WO2022217070A1

WO2022217070A1 - Hgf/sf mimetic compounds

Info

Publication number: WO2022217070A1
Application number: PCT/US2022/024049
Authority: WO
Inventors: An-Hu Li; Satishkumar GADHIYA; Yao ZONG; Ying Zhang; Satish Kumar SAKILAM; Shashikanth PONNALA; Dong Sung Lim
Original assignee: Angion Biomedica Corp.
Priority date: 2021-04-09
Filing date: 2022-04-08
Publication date: 2022-10-13

Abstract

The present disclosure provides substituted [2-(2-thienyl)vinyl]-1H-pyrazole compounds and compositions useful as HGF/SF mimetics.

Description

HGF/SF MIMETIC COMPOUNDS RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Patent Application No. 63/173,031, filed April 9, 2021, the entire contents of which are hereby incorporated by reference. BACKGROUND [0002] Scatter factor (SF; also known as hepatocyte growth factor (HGF), and hereinafter referred to and abbreviated as HGF/SF) is a pleiotropic growth factor that stimulates cell growth, cell motility, morphogenesis and angiogenesis. HGF/SF is produced as an inactive monomer (~100 kDa) which is proteolytically converted to its active form. Active HGF/SF is a heparin-binding heterodimeric protein composed of a 62 kDa α chain and a 34 kDa β chain. HGF/SF has a short half-life of 3-5 min (Chang, H.-K., et al., Mol Ther.2016 Sep; 24(9): 1644– 1654). HGF/SF is a potent mitogen for parenchymal liver, epithelial and endothelial cells (Matsumoto, K, and Nakamura, T., 1997, Biochem. Biophys. Res. Commun.239, 639-44; Boros, P. and Miller, C.M., 1995, Lancet 345, 293-5). It stimulates the growth of endothelial cells and also acts as a survival factor against endothelial cell death (Morishita, R, et al., 1997, Diabetes 46:138-42). HGF/SF synthesized and secreted by vascular smooth muscle cells stimulates endothelial cells to proliferate, migrate and differentiate into capillary-like tubes in vitro (Grant, D.S, et al., 1993, Proc. Natl. Acad. Sci. U S A 90:1937-41; Morishita, R., et al., 1999, Hypertension 33:1379-84). HGF/SF-containing implants in mouse subcutaneous tissue and rat cornea induce growth of new blood vessels from surrounding tissue. HGF/SF protein is expressed at sites of neovascularization including in tumors (Jeffers, M., et al., 1996, J. Mol. Med. 74:505-13; Moriyama, T., et al., 1999, Int. J. Mol. Med. 3:531-6). These findings suggest that HGF/SF plays a significant role in the formation and repair of blood vessels under physiologic and pathologic conditions. SUMMARY [0003] The present disclosure provides compounds useful as HGF/SF mimetics. In some embodiments, the present disclosure describes compounds which provide and/or deliver a terevalefim active moiety (e.g., compounds which are prodrugs of terevalefim). [0004] The present disclosure encompasses the recognition that an agent that provides a terevalefim active moiety and displays certain characteristics is desirable for certain uses and/or applications (e.g., in methods and/or formulations described herein). For example, in some embodiments, an agent that provides a terevalefim active moiety yet is more soluble and/or is easier to formulate and/or is more stable and/or is more amenable to formulation for different routes of administration (e.g., other than intravenous) than terevalefim itself is desirable. [0005] In some embodiments, the present disclosure provides a compound of Formula I: (

I or a pharmaceutically acceptable salt thereof, wherein L, R¹, R², R³, R^a, R^b, m, and n are as defined herein. [0006] In some embodiments, the present disclosure provides a compound of Formula II:

II or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, q, and t are as defined herein. [0007] In some embodiments, the present disclosure provides methods of administering provided compounds or mixtures of provided compounds. In some embodiments, the present disclosure provides methods of treating a disease or disorder selected from fibrotic liver disease, ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease and/or renal fibrosis, lung fibrosis, damaged and/or ischemic organs, transplants or grafts, stroke, and cerebrovascular disease, comprising administering a compound or mixture of compounds provided herein. BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIG. 1 is a graph showing terevalefim concentration over time after intravenous administration of terevalefim and compound I-41a·Cl to a mouse. [0009] FIG. 2 is a graph showing terevalefim concentration over time after intravenous administration of terevalefim and compound I-41a·Cl to a rat. [0010] FIG. 3 is a graph showing terevalefim concentration over time after intravenous and intramuscular administration of compound I-41a·Cl to a mouse. [0011] FIG. 4 is a graph showing terevalefim concentration over time after intravenous or intramuscular administration of terevalefim and compound I-41a·Cl to a mouse. [0012] FIG. 5A is a graph showing BALF turbidity of sham, vehicle and compound groups in an acute lung injury model. FIG. 5B is a graph showing BALF protein of sham, vehicle and compound groups in an acute lung injury model. [0013] FIG.6 is a graph showing BALF turbidity of sham, vehicle and compound groups in a chronic lung injury model. [0014] FIG.7 is a graph showing urine output volume of vehicle and compound groups in a renal ischemia-reperfusion rat model. [0015] FIG.8 is a graph showing urine output volume of vehicle and compound groups in a renal ischemia-reperfusion rat model. [0016] FIG.9 is a graph showing urine output volume of vehicle and compound groups in a renal ischemia-reperfusion rat model. DETAILED DESCRIPTION Compounds and Definitions [0017] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0018] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Table 1 and Table 2 show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure. [0019] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure. [0020] Administering: As used herein, the term “administering” or “administration” typically refers to the administration of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.) As will be understood by those skilled in the art, reading the present disclosure, in some embodiments, one or more particular routes of administration may be feasible and/or useful in the practice of the present disclosure. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration is parenteral, e.g., via intravenous (IV) administration (which in some embodiments may be or comprise IV perfusion) or intramuscular (IM) administration. In some embodiments, one or more instances of perfusion may be performed. [0021] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C_1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C_1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C_1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C_1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C_1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule. [0022] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C_1-12, C_1-10, C_1-8, C_1-6, C_1-4, C_1- ₃, or C_1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. [0023] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C_2-12, C_2-10, C_2-8, C_2-6, C_2-4, or C_2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. [0024] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C_2-12, C_2-10, C_2-8, C_2-6, C_2-4, or C_2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl. [0025] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C_6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. [0026] Carbocyclyl: The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C_3-8 hydrocarbon, or an optionally substituted C_7-10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl. [0027] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, circumstances, individuals, or populations, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable agents, entities, situations, sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, circumstances, individuals, or populations, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, agents, entities, situations, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different agents, entities, situations sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied. [0028] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. [0029] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. [0030] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺ (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). [0031] Partially Unsaturated: As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined. [0032] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, dogs, livestock, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition. [0033] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,

refers to at least

, or

_{Unless otherwise indicated, an “optionally substituted” group may have a suitable} substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above. [0034] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH₂)_0–4R°; –(CH₂)_0–4OR°; -O(CH₂)_0-4R^o, –O– (CH₂)_0–4C(O)OR°; –(CH₂)_0–4CH(OR°)₂; –(CH₂)_0–4SR°; –(CH₂)_0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°; –NO₂; –CN; –N₃; -(CH₂)_0–4N(R°)₂; -(CH₂)_0–4N(R°)₃ ⁺; –(CH₂)_0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH₂)_0– ₄N(R°)C(O)NR°₂; -N(R°)C(S)NR°₂; –(CH₂)_0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)OR°; –(CH₂)_0–4C(O)R°; C(S)R°; –(CH₂)_0–4C(O)OR°; –(CH₂)_0–4C(O)SR°; -(CH₂)_0–4C(O)OSiR°₃; –(CH₂)_0–4OC(O)R°; – OC(O)(CH₂)_0–4SR°; –(CH₂)_0–4SC(O)R°; –(CH₂)_0–4C(O)NR°₂; –C(S)NR°₂; –C(S)SR°; – SC(S)SR°, -(CH₂)_0–4OC(O)NR°₂; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH₂C(O)R°; – C(NOR°)R°; -(CH₂)_0–4SSR°; –(CH₂)_0–4S(O)₂R°; –(CH₂)_0–4S(O)₂OR°; –(CH₂)_0–4OS(O)₂R°; – S(O)₂NR°₂; -(CH₂)_0–4S(O)R°; -N(R°)S(O)₂NR°₂; –N(R°)S(O)₂R°; –N(OR°)R°; –C(NH)NR°₂; – P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4 straight or branched alkylene)O– N(R°)₂; or –(C_1–4 straight or branched alkylene)C(O)O–N(R°)₂, wherein each R° may be substituted as defined below and is independently hydrogen, C_1–6 aliphatic, –CH₂Ph, –O(CH₂)_0– ₁Ph, -CH₂-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. It will be appreciated that a substituent -(CH₂)_0–4N(R°)₃ ⁺ may be associated with a suitable counterion, X°, i.e., such that the substituent can be described as -(CH₂)_0–4N(R°)₃X°. In some embodiments, X° is any suitable counterion. In some embodiments, X° is a halide such as chloride, bromide, or iodide. [0035] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen,

,

–(CH₂)_0–2OH, –

–(CH₂)_0– ₂CH(OR^• )₂, -O(haloR^•), -CN, -N₃, -(CH₂)o-₂C(0)R^•, -(CH₂)₀-₂C(0)OH, -(CH₂)_0-2C(0)OR^•, -(CH₂)_0-2SR-, -(CH₂)_0-2SH, -(CH₂)_0-2NH₂, -(CH₂)_0-2NHR^•, -(CH₂)_0-2NR^• ₂, -NO₂, -SiR^• ₃, - OSiR^• ₃, -C(O)SR^•, — (C_1-4 straight or branched alkylene)C(O)OR-, or -SSR^• wherein each R- is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C_1-4 aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0036] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR*₂, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(0)2R*, =NR*, =N0R*, -O(C(R*₂))_2-3O-, or -S(C(R*₂))_2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C_1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*₂)_2-3O,- w-herein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on the aliphatic group of R* include halogen, - R-, -(haloR-), -OH, -OR-, -O(haloR-), -CN, -C(O)OH, -C(O)OR^•, -NH₂, -NHR^•, -NR^• ₂, or -NO₂, wherein each R- is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -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^t ₂, -C(NH)NR^† ₂, or -N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. It will be appreciated that a substitutable nitrogen atom may be substituted as described above, such that the resulting moiety is neutral (e.g., as in

) or cationic (e.g., as in

). It will further be appreciated that when a nitrogen atom is substituted such that the resulting moiety is cationic, it may be associated with a suitable counterion, X°, as defined and described in classes and subclasses herein, both singly and in combination. [0039] Suitable substituents on the aliphatic group of R^† are independently halogen, –R^•, -(haloR^•), –OH, –OR^•, –O(haloR^•), –CN, –C(O)OH, –C(O)OR^•, –NH₂, –NHR^•, –NR^• ₂, or -NO₂, wherein each R^• is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0040] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. Hepatocyte Growth Factor Mimetics [0041] PCT Application No. PCT/US2003/040917, filed December 19, 2003 and published as WO2004/058721 on July 15, 2004, the entirety of which is hereby incorporated by reference, describes certain compounds that act as HGF/SF mimetics. Such compounds include terevalefim:

or a pharmaceutically acceptable salt thereof (i.e., terevalefim in a pharmaceutically acceptable salt form). [0042] Terevalefim has been demonstrated to be remarkably useful for treatment of a variety of conditions including, for example, fibrotic liver disease, ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease, lung fibrosis, damaged and/or ischemic organs, transplants or grafts, stroke, cerebrovascular disease, and renal fibrosis, among others (see, for example, WO 2004/058721, WO 2010/005580, US 2011/0230407, US 7879898, and WO 2009/064422, each of which is hereby incorporated by reference.) Exemplary methods of using terevalefim for, e.g., administering to patients with delayed graft function after kidney transplantation or with acute lung injury, are described in WO 2021/087392 and WO 2021/183774, each of which is hereby incorporated by reference. In particular, terevalefim is or has been the subject of clinical trials for delayed graft function in recipients of a deceased donor kidney (Clinicaltrials.gov identifier: NCT02474667), acute kidney injury after cardiac surgery involving cardiopulmonary bypass (Clinicaltrials.gov identifier: NCT02771509), and COVID-19 pneumonia (Clinicaltrials.gov identifier: NCT04459676). Without wishing to be bound by any particular theory, it is believed that terevalefim’s HGF mimetic capability imparts a variety of beneficial attributes and activities. [0043] Terevalefim is known by at least the following names: • 3-[(1E)-2-(thiophen-2-yl)ethen-1-yl]-1H-pyrazole; and • (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole. [0044] Those skilled in the art will appreciate that terevalefim has a structure that can exist in various tautomeric forms, including (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole and (E)-5-[2-(2- thienyl)vinyl]-1H-pyrazole, or any mixture thereof. Moreover, those skilled in the art, reading the present disclosure will appreciate that, in many embodiments, teachings described herein are not limited to any particular tautomeric form. [0045] Certain liquid (e.g., for intravenous or intraperitoneal administration) and solid (e.g., for oral administration) formulations of terevalefim have been described. See, for example, PCT Application No. PCT/US2009/004014, filed July 9, 2009 and published as WO2010/005580 on January 14, 2010 (“the ‘580 application”), the entirety of which is hereby incorporated by reference. The ‘580 application generally describes liquid compositions comprising HGF/SF mimetics with increased solubility, wherein said compositions comprise polyethylene glycol, polysorbate or a combination thereof. The ‘580 application also describes, in paragraph [0279], a specific formulation of terevalefim, wherein the formulation comprises 0.5% (w/v) terevalefim in 10% polysorbate 80 (v/v), 50% polyethylene glycol 300 (v/v) and 40% (v/v) phosphate- buffered saline. [0046] Formulation of terevalefim as a liquid composition for intravenous administration presented several challenges. First, terevalefim is poorly soluble in water. Terevalefim has an intrinsic solubility of 2.17 mg/mL in water at pH <2 (e.g., when measured by HPLC), and a solubility of 0.1 mg/mL in RPMI 1640 growth medium. Therefore, additional excipients were required to prepare a liquid formulation of terevalefim that was a solution (e.g., to minimize potential issues of clogging and/or poor injectability), could be manufactured and/or shipped and/or stored in a reasonable volume, and could be administered as a reasonable volume of fluid (e.g., less than 50 mL or less than 100 mL per dose). Preparing a formulation of terevalefim with a suitable osmolality also presented a challenge. Without wishing to be bound by theory, the use of additional excipients in order to solubilize terevalefim may be a source of increased osmolality observed in certain formulations. [0047] The present disclosure encompasses the recognition that an agent that provides a terevalefim active moiety, yet is more soluble and/or is easier to formulate and/or is more stable and/or is more amenable to formulation for different routes of administration (e.g., other than intravenous) than terevalefim itself would be desirable for certain uses and/or applications. In some embodiments, an agent that provides a terevalefim active moiety is a prodrug of terevalefim wherein terevalefim is the intended metabolite for its therapeutic or prophylactic effect. In some embodiments, the present disclosure provides prodrugs of terevalefim (e.g., a compound of Formula I or Formula II). [0048] It will be appreciated that an agent that provides a terevalefim active moiety, once administered, is expected to display comparable therapeutic and/or prophylactic properties as terevalefim itself. [0049] In some embodiments, a prodrug of terevalefim is or comprises a compound (e.g., a compound of Formula I or Formula II) that delivers and/or provides a terevalefim active moiety and has a solubility in water and/or saline of at least 0.5 mg/mL (e.g., from 1 mg/mL to 700 mg/mL, from 1 mg/mL to 100 mg/mL, from 1 mg/mL to 50 mg/mL, or from 1 mg/mL to 10 mg/mL). For example, a solubility of approx.700 mg/mL in saline or PBS buffer was observed for compound I-41a. [0050] In some embodiments, a prodrug of terevalefim is or comprises a compound (e.g., a compound of Formula I or Formula II) that delivers and/or provides a terevalefim active moiety and, when administered, achieves a pharmacokinetic profile that is comparable to and/or improved relative to terevalefim itself. In some embodiments, a pharmacokinetic profile is comparable when a mean plasma concentration (e.g., at a particular time point) and/or a mean AUC is comparable. [0051] In some embodiments, a prodrug of terevalefim is or comprises a compound (e.g., a compound of Formula I or Formula II) that delivers and/or provides a terevalefim active moiety and, when administered, achieves a mean plasma concentration that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the mean plasma concentration achieved when a corresponding amount of terevalefim is administered. In some such embodiments, a prodrug of terevalefim, when administered orally and/or intravenously and/or intramuscularly, achieves a mean plasma concentration that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the mean plasma concentration achieved when a corresponding amount of terevalefim is administered orally and/or intravenously and/or intramuscularly. In some such embodiments, a prodrug of terevalefim, when administered orally and/or intravenously and/or intramuscularly to a mouse, achieves a mean plasma concentration that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the mean plasma concentration achieved when a corresponding amount of terevalefim is administered orally and/or intravenously and/or intramuscularly to a mouse. [0052] In some embodiments, a prodrug of terevalefim is or comprises a compound (e.g., a compound of Formula I or Formula II) that delivers and/or provides a terevalefim active moiety and, when administered, achieves a mean AUC that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the mean AUC achieved when a corresponding amount of terevalefim is administered. In some such embodiments, a prodrug of terevalefim, when administered orally and/or intravenously and/or intramuscularly, achieves a mean AUC that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the mean AUC achieved when a corresponding amount of terevalefim is administered orally and/or intravenously and/or intramuscularly. In some such embodiments, a prodrug of terevalefim, when administered orally and/or intravenously and/or intramuscularly to a mouse, achieves a mean AUC that is at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the mean AUC achieved when a corresponding amount of terevalefim is administered orally and/or intravenously and/or intramuscularly to a mouse. Provided Compounds

[0053] In some embodiments, the present disclosure provides a compound of Formula I: (

or a pharmaceutically acceptable salt thereof, wherein: L is –N(R)-, -O-, -S-, -S(O)-, -SO₂-, -OC(O)-, -SC(O)-, -OC(O)O-, -OC(S)O-, -OC(O)N(R)-, - N(R)C(O)O-, –OP(O)(OR)O-, -OP(S)(OR)O-, -OP(O)(R)O-, -OP(O)(OR)-, - OP(O)(OR)N(R)-, -N(R)P(O)(OR)O-, -OSO₂O-, -OSO₂N(R)-, or -N(R)SO₂O-; R¹ is hydrogen or an optionally substituted group selected from C_1-6 aliphatic, a 3- to 7- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur; R² and R³ are each independently hydrogen or optionally substituted C_1-6 aliphatic; or R² and R³ are taken together to form an oxo; or R² and R³ are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur; each R^a is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 aliphatic; each R^b is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 aliphatic; each R is independently hydrogen or optionally substituted C_1-6 aliphatic; n is 0, 1, 2, or 3; and m is 0, 1, or 2. [0054] In some embodiments, the present disclosure provides a compound of Formula IA: (

IA or a pharmaceutically acceptable salt thereof, wherein L, R¹, R², R³, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0055] In some embodiments, the present disclosure provides a compound of Formula IB: (

IB or a pharmaceutically acceptable salt thereof, wherein L, R¹, R², R³, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0056] In some embodiments, the present disclosure provides a compound of Formula IC: (

IC or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3- to 7- membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and L, R³, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0057] In some embodiments, the present disclosure provides a compound of Formula ID: (

ID or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 3- to 7- membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and L, R³, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0058] In some embodiments, the present disclosure provides a compound of Formula IE: (

IE or a pharmaceutically acceptable salt thereof, wherein L, R¹, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0059] In some embodiments, the present disclosure provides a compound of Formula IF: (

IF or a pharmaceutically acceptable salt thereof, wherein L, R¹, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0060] In some embodiments, the present disclosure provides a compound of Formula IG: (

IG or a pharmaceutically acceptable salt thereof, wherein L, R¹, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0061] In some embodiments, the present disclosure provides a compound of Formula IH: (

IH or a pharmaceutically acceptable salt thereof, wherein L, R¹, R^a, R^b, m, and n are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0062] In some embodiments of any of Formulae I, IA, and IG, the compound is not:

[0063] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, L is – N(R)-, –O-, -OC(O)-, or –OP(O)(OR)O-. In some embodiments, L is –O-, -OC(O)-, or – OP(O)(OR)O-. In some embodiments, L is –N(R)- or –O-. In some embodiments, L is –N(R)-, - N(R)C(O)O-, or –N(R)SO₂O-. In some embodiments, L is –N(R)-. In some embodiments, L is – NH-. In some embodiments, L is -N(R)C(O)O-. In some embodiments, L is –N(R)SO₂O-. In some embodiments, L is –O-, -OC(O)-, -OC(O)O-, -OC(S)O-, -OC(O)N(R)-, –OP(O)(OR)O-, - OP(S)(OR)O-, -OP(O)(R)O-, -OP(O)(OR)-, -OP(O)(OR)N(R)-, -OSO₂O-, or -OSO₂N(R)-. In some embodiments, L is –O-. In some embodiments, L is -OC(O)-. In some embodiments, L is -OC(O)O-. In some embodiments, L is -OC(S)O-. In some embodiments, L is -OC(O)N(R)-. In some embodiments, L is –OP(O)(OR)O-. In some embodiments, L is –OP(O)(OR)O-, wherein the R of L is optionally substituted C_1-6 alkyl. In some embodiments, L is –OP(O)(OR)O-, wherein the R of L is C_1-6 alkyl optionally substituted with one or more of –OH, -O(C_1-6 alkyl), - NH₂, -NH(C_1-6 alkyl), and –N(C_1-6 alkyl)₂. In some embodiments, L is –OP(O)(O-C_1-6 alkyl)O-. In some embodiments, L is –OP(O)(OH)O-. In some embodiments, L is -OP(S)(OR)O-. In some embodiments, L is -OP(O)(R)O-. In some embodiments, L is -OP(O)(OR)-. In some embodiments, L is -OP(O)(OR)N(R)-. In some embodiments, L is -OSO₂O-. In some embodiments, L is -OSO₂N(R)-. In some embodiments, L is -S-, -S(O)-, -SO₂-, or -SC(O)-. In some embodiments, L is -S-. In some embodiments, L is -S(O)-. In some embodiments, L is - SO₂-. In some embodiments, L is -SC(O)-. [0064] In some embodiments, L is selected from:

