5Hz, 1H), 6.40 (d, J =2.4Hz, 1H), 4.40 (dd, J =10.0, 7.0Hz, 1H), 3.97-3.93(m, 5H), 3.81(s, 3H), 3.69(s, 3H), 3.35(dd, J =12.8, 7.0Hz, 1H), 2.69-2.51(m, 1H).

Step 3: To a stirred solution of 3-(3,4-difluoro-2-methoxyphenyl)-2-(2,4-dimethoxybenzyl)-5-phenyl-5-(trifluoromethyl)isoxazolidine (28 mg, 0.055 mmol, 1.0 equivalent) in DCM (2 mL), add 1 mL of trifluoroacetic acid (TFA) at 0 °C. After stirring overnight at room temperature, cool the mixture to 0 °C and alkalize it with a saturated aqueous solution of _NaHCO3 . Extract the mixture with DCM (2 × 10 mL), wash the combined organic layers with brine (1 × 10 mL), and dry _with anhydrous _Na2SO4 . After filtration, the concentrated filtrate was purified by thin-layer chromatography (PE:EtOAc=10:1) to obtain 3-(3,4-difluoro-2-methoxyphenyl)-5-phenyl-5-(trifluoromethyl)isoxazolidine (14 mg, 0.039 mmol, 70.9% yield), a colorless oil. ESI-MS m/z=360.18[M+H] ⁺ ; calculated molecular weight: 359.09.

Step 4: Add 3-(3,4-difluoro-2-methoxyphenyl)-5-phenyl-5-(trifluoromethyl)isoxazolidine (7 mg, 0.0195 mmol, 1.0 equivalent), triethylamine (4 mg, 0.039 mmol, 2.0 equivalent), and dichloromethane (0.5 mL) to the reaction vessel. After cooling to 0°C, add 4-isocyanopyridine (4 mg, 0.0292 mmol, 2.0 equivalent), and stir the mixture overnight at room temperature. Dilute the resulting mixture with _H₂O (5 mL) and extract with dichloromethane (2 x 10 mL). Wash the combined organic layers with brine (1 × 10 mL) and dry _with anhydrous _Na₂SO₄ . After filtration, concentrate the filtrate under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc = 3:1) to give 3-(3,4-difluoro-2-methoxyphenyl)-5-phenyl-N-(pyridin-4-yl)-5-(trifluoromethyl)isoxazolidine-2-carboxamide (1.4 mg, 0.0029 mmol, 14.9% yield, 1:0.3 stereoisomer mixture, purity 99.1%), as a white solid. ^¹H NMR (400MHz, _CDCl₃ , reporting major isomer peaks) δ 8.50 (d, J = 5.5Hz, 2H), 7.79 (s, 1H), 7.48–7.37 (m, 7H), 7.03 (ddd, J = 8.3, 5.7, 2.1Hz, 1H), 6.73 (td, J = 9.2, 7.2Hz, 1H), 5.83 (dd, J = 8.8, 6.3Hz, 1H), 4.02 (d, J = 2.7Hz, 3H), 3.65 (dd, J = 13.5, 8.9Hz, 1H), 2.80 (dd, J = 13.6, 6.2Hz, 1H). ESI-MS m/z = 480.26 [M+H] ^⁺ ; calculated molecular weight: 479.13.

Example 13. Compounds 30-32.

Compounds 30-32.

Step 1: At ℃, m-CPBA (85%, 2.1 mg, 0.0105 mmol, 1.0 equivalent) was added to a stirred DCM solution of rac-4 -((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-tetrahydrothiophene-2-methacinyl)pyridinamide (5.0 mg, 0.0105 mmol, 1.0 equivalent). The mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with saturated _{Na₂SO₃ solution} (2 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine (5 mL) and dried _with anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=1:1) to give rac-4 -((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-oxo-5-(trifluoromethyl)tetrahydrothiophene-2-methacrylamide)pyridinamide (2.2 mg, 0.0045 mmol, 42.7% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 11.20 (s, 1H), 8.49 (d, J =5.5Hz, 1H), 8.41 (d, J =5.5Hz, 1H), 8.36 (s, 1H), 7.89 (d, J =5.5Hz, 1H), 7.78 (br, 1H), 7.09 (ddd, J =8.1, 5.5, 2.2Hz, 1H), 6.98-6.83 (m, 1H), 4.57 (dt, J =13.6, 7.0Hz, 1H), 4.35 (d, J =8.4Hz, 1H), 4.00 (s, 3H), 3.34 (t, J =13.1Hz, 1H), 2.50 (dt, J =11.1 (5.5 Hz, 1H), 1.54 (s, 3H). ESI-MS m/z = 492.24 [M+H] ⁺ ; calculated molecular weight: 491.09.

Step 2: Add m-CPBA (85%, 8.6 mg, 0.042 mmol, 4.0 equivalent) to 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-methacinyl)pyridinamide (5.0 mg, 0.0105 mmol, 1.0 equivalent) in DCM (0.5 mL) at 0 °C. Stir the mixture overnight at room temperature. Quench the resulting mixture with saturated _{Na₂SO₃ solution} (2 mL) and then extract with EtOAc (5 mL × 2). Wash the combined organic layers with brine (5 mL) and dry _with anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=1:2) to give 2-aminomethoxy-4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1,1-dioxo-5-(trifluoromethyl)tetrahydrothiophene-2-methoxyamino)pyridine 1-oxide (2.5 mg, 0.0048 mmol, 45.5% yield, purity 92.1%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 11.37 (d, J =4.9Hz, 1H), 10.99 (s, 1H), 8.48 (dd, J =7.5, 3.1Hz, 1H), 8.35 (d, J =3.2Hz, 1H), 8.21 (d, J =7.2Hz, 1H), 7.48(s, 1H), 6.97-6.88(m, 1H), 6.82(q, J =8.4Hz, 1H), 4.69(d, J =9.9Hz, 1H), 4.34-4.23(m, 1H), 4.07(s, 3H), 2.90(t, J =13.3Hz, 1H), 2.33(dd, J =13.4 (6.8 Hz, 1H), 1.78 (s, 3H). ESI-MS m/z = 524.26 [M+H] ⁺ ; calculated molecular weight: 523.08.

Step 3: To a solution of 2-aminomethoxy-4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1,1-dioxo-5-(trifluoromethyl)tetrahydrothiophene-2-methoxyamino)pyridine 1-oxide (5.0 mg, 0.0096 mmol, 1.0 equivalent) in ethanol (0.5 mL), under argon protection at room temperature, add DIEtOAc (1.2 mg, 0.0096 mmol, 1.0 equivalent), CuI (5.5 mg, 0.0287 mmol, 3.0 equivalent), and Zn powder (1.9 mg, 0.0287 mmol, 3.0 equivalent). Stir the resulting mixture at 60 °C for 2 hours. The resulting mixture was rapidly cooled with ice water (5 mL) and then extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine (5 mL) and dried _over anhydrous _Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc = 2:3) to give 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1,1-dioxo-5-(trifluoromethyl)tetrahydrothiophene-2-methoxyamino)pyridinamide (3.0 mg, 0.0059 mmol, 61.6% yield, purity 94.0%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.86 (s, 1H), 8.49 (d, J =5.7Hz, 1H), 8.40 (d, J =5.5Hz, 1H), 8.22(s, 1H), 7.95(s, 1H), 7.01-6.91(m, 1H), 6.92-6.76(m, 2H), 4.81(d, J =9.8Hz, 1H), 4.43-4.29(m, 1H), 4.07(s, 3H), 2.91(t, J =13.2Hz, 1H), 2.33 (dd, J =13.4, 6.8Hz, 1H), 1.79 (s, 3H). ESI-MS m/z = 508.28 [M+H] ⁺ ; Calculated MW: 507.09.

The preparation method of compound 32 is similar to that described for compound 126.

Example 14. Compound 149.

Compound 149

Step 1: Add 2,3-difluorophenol (4.0 g, 30.75 mmol, 1.0 equivalent) to a flame-dried three-necked flask. After purging with argon three times, add DCM (40 mL) and cool the mixture to 0°C. Add pyridine (3.65 g, 3.73 mL, 46.12 mmol, 1.5 equivalent) to the mixture, and then add propionyl chloride (3.70 g, 3.52 mL, 39.97 mmol, 1.3 equivalent) dropwise at 0°C. Stir the reaction mixture at room temperature for 2 hours. Quench the mixture with HCl (1 mmol/mL, 20 mL), and extract the aqueous layer with DCM (20 mL × 2). The combined organic layers were washed with _H₂O (30 mL), dried with _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:DCM = 100: ₁ to 2:1) to give 2,3-difluoromethylphenylpropionate (5.3 g, 28.47 mmol, 92.6% yield) as a colorless oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.11–6.97 (m, 2H), 6.94–6.77 (m, 1H), 2.64 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).

Step 2: Add 1,2-dichlorobenzene (2.65 mL) and aluminum trichloride (3.8 g, 28.47 mmol, 1.0 equivalent) to the reaction vessel. Purge the mixture three times with argon and then cool to 0°C. Add 2,3-difluorophenylpropionate (5.3 g, in 2.65 mL of dichlorobenzene, 28.47 mmol, 1.0 equivalent) dropwise to the mixture at 0°C and stir at 100°C for 3 hours. After cooling to room temperature, quench the mixture at 0°C with hydrochloric acid solution (1 mmol/mL, 50 mL), and then extract the aqueous layer with dichloromethane (50 mL × 2). The combined organic layers were washed with _H₂O (20 mL × 2), dried on _MgSO₄ , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 100:1 to 50:1) to give 1-(3,4-difluoro-2-hydroxyphenyl)prop-1-one (3.72 g, 19.98 mmol, 70.2% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 12.66 (d, J =1.5Hz, 1H), 7.57-7.50 (m, 1H), 6.70 (td, J =9.3, 6.7Hz, 1H), 3.00 (q, J =7.3Hz, 2H), 1.23 (t, J =7.3Hz, 3H).

Step 3: Add 1-(3,4-difluoro-2-hydroxyphenyl)prop-1-one (3.72 g, 19.98 mmol, 1.0 equivalent), potassium carbonate (5.52 g, 39.97 mmol, 2.0 equivalent), and acetone (37 mL) to the reaction vessel. Cool the mixture to 0°C and add iodomethane (2.11 mL, 4.82 g, 33.97 mmol, 1.7 equivalent) dropwise at 0°C. Stir the reaction mixture at 60°C for 4 hours. After cooling to room temperature, filter the mixture, and wash the solid with ethyl acetate (20 mL × 2). Wash the combined filtrate with brine (20 mL × 2), dry on _MgSO₄ , filter, and concentrate under reduced pressure. The crude product was purified by silica gel chromatography (PE:DCM = 10:1 to 1:1) to give 1-(3,4-difluoro-2-methoxyphenyl)prop-1-one (3.9 g, 19.48 mmol, 97.5% yield), as a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.46–7.40 (m, 1H), 6.91 (td, J = 9.0, 6.8 Hz, 1H), 4.05 (d, J = 2.6 Hz, 3H), 2.94 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H).