[0065] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, R¹ is hydrogen, optionally substituted C_1-6 aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. [0066] In some embodiments, R¹ is hydrogen, optionally substituted C_1-6 aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is hydrogen, optionally substituted C_1-6 alkyl, or optionally substituted 4- to 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is hydrogen, optionally substituted C_1-6 alkyl, or optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is (i) hydrogen; (ii) C_1-6 alkyl optionally substituted with one or more of -N(R°)₂, -OR°, -OC(O)R°, -C(O)OR°, -OC(O)OR°, and - OP(O)(OR°)₂; or (iii) a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted on a substitutable nitrogen atom with –R^†. In some such embodiments, R° is hydrogen or C_1-6 alkyl, or two independent occurrences of R°, taken together with their intervening atom(s), form a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally substituted with R^•. In some such embodiments, R^† is C_1-6 alkyl. In some embodiments, R¹ is (i) hydrogen; (ii) C_1-6 alkyl optionally substituted with one or more of -N(R°)₂, -N(R°)₃ ⁺, -OR°, -OC(O)R°, -C(O)OR°, -OC(O)OR°, and -OP(O)(OR°)₂; or (iii) a 4- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted on a substitutable carbon atom with one or more -C(O)OR° and on a substitutable nitrogen atom with one or more –R^†. In some such embodiments, R° is hydrogen or C1-6 alkyl, or two independent occurrences of R°, taken together with their intervening atom(s), form a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic ring is optionally substituted with R^•. In some such embodiments, R^† is C_1-6 alkyl. In some embodiments, R¹ is (i) hydrogen; (ii) C_1-6 alkyl optionally substituted with one or more of –NH₂, -N(C_1-6 alkyl)₂, –OH, –O(C_1-6 alkyl), -OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (iii) a 5- to 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more C_1-6 alkyl. In some embodiments, R¹ is (i) hydrogen; (ii) C_1-6 alkyl optionally substituted with one or more of –NH₂, -N(C_1-6 alkyl)₂, -N(C_1-6 alkyl)₃ ⁺, –OH, –O(C_1-6 alkyl), -OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (iii) a 4- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more of C_1-6 alkyl, -C(O)OH, and -C(O)(O-C_1-6 alkyl). [0067] In some embodiments, R¹ is hydrogen. [0068] In some embodiments, R¹ is optionally substituted C_1-6 aliphatic. In some embodiments, R¹ is optionally substituted C_1-6 alkyl. In some embodiments, R¹ is C_1-6 alkyl optionally substituted with one or more of –NH₂, -N(C_1-6 alkyl)₂, –OH, –O(C_1-6 alkyl), - OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is C_1-6 alkyl optionally substituted with one or more of –NH₂, -N(C_1-6 alkyl)₂, -N(C_1-6 alkyl)₃ ⁺, –OH, –O(C_1-6 alkyl), -OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is optionally substituted C_1-4 aliphatic. In some embodiments, R¹ is optionally substituted C_1-4 alkyl. In some embodiments, R¹ is C_1-4 alkyl optionally substituted with one or more of –NH₂, - N(C_1-6 alkyl)₂, –OH, –O(C_1-6 alkyl), -OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), - OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is C_1-4 alkyl optionally substituted with one or more of –NH₂, - N(C_1-6 alkyl)₂, -N(C_1-6 alkyl)₃ ⁺, –OH, –O(C_1-6 alkyl), -OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1- ₆ alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is optionally substituted C_1-2 aliphatic. In some embodiments, R¹ is optionally substituted C_1-2 alkyl. In some embodiments, R¹ is C_1-2 alkyl optionally substituted with one or more of –NH₂, -N(C_1-6 alkyl)₂, –OH, –O(C_1-6 alkyl), - OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is C_1-2 alkyl optionally substituted with one or more of –NH₂, -N(C_1-6 alkyl)₂, -N(C_1-6 alkyl)₃ ⁺, –OH, –O(C_1-6 alkyl), -OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0069] In some embodiments, R¹ is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 4- to 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 3-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C_1-6 alkyl. In some embodiments, R¹ is azetidinyl optionally substituted with one or more C_1-6 alkyl. In some embodiments, R¹ is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C_1-6 alkyl. In some embodiments, R¹ is a 5- membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C_1-6 alkyl, -C(O)OH, and -C(O)(O-C_1-6 alkyl). In some embodiments, R¹ is pyrrolidinyl optionally substituted with one or more C_1-6 alkyl. In some embodiments, R¹ is pyrrolidinyl optionally substituted with one or more C_1-6 alkyl, - C(O)OH, and -C(O)(O-C_1-6 alkyl). In some embodiments, R¹ is an optionally substituted 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is an optionally substituted 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C_1-6 alkyl. In some embodiments, R¹ is piperidinyl optionally substituted with one or more C_1-6 alkyl. In some embodiments, R¹ is an optionally substituted 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0070] In some embodiments, R¹ is optionally substituted phenyl. [0071] In some embodiments, R¹ is optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ is optionally substituted 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0072] In some embodiments, when L is –O-, R¹ is not C_1-6 alkyl substituted with –C(O)OH or –C(O)(O-C_1-6 alkyl). In some embodiments, when L is –O-, R¹ is not C_1-2 alkyl substituted with –C(O)OH or –C(O)(O-C_1-6 alkyl). [0073] In some embodiments, R¹ is hydrogen, tert-butyl, or a group selected from:

[0074] In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered saturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 3-membered saturated ring having no heteroatoms in addition to L. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 4- membered saturated or partially unsaturated ring having no heteroatoms in addition to L. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 5-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 6-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 6- membered saturated ring having no heteroatoms in addition to L. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted tetrahydropyranyl. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form a tetrahydropyranyl optionally substituted with one or more of optionally substituted C_1-6 aliphatic, -C(O)OR, -C(O)N(R)₂, and –OR. In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. [0075] In some embodiments, R¹ and R² are taken together with the atoms to which they are attached to form Ring A, e.g., as shown in Formula IC and Formula ID above. In some embodiments, Ring A is an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5- to 6-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 5- to 6- membered saturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 3-membered saturated ring having no heteroatoms in addition to L. In some embodiments, Ring A is an optionally substituted 4-membered saturated or partially unsaturated ring having no heteroatoms in addition to L. In some embodiments, Ring A is an optionally substituted 5-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 6- membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted 6-membered saturated ring having no heteroatoms in addition to L. In some embodiments, Ring A is optionally substituted tetrahydropyranyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one or more of optionally substituted C_1-6 aliphatic, -C(O)OR, -C(O)N(R)₂, and –OR. In some embodiments, Ring A is an optionally substituted 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. [0076] In some embodiments, Ring A is selected from:

the atoms to which they are attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur, then R² and R³ are not taken together to form an oxo. [0078] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, R² is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R² is hydrogen. In some embodiments, R² is optionally substituted C_1-6 aliphatic. In some embodiments, R² is optionally substituted C_1-6 alkyl. In some embodiments, R² is optionally substituted C_1-4 aliphatic. In some embodiments, R² is optionally substituted C_1-4 alkyl. In some embodiments, R² is optionally substituted C_1-2 aliphatic. In some embodiments, R² is optionally substituted C_1-2 alkyl. [0079] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, R³ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R³ is hydrogen. In some embodiments, R³ is optionally substituted C_1-6 aliphatic. In some embodiments, R³ is optionally substituted C_1-6 alkyl. In some embodiments, R³ is optionally substituted C_1-4 aliphatic. In some embodiments, R³ is optionally substituted C_1-4 alkyl. In some embodiments, R³ is optionally substituted C_1-2 aliphatic. In some embodiments, R³ is optionally substituted C_1-2 alkyl. [0080] In some embodiments, at least one of R² and R³ is hydrogen. In some embodiments, both of R² and R³ are hydrogen. [0081] In some embodiments, R² and R³ are taken together to form an oxo. [0082] In some embodiments, when R² and R³ are taken together to form an oxo, R¹ is not C_1-6 alkyl or optionally substituted phenyl. In some embodiments, when R² and R³ are taken together to form an oxo, R¹ is not methyl, phenyl, or 4-chlorophenyl. In some embodiments, when L is –NH- and R² and R³ are taken together to form an oxo, R¹ is not C_1-6 alkyl or optionally substituted phenyl. In some embodiments, when L is –NH- and R² and R³ are taken together to form an oxo, R¹ is not methyl, phenyl, or 4-chlorophenyl. [0083] In some embodiments, when R² and R³ are taken together to form an oxo, L is –N(R)- or –O-. In some embodiments, when R² and R³ are taken together to form an oxo, L is –N(R)-. In some embodiments, when R² and R³ are taken together to form an oxo, L is –O-. [0084] In some embodiments, R² and R³ are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R² and R³ are taken together with the carbon atom to which they are attached to form an optionally substituted 3-membered saturated ring having 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R² and R³ are taken together with the carbon atom to which they are attached to form an optionally substituted 4-membered saturated ring having 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R² and R³ are taken together with the carbon atom to which they are attached to form an optionally substituted 5-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R² and R³ are taken together with the carbon atom to which they are attached to form an optionally substituted 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur. [0085] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, each R^a is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 alkyl. In some embodiments, each R^a is independently halogen, -CN, -CO₂R, - C(O)N(R)₂, or –NO₂. In some embodiments, each R^a is independently -N(R)₂, -OR, -SR, or optionally substituted C_1-6 alkyl. [0086] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, each R^b is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 alkyl. In some embodiments, each R^b is independently halogen, -CN, -CO₂R, - C(O)N(R)₂, or –NO₂. In some embodiments, each R^b is independently -N(R)₂, -OR, -SR, or optionally substituted C_1-6 alkyl. [0087] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, each R is independently hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C_1-6 aliphatic. In some embodiments, R is optionally substituted C_1-6 alkyl. In some embodiments, R is C_1-6 alkyl optionally substituted with one or more of –N(C_1-6 alkyl)₂ and optionally substituted 5- to 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted C_1-4 aliphatic. In some embodiments, R is optionally substituted C_1-4 alkyl. In some embodiments, R is C_1-4 alkyl optionally substituted with one or more of –N(C_1-6 alkyl)₂ and optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted C_1-2 aliphatic. In some embodiments, R is optionally substituted C_1-2 alkyl. In some embodiments, R is C_1-2 alkyl optionally substituted with one or more of –N(C_1-6 alkyl)₂ and optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0088] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [0089] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, and IH, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0090] In some embodiments, the present disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

- a

[0091] In some embodiments, the present disclosure provides a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: Z is a covalent bond or a bivalent or trivalent linking moiety that is an optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R’)-, -C(O)-, - C(S)-, -C(NR’)-, -C(NOR’)-, -C(NN(R’)₂)-, -OC(O)-, -C(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, - C(NR’)O-, -OC(NR’)-, -C(NR’)NR’-, -N(R’)C(NR’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, - OC(O)N(R’)-, -N(R’)C(O)S-, -SC(O)N(R’)-, -N(R’)C(NR’)N(R’)-, -SO₂-, -SO₂N(R’)-, - N(R’)SO₂-, -OP(O)(OH)O-, -OP(S)(OH)O-, -OP(S)(SH)O-, -OP(S)(COOH)O-, - OP(O)(COOH)O-, -OP(O)(NR₂)O-, -NP(O)(OH)O-, -OP(O)(OH)N-, or –Cy-; each Cy is independently an optionally substituted, mono- or bicyclic, 3- to 10-membered, bivalent or trivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S; each L² is independently –N(R’)-, -O-, -S-, -S(O)-, -SO₂-, -OC(O)-, -SC(O)-, -OC(O)O-, - OC(S)O-, -OC(O)N(R’)-, -N(R’)C(O)O-, –OP(O)(OR’)O-, -OP(S)(OR’)O-, -OP(O)(R’)O-, - OP(O)(OR’)-, -OP(O)(OR’)N(R’)-, -N(R’)P(O)(OR’)O-, -OSO₂O-, -OSO₂N(R’)-, or - N(R’)SO₂O-; each R⁴ and R⁵ are independently hydrogen or optionally substituted C_1-6 aliphatic; or R⁴ and R⁵ are taken together to form an oxo; or R⁴ and R⁵ are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur; each R^c is independently halogen, -CN, -CO₂R’, -C(O)N(R’)₂, -N(R’)₂, -OR’, -SR’, or optionally substituted C_1-6 aliphatic; each R^d is independently halogen, -CN, -CO₂R’, -C(O)N(R’)₂, -N(R’)₂, -OR’, -SR’, or optionally substituted C_1-6 aliphatic; each R’ is independently hydrogen or optionally substituted C_1-6 aliphatic; each p is independently 0, 1, 2, or 3; each q is independently 0, 1, or 2; and t is 2 or 3. [0092] In some embodiments, the present disclosure provides a compound of Formula IIA:

IIA or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0093] In some embodiments, the present disclosure provides a compound of Formula IIB: (

or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0094] In some embodiments, the present disclosure provides a compound of Formula IIC:

or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0095] In some embodiments, the present disclosure provides a compound of Formula IID:

or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0096] In some embodiments, the present disclosure provides a compound of Formula IIE:

IIE or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0097] In some embodiments, the present disclosure provides a compound of Formula IIF: (

or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0098] In some embodiments, the present disclosure provides a compound of Formula IIG:

⁽

or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0099] In some embodiments, the present disclosure provides a compound of Formula IIH: (

or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0100] In some embodiments, the present disclosure provides a compound of Formula IIJ: (

or a pharmaceutically acceptable salt thereof, wherein L², R⁴, R⁵, R^c, R^d, Z, p, and q are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. [0101] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, Z is a bivalent or trivalent linking moiety that is an optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, - C(NOR’)-, -C(NN(R’)₂)-, -OC(O)-, -C(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, -C(NR’)O-, - OC(NR’)-, -C(NR’)NR’-, -N(R’)C(NR’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -OC(O)N(R’)-, - N(R’)C(O)S-, -SC(O)N(R’)-, -N(R’)C(NR’)N(R’)-, -SO₂-, -SO₂N(R’)-, -N(R’)SO₂-, - OP(O)(OH)O-, -OP(S)(OH)O-, -OP(S)(SH)O-, -OP(S)(COOH)O-, -OP(O)(COOH)O-, - OP(O)(NR₂)O-, -NP(O)(OH)O-, -OP(O)(OH)N-, or –Cy-. In some embodiments, Z is a bivalent or trivalent linking moiety that is an optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent or trivalent linking moiety that is an optionally substituted, straight or branched, saturated or unsaturated C_1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent or trivalent linking moiety that is an optionally substituted, straight or branched, saturated or unsaturated C_3-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. [0102] In some embodiments, Z is a covalent bond. In some embodiments, when t is 2, Z is a covalent bond. In some embodiments, when t is 3, Z is not a covalent bond. [0103] In some embodiments, when t is 2, Z is a covalent bond or a bivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R’)-, -C(O)-, - C(S)-, -C(NR’)-, -C(NOR’)-, -C(NN(R’)₂)-, -OC(O)-, -C(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, - C(NR’)O-, -OC(NR’)-, -C(NR’)NR’-, -N(R’)C(NR’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, - OC(O)N(R’)-, -N(R’)C(O)S-, -SC(O)N(R’)-, -N(R’)C(NR’)N(R’)-, -SO₂-, -SO₂N(R’)-, - N(R’)SO₂-, -OP(O)(OH)O-, -OP(S)(OH)O-, -OP(S)(SH)O-, -OP(S)(COOH)O-, - OP(O)(COOH)O-, -OP(O)(NR₂)O-, -NP(O)(OH)O-, -OP(O)(OH)N-, or –Cy-. [0104] In some embodiments, when t is 3, Z is a trivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, - C(NOR’)-, -C(NN(R’)₂)-, -OC(O)-, -C(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, -C(NR’)O-, - OC(NR’)-, -C(NR’)NR’-, -N(R’)C(NR’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -OC(O)N(R’)-, - N(R’)C(O)S-, -SC(O)N(R’)-, -N(R’)C(NR’)N(R’)-, -SO₂-, -SO₂N(R’)-, -N(R’)SO₂-, - OP(O)(OH)O-, -OP(S)(OH)O-, -OP(S)(SH)O-, -OP(S)(COOH)O-, -OP(O)(COOH)O-, - OP(O)(NR₂)O-, -NP(O)(OH)O-, -OP(O)(OH)N-, or –Cy-. [0105] In some embodiments, Z is a bivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, - C(NOR’)-, -C(NN(R’)₂)-, -OC(O)-, -C(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, -C(NR’)O-, - OC(NR’)-, -C(NR’)NR’-, -N(R’)C(NR’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -OC(O)N(R’)-, - N(R’)C(O)S-, -SC(O)N(R’)-, -N(R’)C(NR’)N(R’)-, -SO₂-, -SO₂N(R’)-, -N(R’)SO₂-, - OP(O)(OH)O-, -OP(S)(OH)O-, -OP(S)(SH)O-, -OP(S)(COOH)O-, -OP(O)(COOH)O-, - OP(O)(NR₂)O-, -NP(O)(OH)O-, -OP(O)(OH)N-, or –Cy-. In some embodiments, Z is a bivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent, optionally substituted, straight or branched, saturated or unsaturated C_3-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent, straight or branched, saturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent, straight or branched, saturated C_1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent, straight or branched, saturated C_3-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-. In some embodiments, Z is a bivalent, straight or branched, saturated C_1-8 hydrocarbon chain, wherein one methylene unit is replaced by –Cy-. In some embodiments, Z is a bivalent, straight or branched, saturated C_1-6 hydrocarbon chain, wherein one methylene unit is replaced by –Cy-. In some embodiments, Z is a bivalent, straight or branched, saturated C_3-8 hydrocarbon chain, wherein one methylene unit is replaced by –Cy-. In some embodiments, Z is a bivalent, straight or branched, saturated C_1-8 hydrocarbon chain. In some embodiments, Z is a bivalent, straight or branched, saturated C_1-6 hydrocarbon chain. In some embodiments, Z is a bivalent, straight or branched, saturated C_1-4 hydrocarbon chain. [0106] In some embodiments, Z is a bivalent linking moiety selected from:

[0107] In some embodiments, Z is a trivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, - C(NOR’)-, -C(NN(R’)₂)-, -OC(O)-, -C(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, -C(NR’)O-, - OC(NR’)-, -C(NR’)NR’-, -N(R’)C(NR’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -OC(O)N(R’)-, - N(R’)C(O)S-, -SC(O)N(R’)-, -N(R’)C(NR’)N(R’)-, -SO₂-, -SO₂N(R’)-, -N(R’)SO₂-, - OP(O)(OH)O-, -OP(S)(OH)O-, -OP(S)(SH)O-, -OP(S)(COOH)O-, -OP(O)(COOH)O-, - OP(O)(NR₂)O-, -NP(O)(OH)O-, -OP(O)(OH)N-, or –Cy-. In some embodiments, Z is a trivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain. In some embodiments, Z is a trivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-6 hydrocarbon chain. In some embodiments, Z is a trivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-4 hydrocarbon chain. In some embodiments, Z is a trivalent, straight or branched, saturated C_1-8 hydrocarbon chain. In some embodiments, Z is a trivalent, straight or branched, saturated C_1-6 hydrocarbon chain. In some embodiments, Z is a trivalent, straight or branched, saturated C_1-4 hydrocarbon chain. [0108] In some embodiments, Z is a trivalent linking moiety selected from:

[0109] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each Cy is independently an optionally substituted, mono- or bicyclic, 3- to 10-membered, bivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, when t is 2, each Cy is independently an optionally substituted, mono- or bicyclic, 3- to 10-membered, bivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, each Cy is independently an optionally substituted, mono- or bicyclic, 3- to 10- membered, trivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, when t is 3, each Cy is independently an optionally substituted, mono- or bicyclic, 3- to 10-membered, trivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S. [0110] In some embodiments, each Cy is independently an optionally substituted, monocyclic, 3- to 7-membered, bivalent or trivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-2 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, each Cy is independently an optionally substituted, monocyclic, 3- to 7-membered, bivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-2 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, each Cy is independently an optionally substituted bivalent or trivalent ring selected from 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C_3-7 cycloaliphatic ring, phenyl, and 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each Cy is independently an optionally substituted bivalent ring selected from 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C_3-7 cycloaliphatic ring, phenyl, and 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0111] In some embodiments, Cy is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 5- to 6- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 3-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted piperazine ring. In some embodiments, Cy is a piperazine ring. In some embodiments, Cy is an optionally substituted 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0112] In some embodiments, Cy is an optionally substituted C_3-7 cycloaliphatic ring. In some embodiments, Cy is an optionally substituted C_3-7 cycloalkyl ring. In some embodiments, Cy is an optionally substituted C₃ cycloaliphatic ring (e.g., a C₃ cycloalkyl ring). In some embodiments, Cy is an optionally substituted C₄ cycloaliphatic ring (e.g., a C₄ cycloalkyl ring). In some embodiments, Cy is an optionally substituted C₅ cycloaliphatic ring (e.g., a C₅ cycloalkyl ring). In some embodiments, Cy is an optionally substituted C₆ cycloaliphatic ring (e.g., a C₆ cycloalkyl ring). In some embodiments, Cy is an optionally substituted C₇ cycloaliphatic ring (e.g., a C₇ cycloalkyl ring). [0113] In some embodiments, Cy is an optionally substituted phenyl ring. [0114] In some embodiments, Cy is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0115] In some embodiments, each Cy is independently an optionally substituted, bicyclic, 8- to 10-membered, bivalent or trivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, each Cy is independently an optionally substituted, bicyclic, 8- to 10-membered, bivalent or trivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, each Cy is independently an optionally substituted bivalent or trivalent ring selected from 8- to 10-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C_8-10 cycloaliphatic ring, 8- to 10-membered aryl ring, and 8- to 10-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0116] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each L² is independently –N(R)-, -N(R)C(O)O-, or –N(R)SO₂O-. In some embodiments, L² is –N(R)-. In some embodiments, L² is –NH-. In some embodiments, L² is -N(R)C(O)O-. In some embodiments, L² is –N(R)SO₂O-. In some embodiments, each L² is independently –O-, - OC(O)-, -OC(O)O-, -OC(S)O-, -OC(O)N(R)-, –OP(O)(OR)O-, -OP(S)(OR)O-, -OP(O)(R)O-, - OP(O)(OR)-, -OP(O)(OR)N(R)-, -OSO₂O-, or -OSO₂N(R)-. In some embodiments, L² is –O-. In some embodiments, L² is -OC(O)-. In some embodiments, L² is -OC(O)O-. In some embodiments, L² is -OC(S)O-. In some embodiments, L² is -OC(O)N(R)-. In some embodiments, L² is –OP(O)(OR)O-. In some embodiments, L² is –OP(O)(O-C_1-6 alkyl)O-. In some embodiments, L² is –OP(O)(OH)O-. In some embodiments, L² is -OP(S)(OR)O-. In some embodiments, L² is -OP(O)(R)O-. In some embodiments, L² is -OP(O)(OR)-. In some embodiments, L² is -OP(O)(OR)N(R)-. In some embodiments, L² is -OSO₂O-. In some embodiments, L² is -OSO₂N(R)-. In some embodiments, each L² is independently is -S-, -S(O)-, -SO₂-, or -SC(O)-. In some embodiments, L² is -S-. In some embodiments, L² is -S(O)-. In some embodiments, L² is -SO₂-. In some embodiments, L² is -SC(O)-. [0117] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each R⁴ is independently hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is optionally substituted C_1-6 aliphatic. In some embodiments, R⁴ is optionally substituted C_1-6 alkyl. In some embodiments, R⁴ is optionally substituted C_1-4 aliphatic. In some embodiments, R⁴ is optionally substituted C_1-4 alkyl. In some embodiments, R⁴ is optionally substituted C_1-2 aliphatic. In some embodiments, R⁴ is optionally substituted C_1-2 alkyl. [0118] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each R⁵ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is optionally substituted C_1-6 aliphatic. In some embodiments, R⁵ is optionally substituted C_1-6 alkyl. In some embodiments, R⁵ is optionally substituted C_1-4 aliphatic. In some embodiments, R⁵ is optionally substituted C_1-4 alkyl. In some embodiments, R⁵ is optionally substituted C_1-2 aliphatic. In some embodiments, R⁵ is optionally substituted C_1-2 alkyl. [0119] In some embodiments, at least one of R⁴ and R⁵ is hydrogen. In some embodiments, each of R⁴ and R⁵ is hydrogen. [0120] In some embodiments, R⁴ and R⁵ are taken together to form an oxo. [0121] In some embodiments, R⁴ and R⁵ are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R⁴ and R⁵ are taken together with the carbon atom to which they are attached to form an optionally substituted 3-membered saturated ring having 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R⁴ and R⁵ are taken together with the carbon atom to which they are attached to form an optionally substituted 4-membered saturated or partially unsaturated ring having 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R⁴ and R⁵ are taken together with the carbon atom to which they are attached to form an optionally substituted 5-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R⁴ and R⁵ are taken together with the carbon atom to which they are attached to form an optionally substituted 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur. [0122] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each R^c is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 alkyl. In some embodiments, each R^c is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, or –NO₂. In some embodiments, each R^c is independently -N(R)₂, -OR, - SR, or optionally substituted C_1-6 alkyl. [0123] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each R^d is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 alkyl. In some embodiments, each R^d is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, or –NO₂. In some embodiments, each R^d is independently -N(R)₂, -OR, - SR, or optionally substituted C_1-6 alkyl. [0124] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each R’ is independently hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R’ is hydrogen. In some embodiments, R’ is optionally substituted C_1-6 aliphatic. In some embodiments, R’ is optionally substituted C_1-6 alkyl. In some embodiments, R’ is optionally substituted C_1-4 aliphatic. In some embodiments, R’ is optionally substituted C_1-4 alkyl. In some embodiments, R’ is optionally substituted C_1-2 aliphatic. In some embodiments, R’ is optionally substituted C_1-2 alkyl. [0125] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each p is independently 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. [0126] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, each q is independently 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. [0127] In some embodiments of any of Formulae II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, t is 2. In some embodiments, t is 3. [0128] In some embodiments, the present disclosure provides a compound selected from Table 2, or a pharmaceutically acceptable salt thereof. Table 2.

[0129] It will be appreciated that, throughout the present disclosure, a pyrazole depicted with a moiety bonded to a bracket around both nitrogen atoms is intended to encompass compounds where either nitrogen is substituted. For example, the bracketed pyrazole:

encompasses both 3-fluoro-1-methyl-1H-pyrazole, i.e.,

, and 5-fluoro-1-methyl- 1H-pyrazole, i.e.,

. [0130] Accordingly, it will be appreciated that Formula I encompasses compounds of both Formula IA and Formula IB. Similarly, it will be appreciated that Formula II encompasses compounds wherein each bracketed pyrazole is independently substituted on either nitrogen as described herein, i.e., Formula II encompasses compounds of Formula IIC, Formula IID, Formula IIE, Formula IIF, Formula IIG, Formula IIH, and Formula IIJ. Furthermore, Formula IIA encompasses compounds of Formula IIC, Formula IID, and Formula IIE; and Formula IIB encompasses compounds of Formula IIF, Formula IIG, Formula IIH, and Formula IIJ. [0131] In some embodiments, the present disclosure provides mixtures of two or more compounds described herein. For example, in some embodiments, the present disclosure provides a mixture of two or more compounds described herein that differ only in a substitution pattern on a pyrazole ring (e.g., on the pyrazole nitrogens). [0132] In some embodiments, a mixture comprises a compound of Formula IA, or a pharmaceutically acceptable salt thereof, and a compound of Formula IB, or a pharmaceutically acceptable salt thereof. In some embodiments, a mixture comprises a compound of Formula IC, or a pharmaceutically acceptable salt thereof, and a compound of Formula ID, or a pharmaceutically acceptable salt thereof. In some embodiments, a mixture comprises a compound of Formula IE, or a pharmaceutically acceptable salt thereof, and a compound of Formula IF, or a pharmaceutically acceptable salt thereof. In some embodiments, a mixture comprises a compound of Formula IG, or a pharmaceutically acceptable salt thereof, and a compound of Formula IH, or a pharmaceutically acceptable salt thereof. [0133] In some embodiments, a mixture comprises two or more of: (i) a compound of Formula IIC, or a pharmaceutically acceptable salt thereof; (ii) a compound of Formula IID, or a pharmaceutically acceptable salt thereof; and (iii) a compound of Formula IIE, or a pharmaceutically acceptable salt thereof. In some embodiments, a mixture comprises: (i) a compound of Formula IIC, or a pharmaceutically acceptable salt thereof; (ii) a compound of Formula IID, or a pharmaceutically acceptable salt thereof; and (iii) a compound of Formula IIE, or a pharmaceutically acceptable salt thereof. [0134] In some embodiments, a mixture comprises two or more of: (i) a compound of Formula IIF, or a pharmaceutically acceptable salt thereof; (ii) a compound of Formula IIG, or a pharmaceutically acceptable salt thereof; (iii) a compound of Formula IIH, or a pharmaceutically acceptable salt thereof; and (iv) a compound of Formula IIJ, or a pharmaceutically acceptable salt thereof. In some embodiments, a mixture comprises three or more of: (i) a compound of Formula IIF, or a pharmaceutically acceptable salt thereof; (ii) a compound of Formula IIG, or a pharmaceutically acceptable salt thereof; (iii) a compound of Formula IIH, or a pharmaceutically acceptable salt thereof; and (iv) a compound of Formula IIJ, or a pharmaceutically acceptable salt thereof. In some embodiments, a mixture comprises: (i) a compound of Formula IIF, or a pharmaceutically acceptable salt thereof; (ii) a compound of Formula IIG, or a pharmaceutically acceptable salt thereof; (iii) a compound of Formula IIH, or a pharmaceutically acceptable salt thereof; and (iv) a compound of Formula IIJ, or a pharmaceutically acceptable salt thereof. [0135] In some embodiments, provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977). [0136] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, a pharmaceutically acceptable salt comprises a suitable anionic counterion (e.g., X°), such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate or aryl sulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C_1–4alkyl)₄ ⁺ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate. It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include Formulae IA, IB, IC, ID, IE, IF, IG, and IH, and compound species of such formulae disclosed herein; and reference to a compound of Formula II is intended to also include Formulae IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ, and compound species of such formulae disclosed herein. Preparing Provided Compounds [0137] In some embodiments, provided compounds are prepared according to the following Scheme:

wherein X¹ is a suitable leaving group and L, R¹, R², R³, R^a, R^b, m, and n are as defined above for Formula I. Accordingly, in some embodiments, a compound of Formula I is prepared by a process comprising contacting compound A.1 with compound A.2 under suitable conditions (e.g., suitable alkylation conditions). In some embodiments, such a process further comprises an optional deprotection step (e.g., after contacting compound A.2 with compound A.1) under suitable deprotection conditions. In some embodiments, X¹ is a halogen (e.g., chloro or bromo). [0138] In some embodiments, provided compounds are prepared according to the following Scheme: ⁽

wherein R¹, R^a, R^b, m, and n are as defined above for Formula I. Accordingly, in some embodiments, compound A.3 is prepared by a process comprising contacting compound A.1 with formaldehyde under suitable conditions. In some embodiments, a compound of Formula I is prepared by a process comprising contacting compound A.3 with compound A.4 under suitable coupling conditions (e.g., conditions comprising 2,4,6-trichlorobenzoyl chloride, N,N- dimethylaminopyridine, and/or triethylamine). In some embodiments, such a process further comprises an optional deprotection step (e.g., after contacting compound A.3 with compound A.4) under suitable deprotection conditions. [0139] In some embodiments, provided compounds are prepared according to the following Scheme: (

wherein each X² is independently a suitable leaving group and L, R¹, R^a, R^b, m, and n are as defined above for Formula I. Accordingly, in some embodiments, a compound of Formula I is prepared by a process comprising contacting compound A.1 with compound A.5. In some embodiments, such a process further comprises contacting the resulting mixture with compound A.6 in the presence of a suitable base (e.g., triethylamine or diisopropylethylamine) to provide a compound of Formula I. In some embodiments, such a process further comprises an optional deprotection step (e.g., after contacting compound A.1 with compound A.5 and/or contacting the resulting mixture with compound A.6) under suitable deprotection conditions. In some embodiments, each X² is independently a suitable leaving group such as halogen (e.g., chloro) or haloalkoxy (e.g., -OCCl₃). In some embodiments, a compound A.5 is phosgene or triphosgene. [0140] In some embodiments, provided compounds are prepared according to the following Scheme:

wherein Ring A, L, R³, R^a, R^b, m, and n are as defined above for Formula I. Accordingly, in some embodiments, a compound of Formula I is prepared by a process comprising contacting compound A.7 with compound A.1 in the presence of a suitable acid (e.g., PPTS). In some embodiments, such a process further comprises an optional deprotection step (e.g., after contacting compound A.7 with compound A.1) under suitable deprotection conditions. In some embodiments, such a process further comprises an optional functionalization step (e.g., after contacting compound A.7 with compound A.1) under suitable conditions, such as reductive amination conditions and/or amide coupling conditions. [0141] In some embodiments, provided compounds are prepared according to the following Scheme: _t ^×

wherein X³ is a suitable leaving group and L², R⁴, R⁵, R^c, R^d, Z, p, q, and t are as defined above for Formula II. Accordingly, in some embodiments, a compound of Formula II is prepared by a process comprising contacting compound B.1 with compound B.2 under suitable conditions (e.g., suitable alkylation conditions). In some embodiments, such a process further comprises an optional deprotection step (e.g., after contacting compound B.2 with compound B.1) under suitable deprotection conditions. In some embodiments, X³ is a halogen (e.g., chloro or bromo). Compositions [0142] The present disclosure also provides compositions comprising a compound provided herein and one or more other components. In some embodiments, provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I, IA, IB, IC, ID, IE, IF, IG, IH, II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ). In some embodiments, provided compositions comprise and/or deliver a mixture of compounds described herein (e.g., a mixture of two or more compounds that differ only in substitution pattern on a pyrazole ring). [0143] In some embodiments, a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I, IA, IB, IC, ID, IE, IF, IG, IH, II, IIA, IIB, IIC, IID, IIE, IIF, IIG, IIH, and IIJ) and further comprises a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art. [0144] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc. [0145] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein. Uses [0146] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays. [0147] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, provided compounds are administered orally. In some embodiments, provided compounds are administered parenterally (e.g., intravenously or intramuscularly, etc.). [0148] In some embodiments, the present disclosure provides methods of treating (e.g., lessening the severity of, such as by delaying onset and/or reducing degree and/or frequency of one or more features of) a disease or disorder selected from fibrotic liver disease, ischemia- reperfusion injury, cerebral infarction, ischemic heart disease, renal disease and/or renal fibrosis, lung fibrosis, damaged and/or ischemic organs, transplants or grafts, stroke, and cerebrovascular disease, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0149] In some embodiments, the present disclosure provides methods of treating a fibrotic liver disease, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. In some embodiments, a fibrotic liver disease is liver fibrosis or cirrhosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non- alcoholic steatohepatitis, extrahepatic obstructions, cholangiopathies (e.g., primary biliary cirrhosis or sclerosing cholangitis), autoimmune liver disease, or inherited metabolic disorders (Wilson’s disease, hemochromatosis, or alpha-1 antitrypsin deficiency). [0150] In some embodiments, the present disclosure provides methods of treating ischemia- reperfusion injury, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating ischemia-reperfusion injury of the liver (e.g., after liver transplantation). In some embodiments, the present disclosure provides methods of treating ischemia-reperfusion injury of the kidney (e.g., after kidney transplantation). [0151] In some embodiments, the present disclosure provides methods of treating cerebral infarction (i.e., stroke), comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0152] In some embodiments, the present disclosure provides methods of treating ischemic heart disease, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating chronic heart failure, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0153] In some embodiments, the present disclosure provides methods of treating renal disease and/or renal fibrosis, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating chronic renal dysfunction. In some embodiments, the present disclosure provides methods of treating acute renal dysfunction. In some embodiments, the present disclosure provides methods of treating acute kidney injury. In some embodiments, the present disclosure provides methods of treating acute kidney injury associated with cardiac surgery (e.g., cardiac surgery involving cardiopulmonary bypass). In some embodiments, the present disclosure provides methods of treating renal disease associated with ischemia, diabetes, cardiovascular disease, or administration of chemotherapy, antibiotics or radiocontrast agents. In some embodiments, the present disclosure provides methods of treating and/or preventing delayed graft function (e.g., in patients who have received a kidney transplantation). [0154] In some embodiments, the present disclosure provides methods of treating a respiratory disease, disorder or condition, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0155] In some embodiments, the present disclosure provides methods of treating lung fibrosis, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating idiopathic pulmonary fibrosis. [0156] In some embodiments, the present disclosure provides methods of treating acute lung injury, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating acute lung injury. In some embodiments, the present disclosure provides methods of treating acute lung injury associated with COVID-19 pneumonia. In some embodiments, the present disclosure provides methods of treating acute respiratory distress syndrome. In some embodiments, the present disclosure provides methods of treating acute lung injury, acute respiratory distress syndrome, pneumonia (e.g., influenza-associated pneumonia or COVID-19- associated pneumonia), pulmonary edema, TGFβ1-induced lung injury, emphysema, chemically- induced (e.g., chlorine gas) lung injury, thermally-induced (e.g., smoke or burn) lung injury, shock-induced lung injury (e.g., lipopolysaccharide-induced shock), ischemic reperfusion lung injury, hemorrhagic shock lung injury, radiation-induced lung injury, blunt trauma to lung, and lung transplantation injury. [0157] In some embodiments, the present disclosure provides methods of treating a chronic obstructive pulmonary disease such as emphysema, secondary effects of tobacco abuse or smoking, chronic bronchitis, asthma, cystic fibrosis, alpha-1 antitrypsin deficiency, bronchiectasis, or some forms of bullous lung diseases, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0158] In some embodiments, the present disclosure provides methods of treating demyelinating diseases and traumatic diseases of the central nervous system, such as spinal cord injury, traumatic brain injury, multiple sclerosis, or hereditary neurodegenerative diseases, such as, but not limited to, leukodystrophies including metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus- Merzbacher disease and Alexander's disease, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0159] In some embodiments, the present disclosure provides methods of treating fibrotic diseases of connective tissue, such as, but not limited to, scleroderma, systemic sclerosis, generalized scleroderma, limited scleroderma and post-surgical adhesions, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0160] In some embodiments, the present disclosure provides methods of treating muscular dystrophy, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0161] In some embodiments, the present disclosure provides methods of treating amyotrophic lateral sclerosis, comprising administering a compound or mixture of compounds provided herein to a subject in need thereof. [0162] In some embodiments, the present disclosure provides methods of treating acute injuries (e.g., acute organ injuries, such as acute lung injury, acute liver injury, or acute kidney injury), as well as for treating chronic injuries (e.g., chronic organ injuries, such as chronic lung injury, chronic liver injury, or chronic kidney injury). In some embodiments, provided methods are useful for treating fibrosis associated with an acute injury, such as that incurred from trauma and/or surgery and/or infection (e.g., a viral infection). In some embodiments, provided methods are useful for treating damaged and/or ischemic organs, transplants, or grafts, as well as ischemia/reperfusion injury or post-surgical scarring. EXAMPLES [0163] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Synthesis of Provided Compounds [0164] Example 1. (E)-(3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2- (dimethylamino)acetate (I-1a)