Step 4: Add 1-(3,4-difluoro-2-methoxyphenyl)prop-1-one (3.5 g, 17.48 mmol, 1.0 equivalent), triethylamine (4.44 g, 6.10 mL, 43.88 mmol, 2.5 equivalent), and dichloromethane (35 mL) to the reaction vessel. Cool the reaction mixture to 0°C, purge it three times with argon, and add trimethylsilyl trifluoromethanesulfonate (3.8 mL, 4.66 g, 20.98 mmol, 1.2 equivalent) dropwise to the mixture at 0°C. Stir the reaction mixture at 0°C for 1 hour and then rapidly cool it with saturated _NaHCO3 aqueous solution (10 mL). The aqueous layer was extracted with DCM (20 mL × 2), and the combined organic layer was washed with _H₂O (20 mL), dried on _MgSO₄ , filtered, and concentrated under reduced pressure to give crude product ((1-(3,4-difluoro-2-methoxyphenyl)prop-1-en-1-yl)oxy)trimethylsilane (4.08 g, 14.99 mmol, 100% yield), which was used directly for the next step without further processing. Tin tetrachloride (6.83 g, 3.08 mL, 26.21 mmol, 1.5 equivalents) was added to the reaction vessel. After cooling to -30 °C, 1,1,1-trifluoro-2-propanone (2.55 g, 2.04 mL, 22.72 mmol, 1.3 equivalents) was added to the mixture at -30 °C. The mixture was stirred at -30°C for 30 minutes, and then (((1-(3,4-difluoro-2-methoxyphenyl)prop-1-en-1-yl)oxy)trimethylsilane (4.08 g, in 3.5 mL DCM, 14.99 mmol, 100%, 1.0 equivalent) was added at -30°C. After stirring at -30°C for 3 hours, the reaction was quenched with saturated _NaHCO3 aqueous solution (10 mL). After filtration, the filtrate was extracted with DCM (20 mL × 2). The combined organic layers were washed with _H2O (20 mL) and filtered through MgSO4. _4. Dry, filter, and concentrate under reduced pressure. The crude product was purified by silicone chromatography (PE:DCM = 200:1 to 1:1) to give 1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-3-hydroxy-2,3-dimethyl-1-butanone (3.0 g, 9.61 mmol, 64.2% yield), a mixture of two diastereomers.

Step 5: Add 1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-3-hydroxy-2,3-dimethyl-1-butanone (3.0 g, 9.61 mmol, 1.0 equivalent), pyridine (4.56 g, 4.66 mL, 57.65 mmol, 6 equivalent), and toluene (30 mL) to the reaction vessel. Purge the mixture three times with argon, then add thiocyanate (5.14 g, 3.14 mL, 43.24 mmol, 4.5 equivalent) dropwise at room temperature. Stir the reaction at 90 °C for 16 hours and quench with hydrochloric acid (1 mmol/mL, 10 mL) at 0 °C. Extract the aqueous phase with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:DCM = 200:1 to 20:1) to give (Z)-1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-2,3-dimethylbut-2-en-1-one (860 mg, 2.92 mmol, 30.2% yield) as a yellow oil. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.62 (dd, J = 8.7, 6.1 Hz, 1H), 7.04–6.92 (m, 1H), 3.99 (s, 3H), 2.04 (s, 3H), 1.68 (s, 3H). (E)-1-(3,4-difluoro-2-methoxyphenyl)-4,4,4-trifluoro-2,3-dimethylbut-2-en-1-one (1.61 g, 5.47 mmol, 56.9% yield) was a yellow solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.71–7.61 (m, 1H), 7.01–6.90 (m, 1H), 3.95 (s, 3H), 1.94 (s, 3H), 1.90 (s, 3H).

Step 6: Add (Z)-1-(3,4-difluoro-2-methoxyphenyl)-4,4,4- _trifluoro -2,3-dimethylbut-2-en-1-one (860 mg, 2.92 mmol, 1.0 equivalent) and _Al₂O₃ (1.49 g, 14.61 mmol, 5.0 equivalent) to the reaction vessel. After purging with argon three times, add 2-ethyl 2-methylacetate (1.05 g, 0.966 mL, 8.77 mmol, 3.0 equivalent) to the mixture at room temperature. Stir the reaction at 50 °C for 3 hours, cool to room temperature, filter, and wash the filter cake with DCM (20 mL × 2). The combined filtrate was reduced pressure and concentrated, and purified by silicone chromatography (PE:DCM = 100:1 to 1:1) to give ethyl 2-((4-(3,4-difluoro-2-methoxyphenyl)-1,1,1-trifluoro-2,3-dimethyl-4-oxobut-2-yl)thio)ethyl acetate (500 mg, 1.21 mmol, 41.3% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.30-7.26 (m, 1H), 6.90 (dt, J =10.0, 8.0Hz, 1H), 4.19 (q, J =7.0Hz, 2H), 4.08 (s, 3H), 3.84 (q, J =6.8Hz, 1H), 3.50-3.36(m, 2H), 1.43(d, J =7.0Hz, 3H), 1.32-1.24(m, 6H).

Step 7: Add ethyl 2-[(4-(3,4-difluoro-2-methoxyphenyl)-1,1,1-trifluoro-2,3-dimethyl-4-oxobut-2-yl)thio] (530 mg, 1.28 mmol, 1.0 equivalent), guanidine (217 mg, 0.234 mL, 2.0 equivalent), and benzene (5.3 mL) to the reaction vessel. Stir the mixture at 60 °C for 16 hours and then concentrate under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=10:1) to give ethyl 3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxy-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (420 mg, 1.01 mmol, 79.3% yield), which was a grayish-white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.51-7.42 (m, 1H), 6.97-6.82 (m, 1H), 5.09 (s, 1H), 4.13-3.89 (m, 6H), 2.86 (q, J =7.6Hz, 1H), 1.74 (s, 3H), 1.02 (t, J =6.7Hz, 3H), 0.88 (d, J =7.4Hz, 3H).

Step 8: Add ethyl 3-(3,4-difluoro-2-methoxyphenyl)-3-hydroxy-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (350 mg, 0.844 mmol, 1.0 equivalent), pyridine (400 mg, 0.409 mL, 5.07 mmol, 6.0 equivalent), and toluene (7 mL) to the reaction vessel. After purging with argon three times, add thiocyanate (452 mg, 0.275 mL, 3.8 mmol, 4.5 equivalent) to the mixture at room temperature. Stir the reaction at 90 °C for 5 hours, cool to room temperature, and quench with hydrochloric acid (1 mmol/mL, 10 mL) at 0 °C. The aqueous layer was extracted with EtOAc (20 mL × 2), and the combined organic layer was washed with brine (40 mL), dried _on anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain crude ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrothiophene-2-carboxylate (330 mg, 0.832 mmol, 98.6% yield), a yellow oily substance that requires no further processing and can be used directly in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.89-6.82 (m, 1H), 6.79-6.68 (m, 1H), 4.10-4.05 (m, 2H), 3.91 (s, 3H), 3.37 (q, J =7.4Hz, 1H), 1.76 (s, 3H), 1.12 (t, J =7.1Hz, 3H), 1.06 (d, J =7.5Hz, 3H).

Step 9: Add ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrothiophene-2-carboxylate (330 mg, 0.832 mmol, 1.0 equivalent) and ethanol (15 mL) to the reaction vessel. After purging with argon three times, add Pd/C (1.06 g, 5% w/w.) and Pd(OH) _₂ (993 mg, 10% w/w.) to the mixture at room temperature. Purge the reaction mixture three times with hydrogen and then stir at 40 °C for 16 hours. After cooling to room temperature, filter the mixture, and wash the filter cake with ethanol (10 mL × 2). The combined filtrate was concentrated under reduced pressure and purified by thin-layer chromatography (PE:DCM:EtOAc = 40:10: ¹ ) to give rac-ethyl (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (110 mg, 0.276 mmol, 33.2% yield). ¹H NMR (400 MHz, _CDCl₃ ) δ 7.78–7.69 (m, 1H), 6.78 (q, J = 8.8 Hz, 1H), 4.77 (d, J = 6.7 Hz, 1H), 4.36 (t, J = 7.0 Hz, 1H), 4.00–3.90 (m, 5H), 2.69 (p, J = 7.0 Hz, 1H). J =6.2Hz, 1H), 1.70 (s, 3H), 1.01 (d, J =7.3Hz, 3H), 0.93 (t, J =7.1Hz, 3H).

Step 10: Add (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid rac- ethyl ester (110 mg, 0.276 mmol, 1.0 equivalent) and THF (2.2 mL) to the reaction vessel. After cooling to 0°C, add LiOH (19.84 mg, dissolved in 1.1 mL _H₂O , 0.828 mmol, 3.0 equivalent) at 0°C. Stir the reaction mixture at room temperature for 16 hours. Dilute the reactant with ice water (10 mL) and then acidify with hydrochloric acid (1 mmol/mL, 0.828 mL) to pH 6. The aqueous layer was extracted with EtOAc (10 mL × 2), and the combined organic layer was washed with brine (20 mL × 2 ₎ , dried with _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain crude rac- (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (90 mg, 0.243 mmol, 88.0% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.88-6.76 (m, 2H), 4.51 (dd, J =11.6Hz, 1H), 4.38 (dd, J =11.6, 5.5Hz, 1H), 4.00 (d, J =2.2Hz, 3H), 2.63-2.53(m, 1H), 1.84(s, 3H), 0.84-0.76(m, 3H).

Step 11: Add rac- (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (90 mg, 0.243 mmol, 1.0 equivalent), methyl 4-amino-2-pyridinecarboxylate (48 mg, 0.315 mmol, 1.3 equivalent), and _CH3CN (2.0 mL) to the reaction vessel. After cooling to 0°C, add 1-methyl-1H-imidazole (49 mg, dissolved in 0.2 mL MeCN, 0.607 mmol, 2.5 equivalent) and TCFH (102 mg, dissolved in 0.2 mL MeCN, 0.364 mmol, 1.5 equivalent) at 0°C. The reactants were stirred at room temperature for 16 hours, quenched with ice water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried _{with Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc = 1:3) to give rac-methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-methamino)pyridinecarboxylate (82 mg, 0.162 mmol, 66.9% yield), a white solid. ESI-MS m/z = 505.30 [M+H] ⁺ ; Calculated molecular weight: 504.11.

Step 12: Add rac-methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-methoxyamino)pyridinecarboxylate (82 mg, 0.162 mmol, 1 equivalent) and _NH3 (7 mmol/mL, MeOH solution, 2.0 mL, 14.0 mmol, 86.13 equivalents) to the reaction vessel. Stir the reaction mixture at 5°C for 16 hours, then concentrate under reduced pressure. The crude product was purified by thin-layer chromatography (PE:EtOAc=1:1) to obtain rac-4 -((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-methoxyamino)pyridinamide (50 mg, 0.102 mmol, 62.9% yield, 99.4% purity) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 9.80 (s, 1H), 8.45 (d, J =5.6Hz, 1H), 8.29 (dd, J =5.6, 2.1Hz, 1H), 8.14 (d, J =2.2Hz, 1H), 8.04 (d, J =4.4Hz, 1H), 6.97-6.91(m, 1H), 6.88-6.79(m, 1H), 6.01(d, J =4.4Hz, 1H), 4.83(d, J =11.5Hz, 1H), 4.55(dd, J =11.5, 5.5Hz, 1H), 4.06(d, J =2.4Hz, 3H), 2.67(p, J =7.1Hz, 1H), 1.91(s, 3H), 0.88(d, J =5.0Hz, 3H). ESI-MS m/z = 490.29 [M+H] ⁺ ; calculated molecular weight: 489.46.

The preparation method of compound 32 is similar to that described for compound 126.

Example 15. The provided technique can suppress the activation of the Nav1.8 channel.

According to the consensus of those skilled in the art, many techniques are available for evaluating the startup status of Nav1.8, including the method described in this disclosure. This section will provide examples to illustrate the specific methodology.

Cell Culture and Preparation: HEK293 cells stably expressing hNav1.8 sodium channels were placed in 35 mm culture dishes and cultured at 37°C in a 5% _CO2 incubator until a confluence of no more than 70-80%. The cell culture medium was discarded [DMEM (Gibco C11995500BT) supplemented with 10% fetal bovine serum (Gibco 10099141C) and 100 μg/mL hygromycin (Gibco 10687010)]. The hNav1.8-HEK293 cells were then rinsed with extracellular fluid. The cells were then digested with 0.25% trypsin-EDTA (Gibco C25200056) for 3-5 minutes. The digestive fluid was then removed, and the cells were resuspended in the extracellular fluid using a pipette, gently blowing them up and down several times. Finally, the resuspended cells were transferred to a special culture dish for recording.