[0165] Step 1: To a solution of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 3.876 g, 22.0 mmol) in diethyl ether (20 mL) was added 37% formaldehyde in water (1.8 mL, 22.0 mmol). The resulting mixture was stirred at room temperature overnight, and then evaporated to dryness under reduced pressure to afford the desired product (E)-(3-(2-(thiophen-2-yl)vinyl)-1H- pyrazol-1-yl)methanol (1-2, 4.0 g, yield: 87%) as a white solid. ¹H-NMR (300 MHz, DMSO- d₆): δ (ppm): 7.75 (d, J = 0.95 Hz, 1H), 7.43 (d, J = 2.55 Hz, 1H), 7.31 (d, J = 8.11 Hz, 1H), 7.18 (d, J = 1.50 Hz, 1H), 7.03 (m, 1H), 6.82 (d, J = 8.13 Hz, 1H), 6.74 (t, J = 3.80 Hz, OH), 6.56 (d, J = 1.20 Hz, 1H), 5.32 (d, J = 3.80 Hz, 1H). [0166] Step 2: Under N₂, to a stirred solution of 2-(dimethylamino)acetic acid (1-3, 50 mg, 0.48 mmol) in dry toluene (3 mL) were added successively Et₃N (0.15 mL, 0.96 mmol) and a solution of 2,4,6-trichlorobenzoyl chloride (0.1 mL, 0.6 mL) in toluene (3 mL). After stirring at room temperature for 30 min, a solution of (E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methanol (1-2, 50 mg, 0.24 mmol) and DMAP (5 mg, 0.05 mmol) in toluene was added, and the reaction mixture was stirred for 1 h. The reaction was quenched with saturated NaHCO₃ aqueous solution (10 mL). Organic layer was collected and the aqueous layer was extracted with DCM (2 × 10 mL). Organic layers were combined, dried over Na₂SO₄, filtered, and evaporated to dryness to give the crude product, which was purified using silica gel column chromatography to give (E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-(dimethylamino)acetate (I-1a, 38 mg, yield 55 %) as a light brown oil. ¹H-NMR (300 MHz, CDCl₃): δ (ppm): 7.62 (d, J = 2.4 Hz, 1H), 7.26-7.19 (m, 2H), 7.06 (d, J = 3.3 Hz, 1H), 7.02-6.89 (m, 2H), 6.45 (d, J = 2.4 Hz, 1H), 6.04 (s, 1H), 3.3 (s, 2H), 2.42 (s, 6H). MS (ESI+): m/z: 292.37 (M+H)⁺. [0167] Example 2. (E)-(3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 1- methylpyrrolidine-3-carboxylate (I-2a)

[0168] Compound I-2a was prepared by following the same procedure described in Step 2 for synthesizing I-1a.20 mg of I-2a was obtained in 37% yield as light brown oil.¹H-NMR (300 MHz, CDCl₃): δ (ppm): 7.62 (d, J = 2.4 Hz, 1H), 7.26-7.19 (m, 2H), 7.06 (d, J = 3.3 Hz, 1H), 7.02-6.89 (m, 2H), 6.45 (d, J = 2.4 Hz, 1H), 6.04 (s, 1H), 3.3 (s, 2H), 2.42 (s, 6H). MS (ESI+): m/z: 292.37 (M+H)⁺. [0169] Example 3. (E)-(3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl pyrrolidine- 3-carboxylate hydrochloride (I-3a·HCl)

[0170] Step 1: (E)-1-tert-Butyl 3-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) pyrrolidine-1,3-dicarboxylate (3-2) was prepared by following the same procedure described in Step 2 for synthesizing I-1a. The product was obtained in 61% yield. MS (ESI⁺): m/z: 404.5 (M+H)⁺. [0171] Step 2: (E)-1-tert-Butyl 3-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) pyrrolidine-1,3-dicarboxylate (3-2, 310 mg, 0.77 mmol) was dissolved in 4 M HCl solution in dioxane (5 mL) and the reaction mixture was stirred at room temperature for 20 min. The solvent and excess HCl were evaporated, and the residue was further dried under high vacuum to give (E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl pyrrolidine-3-carboxylate hydrochloride (I-3a·HCl, 256 mg, yield: 98%) as an off-white solid. ¹H-NMR (300 MHz, CDCl₃): δ (ppm): 7.58 (d, J = 2.4 Hz, 1H), 7.26-7.19 (m, 2H), 7.06 (d, J = 3.3 Hz, 1H), 7.00-6.97 (m, 1H), 6.92-6.86 (m, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.02 (d, J = 2.4 Hz, 2H), 3.56-3.24 (m, 5H), 2.32- 2.21 (m, 2H). MS (ESI⁺): m/z: 304.3 (M+H)⁺. [0172] Example 4. (R,E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-amino-3- methylbutanoate hydrochloride (I-4a-i·HCl)

[0173] Step 1: To a suspension of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 176 mg, 1.0 mmol) and Cs₂CO₃ (684 mg, 2 mmol) in DMF (5 mL) was added chloromethyl (tert- butoxycarbonyl)-D-valinate (4-1, 318 mg, 1.2 mmol) dropwise. The reaction mixture was stirred at 50 °C for 4 h, After cooling to room temperature, the reaction mixture was evaporated to dryness and residue was purified using an ISCO CombiFlash® (silica gel, eluted with 0-40% EtOAc in hexane to give (R,E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-((tert- butoxycarbonyl)amino)-3-methylbutanoate (4-2, 307 mg, yield: 76%). MS (ESI⁺): m/z: 406.42 (M+H)⁺. [0174] Step 2: To a solution of (R,E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2- ((tert-butoxycarbonyl)amino)-3-methylbutanoate (4-2, 81 mg, 0.2 mmol) in DCM (1 mL) was added 4 M HCl in dioxane (1 mL). The resulting mixture was stirred at room temperature for 3 h. White solid was formed in the reaction mixture. The solvent was removed under reduced pressure to give (R,E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-amino-3- methylbutanoate hydrochloride (I-4a-i·HCl) as a white solid (63 mg, yield: 92%).¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.32 (m, 1H), 7.14 (d, J = 3.6 Hz, 1H), 7.02 (m, 1H), 6.86 (m, 1H), 6.29 (d, J = 11.1 Hz, 1H), 6.13 (d, J = 11.1 Hz, 1H), 3.98 (d, J = 4.5 Hz, 1H), 2.27-2.20 (m, 1H), 0.97-0.94 (m, 6H). MS (ESI⁺): m/z: 365 (M+H)⁺. [0175] Example 5. (S,E)-(3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-((tert- butoxycarbonyl)oxy)propanoate (I-5a-i)

Step 2 1^-1 _I-5a-i [0176] Step 1: To a solution of (S)-2-((tert-butoxycarbonyl)oxy)propanoic acid (5-1, 190 mg, 1 mmol) in a mixture of water and DCM (1:1, 10 mL) was added NaHCO3 (336 mg, 4 mmol) and n-Bu₄NHSO₄ (34 mg, 0.1 mmol). The reaction mixture was cooled to 0 °C, chloromethyl chlorosulfate (196 mg, 1.2 mmol) was added. The resulting mixture was stirred at room temperature overnight. The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to dryness to give the crude product (5-3) as a viscous oil, which was used directly in the next step without further purification. MS (ESI⁺): m/z: 239 (M+H)⁺. [0177] Step 2: To a suspension of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 176 mg, 1.0 mmol) and Cs₂CO₃ (684 mg, 2 mmol) in DMF (5 mL) was added (S)-chloromethyl 2-((tert- butoxycarbonyl)oxy)propanoate (5-3, 285 mg, 1.2 mmol) in DMF (1 mL) dropwise. The reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the reaction mixture was evaporated to dryness and residue was purified using an ISCO CombiFlash® (silica gel, eluted with 0-40% EtOAc in hexane to give (S,E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-((tert-butoxycarbonyl)oxy)propanoate (I-5a-i, 295 mg, yield: 78%). ¹H NMR (300 MHz, CDCl₃) δ 7.60 (d, J = 2.4 Hz, 1H), 7.30-7.20 (m, 2H), 7.08 (d, J = 4 Hz, 1H), 7.0-6.97 (m, 1H), 6.92-6.87 (m, 1H), 6.45 (d, J = 2.7 Hz, 1H), 6.18 (d, J = 10.8 Hz, 1H), 6.0 (d, J = 10.8 Hz, 1H), 4.91 (q, 1H), 1.47-1.45 (m, 12H). MS (ESI⁺): m/z: 379.6 (M+H)⁺. [0178] Example 6. (S,E)-(3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2- hydroxypropanoate (I-6a-i)

[0179] To a solution of (S,E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-((tert- butoxycarbonyl)oxy)propanoate (I-5a-i, 37.8 mg, 0.1 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction was evaporated to dryness under reduced pressure to give the desired (S,E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl 2-hydroxypropanoate (I-6a-i, 35 mg, yield: 90%).¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 2.4 Hz, 1H), 7.31-7.21 (m, 2H), 7.09 (d, J = 4 Hz, 1H), 7.0-6.98 (m, 1H), 6.93-6.88 (m, 1H), 6.47 (d, J = 2.7 Hz, 1H), 6.15-6.04 (m, 2H), 4.31 (q, 1H), 1.40 (d, 3H). MS (ESI⁺): m/z: 279.3 (M+H)⁺. [0180] Example 7. (E)-Di-tert-butyl ((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) phosphate (I-7a) and (E)-di-tert-butyl ((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) phosphate (I-7b)

I-7a ^I-7b [0181] To a mixture of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 1.0 g, 5.68 mmol) and Cs₂CO₃ (2.4 g, 7.38 mmol) was added a solution of di-tert-butyl (chloromethyl) phosphate (1.47 g, 5.68 mmol) in DMA (2.0 mL). The resulting mixture was stirred at 55 °C for 5 h. LC- MS indicated 90% conversion of starting material 1-1. The reaction mixture was cooled down to room temperature, diluted with water (40 mL), and extracted with Et₂O (4 × 50 mL). The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness to give the crude material, which was purified using an ISCO CombiFlash® (alumina column, eluted with 0-30% ethyl acetate in hexane) to afford (E)-di-tert- butyl ((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) phosphate (I-7a) and (E)-di-tert- butyl ((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) phosphate (I-7b), as a mixture of isomers in a ratio of 2:3, as a colorless oil (1.96 g, yield: 88%) ¹H-NMR (300 MHz, DMSO-d₆): δ (ppm): 7.85 (d, J = 2.4 Hz, 1 H), 7.55-7.33 (m, 2 H), 7.23 (dd, J₁ = 10.8 Hz, J₂ = 3.3 Hz, 1 H), 6.84-6.64 (m, 1 H), 5.95-5.76 (m, 2 H), 1.36 (s, 18 H). MS (ESI⁺): m/z: 399.41(M+H) ⁺. [0182] Example 8. Sodium (E)-tert-butyl ((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methyl) phosphate (I-8a·Na) and Sodium (E)-tert-butyl ((5-(2-(thiophen-2-yl)vinyl)-1H- pyrazol-1-yl)methyl) phosphate (I-8b·Na)

I-7a ^{I-7b I-8a⋅} ^{Na I-8b⋅} ^Na [0183] To a mixture of (E)-di-tert-butyl ((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methyl) phosphate (I-7a) and (E)-di-tert-butyl ((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methyl) phosphate (I-7b) (approx.2:3 ratio, 303 mg, 0.76 mmol) was added 15 mL of MeOH and 0.1 M NaOH solution (1:1 (v/v)). The reaction mixture was stirred at 50 °C for 2 h. LC-MS indicated the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and washed with ethyl acetate. The aqueous phase was collected and azeotroped with toluene to dryness to give sodium (E)-tert-butyl ((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) phosphate (I-8a·Na) and sodium (E)-tert-butyl ((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl) phosphate (I- 8b·Na), as a mixture of isomers in a ratio of 2:3, as a yellowish solid (150 mg, yield: 50%).¹H- NMR (300 MHz, DMSO-d₆): δ (ppm) 7.78 (d, J = 2.4 Hz, 1 H), 7.50-7.40 (m, 1 H), 7.32-7.27 (m, 2 H), 7.17 (m, J = 3.6 Hz, 1 H), 7.06 -7.01 (m, 1 H), 6.84-6.64 (m, 1 H), 5.61-5.46 (m, 2 H), 1.22 (d, J = 6.6 Hz, 9 H). MS (ESI⁺): m/z: 343.24. (M+H) ⁺. [0184] Example 9. Sodium (E)-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl phosphate (I-9a·Na₂) and Sodium (E)-(5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl phosphate (I-9b·Na2)