Compound preparation: Prepare the compound storage solution using dimethyl sulfoxide (DMSO) and store at -20°C. On the day of testing, thaw the compound storage solution and dilute to a moderate concentration with DMSO, then dilute 500-fold with extracellular fluid to the final concentration. During extracellular administration, deliver the compound-containing extracellular fluid to the cells to be recorded using gravity. Continue administration for at least 60 seconds until a stable hNav1.8 sodium current is observed, or stop administration for a maximum of 180 seconds. Test at least 2 cells ( n) for each concentration. 2 ).

Electrophysiological recording procedure: Current recording was performed in HEK293 cells stably expressing hNav1.8 sodium channels. During recording, the extracellular fluid used for cell perfusion contained: 140 mM NaCl, 5 mM KCl, ₁ mM CaCl₂, 1.25 mM _MgCl₂ , 10 mM HEPES, and 10 mM glucose, adjusted to pH 7.4 with NaOH. Microelectrodes (tip resistance 3-5 megohms) were drawn using a borosilicate glass capillary puller (Sutter instrument BF150-86-10), and intracellular fluid (130 mM CsF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES, adjusted to pH 7.2 with CsOH) was injected before use. Data was acquired using a Multiclamp 700B amplifier (Molecular Devices). The signal was filtered at 2 kHz using pClamp 10 software and sampled at 10 kHz. Cells were clamped at -120 mV, and hNav1.8 sodium current was induced using the following voltage stimulation program: a 20-second 0 mV depolarization potential (T1) was applied to induce a sodium current, followed by a 5-second -40 mV inactivation potential, then a 20-second 0 mV depolarization potential (T2) to induce a second sodium current, and finally a 100-millisecond -120 mV voltage was applied. All measurements were performed at room temperature.

Data Processing: Data was extracted and analyzed using pClamp 10, GraphPad Prism 8, and Microsoft Excel. The peak amplitude of the hNav1.8 sodium current (induced at 0 mV, T1) was calculated using Clampfit and exported to Excel and GraphPad Prism 8 for further analysis. To calculate the concentration ( _IC50 ) at which the tested compound blocks 50% of the current, the normalized concentration-inhibition relationship was fitted in Rrism 8 software using the following equation:

Y = Minimum + (Maximum - Minimum) / (1 + 10^((LogIC ₅₀ - [X]) * HillSlope)) where Y is the inhibition rate corresponding to X, [X] is the logarithm of the compound concentration in the extracellular fluid, and HillSlope is the Hill coefficient. The inhibition rate is calculated as (1 - I / Io ) * 100%, where Io and I are the baseline current and the current amplitude measured in the presence of the analyte, respectively. At least two cells must be tested for each concentration.

Table 2 provides the corresponding data for the specific compounds listed in the above tests. Unless otherwise stated, the following are inhibition rates at 100 nM: A>=80%; B<80% and>=50%; C<50% and>=20%; D<20%.

Table 2. Corresponding results for the listed compounds.

While various embodiments have been described and illustrated herein, it will be readily apparent to those skilled in the art that various other methods and/or structures can be devised to perform the functions described herein and/or obtain the results and/or one or more advantages described herein, and each such variation and/or modification is considered to be included. More generally, it will be readily understood by those skilled in the art that all parameters, dimensions, materials, and configurations described herein are exemplary, and actual parameters, dimensions, materials, and/or configurations may depend on one or more specific applications using the guidance of this disclosure. Those skilled in the art will recognize, or can determine by routine experimentation alone, that many equivalent methods exist for the embodiments of this disclosure. Therefore, it should be understood that the above embodiments are presented by way of example only, and the claimed technology may be implemented in ways other than those specifically described and claimed, within the scope of the appended claims and their equivalents. Furthermore, any combination of two or more features, systems, articles, materials, kits, and/or methods, provided that such features, systems, articles, materials, kits, and/or methods are not contradictory, is also included within the scope of this disclosure.

Claims (592)