[0185] To a mixture of (E)-di-tert-butyl ((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methyl) phosphate (I-7a) and (E)-di-tert-butyl ((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methyl) phosphate (I-7b) (approx.2:3 ratio, 343 mg, 0.86 mmol) in DCM (4 mL) was added TFA (0.2 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h. LC-MS indicated the reaction was complete. The reaction mixture was diluted with 50 mL of ether. The crude product was collected by filtration and triturated with DCM, and then treated with 1.5 mL of a mixture of MeOH and 0.1 M NaOH solution (1:1 (v/v)). After stirring for 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in water and washed with ethyl acetate. The aqueous phase was azeotroped with toluene to dryness to provide sodium (E)- (3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl phosphate (I-9a·Na₂) and sodium (E)-(5-(2- (thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methyl phosphate (I-9b·Na2) as a mixture of isomers in a ratio of 2:3, as an off-white fine powder (28.3 mg, yield: 10%). ¹H-NMR (300 MHz, D2O): δ (ppm) 7.46 (d, J =1.8 Hz, 1 H), 7.30 (m, 2 H), 7.19 (d, J = 3.3 Hz, 1 H), 6.98 (m, 2 H), 6.54 (d, J = 1.8 Hz, 1 H), 5.62(d, J = 4.2 Hz, 2 H). MS (ESI⁺): m/z: 287.11. (M+H) ⁺. [0186] Example 10. (E)-Ethyl 2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)acetate (I-10a)

[0187] To a solution of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 400 mg, 2.27 mmol) in THF (4.0 mL) was added potassium tert-butoxide (382 mg, 3.41 mmol) with stirring. After the solid was completely dissolved, ethyl 2-(chloromethoxy) acetate (10-1, 400 mg, 2.62 mmol) was added dropwise. The reaction mixture was stirred at 50 °C for 3 h, concentrated under reduced pressure to give the crude product, which was purified using an ISCO CombiFlash® (silica gel, eluted with 0-40% ethyl acetate in hexane) to afford (E)-ethyl 2-((3-(2- (thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)acetate (I-10a, 230 mg, yield: 34%) as a colorless oil.¹H-NMR (300 MHz, CDCl₃): δ (ppm) 7.55 (m, 1 H), 7.32-7.20 (m, 2 H), 7.16 (dd, J₁= 21.9 Hz, J₂= 5.4 Hz, 1 H), 7.09-7.00 (m, 1 H), 6.90 (dd, J₁= 16.2 Hz, J₂= 4.8 Hz, 1 H), 5.67 (m, 2 H), 4.20 (m, 4 H), 1.26 (dt, J₁= 7.2 Hz, J₂= 2.4 Hz, 3 H). MS (ESI⁺): m/z: 293.22 (M+H) ⁺. [0188] Example 11. (E)-Ethyl 2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)propanoate (I-11a)

[0189] Compound I-11a was prepared by following the same procedure described in Example 10. Compound I-11a was obtained in 42% yield as a colorless oil.¹H-NMR (300 MHz, DMSO-d₆): δ (ppm) 7.83 (d, J = 2.4 Hz, 1 H), 7.52-7.34 (m, 2 H), 7.29-7.18 (m, 1 H), 7.08-6.99 (m, 1 H), 6.87 (m, 1 H), 6.64 (m, 1 H), 5.72-5.37 (m, 2 H), 4.16 (q, J = 6.9 Hz, 1 H), 4.02 (q, J = 7.2 Hz, 2 H), 1.86 (m, 6 H). MS (ESI⁺): m/z: 307.24 (M + H) ⁺. [0190] Example 12. Sodium (E)-2-((3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)propanoate (I-12a·Na)

[0191] To (E)-ethyl 2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)propanoate (I- 11a, 76.3 mg, 0.25 mmol) was added 1.25 mL of a mixture of MeOH and 0.2 M NaOH solution (1:1 (v/v)). The reaction mixture was stirred 50 °C for 2 h. LC-MS indicated the reaction was complete. The solvent was removed by azeotroping with toluene to dryness to afford sodium (E)- 2-((3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)propanoate (I-12a·Na, 77.1 mg, yield: 100%) as a white powder. ¹H-NMR (300 MHz, D₂O): δ (ppm) 7.73 (d, J = 2.1 Hz, 1 H), 7.44- 7.35 (m, 2 H), 7.25-7.31 (m, 2 H), 7.16-6.99 (m, 2 H), 6.70 (m, 1 H), 5.64-5.22 (m, 2 H), 1.05 (d, J = 6.6 Hz, 3 H). MS (ESI⁺): m/z: 279.22 (M + H) ⁺. [0192] Example 13. Sodium (E)-2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)acetate (I-13a·Na)

[0193] Compound I-13a·Na was prepared by following the same procedure described in Example 12. Compound I-13a·Na was obtained from I-10a in 95% yield as a white powder.¹H- NMR (300 MHz, D₂O): δ (ppm) 7.75 (d, J = 2.4 Hz, 1 H), 7.43-7.36 (m, 2 H), 7.31-7.25 (m, 2 H), 7.15-6.99 (m, 2 H), 6.70 (m, 1 H), 5.53-5.36 (m, 2 H), 3.55 (d, J = 4.8 Hz, 2 H). MS (ESI⁺): m/z: 265.21 (M + H) ⁺. [0194] Example 14. (E)-1-((2-Methoxyethoxy)methyl)-3-(2-(thiophen-2-yl)vinyl)-1H- pyrazole (I-14a) and (E)-1-((2-methoxyethoxy)methyl)-5-(2-(thiophen-2-yl)vinyl)-1H- pyrazole (I-14b)

[0195] To a stirred mixture of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 500 mg, 2.84 mmol) in anhydrous dichloromethane (DCM, 5.0 mL), 2-methoxyethoxymethyl chloride (14-1, 0.363 mL, 3.18 mmol) was added dropwise at 0 °C, followed by slow addition of triethylamine (TEA, 0.63 mL, 4.51 mmol). The resulting mixture was stirred at room temperature for 30 min. LC-MS showed the reaction was complete. The reaction was quenched with water, extracted with DCM and evaporated to dryness in vacuo. The crude product was purified by silica gel flash chromatography (using an ISCO CombiFlash®) to afford (E)-1-((2- methoxyethoxy)methyl)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (I-14a) and (E)-1-((2- methoxyethoxy)methyl)-5-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (I-14b) as a mixture of isomers in a ratio of 1:2.5 (600 mg, yield: 80%). ¹H-NMR (300 MHz, CDCl₃): δ 7.54 (d, J = 2.5 Hz, 1 H), 7.19 (d, J = 6.3 Hz, 2 H), 7.06 (m, 1H), 6.97 (m, 2H), 6.49 (d, J = 2.5 Hz, 1 H), 5.47 (s, 2H), 3.66 (m, 2H), 3.50 (m, 2H), 3.36 (s, 3H). MS (ESI⁺): m/z: 265.21 (M+H)⁺. [0196] Example 15. (E)-4-(2-((3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethyl)morpholine (I-15a) and (E)-4-(2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol- 1-yl)methoxy)ethyl)morpholine (I-15b)

[0197] Step 1: At 0 °C, to acetyl bromide (1.06 mL, 14.3 mmol) was added 1,3-dioxolane (15-1, 0.94 mL, 13.5 mmol) dropwise slowly. The resulting mixture was stirred at the same temperature for 30 min. Judged by ¹H-NMR, a rapid reaction occurred giving quantitative conversion to afford 2-(bromomethoxy)ethyl acetate (15-2, 2.66 g, 13.5 mmol, yield: 100%) as a clear oil.¹H-NMR (300 MHz, CDCl₃): δ 5.68 (s, 2H), 4.26 (m, 2H), 3.84 (m, 2H), 2.07 (s, 3H). [0198] Step 2: To a stirred mixture of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 1.19 g, 6.75 mmol) in anhydrous THF (5.0 mL) was added potassium tert-butoxide (t-BuOK, 1.5 g, 13.5 mmol). The resulting mixture was stirred at 70 °C for 30 min, then 2-(bromomethoxy)ethyl acetate (15-2, 2.66 g, 13.5 mmol) was added, and the reaction was stirred at 70 °C overnight. LC-MS showed the reaction was complete. After cooling to room temperature, the reaction was quenched with water, extracted with DCM, and evaporated to dryness in vacuo. The crude product was purified using an ISCO CombiFlash® (silica gel) to afford a mixture of (E)-2-((3- (2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl acetate and (E)-2-((5-(2-(thiophen-2- yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl acetate (15-3, 1.045 g, yield: 53%). MS (ESI⁺): m/z: 293.18 (M+H)⁺. [0199] Step 3: To a stirred mixture of 15-3 (1.045 g, 3.57 mmol) in methanol (5.0 mL) was added NaOH (214 mg, 5.36 mmol) in water (5.0 mL). The resulting mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was neutralized with hydrochloride solution (1M in H₂O) and the solvent was removed in vacuo. The product was extracted with DCM and the combined organic phases were dried with Na₂SO₄, filtered, and evaporated to dryness under reduced pressure. The crude product was purified using an ISCO CombiFlash® (silica gel) to afford a mixture of (E)-2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol- 1-yl)methoxy)ethan-1-ol and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethanol (15-4, 894 mg, yield: 100%). MS (ESI⁺): m/z: 251.20 (M+H)⁺. [0200] Step 4: Under N₂, to a stirred mixture of 15-4 (333mg, 1.33 mmol) and triethylamine (0.37 ml, 2.66 mmol) in anhydrous DCM (4.0 mL) was added methanesulfonyl chloride (0.27 ml, 2.00 mmol) dropwise at 0 °C. After LC-MS showed the reaction was complete, the reaction mixture was quenched with water and extracted with DCM. The combined organic phases were dried with Na₂SO₄, filtered, and evaporated to dryness in vacuo. The crude product (15-5) was used directly for next step without further purification. MS (ESI⁺): m/z: 329.23 (M+H)⁺. [0201] Step 5: To a stirred solution of 15-5 (436 mg, 1.33 mmol) in anhydrous DMF (4.0 mL) was added morpholine (0.35 ml, 3.99 mmol) dropwise. The resulting mixture was stirred at 60 °C for 30 min. LC-MS showed the reaction was complete. Solvent was removed in vacuo and the crude product was purified using an ISCO CombiFlash® (silica gel) to afford (E)-4-(2-((3-(2- (thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl)morpholine (I-15a) and (E)-4-(2-((5-(2- (thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl)morpholine (I-15b) as a mixture of isomers in a ratio of 2.5:1 (74 mg, yield: 17.4%). ¹H-NMR (300 MHz, methanol-d₄): δ 7.53 (d, J = 2.3 Hz, 1 H), 7.22 (m, 2 H), 7.06 (d, J = 3.5 Hz, 1 H), 6.93 (m, 2H), 6.49 (m, 1 H), 5.44 (s, 2H), 3.67 (m, 6H), 2.50 (m, 6H). MS (ESI⁺): m/z: 320.27 (M + H)⁺. [0202] Example 16. (E)-2-((3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl acetate (I-16a) and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl acetate (I-16b)

[0203] Under N₂, to a stirred mixture of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 1.0 g, 5.67 mmol) in anhydrous THF (20 mL) was added t-BuOK (1.27 g, 11.34 mmol), and the mixture was stirred at 70 °C for 30 min, then 2-(bromomethoxy)ethyl acetate (15-2, 2.24 g, 11.34 mmol) was added. The resulting mixture was stirred at 70 °C overnight, and then poured into water (20 mL), extracted with DCM (2 × 25 mL). The organic layers were combined, dried over Na₂SO₄, filtered, and the filtrate concentrated in vacuo. The crude product was purified using an ISCO CombiFlash® (silica gel) to afford (E)-2-((3-(2-(thiophen-2-yl)vinyl)-1H- pyrazol-1-yl)methoxy)ethyl acetate (I-16a) and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethyl acetate (I-16b) as a mixture of isomers in a ratio of 89:11, as a pale brown thick liquid (0.81 g, yield: 49%). ¹H-NMR (300 MHz, CD₃OD): δ (ppm) 7.75 (d, J = 2.4 Hz, 1 H), 7.31–7.30 (m, 2 H), 7.12 (d, J = 3.3 Hz, 1 H), 7.02–6.99 (m, 1 H), 6.86 (d, J = 16.2 Hz, 1 H), 6.61 (d, J = 3.0 Hz, 1 H), 5.45 (s, 2 H), 4.14 (t, J = 4.8 Hz, 2 H), 3.69 (t, J = 4.8 Hz, 2 H), 1.99 (s, 3 H). MS (ESI⁺): m/z: 293.18 (M+H)⁺. [0204] Example 17. (E)-2-((3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethan- 1-ol (I-17a) and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethanol (I-17b)