A compound represented by general formula I, or a salt thereof: in R1 is a substituted group selected from the following structures: a 6-10 membered aryl group, a 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-10 membered heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a bicyclic group, wherein the first ring is attached to a nitrogen atom and is a benzene ring or a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the second ring is a benzene ring, a 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-10 membered heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R1 is ; R 1' is R', or R 1 and R 1' together with the nitrogen atom to which they are attached form an optional substituted 3-6 membered ring, which may contain 0-3 heteroatoms in addition to the nitrogen atom; R2 is a substituted group, selected from phenyl groups and 5-6 membered heteroaryl groups having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or R2 is ; R3 and R4 are each independently hydrogen, -CN, or R; X is -O-, -S-, -S(O)-, -S(O) 2- or -C( Rx ) 2- , where each Rx is independently hydrogen, a optionally substituted C1- C6 aliphatic group, -OR or -N(R) 2 ; W is N, C, or C(R w ), where R w is hydrogen or an alternatively substituted C1 - C6 aliphatic group, -OR, or -N(R) 2 , where Z is C when W is C; Z is N, C or C(R z ), where R z is hydrogen or an alternatively substituted C1- C6 aliphatic group, -OR or -N(R) 2 , where when Z is C, W is C or Y is -C(R y ) = ; Y is -O-, -S-, -N( Ry )-, -C( Ry ) 2- or -C( Ry )=, where each Ry is independently hydrogen, a optionally substituted C1- C6 aliphatic group, -OR or -N(R) 2 , and when Y is -C( Ry )=, Z is C; Ring A and ring B are each independently substituted 5-6 membered aromatic rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R s1 is independently a halogen, -CN,R s11 , -OR s11  , -NR  s11Rs12 , -C(O)R s11  , -C(O)NR s11 R  s12 , -S(O)2  NRs11R s12 , -S(O)2NR s11 R s12  , or -OS(O) 2  NR  s11Rs12 . Each R s2 is independently a halogen, -CN,R s21 , -OR s21  , -NR  s21Rs22, -C(O)R s21 , -C(O)NR s21 R s22  , -S(O)2NR s21  , -S(O)(NR s22 )R s21  , -S(O)NR s21  R s22 , or -OS(O) 2 NR  s21 R s22 . s1 and s2 are each independently 0, 1, 2, 3, 4, or 5; Rs11 , Rs12 , Rs21 and Rs22 are each independently R'; Each They are all independent single or double keys; Each R' is independently R, -OR, -C(O)R, -C(O)OR, -S(O)R, or -S(O) 2R ; Each R is independently a hydrogen or optionally substituted group, said group being selected from: C1 - C6 aliphatic, C1 - C6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-10 membered cycloaliphatic, 3-10 membered heterocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 membered aryl, 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 membered aryl- C1 - C6 aliphatic, and 5-10 membered heteroaryl- C1 - C6 aliphatic having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on the same atom can be optionally and independently formed with the atom to form a substituted 3-10 membered ring, which, in addition to the atom, may also contain 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on two atoms can optionally and independently form a substituted 3-10 membered ring together with the spacer atom between them, said ring may also contain 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, in addition to said spacer atom; and When X is -O-, W is not -CH-, or Z is not -CH-, or Y is not -C(R y ) 2 -. The compound as described in claim 1 has the structure of formula Ia: Or its salt. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted 6-10 aryl group. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted phenyl group. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted naphthyl group. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-10 heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is a substituted 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is a substituted 5-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-membered heteroaryl group having one heteroatom. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-membered heteroaryl group having a nitrogen heteroatom. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-membered heteroaryl group having a sulfur heteroatom. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-membered heteroaryl group having a nitrogen heteroatom and an oxygen atom. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-membered heteroaryl group having a nitrogen heteroatom and a sulfur atom. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-membered heteroaryl group having two nitrogen atoms. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted 6-membered heteroaryl group having a nitrogen atom. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 6-membered heteroaryl group having two nitrogen atoms. The compound as claimed in any one of claims 1 to 2, wherein R 1 is a substituted 9-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 9-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 10-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 3- to 10-membered heterocyclic group having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 3- to 10-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 3-7 membered heterocyclic group having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted 6-membered heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted bicyclic ring. The compound as described in claim 27, wherein the first ring is an optional substituted benzene ring. The compound as claimed in claim 27, wherein the first ring is a optionally substituted 5-6 membered heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. The compound as claimed in claim 27, wherein the first ring is a optionally substituted 5-6 membered heteroaryl ring having 1-2 independently selected heteroatoms of nitrogen, oxygen, and sulfur. The compound as described in any of claims 27 to 30, wherein the second ring is an optional substituted benzene ring. Compounds as described in any of claims 27 to 30, wherein the second ring is a optionally substituted 5-6 membered heteroaryl ring having 1-4 independently selected heteroatoms of nitrogen, oxygen, and sulfur. Compounds as described in any of claims 27 to 30, wherein the second ring is a optionally substituted 5-6 membered heteroaryl ring having 1-2 independently selected heteroatoms of nitrogen, oxygen, and sulfur. Compounds as described in any of claims 27 to 30, wherein the second ring is an optional substituted 3- to 10-membered heterocyclic ring having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. Compounds as described in any of claims 27 to 30, wherein the second ring is an optional substituted 3- to 10-membered heterocyclic ring having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. Compounds as described in any of claims 27 to 30, wherein the second ring is an optional substituted 5-6 membered heterocyclic ring having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. Compounds as described in any of claims 27 to 30, wherein the second ring is an optional substituted 5-6 membered heterocyclic ring having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. The compound as described in any of claims 27 to 30, wherein the second ring is an optional substituted 5-membered heterocyclic ring having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. The compound as described in any of claims 27 to 30, wherein the second ring is an optionally substituted 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound as described in any of claims 27 to 39, wherein the first ring and the second ring are fused. The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. . The compound as described in any one of claims 1 to 2, wherein R1 is The compound as described in claim 61, wherein ring A is an optionally substituted phenyl group. The compound as claimed in claim 61, wherein ring A is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound as claimed in claim 61, wherein ring A is a 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound as described in any of claims 61 to 64, wherein s1 is 1-5. The compound as described in any of claims 61 to 64, wherein s1 is 1 or 2. The compound as described in any one of claims 1 to 2, wherein R1 is a phenyl group optionally substituted with 1 to 5 Rs1 . The compound as described in any one of claims 1 to 2, wherein R1 is a phenyl group substituted with two or more Rs1 . The compound as claimed in any one of claims 1 to 2, wherein R 1 is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is optionally substituted by 1 to 5 R s1 . The compound as claimed in any one of claims 1 to 2, wherein R1 is a 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is optionally substituted by 1 to 5 Rs1 . The compound according to any of the foregoing claims, wherein R1 is substituted. The compound according to any of the preceding claims, wherein R1 is substituted by 1-2 substituents. The compound according to any of the foregoing claims, wherein the substituent is located at position 2 ( R1 is attached to the nitrogen atom at position 1). The compound according to any of the foregoing claims, wherein the substituent is located at the 3 position (R 1 is attached to the nitrogen atom at the 1 position). The compound according to any of the foregoing claims, wherein the substituent is located at position 4 ( R1 is attached to the atom of nitrogen at position 1). The compound as described in any of claims 1 to 2, wherein R1 is Among them, Ra1 , Rb1 , Rc1 , Rd1 and Re1 are each independently Rs1 . The compound as described in claim 76, wherein R1 is... . The compound as described in claim 76, wherein R1 is... . The compound as described in claim 76, wherein R1 is... . The compound as described in claim 76, wherein R1 is... . The compound as described in claim 76, wherein R1 is... . The compound as described in any of claims 1 to 2, wherein R1 is Furthermore, Rf1 , Rg1 , Rh1 , and Ri1 are each independently Rs1 . The compound as described in claim 82, wherein R1 is . The compound as described in claim 82, wherein R1 is . The compound as described in any of claims 1 to 2, wherein R1 is Furthermore, Rj1 , Rk1 , Rl1 , and Rm1 are each independently Rs1 . The compound as described in claim 85, wherein R1 is . The compound as claimed in any of claims 1 to 86, wherein each substituent on R1 is independently Rs1 , wherein each Rs1 is independently selected from a halogen, -CN, Rs11 , -ORs11 , -NRs11Rs12 , -C(O) Rs11 , -C(O)NRs11Rs12, -S( O ) 2NRs11Rs12, -S(O)2Rs11 , -S(O) Rs11 , -S( O )( NRs12 ) Rs11 , and -OS(O) 2NRs11Rs12 , wherein Rs11 and Rs12 are each independently -H or optionally substituted groups selected from C1 - C2. A 6- aliphatic group or a 5-6 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the group is optionally substituted by one or more (e.g. 1-3) substituents independently selected from halogen, -OH or =O. The compound as claimed in any of claims 1 to 86, wherein each substituent on R1 is independently Rs1 , wherein each Rs1 is independently selected from a halogen, -CN, Rs11 , -ORs11 , -NRs11Rs12 , -C(O) Rs11 , -C(O)NRs11Rs12, -S( O ) 2NRs11Rs12, -S(O)2Rs11 , -S(O) Rs11 , -S( O )( NRs12 ) Rs11 , and -OS(O) 2NRs11Rs12 , wherein Rs11 and Rs12 are each independently -H or optionally substituted groups selected from C1 - C2. A 6- aliphatic group or a 5-6 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the group is optionally substituted by one or more (e.g. 1-3) substituents independently selected from halogen, -OH or =O. The compound as claimed in any of claims 1 to 86, wherein each substituent on R1 is independently Rs1 , wherein each Rs1 is independently selected from a halogen, -CN, Rs11 , -ORs11 , -NRs11Rs12 , -C(O) Rs11 , -C(O)NRs11Rs12, -S( O ) 2NRs11Rs12, -S(O)2Rs11 , -S(O) Rs11 , -S( O )( NRs12 ) Rs11 , and -OS(O) 2NRs11Rs12 , wherein Rs11 and Rs12 are each independently -H or optionally substituted groups selected from C1 - C2. A 6- aliphatic group or a 5-6 membered ring having 0-4 nitrogen atoms, the group being optionally substituted by one or more (e.g., 1-3) substituents independently selected from halogens, -OH or =O. The compound as claimed in any of claims 1 to 86, wherein each substituent on R1 is independently Rs1 , wherein each Rs1 is independently selected from a halogen, -CN, Rs11 , -ORs11 , -NRs11Rs12 , -C(O) Rs11 , -C(O)NRs11Rs12, -S( O ) 2NRs11Rs12, -S(O)2Rs11 , -S(O) Rs11 , -S( O )( NRs12 ) Rs11 , and -OS(O) 2NRs11Rs12 , wherein Rs11 and Rs12 are each independently -H or optionally substituted groups selected from C1 - C2. A 6- aliphatic group or a 5-6 membered saturated ring having 1-2 nitrogen atoms, wherein the group is optionally substituted by one or more (e.g., 1-3) substituents independently selected from halogens, -OH or =O. The compound according to any of the foregoing claims, wherein R s1 is a halogen. The compound as described in any of claims 87 to 91, wherein R s1 is F. The compound as described in any of claims 87 to 92, wherein R s1 is Cl. The compound as described in any of claims 87 to 93, wherein R s1 is Br. The compound as described in any of claims 87 to 94, wherein R s1 is I. The compound as described in any of claims 87 to 95, wherein R s1 is -CN. The compound according to any of the foregoing claims, wherein R s1 is R s11 . The compound according to any of the foregoing claims, wherein R s1 is -OR s11 . The compound according to any of the foregoing claims, wherein R s1 is -NR s11 R s12 . The compound according to any of the foregoing claims, wherein R s1 is -C(O)NR s11 R s12 . The compound according to any of the foregoing claims, wherein R s1 is -S(O) 2 NR s11 R s12 . The compound according to any of the foregoing claims, wherein R s1 is -S(O) 2 R s11 . The compound according to any of the foregoing claims, wherein R s1 is -S(O)R s11 . The compound according to any of the foregoing claims, wherein R s1 is -S(O)(NR s12 )R s11 . The compound according to any of the foregoing claims, wherein R s1 is -OS(O) 2 NR s11 R s12 . The compound as described in any of claims 87 to 105, wherein Rs12 is an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 87 to 105, wherein Rs12 is an optional substituted C1 - C6 alkyl group. The compound as described in any of claims 87 to 105, wherein R s12 is methyl. The compound as described in any of claims 87 to 105, wherein R s12 is -H. The compound according to any of the preceding claims, wherein R s11 is a C1 - C6 aliphatic group optionally substituted by one or more (e.g., 1-3) substituents independently selected from halogen, -OH or =O. The compound as claimed in claim 110, wherein R s11 is a C1 - C6 alkyl group optionally substituted with one or more (e.g., 1-3) substituents independently selected from halogen or -OH. The compound as described in any of claims 110 to 111, wherein R s11 is a C1 - C4 alkyl group optionally substituted by one or more (e.g., 1-3) substituents independently selected from halogen, -OH or =O. The compound as described in any one of claims 110 to 112, wherein R s11 is a C1 - C6 alkyl group. The compound as described in any one of claims 110 to 112, wherein R s11 is a C1 - C3 alkyl group. The compound as described in any of claims 97 to 112, wherein R s11 is methyl. The compound as described in any of claims 97 to 112, wherein R s11 is -CH 2 OH. The compound as described in any of claims 97 to 112, wherein R s11 is -CHF 2 . The compound as described in any of claims 97 to 112, wherein R s11 is -CH(OH)CH 2 OH. The compound as described in any of claims 97 to 112, wherein R s11 is -C(OH)(Me) 2 . The compound as described in any of claims 97 to 112, wherein R s11 is -C(OH)(Me) 2 . The compound as described in any of claims 87 to 109, wherein R s11 is a substituted 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 87 to 109, wherein R s11 is an optional substituted 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 87 to 109, wherein R s11 is optionally substituted. . The compound as described in any of claims 87 to 109, wherein R s11 is an optional substituted 5-membered heterocyclic group having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 87 to 109, wherein R s11 is an optional substituted 6-membered heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 87 to 109, wherein R s11 is optionally substituted. . The compound as described in any of claims 87 to 109, wherein R s11 is The compound as described in any of claims 87 to 109, wherein R s11 is optionally substituted. . The compound as described in any of claims 87 to 109, wherein R s11 is -H. The compound as described in any of claims 87 to 105, wherein Rs1 is -CONH2 . The compound as described in any of claims 87 to 105, wherein R s1 is -CONHCH 3 . The compound as described in any of claims 87 to 105, wherein R s1 is -S(O) 2 NH 2 . The compound as described in any of claims 87 to 105, wherein R s1 is -S(O) 2 Me. The compound as described in any of claims 87 to 105, wherein R s1 is -S(O)Me. The compound as described in any of claims 87 to 105, wherein R s1 is -S(NH)(O)Me. The compound as described in any of claims 87 to 105, wherein R s1 is -S(NMe)(O)Me. The compound as described in any of claims 87 to 105, wherein R s1 is -OH. The compound as described in any of claims 87 to 105, wherein R s1 is -OMe. The compound as described in any of claims 87 to 105, wherein Rs1 is -NH2 . The compound as described in any of claims 87 to 105, wherein R s1 is -OCH 2 CH(OH)CH 2 (OH). The compound as described in any of claims 1 to 70, wherein R1 is not substituted. The compound as described in any of claims 1 to 2, wherein R1 is And Ra1 , Rb1 , Rc1, Rd1 , and Re1 are each independently Rs1 , wherein Ra1 , Rb1 , Rc1 , Rd1 , and Re1 are each independently selected from halogens, -CN , -ORs11 , -NRs11Rs12 , -CONRs11Rs12 , -SO2NRs11Rs12 , and , wherein R s11 and R s12 are each independently -H or optionally substituted C 1 -C 6 aliphatic groups. The compound as claimed in claim 142, wherein Ra1 , Rb1 , Rc1 , Rd1 and Re1 are each independently selected from halogens, -CN, -ORs11 , -NRs11Rs12 , -CONRs11Rs12 , -SO2NRs11Rs12 and Rs11 and Rs12 are each independently -H or C1 - C6 alkyl. The compound as described in claim 142, wherein R1 is And Rb1 is a halogen, -CN, -OR s11 , -NR s11 R s12 , -CONR s11 R s12 , -SO 2 NR s11 R s12 or Each R s11 is independently a -H or C 1 -C 6 aliphatic group. The compound as described in claim 142, wherein R1 is And R b1 is -CONR s11 R s12 , -SO 2 NR s11 R s12 or , where R s11 is -H or C 1 - C 6 aliphatic group. The compound as described in claim 142, wherein R1 is And Rb1 is -CONH2 , -SO2NH2 or . The compound as described in any of claims 142 to 143, wherein R1 is The compound as described in any of claims 142 to 143, wherein R1 is The compound according to any of the foregoing claims, wherein Re1 is -OR s11 . The compound as described in any of claims 142 to 143, wherein R1 is The compound as described in any of claims 148 to 150, wherein Rb1 is selected from halogens, -CN, -OMe, -CONH2 and -SO2NH2 . The compound as described in any of claims 142 to 143, wherein R1 is , and Rb1 and Rc1 are each independently selected from halogens, -CN, -OMe, -C(O) NH2 and -SO2NH2 . The compound as described in any of claims 142 to 143, wherein R1 is Rb1 is selected from halogens, -CN, -OMe, -C(O) NH2 and -SO2NH2 , and Rc1 is selected from -F and -CN. The compound as described in any one of claims 1 to 2, wherein R1 is selected from The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-10 heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-6 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 5-6 membered heteroaryl group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 2, wherein R 1 is an optional substituted 6-membered heteroaryl group having one or two heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted pyridinyl group. The compound as described in any one of claims 1 to 2, wherein R 1 is pyridyl. The compound as described in any of claims 1 to 2, wherein R1 is . The compound as described in any of claims 1 to 2, wherein R1 is . The compound as described in any of claims 1 to 2, wherein R1 is . The compound as described in any of claims 1 to 2, wherein R1 is Furthermore, Rf1 , Rg1 , Rh1 , and Ri1 are each independently Rs1 , where each Rs1 is independently selected from halogens, -CN, -ORs11 , -NRs11Rs12 , -C(O) Rs11 , -C(O)NRs11Rs12 , -SO2NRs11Rs12 , and ... Each R s11 is independently -H or optionally substituted C 1 -C 6 aliphatic group. The compound as described in claim 164, wherein R1 is ... . The compound as described in claim 164, wherein R1 is ... . The compound as described in any of claims 164 to 166, wherein R g1 is selected from halogen, -CN, -OR s11 , -NR s11 , R s12 , or , wherein R s11 and R s12 are each independently -H or optionally substituted C 1 -C 6 aliphatic groups. The compound as described in any of claims 164 to 166, wherein R g1 is selected from halogen, -CN, -OR s11 , -NR s11 , R s12 , or Rs11 and Rs12 are each independently a C1 - C6 aliphatic group that is either -H or optionally substituted with halogen or -OH. The compound as described in any of claims 164 to 166, wherein R g1 is -C(O)N(R s1 ) 2 , -S(O) 2 N(R s1 ) 2 , -S(O)R s1 , -S(O) 2 R s1 , -S(O) (=NR s1 ) or -OS(O) 2 N(R s1 ) 2 , wherein each R s1 is independently -H or C 1 -C 6 aliphatic group. Compounds as described in any of claims 164 to 166, wherein R g1 is an optional substituted 3-10 membered heterocyclic group having 1-4 heteroatoms. The compound as described in any of claims 164 to 166, wherein R g1 is an optional substituted 3-6 membered heterocyclic group having 1-3 heteroatoms. The compound as described in any of claims 164 to 166, wherein R g1 is an optional substituted 6-membered heterocyclic group having 1 to 3 heteroatoms. The compound as described in claim 166, wherein Ri1 is selected from halogens, -CN, -OR s11 , -C(O)NR s11 R s12 , -S(O) 2NR s11 R s12 , or , where R s11 is -H or C 1 - C 6 aliphatic group. The compound as described in claim 173, wherein Ri1 is a halogen. The compound as described in claim 173, wherein Ri1 is F. The compound as described in any one of claims 1 to 2, wherein R1 is selected from The compound as described in any of claims 1 to 2, wherein R1 is R j1 , R k1 , R l1 , and R m1  are each independently selected from halogens, -CN, -ORs11 , -NR  s11 Rs12, -C(O)R s11 , -C(O)NR s11 R s12 , -S(O) 2 NRs11R  s12 , and , wherein R s11 and R s12 are each independently -H or optionally substituted C 1 -C 6 aliphatic groups. The compound as described in claim 177, wherein R1 is . The compound as described in any of claims 177 to 178, wherein Rk1 is selected from halogens, -CN, -ORs1 , -N( Rs1 ) 2 , -C(O)N( Rs1 ) 2 , -S(O) 2N ( Rs1 ) 2 , or Each R s1 is independently a -H or C 1 -C 6 aliphatic group. The compound as described in any of claims 177 to 179, wherein R k1 is selected from halogens, -CN, -OH, -C(O) NH₂ , -S(O) ₂NH₂ , or ... . The compound as described in any of claims 1 to 2, wherein R1 is The compound as described in any one of claims 1 to 2, wherein R 1 is an optional substituted pyridine N-oxide. The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. The compound as described in any one of claims 1 to 2, wherein R1 is optionally substituted. The compound as described in any of claims 1 to 2, wherein R1 is The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , , , , The compound as described in any one of claims 1 to 2, wherein R1 is selected from , The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , , , , , and And substituents selected from halogens, -CN, -OR s1 , -N(R s1 ) 2 , -C(O)N(R s1 ) 2 , -S(O) 2N (R s1 ) 2 and Each Rs1 is independently -H or optionally substituted C1 - C6 aliphatic group. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , , , , , and And substituents selected from halogens, -CN, -OR s1 , -N(R s1 ) 2 , -C(O)N(R s1 ) 2 , -S(O) 2N (R s1 ) 2 and Each R s1 is independently a -H or C 1 -C 6 aliphatic group. The compound as claimed in any one of claims 1 to 2, wherein R 1 is a substituted 5-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , , , , The compound as described in any one of claims 1 to 2, wherein R1 is selected from , The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , , , , , and And substituents selected from halogens, -CN, -OR s1 , -N(R s1 ) 2 , -C(O)N(R s1 ) 2 , -S(O) 2N (R s1 ) 2 and Each Rs1 is independently -H or optionally substituted C1 - C6 aliphatic group. The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , , , , , and And substituents selected from halogens, -CN, -OR s1 , -N(R s1 ) 2 , -C(O)N(R s1 ) 2 , -S(O) 2N (R s1 ) 2 and Each R s1 is independently a -H or C 1 -C 6 aliphatic group. The compound as claimed in any one of claims 1 to 2, wherein R1 is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is substituted by two or more Rs1 . The compound as claimed in any one of claims 1 to 2, wherein R1 is a 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is substituted by two or more Rs1 . The compound as described in any one of claims 1 to 2, wherein R1 is a 2-pyridyl group substituted by two or more Rs1 . The compound as described in any one of claims 1 to 2, wherein R1 is a 3-pyridyl group substituted by two or more Rs1 . The compound as described in any one of claims 1 to 2, wherein R1 is a 4-pyridyl group substituted by two or more Rs1 . The compound as described in any of claims 68 to 200, wherein R1 is substituted by two Rs1 . The compound as described in any of claims 68 to 201, wherein two R s1 groups together with the spacer atom between them form an optional substituted 5-6 membered ring, which, in addition to the spacer atom, contains 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 68 to 201, wherein two R s1 groups together with the spacer atom between them form an optional substituted 5-membered ring, which, in addition to the spacer atom, contains 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 68 to 201, wherein two R s1 groups together with the spacer atom between them form an optional substituted 6-membered ring, which, in addition to the spacer atom, contains 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 68 to 204, wherein an R s1 group is located at position 2, an R s1 group is located at position 3, and R 1 is attached to a nitrogen atom at position 1. The compound as described in any of claims 68 to 204, wherein an R s1 group is located at position 3, an R s1 group is located at position 4, and R 1 is attached to a nitrogen atom at position 1. The compound as described in any of claims 68 to 202, wherein R1 is an optional substituted group selected from... , , , and . The compound as described in any of claims 68 to 206, wherein R1 is selected from The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , and Each substituent is independently R s1 . The compound as described in any one of claims 1 to 2, wherein R1 is an optional substituted group selected from... , , , ,and Each substituent is independently selected from halogens, -CN, -OR s11 , -NR s11 R s12 , -C(O)R s11 , -C(O)NR s11 R s12 , -S(O) 2NR s11 R s12 , and , wherein Rs11 and Rs12 are each independently -H or optionally substituted C1 - C6 aliphatic groups. The compound as described in any of claims 68 to 206, wherein R1 is an optional substituted group selected from... , , , and Each substituent is independently selected from halogens, -CN, -OR s11 , -NR s11 R s12 , -C(O)R s11 , -C(O)NR s11 R s12 , -S(O) 2NR s11 R s12 , and... , where R s11 and R s12 are each independently -H or C 1 -C 6 aliphatic groups. The compound according to any of the foregoing claims, wherein R 1' is hydrogen. The compound as claimed in claim 1, wherein R1 and R1 ' together with the nitrogen atom to which they are attached form an optional substituted 3-6 membered ring, which, in addition to the nitrogen atom, contains 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in claim 1, wherein R1 and R1 ' together with the nitrogen atom to which they are attached form a substituted 5-6 membered heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as claimed in claim 1, wherein R1 and R1 ' together with the nitrogen atom to which they are attached form a substituted 6-membered heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as claimed in claim 1, wherein R1 and R1 ' together with the nitrogen atom to which they are attached form an optional substituted compound. . The compound as claimed in claim 1, wherein R1 and R1 ' together with the nitrogen atom to which they are attached form or . A compound having the structure of formula II: Or its salts, wherein each variable is defined independently as in Request 1. The compound as described in any of claims 1 to 218, wherein R2 is an optional substituted phenyl group. The compound as described in any of claims 1 to 218, wherein R2 is a phenyl group. The compound as described in any of claims 1 to 218, wherein R2 is... The compound as described in claim 221, wherein ring B is an optionally substituted phenyl group. The compound as claimed in claim 221, wherein ring B is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound as claimed in claim 221, wherein ring B is a 6-membered heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound as described in any of claims 221 to 224, wherein s2 is 1-5. The compound as described in any of claims 221 to 224, wherein s2 is 1, 2, or 3. The compound as described in any of claims 1 to 218, wherein R2 is... Furthermore, Ra2 , Rb2 , Rc2 , Rd2 , and Re2 are each independently Rs2 . The compound as described in claim 227, wherein R2 is... . The compound according to any of the preceding claims, wherein each Rs2 is independently selected from halogen, -CN, -ORs21 , -NRs21Rs22 , -C(O) NRs21Rs22 or -S(O) 2NRs21Rs22 . The compound according to any of the foregoing claims, wherein Rs21 and Rs22 are each independently -H or optionally substituted C1-6 aliphatic groups. The compound according to any of the foregoing claims, wherein Rs21 and Rs22 are each independently -H or C1-6 aliphatic groups. The compound according to any of the foregoing claims, wherein R s22 is -H. The compound as described in any of claims 227 to 228, wherein Ra2 is -OR s21 . The compound as described in any of claims 227 to 228, wherein Ra2 is -OR s21 and R s21 is an optional substituted C1-6 alkyl group. The compound as described in any of claims 227 to 228, wherein Ra2 is -OMe. The compound as described in any of claims 229 to 235, wherein Rb2 is a halogen. The compound as described in any of claims 229 to 235, wherein Rb2 is F. The compound as described in any of claims 229 to 235, wherein Rb2 is Cl. The compound as described in any of claims 229 to 235, wherein Rb2 is Br. The compound as described in any of claims 229 to 235, wherein Rb2 is I. The compound as described in any of claims 229 to 240, wherein Rc2 is a halogen. The compound as described in any of claims 229 to 240, wherein Rc2 is F. The compound as described in any of claims 229 to 240, wherein Rc2 is Cl. The compound as described in any of claims 229 to 240, wherein Rc2 is Br. The compound as described in any of claims 229 to 240, wherein Rc2 is I. The compound as described in any of claims 1 to 228, wherein R2 is... The compound as described in any of claims 1 to 228, wherein R2 is... The compound as claimed in any one of claims 1 to 218, wherein R2 is a substituted 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 218, wherein R2 is a substituted 5-6 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 218, wherein R2 is an optional substituted 5-6 membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 250, wherein R3 and R4 are each independently a hydrogen, -CN, or an alternatively substituted group selected from C1 - C6 aliphatic, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-10 membered heterocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R3 and R4 together with the carbon atom to which they are attached form an alternatively substituted 3-6 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound as described in any of claims 1 to 250, wherein R3 is R. The compound as described in any of claims 1 to 250, wherein R3 is hydrogen. The compound as described in any of claims 1 to 250, wherein R 3 is -CN. The compound as claimed in any one of claims 1 to 250, wherein R3 is an optional substituted C1 - C6 aliphatic group. The compound as claimed in any one of claims 1 to 250, wherein R3 is an optional substituted C1 - C6 alkyl group. The compound as claimed in any one of claims 1 to 250, wherein R3 is an optional substituted C1 - C3 alkyl group. The compound as described in any one of claims 1 to 250, wherein R3 is an optional substituted methyl group. The compound as described in any one of claims 1 to 250, wherein R3 is a methyl group. The compound as described in any of claims 1 to 250, wherein R3 is a methyl group substituted with halogen. The compound as described in any of claims 1 to 250, wherein R3 is -CF3 . The compound as described in any of claims 1 to 250, wherein R3 is -CHF2 . The compound as described in any one of claims 1 to 250, wherein R3 is an optional substituted ethyl group. The compound as described in any one of claims 1 to 250, wherein R3 is an ethyl group substituted with halogen. The compound as described in any of claims 1 to 250, wherein R3 is -CH2CF3 . The compound as described in any one of claims 1 to 250, wherein R3 is an optional substituted n-propyl group. The compound as described in any of claims 1 to 250, wherein R3 is a halogen-substituted n-propyl group. The compound as described in any one of claims 1 to 250, wherein R3 is an optional substituted isopropyl group. The compound as described in any of claims 1 to 250, wherein R3 is an isopropyl group substituted with halogen. The compound as described in any one of claims 1 to 250, wherein R3 is isopropyl. The compound as described in any one of claims 1 to 250, wherein R3 is an optional substituted phenyl group. The compound as described in any one of claims 1 to 250, wherein R3 is a phenyl group. The compound as claimed in any one of claims 1 to 250, wherein R3 is an optional substituted 6-10 aryl- C1 - C6 aliphatic group. The compound as described in any of claims 1 to 250, wherein R3 is an optional substituted -CH2 - Ph. The compound as described in any of claims 1 to 250, wherein R3 is -CH2 -Ph. The compound as described in any of claims 1 to 250, wherein R3 is... , and Ra3 , Rb3 , Rc3 , Rd3 and Re3 are each independently Rs3 , wherein Rs3 is Rs31 , halogen, -CN, -ORs31 , -NRs31Rs32 , -C(O) NRs31Rs32 and -S(O) 2Rs31Rs32 , wherein Rs31 and Rs32 are each independently -H or C1 - C6 aliphatic groups that can be optionally substituted by halogen. The compound as described in claim 276, wherein R3 is... . The compound as described in any of claims 276 to 277, wherein Ra3 is an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 276 to 277, wherein Ra3 is an optional substituted C1 - C6 alkyl group. The compound as described in any of claims 276 to 277, wherein Ra3 is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 276 to 277, wherein Ra3 is an optional substituted methyl group. The compound as described in any of claims 276 to 277, wherein Ra3 is a methyl group. The compound as described in any of claims 276 to 277, wherein Ra3 is -CF3 or -CHF2 . The compound as described in any of claims 276 to 277, wherein Ra3 is a halogen. The compound as described in any of claims 276 to 277, wherein Ra3 is F. The compound as described in claim 276, wherein R3 is... . The compounds described in claims 276 and any of 278 to 286, wherein Rb3 is an optional substituted C1 - C6 aliphatic group. The compound as described in claims 276 and any one of 278 to 286, wherein Rb3 is an optional substituted C1 - C6 alkyl group. The compounds described in claims 276 and any of 278 to 286, wherein Rb3 is an optional substituted C1 - C3 alkyl group. The compound as described in claims 276 and any one of 278 to 286, wherein Rb3 is an optional substituted methyl group. The compound as described in claims 276 and any of 278 to 286, wherein Rb3 is methyl. The compound as described in claims 276 and any one of 278 to 286, wherein Rb3 is -CF3 or -CHF2 . The compound as described in claims 276 and any one of 278 to 286, wherein Rb3 is an ethyl group substituted with halogen. The compound as described in claims 276 and any one of 278 to 286, wherein Rb3 is a halogen. The compound as described in claims 276 and any of 278 to 286, wherein Rb3 is F. The compound as described in claims 276 and any of 278 to 286, wherein Rb3 is -OR s31 . The compound as claimed in claim 296, wherein Rb3 is -ORs31 and Rs31 is -H or an optional substituted C1 - C6 alkyl group. The compound as claimed in claim 296, wherein Rb3 is -ORs31 and Rs31 is an optional substituted C1 - C6 alkyl group. The compound as described in claim 296, wherein Rb3 is -OMe. The compound as described in any of claims 276, 278 to 285, and 287 to 299, wherein R3 is . The compounds described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is an optional substituted C1 - C6 alkyl group. The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is an optional substituted methyl group. The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is a methyl group. The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is -CF3 . The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is -CHF2 . The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is a halogen. The compound as described in any of claims 276, 278 to 285 and 287 to 300, wherein Rc3 is F. The compound as claimed in any one of claims 1 to 250, wherein R3 is a substituted 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 250, wherein R3 is an optional substituted 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 250, wherein R3 is an optional substituted 6-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 250, wherein R3 is an optional substituted pyridinyl group. The compound as described in any one of claims 1 to 250, wherein R3 is pyridyl. The compound as described in any of claims 313 to 314, wherein the pyridinyl group is The compound as described in any of claims 313 to 314, wherein the pyridinyl group is The compound as described in any of claims 313 to 314, wherein the pyridinyl group is The compound as described in any of claims 1 to 250, wherein R3 is an optional substituted 3- to 10-membered heterocyclic group having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 1 to 250, wherein R3 is an optional substituted 3- to 6-membered heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 1 to 250, wherein R3 is an optional substituted 5-6 membered heterocyclic group having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any one of claims 1 to 250, wherein R3 is an optional substituted 3- to 6-membered cycloalkyl group. The compound as described in any of claims 1 to 321, wherein R4 is R. The compound as described in any of claims 1 to 321, wherein R 4 is hydrogen. The compound as described in any of claims 1 to 321, wherein R 4 is -CN. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted C1 - C6 aliphatic group. The compound as described in any one of claims 1 to 321, wherein R4 is an optional substituted C1 - C6 alkyl group. The compound as described in any one of claims 1 to 321, wherein R4 is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted methyl group. The compound as described in any of claims 1 to 321, wherein R4 is a methyl group substituted with halogen. The compound as described in any of claims 1 to 321, wherein R4 is a methyl group. The compound as described in any of claims 1 to 321, wherein R4 is -CF3 . The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted ethyl group. The compound as described in any of claims 1 to 321, wherein R4 is an ethyl group substituted with halogen. The compound as described in any of claims 1 to 321, wherein R4 is -CH2CF3 . The compound as described in any of claims 1 to 321, wherein R4 is -CHF2 . The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted n-propyl group. The compound as described in any of claims 1 to 321, wherein R4 is a halogen-substituted n-propyl group. The compound as described in any of claims 1 to 321, wherein R4 is n-propyl. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted isopropyl group. The compound as described in any of claims 1 to 321, wherein R4 is an isopropyl group substituted with halogen. The compound as described in any of claims 1 to 321, wherein R4 is isopropyl. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted phenyl group. The compound as described in any of claims 1 to 321, wherein R4 is a phenyl group. The compound as claimed in any one of claims 1 to 321, wherein R4 is an optional substituted 6-10 aryl- C1 - C6 aliphatic group. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted -CH2 - Ph. The compound as described in any of claims 1 to 321, wherein R4 is -CH2 -Ph. The compound as described in any of claims 1 to 321, wherein R4 is Furthermore, Ra4 , Rb4 , Rc4 , Rd4 , and Re4 are each independently Rs4 , wherein Rs4 is Rs41 , halogen, -CN, -ORs41 , -NRs41Rs42 , -C(O) NRs41Rs42 , and -S(O) 2Rs41Rs42 , wherein Rs41 and Rs42 are each independently -H or C1 - C6 aliphatic groups that can be selectively substituted by halogen . The compound as claimed in claim 347, wherein Ra4 is -H or a C1 - C6 aliphatic group that may be optionally substituted with halogen. The compound as described in any of claims 347 to 348, wherein Ra4 is an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 347 to 348, wherein Ra4 is an optional substituted C1 - C6 alkyl group. The compound as described in any of claims 347 to 348, wherein Ra4 is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 347 to 348, wherein Ra4 is an optional substituted methyl group. The compound as described in any of claims 347 to 348, wherein Ra4 is a methyl group. The compound as described in any of claims 347 to 348, wherein Ra4 is -CF3 . The compound as described in any of claims 347 to 348, wherein Ra4 is a halogen. The compound as described in any of claims 347 to 348, wherein Ra4 is F. The compound as described in any of claims 347 to 356, wherein Rb4 is -H or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 347 to 357, wherein Rb4 is an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 347 to 357, wherein Rb4 is an optional substituted C1 - C6 alkyl group. The compound as described in any of claims 347 to 357, wherein Rb4 is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 347 to 357, wherein Rb4 is an optional substituted methyl group. The compound as described in any of claims 347 to 357, wherein Rb4 is a methyl group. The compound as described in any of claims 347 to 357, wherein Rb4 is -CF3 . The compound as described in any of claims 347 to 357, wherein Rb4 is a halogen. The compound as described in any of claims 347 to 357, wherein Rb4 is F. The compound as described in any of claims 347 to 357, wherein Rb4 is -OR s41 . The compound as claimed in any one of claims 347 to 357, wherein Rb4 is -ORs41 and Rs41 is -H or an optional substituted C1 - C6 alkyl group. The compound as claimed in any one of claims 347 to 357, wherein Rb4 is -ORs41 and Rs41 is an optional substituted C1 - C6 alkyl group. The compound as described in any of claims 347 to 357, wherein Rb4 is -OMe. The compound as described in any of claims 347 to 369, wherein Rc4 is -H or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 347 to 370, wherein Rc4 is an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 347 to 370, wherein Rc4 is an optional substituted C1 - C6 alkyl group. The compound as described in any of claims 347 to 370, wherein Rc4 is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 347 to 370, wherein Rc4 is an optional substituted methyl group. The compound as described in any of claims 347 to 370, wherein Rc4 is a methyl group. The compound as described in any of claims 347 to 370, wherein Rc4 is -CF3 . The compound as described in any of claims 347 to 370, wherein Rc4 is -CF3 . The compound as described in any of claims 347 to 370, wherein Rc4 is a halogen. The compound as described in any of claims 347 to 370, wherein Rc4 is F. The compound as described in any of claims 347 to 356, wherein R4 is The compound as described in claims 347 and any of 357 to 369, wherein R4 is . The compound as described in claims 347 and any one of 370 to 379, wherein R4 is . The compound as claimed in any one of claims 1 to 321, wherein R4 is a substituted 5-6 member heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any of claims 1 to 321, wherein R4 is an optional substituted 6-membered heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as claimed in any one of claims 1 to 321, wherein R4 is an optional substituted 6-membered heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted pyridinyl group. The compound as described in any of claims 1 to 321, wherein R4 is pyridyl. The compound as described in any of claims 386 to 387, wherein the pyridinyl group is The compound as described in any of claims 386 to 387, wherein the pyridinyl group is The compound as described in any of claims 386 to 387, wherein the pyridinyl group is The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted 3- to 10-membered heterocyclic group having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted 3- to 6-membered heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted 5-6 membered heterocyclic group having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as described in any of claims 1 to 321, wherein R4 is an optional substituted 3- to 6-membered cycloalkyl group. Compounds as described in any of claims 1 to 250, wherein R3 and R4 together with the carbon atoms to which they are attached form optional substituted 3-6-membered rings having 0-3 heteroatoms. The compound as claimed in claim 395, wherein R3 and R4 together with the carbon atoms to which they are attached form optional substituted 3-6 membered rings having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as claimed in claim 395, wherein R3 and R4 together with the carbon atoms to which they are attached form optional substituted 5-6 membered rings having 1-2 independent heteroatoms selected from nitrogen, oxygen and sulfur. The compound as claimed in claim 395, wherein R3 and R4 together with the carbon atoms to which they are attached form optional substituted 3-6 membered cycloalkyl rings. The compound as claimed in claim 395, wherein R3 and R4 together with the carbon atoms to which they are attached form a 3-6 membered cycloalkyl ring. The compound as claimed in claim 395, wherein R3 and R4 together with the carbon atoms to which they are attached form halogen-substituted 3-6-membered cycloalkyl rings. The compound as claimed in claim 400, wherein R3 and R4 together with the carbon atoms to which they are attached form a -F-substituted 3-6-membered cycloalkyl ring. The compound as described in claim 395, wherein R3 and R4, together with the carbon atoms to which they are attached, form a halogen-substituted compound. . The compound as described in claim 395, wherein R3 and R4 together with the carbon atoms to which they are attached form a -F substituted compound. . The compound as described in claim 395, wherein R3 and R4 together with the carbon atoms to which they are attached form . The compound as described in any of claims 1 to 250 , wherein -CR3R4- is selected from: . The compound according to any of the foregoing claims, wherein the carbon atoms connecting R3 and R4 are achiral. The compound as described in any of claims 1 to 404, wherein the carbon atoms connecting R3 and R4 are chiral and have an R configuration. The compound as described in any of claims 1 to 404, wherein the carbon atoms connecting R3 and R4 are chiral and have an S configuration. The compound as described in any of claims 1 to 408, wherein X is -O-. The compound as described in any of claims 1 to 408, wherein X is -S-. The compound as described in any of claims 1 to 408, wherein X is -S(O)-. The compound as described in any of claims 1 to 408, wherein X is -S(O) 2- . Compounds as claimed in any of claims 1 to 408, wherein X is -C( Rx ) 2- and each Rx is independently hydrogen, optionally substituted C1 - C6 aliphatic group, -OR or -N(R) 2 . The compound as claimed in any one of claims 1 to 408, wherein X is -C( Rx ) 2- and each Rx is independently hydrogen or an optional substituted C1 - C6 aliphatic group. The compound as claimed in any of claims 1 to 408, wherein X is -C( Rx ) 2- and each Rx is independently hydrogen or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 1 to 408, wherein X is -C( Rx ) 2- and each Rx is independently -OR. The compound as described in any of claims 1 to 408, wherein X is -C( Rx ) 2- and each Rx is independently -N(R) 2 . The compound as described in any of claims 1 to 417, wherein W is N. The compound as described in any of claims 1 to 417, wherein W is C and Z is C, and the bond between W and Z is a double bond. Compounds as described in any of claims 1 to 417, wherein W is C(R w ), R w is hydrogen, optionally substituted C1 - C6 aliphatic group, -OR or -N(R) 2 . The compound as claimed in any one of claims 1 to 417, wherein W is C( Rw ), Rw is hydrogen or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 1 to 417, wherein W is C(R w ) and R w is -OR. The compound as described in any of claims 1 to 417, wherein W is C(R w ) and R w is -N(R) 2 . The compound as described in any of claims 1 to 417, wherein W is CH. Compounds as described in any of claims 1 to 417, wherein W is C(R w ) and R w is an optional substituted C1- C6 aliphatic group, -OR or -N(R) 2 . The compound as described in any of claims 1 to 417, wherein W is C( Rw ), and Rw is an optional substituted C1 - C6 aliphatic group. The compound as claimed in any one of claims 1 to 417, wherein W is C( Rw ), and Rw is an optional substituted C1 - C6 alkyl group. The compound as claimed in any one of claims 1 to 417, wherein W is C( Rw ), and Rw is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 1 to 417, wherein W is C(R w ) and R w is an optional substituted methyl group. The compound as described in any of claims 1 to 417, wherein W is C(R w ) and R w is a methyl group. The compound as described in any of claims 1 to 417, wherein W is C(R w ) and R w is a methyl group substituted with halogen. The compound as described in any of claims 1 to 417, wherein W is C(R w ) and R w is -CF3 . The compound as described in any of claims 1 to 417, wherein W is C(R w ) and R w is -OH. The compound as claimed in any of claims 1 to 417, wherein W is C(R w ), R w is OR and R is an optional C1 - C6 aliphatic group. Compounds as described in any of claims 1 to 417, wherein W is C(R w ) and R w is an optional substituted NHR. The compound as claimed in any of claims 1 to 417, wherein W is C(R w ), R w is -N(R) 2 , and each R is independently -H or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 1 to 436, wherein Rw and R3 are in the trans configuration. The compound as described in any of claims 1 to 437, wherein Z is N. The compound as described in any of claims 1 to 437, wherein Z is C and Y is -C(R y )=. The compound as claimed in any one of claims 1 to 437, wherein Z is C( Rz ), wherein Rz is hydrogen or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 1 to 437, wherein Z is -CH-. The compound as claimed in any one of claims 1 to 437, wherein Z is C(R z ), and R z is an optional substituted C1 - C6 aliphatic group. The compound as claimed in any one of claims 1 to 437, wherein Z is C(R z ), and R z is an optional substituted C1 - C6 alkyl group. The compound as claimed in any one of claims 1 to 437, wherein Z is C(R z ), and R z is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 1 to 437, wherein Z is C(R z ), where R z is an optional substituted methyl group. The compound as described in any of claims 1 to 437, wherein Z is C(R z ), and R z is a methyl group. The compound as described in any of claims 1 to 437, wherein Z is C(R z ), and R z is -CF3 . The compound as described in any of claims 1 to 437, wherein Z is C(R z ), and R z is -OR. The compound as described in any of claims 1 to 437, wherein Z is C(R z ), and R z is -N(R) 2 . The compound as described in any of claims 440 to 447, wherein Rz and R3 are in cis configuration. The compound as described in any of claims 1 to 450, wherein Y is -O-. The compound as described in any of claims 1 to 450, wherein Y is -S-. The compound as claimed in any one of claims 1 to 450, wherein Y is -N( Ry )- and Ry is independently hydrogen or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 1 to 450, wherein Y is -N( Ry )- and Ry is hydrogen. The compound as claimed in any one of claims 1 to 450, wherein Y is -N( Ry )- and Ry is an optional substituted C1 - C6 aliphatic group. The compound as claimed in any one of claims 1 to 450, wherein Y is -N( Ry )- and Ry is an optional substituted C1 - C6 alkyl group. The compound as claimed in any one of claims 1 to 450, wherein Y is -N( Ry )- and Ry is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 1 to 450, wherein Y is -N( Ry )- and Ry is a methyl group. Compounds as claimed in any of claims 1 to 450, wherein Y is -C( Ry ) 2- and each Ry is independently hydrogen, optionally substituted C1 - C6 aliphatic group, -OR or -N(R) 2 . The compound as claimed in any one of claims 1 to 450, wherein Y is -C( Ry ) 2- , and each Ry is independently hydrogen or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 1 to 450, wherein Y is -CH2- . The compound as claimed in any one of claims 1 to 450, wherein Y is -CH( Ry )- and Ry is an optional substituted C1 - C6 aliphatic group. The compound as claimed in any one of claims 1 to 450, wherein Y is -CH( Ry )- and Ry is an optional substituted C1 - C6 alkyl group. The compound as claimed in any one of claims 1 to 450, wherein Y is -CH( Ry )- and Ry is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 1 to 450, wherein Y is -CH( Ry )- and Ry is a methyl group. The compound as described in any of claims 1 to 450, wherein Y is -C( Ry ) 2- , and each Ry is independently -OR. The compound as described in any of claims 1 to 450, wherein Y is -C( Ry ) 2- and each Ry is independently -N(R) 2 . The compound as described in any of claims 462 to 467, wherein R3 and Ry are in the trans configuration. The compound as claimed in any one of claims 1 to 450, wherein Y is -C( Ry )= and Z is C, the bond between Y and Z is a double bond, and Ry is hydrogen or an optional substituted C1 - C6 aliphatic group. The compound as described in any of claims 1 to 450, wherein Y is -C( Ry )= and Z is C, the bond between Y and Z is a double bond, and Ry is hydrogen. The compound as claimed in any of claims 1 to 450, wherein Y is -C( Ry )= and Z is C, the bond between Y and Z is a double bond, and Ry is an optional substituted C1 - C6 aliphatic group. The compound as claimed in any one of claims 1 to 450, wherein Y is -C( Ry )= and Z is C, the bond between Y and Z is a double bond, and Ry is an optional substituted C1 - C6 alkyl group. The compound as claimed in any one of claims 1 to 450, wherein Y is -C( Ry )= and Z is C, the bond between Y and Z is a double bond, and Ry is an optional substituted C1 - C3 alkyl group. The compound as described in any of claims 1 to 404, wherein Selected from: A compound selected from Table 1 or its salt. The compound described in any of the foregoing claims is a pharmaceutically acceptable salt. The compound according to any of the foregoing claims has an enantiomeric purity of about 80% or at least about 80%. The compound according to any of the foregoing claims has an enantiomeric purity of about 90% or at least about 90%. The compound according to any of the foregoing claims has an enantiomeric purity of about 95% or at least about 95%. The compound according to any of the foregoing claims has an enantiomeric purity of about 98% or at least about 98%. The compound according to any of the foregoing claims has a purity of about 90% or at least about 90%. The compound according to any of the foregoing claims has a purity of approximately 95%, or at least approximately 95%. The compound according to any of the foregoing claims has a purity of about 98% or at least about 98%. The compound according to any of the foregoing claims has a purity of about 98% or at least about 98%. A pharmaceutical composition comprising a compound as described in any of the preceding claims and a pharmaceutically acceptable carrier. A method of treating a condition, disorder, or disease, comprising administering to a subject suffering from the condition, disorder, or disease an effective amount of any one of claims 1 to 485. A method of treating a condition, disorder, or disease, comprising delivering to a subject suffering from the condition, disorder, or disease an effective amount of any one of claims 1 to 485. A method for preventing a condition, disorder, or disease, comprising administering an effective amount of any one of the compounds or drug combinations described in claims 1 to 485 to a subject susceptible to the condition, disorder, or disease. A method for preventing a condition, disorder, or disease, comprising delivering an effective amount of any one of the compounds or drug combinations described in claims 1 to 485 to a subject susceptible to the condition, disorder, or disease. The method described in any of requests 486 to 489, wherein the condition, disorder, or disease is related to Nav1.8 activation. The method described in any of claims 486 to 489, wherein the symptom, disorder, or disease is or includes pain. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, peroneal atrophy syndrome, urinary or fecal incontinence, pathological cough, or arrhythmia. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes neuropathic pain, musculoskeletal pain, osteoarthritis pain, acute pain, acute postoperative pain, postoperative pain, hallux valgus pain, abdominoplasty pain, hernia pain, or visceral pain. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes postherpetic neuralgia, microneuropathy, idiopathic microneuropathy, diabetic neuropathy, or diabetic peripheral neuropathy. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes migraine, post-ischemic neurodegeneration, epilepsy, arthritis, cardiogenic pain due to ischemic myocardial infarction, acute pain, chronic pain, throbbing pain, neuropathic pain, postoperative pain, pain caused by neuralgia (e.g., postherpetic neuralgia, traumatic neuralgia, fibromyalgia, trigeminal neuralgia), pain caused by diabetic neuropathy, toothache, cancer pain, or inflammatory pain (such as arthritis and osteoarthritis). The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes spontaneous pain, acute pain, preoperative pain, perioperative pain, or postoperative pain. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes neuropathic pain, pain sensation, toothache, AIDS pain, heart pain caused by ischemic myocarditis, pain caused by migraine, joint pain, neurosis, neurodegeneration, retinopathy, neurodermatitis, stroke, bladder hypersensitivity, urinary incontinence, vulvitis, gastrointestinal diseases such as irritable bowel syndrome, gastroesophageal reflux disease, enteritis, ileitis, gastroduodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, pancreatitis, etc. Inflammatory diseases, respiratory diseases such as allergic and non-allergic rhinitis, asthma, or chronic obstructive pulmonary disease; skin, eye, or mucous membrane irritation; atopic dermatitis, eczema, pruritus, fever, muscle spasms, hiccups, movement disorders, depression, Huntington's disease, memory impairment, cognitive impairment, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratoacanthoma, alopecia, Meniere's disease, tinnitus, hyperhearing, anxiety, or benign prostatic hyperplasia. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes acute pain, chronic pain, spontaneous pain, essential pain, neuropathic pain, peripheral neuropathy, migraine, post-ischemic neurodegeneration, multiple sclerosis, epilepsy, peroneal muscle atrophy syndrome, post-ischemic neurodegeneration, epilepsy, trigeminal neuralgia, trigeminal automatic headache, diabetic neuropathy, sciatica, optic neuritis, AIDS-related sensory neuropathy, burning mouth syndrome, spinal stenosis, carpal tunnel syndrome, chemotherapy-induced peripheral neuropathy, radicular pain, nerve avulsion, brachial plexus injury, and antiretroviral transcription disorder. Neuropathic pain induced by toxic therapy, spinal cord injury, primary small fibroneuropathy, primary sensory neuropathy, inflammatory pain, rheumatoid arthritis pain, cancer pain, intestinal pain, visceral pain, musculoskeletal pain, acute pain from fractures, musculoskeletal injury, chronic low back pain, phantom limb pain, chronic pelvic pain, intestinal pain, pancreatitis, renal colic, burn pain, preoperative pain, perioperative pain, postoperative pain, osteoarthritis, toothache, vulvar pain, fibromyalgia, urinary incontinence, pathological cough, arrhythmia, hereditary erythematous urticaria, asthma, pruritus, allergic or contact dermatitis, renal failure, cholestasis, or arrhythmia. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is or includes atopic dermatitis, eczema, seborrheic eczema, pruritus, skin inflammation, or psoriasis. The method described in any of claims 486 to 489, wherein the condition, disorder, or disease is skin inflammation. A method for inhibiting voltage-gated sodium channels in a subject, comprising administering or delivering to the subject an effective amount of the compound or drug combination described in any one of claims 1 to 485. The method as described in claim 501, wherein the voltage-gated sodium channel is or includes Nav1.8. The method of any of claims 486 to 502, wherein said compound or composition is administered orally or by delivery. The method of any of claims 486 to 502, wherein the compound or composition is administered or delivered by intravenous injection. The method of any of claims 486 to 502, wherein the compound or composition is administered or delivered via subcutaneous injection. The method of any of claims 486 to 502, wherein the compound or composition is administered or delivered topically. The method of any of claims 486 to 506, wherein the compound or pharmaceutical composition is administered in combination with one or more additional treatments, each additional treatment being independently administered or delivered simultaneously, before, or after the compound or composition. The method of any of claims 486 to 506, wherein said compound or pharmaceutical composition is delivered in combination with one or more additional treatments, each additional treatment may be administered or delivered independently, simultaneously with, before, or after said compound or composition. A method for inhibiting a voltage-gated sodium channel in a system, comprising administering or delivering an effective amount of the compound or pharmaceutical composition described in any one of claims 1 to 485 to the system. The method as described in claim 509, wherein the voltage gate sodium channel is or includes Nav1.8. The method described in any of claims 509 to 510, wherein the system is or includes cells. The method described in any of claims 509 to 510, wherein the system is or includes an organization. The method described in any of claims 509 to 510, wherein said system is or includes an organ. The method described in any of claims 509 to 510, wherein said system is a living organism. The method described in any of claims 509 to 510, wherein the system is a subject. A method comprising: making a compound having the structure of formula III-a or a salt thereof: With The reaction of a compound or its salt with the structure IV-a to provide a compound or its salt having the structure IV-a: Where Rm1 is R', and the other variables are independent as described in any of the aforementioned requests. A method comprising: making a compound having the structure of formula III-b or a salt thereof: With The reaction of a compound or its salt with the structure IV-b yields a compound or its salt having the structure IV-b: Where Rm1 is R', and the other variables are independent as described in any of the aforementioned requests. A method comprising: making a compound having the structure of formula III-c or a salt thereof: With The reaction of a compound or its salt with the structure IV-c to provide a compound or its salt having the structure IV-c: Where Rm1 is R', and the other variables are independent as described in any of the aforementioned requests. One method involves making a compound having the structure of formula III-d or a salt thereof: R 2 -NH-C(R y ) 2 -C(R 3 )(R 4 )-OH, III-d Reaction with compounds having the HC(O)C(O)OR m1 structure or their salts to provide compounds having the IV-d structure or their salts: Where Rm1 is R', and the other variables are independent as described in any of the aforementioned requests. The method described in any of claims 516 to 519, wherein the method is carried out in the presence of an acid. The method described in any of claims 516 to 519, wherein the method is carried out in the presence of sulfuric acid. The method described in any of claims 516 to 519, wherein the method is carried out in the presence of concentrated sulfuric acid. The method described in any of claims 516 to 519, wherein the method is carried out in the presence of p-toluenesulfonic acid (TsOH), pyridinium p-toluenesulfonic acid (PPTS), or boron trifluoride ether ( BF3 · Et2O ). One method involves making a compound having the structure of formula III-e or a salt thereof: With The reaction of a compound or its salt with the structure IV-a to provide a compound or its salt having the structure IV-a: Where Rm1 is R', LG is a leaving group (e.g., -Br, -OTs, etc.), and the other variables are independent as described in any of the aforementioned claims. One method involves making a compound having the structure of formula III-f or a salt thereof: With The reaction of a compound or its salt with the structure IV-a to provide a compound or its salt having the structure IV-a: Where Rm1 is R', LG is a leaving group (e.g., -Br, -OTs, etc.), and the other variables are independent as described in any of the aforementioned claims. One method involves reacting a compound having the structure of formula III-g or a salt thereof: Reaction with compounds having the Rw- C(O)-C(O) ORm1 structure or their salts to provide compounds having the IV-g structure or their salts: Where Rm1 is R', and the other variables are independent as described in any of the aforementioned requests. One method involves making a compound having the structure of formula III-h or a salt thereof: C(R 3 )(R 4 )=C(R y )-C(O)-R 2 , III-h Reaction with compounds having the Rw - CH(SH)-C(O)OR m1 structure or their salts to provide compounds having the IV-h structure or their salts: Optionally, compounds of formula IV-h or their salts can be converted into compounds of formula IV-h-2 or IV-h-3: Or its salt; optionally, a compound of formula IV-h-2 or its salt may be converted to a compound of formula IV-h-3 or its salt; and optionally, a compound of formula IV-h-2 or IV-h-3 or its salt may be converted to a compound of formula IV-h-4: Or its salt; Where Rm1 is R', and the other variables are independent as described in any of the aforementioned requests. One method involves making a compound having the structure of formula III-i or a salt thereof: O - -N + (PG)=C(R z )(R 2 ), III-i Reacts with compounds having the C( R3 )( R4 )=C( Ry ) 2 structure or their salts to provide compounds having the IV-i structure or their salts: Optionally, compounds of formula IV-i or their salts can be converted into compounds of formula IV-i-2: Or its salts; optionally, a compound of formula IV-i-2 or its salts may be converted into a compound of formula IV-i-3: Or its salt (e.g., by reaction with a compound having an O=C=NR 1 structure or its salt); wherein PG is R' or a suitable protecting group (e.g., -CH 2- (optionally substituted aromatic group (e.g., phenyl))), and each other variable is independently as described in any of the preceding claims. The method described in claim 524, wherein the method is performed in the presence of an alkali. The method as described in claim 529, wherein the alkali is potassium carbonate. A method comprising contacting a compound of formula I (where X is S) with an oxidizing agent to provide a compound having the structure of formula I or a salt thereof, wherein X is -S(O)-. The method as described in claim 531, wherein the oxidant is m-chloroperoxybenzoic acid (m-CPBA). The method described in any of claims 516 to 532, wherein the method is performed below 0°C. The method described in any of claims 516 to 532, wherein the method is performed below -10°C. The method described in any of claims 516 to 532, wherein the method is performed below -20°C. The method described in any of claims 516 to 532, wherein the method is performed below -30°C. The method described in any of claims 516 to 532, wherein the method is performed below -40°C. The method described in any of claims 516 to 532, wherein the method is performed below -50°C. The method described in any of claims 516 to 532, wherein the method is performed below -60°C. The method described in any of claims 516 to 532, wherein the method is performed below -70°C. The method described in any of claims 516 to 532, wherein the method is performed at approximately -78°C. The method described in any of claims 516 to 532, wherein the method is performed at a temperature of approximately -78°C to 0°C. The method described in any of claims 516 to 532, wherein the method is performed at approximately -78°C to -10°C. The method described in any of claims 516 to 532, wherein the method is performed at approximately -78°C to -20°C. The method described in any of claims 516 to 532, wherein the method is performed at approximately -78°C to -30°C. The method described in any of claims 516 to 532, wherein the method is performed at approximately -78°C to -40°C. The method described in any of claims 516 to 532, wherein the method is performed at a temperature of approximately -40°C to 0°C. The method described in any of claims 516 to 532, wherein the method is performed at approximately -40°C to -10°C. The method described in any of claims 516 to 532, wherein the method is performed at approximately -40°C to -20°C. The method described in any of claims 516 to 532, wherein the method is performed at a temperature of approximately -78°C to 120°C. The method described in any of requests 516 to 550, wherein the method takes approximately 1 hour. The method described in any of requests 516 to 550, wherein the method takes approximately 50 minutes. The method described in any of requests 516 to 550, wherein the method takes approximately 40 minutes. The method described in any of requests 516 to 550, wherein the method takes approximately 30 minutes. The method described in any of requests 516 to 550, wherein the method takes approximately 20 minutes. The method described in any of requests 516 to 550, wherein the method takes approximately 10 minutes. The method described in any of requests 516 to 550, wherein the method takes less than 2 hours. The method described in any of requests 516 to 550, wherein the method takes less than 3 hours. The method described in any of requests 516 to 550, wherein the method takes less than 4 hours. The method described in any of requests 516 to 550, wherein the method takes less than 5 hours. The method described in any of requests 516 to 550, wherein the method takes less than 6 hours. The method described in any of requests 516 to 550, wherein the method takes less than 12 hours. The method described in any of claims 516 to 550, wherein the method takes less than 24 hours. The method described in any of claims 516 to 563, wherein Rm1 is an optional substituted C1 - C6 aliphatic group. The method as described in any of claims 516 to 563, wherein R m1 is an optional substituted C1 - C6 alkyl group. The method described in any of claims 516 to 563, wherein R m1 is ethyl. The method described in any of claims 516 to 563, wherein R m1 is a methyl group. The method described in any of requests 516 to 567, wherein R3 is R. The method described in any of claims 516 to 567, wherein R3 is hydrogen. The method described in any of claims 516 to 567, wherein R3 is an optional substituted C1 - C6 aliphatic group. The method as described in any of claims 516 to 567, wherein R3 is an optional substituted C1 - C6 alkyl group. The method as described in any of claims 516 to 567, wherein R3 is an optional substituted C1 - C3 alkyl group. The method as described in any of claims 516 to 567, wherein R3 is a C1 - C3 alkyl group substituted with halogen. The method described in any of claims 516 to 567, wherein R3 is a C1 - C3 alkyl group. The method described in any of claims 516 to 567, wherein R3 is a methyl group. The method described in any of requests 516 to 567, wherein R3 is -CF3 . The method described in any of claims 516 to 567, wherein R3 is an optional substituted benzyl group. The method described in any of claims 516 to 567, wherein R3 is benzyl. The method described in any of requests 516 to 578, wherein R4 is R. The method described in any of claims 516 to 578, wherein R4 is hydrogen. The method described in any of claims 516 to 578, wherein R4 is an optional substituted C1 - C6 aliphatic group. The method as described in any of claims 516 to 578, wherein R4 is an optional substituted C1 - C6 alkyl group. The method as described in any of claims 516 to 578, wherein R4 is an optional substituted C1 - C3 alkyl group. The method as described in any of claims 516 to 578, wherein R4 is a C1 - C3 alkyl group substituted with halogen. The method as described in any of claims 516 to 578, wherein R4 is a C1 - C3 alkyl group. The method described in any of claims 516 to 578, wherein R4 is a methyl group. The method described in any of requests 516 to 578, wherein R4 is -CF3 . The method described in any of claims 516 to 578, wherein R4 is an optional substituted benzyl group. The method described in any of claims 516 to 578, wherein R4 is benzyl. The method of any of claims 516 to 589 includes converting -C(O)OR m1 to -COOH or a salt thereof to provide a compound having the structure of formula II or a salt thereof. The method of any of claims 516 to 590 includes reacting -C(O)OH or its salt form with NHR 1 R 1' or its salt to provide a compound having the structure of formula I or a salt thereof. The method of any of claims 516 to 589 includes reacting -C(O)OR m1 with NHR 1 R 1' or a salt thereof to provide a compound having the structure of formula I or a salt thereof.