[0205] Under N₂, to a stirred mixture of (E)-2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethyl acetate (I-16a) and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethyl acetate (I-16b) as a mixture of isomers in a ratio of 89:11 (710 mg, 2.43 mmol) in MeOH (10 mL), was added aqueous 2 M NaOH (5 mL). The resulting mixture was stirred at room temperature for 1 h, then MeOH was evaporated. The pH of the aqueous layer was adjusted to ~6-7 by controlled addition of 6 N HCl. The product was extracted into DCM (2 × 20 mL). The organic layers were combined, dried over Na₂SO₄, filtered, and the filtrate concentrated in vacuo. The crude product was purified using an ISCO CombiFlash® (silica gel) to afford (E)-2- ((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethan-1-ol (I-17a) and (E)-2-((5-(2- (thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethanol (I-17b) as a mixture of isomers in a ratio of 79:21 (590 mg, yield: 97%). MS (ESI⁺): ¹H-NMR (300 MHz, CD₃OD): δ (ppm) 7.75 (d, J = 2.4 Hz, 1 H), 7.34–7.29 (m, 2 H), 7.12 (d, J = 3.6 Hz, 1 H), 7.02–6.99 (m, 1 H), 6.86 (d, J = 16.2 Hz, 1 H), 6.59 (d, J = 2.4 Hz, 1 H), 5.46 (s, 2 H), 3.65–3.60 (m, 2 H), 3.56–3.53 (m, 2 H). MS (ESI⁺): m/z: 251.20 (M+H)⁺. [0206] Example 18. (E)-2-((3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl dihydrogen phosphate (I-18a) and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethyl dihydrogen phosphate (I-18b)

[0207] Under N₂, a stirred mixture of (E)-2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethan-1-ol (I-17a) and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethanol (I-17b) as a mixture of isomers in ratio of 79:21 (100 mg, 0.399 mmol) in P(OMe)₃ (1 mL) was cooled to 0 °C, then POCl₃ (37 µL, 0.399 mmol) was added slowly. The reaction mixture was stirred at same temperature for 30 min, quenched with ice-water, extracted with DCM (2 × 25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified using an ISCO CombiFlash® (silica gel) to afford (E)-2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl dihydrogen phosphate (I-18a) and (E)-2-((5-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethyl dihydrogen phosphate (I-18b) as a mixture of isomers in a ratio of 89:11 ratio, as a pale yellow thick liquid (7.5 mg, yield: 6%). ¹H-NMR (300 MHz, CD3OD): 5 (ppm) 7.77 (d, J= 2.7 Hz, 1 H), 7.35-7.29 (m, 2 H), 7.13 (d, J= 3.6 Hz, 1 H), 7.06-6.98 (m, 1 H), 6.85 (d, J= 15.0 Hz, 1 H), 6.60 (d, J= 2.1 Hz, 1 H), 5.48 (s, 2 H), 4.06-401 (m, 2 H), 3.70-3.68 (m, 2 H). MS (ESI⁺): m/z: 331.20 (M+H)⁺.

[0208] Example 19. (E)-Pyrrolidin-3-yl 3-(2-(thiophen-2-yl)vinyl)-LH-pyrazole-l- carboxylate (I-19a) and (E)-pyrrolidin-3-yl 3-(2-(thiophen-2-yl)vinyl)-lH-pyrazole-l- carboxylate hydrochloride (I-19a.HCl)

[0209] Step 1: (E)-3-(2-(thiophen-2-yl)vinyl)-l//-pyrazole (1-1, 1.0 g, 5.7 mmol) was treated with phosgene (20% in toluene, 14 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, and then evaporated to dryness under reduced pressure to yield a crude carbamoyl chloride intermediate, which was dissolved in anhydrous DCM (15 mL). In another flask, tert-butyl 3-hydroxypyrrolidine-l -carboxylate (19-1, 1.06 g, 5.7 mmol) and triethylamine (1.2 mL, 7.5 mmol) were dissolved in DCM (20 mL) and cooled to 0 °C. The carbamoyl chloride intermediate in DCM was added dropwise to the solution of 19-1 and triethylamine, and the reaction mixture was stirred at room temperature for 16 h. The reaction was then quenched with saturated sodium bicarbonate (20 mL). Organic layer was separated, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified using an ISCO CombiFlash® (silica gel) to give (E)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl 3-(2-(thiophen-2-yl)vinyl)-lH - pyrazole-l-carboxylate (19-2, 660 mg, yield: 30%). MS (ESI+): miz: 390.5 (M+H)⁺.

[0210] Step 2: To a solution of (E)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl 3-(2-(thiophen-2- yl)vinyl)-1H -pyrazole-l -carboxylate (19-2, 660 mg, 1.7 mmol) in anhydrous DCM (5 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 15 min, and then solvent and excess TFA were removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (20 mL) and MeOH (0.5 mL) and an excess of resin-bound triethylamine was added into the solution. The mixture was stirred for 15 min until the pH of the reaction mixture reached around 7.5. The resin was removed by filtration, and the filtrate was evaporated to dryness to give (E)-pyrrolidin-3-yl 3 -(2-(thiophen-2-yl)vinyl)-lH/-pyrazole-l -carboxylate (I- 19a, 440 mg, yield: 90%) as a buff white solid. ¹H-NMR (300 MHz, CDCh): 5 (ppm): 8.23 (s, 1H), 7.42-6.74 (m, 6H), 5.71 (s, 1H), 3.66-3.29 (5H), 2.42 (s, 2H). MS (ESI+): m/z: 290.5 (M+H)⁺.

[0211] Step 3; Compound I-19a·HCl was prepared by following the same procedure described in Step 2 of Example 4. Compound I-19a HCl was obtained from 19-2 in 90% yield as a white powder. ¹H-NMR (300 MHz, CDCh): 5 (ppm): 8.23 (s, 1H), 7.42-6.74 (m, 6H), 5.71 (s, 1H), 3.66-3.29 (5H), 2.42 (s, 2H). MS (ESI-): m/z 290.5 (M+H)⁺.

[0212] Example 20. (E)-N-(l-Methylpyrrolidin-3-yl)-3-(2-(thiophen-2-yl)vinyl)-1H- pyrazole-l-carboxamide (I-20a)

[0213] At 0 °C, to a stirred solution of (E)-3-(2-(thiophen-2-yl)vinyl)-1H -pyrazole (1-1, 176 mg, 1.0 mmol) and DIPEA (517 mg, 4.0 mmol) in DCM (3.0 mL) was added triphosgene (300 mg, 1.0 mmol) in DCM (2.0 mL). The resulting mixture was stirred at the same temperature for 1 h. A solution of l-methylpyrrolidin-3 -amine (20-1, 150 mg, 1.5 mmol) and DIPEA (130 mg, 1.0 mmol) in DCM (1.0 mL) was added dropwise and the reaction mixture was stirred overnight at room temperature. LC-MS indicated the reaction was complete. The reaction was quenched by saturated aqueous NH4CI and extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The crude material was purified using an ISCO CombiFlash® (silica gel, eluted with 0-100% ethyl acetate in hexanes, followed with 0-5% MeOH in DCM) to afford (E)-7V-(l-methylpyrrolidin-3-yl)-3-(2-(thiophen- 2-yl)vinyl)-1H -pyrazole-l -carboxamide (I-20a, 18.9 mg, yield: 6%) as a white solid. ¹H-NMR (300 MHz, CDCh): δ (ppm): 8.13 (d, J= 1.5 Hz, 1 H), 7.31 (d, J= 8.1 Hz, 1 H), 7.23 (d, J= 2.5 Hz, 1 H), 7.10 (d, J= 1.8 Hz, 1 H), 7.05 (dd, J₁ = 5.1 Hz, J₂= 3.6 Hz, 1 H), 6.85 (d, J= 8.1 Hz, 1 H), 6.52 (d, J= 1.35 Hz, 1 H), 4.57 (m, 1 H), 3.04 (m, 1 H), 2.86 (dd, J₁ = 5.1 Hz, J₂ = 1.5 Hz, 1 H), 2.72 (dd, Ji = 5.1 Hz, J₂= 3.3 Hz, 1 H), 2.43 (m, 6 H). MS (ESI): m/z: 303.28 (M + H)⁺. [0214] Example 21. (E)-N-(Pyrrolidin-3-yl)-3-(2-(thiophen-2-yl)vinyl)-LH-pyrazole-l- carboxamide hydrochloride (I-21a*HCl)

[0215] Step 1: Triphosgene (300 mg, 1.0 mmol) in DCM (2.0 mL) was added at 0 °C to a solution of (E)-3-(2-(thiophen-2-yl)vinyl)-l#-pyrazole (1-1, 176 mg, 1.0 mmol) and DIPEA (517 mg, 4.0 mmol) in DCM (3.0 mL). The reaction mixture was stirred at room temperature for 1 h. A solution of tert-butyl 3 -aminopyrrolidine- 1 -carboxylate (21-1, 279 mg, 1.5 mmol) and DIPEA (130 mg, 1.0 mmol) in DCM (1.0 mL) was added dropwise. The reaction mixture was stirred overnight and then quenched by saturated aqueous NH4CI. The organic layer was collected and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was purified using an ISCO CombiFlash® (alumina column, eluted with 0-100% ethyl acetate in hexanes) to afford (E)-tert-butyl 3-(3-(2-(thiophen-2-yl)vinyl)-12/-pyrazole-l- carb oxamido)py rroli dine- 1 -carboxyl ate (21-2, 236 mg containing -30% of 1-1) as a yellowish oil, which was used directly in the next step without further purification.

[0216] Step 2: To a solution (E)-tert-butyl 3-(3-(2-(thiophen-2-yl)vinyl)-l//-pyrazole-l- carboxamido)pyrrolidine-l -carboxylate (21-2, 109 mg containing -30% of 1-1) in DCM (2 mL) was added 4.0 M HC1 in dioxane (0.5 mL) dropwise with stirring. After stirring at room temperature for 2 h, LC-MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and washed with DCM to remove excess 1-1. The aqueous layer was collected and azeotroped with toluene to dryness to afford (E)-N -(pyrrolidin-3-yl)-3-(2-(thiophen-2-yl)vinyl)-lH -pyrazole-l-carboxamide hydrochloride (I-21a·HCl, 60 mg, yield: 92.5%) as an off-white solid. ^lH-NMR (300 MHz, CD3OD): 5 (ppm): 8.19 (d, J= 1.35 Hz,l H), 7.48 (d, J= 8.1 Hz, 1 H), 7.35 (d, J= 2.6 Hz, 1 H), 7.18 (d, J= 1.7 Hz, 1 H), 7.03 (dd, Ji = 5.1 Hz, J₂= 3.6 Hz, 1 H), 6.91 (d, J= 8.1 Hz, 1 H), 6.76 (d, J= 1.4 Hz, 1 H), 4.60 (m, 1 H), 3.57 (m, 3 H), 3.43 (m, 3 H), 2.41 (m, 1 H), 2.25 (m, 1 H). MS (ESI): m/z: 289.29 (M + H)⁺.

[0217] EExxaammppllee 2222:: (S,E)-(3-(2-(Thiophen-2-yl)vinyl)-1H-pyrazol-l-yl)methyl 2- aminopropanoate (I-22a-i)

[0218] Into a solution of (E)-3-(2-(thiophen-2-yl)vinyl)-1H -pyrazole (1-1, 0.44 g, 2.5 mmol) and (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)propanoate (22-1, 0.60 g, 2.5 mmol) in dimethylacetamide (DMA, 2 mL) was added cesium carbonate (0.98 g, 2.9 mmol). The reaction mixture was stirred at room temperature for 1 h, then directly loaded over silica gel, and purified using an ISCO CombiFlash® (silica gel column) to give crude (S,E)-(3-(2-(thiophen-2-yl)vinyl)- 1H-pyrazol-l-yl)methyl 2-((tert-butoxycarbonyl)amino)propanoate, which was directly treated with TFA (2 mL) in DCM (5 mL). After the reaction was complete, solvent and excess TFA were evaporated to dryness, and the crude material was washed with saturated sodium bicarbonate (10 mL) and extracted with DCM (2 x 10 mL). Organic layers were combined, dried over sodium sulfate, filtered, and evaporated to dryness to give (S,E)-(3-(2-(thiophen-2-yl)vinyl)- 1H -pyrazol-l-yl)methyl 2-aminopropanoate (I-22a-i, 60 mg, yield 10% over two steps). ¹H- NMR (300 MHz, CDCh): 5 (ppm): 7.60-7.52 (m, IH), 7.33-7.16 (m, 3H), 7.06-6.87 (m, 3H), 6.45-6.36 (m, IH), 6.02 (d, J= 7.8 Hz, IH), 5.87 (s, IH), 4.93 (s,lH), 3.63-3.46 (m, IH), 1.32- 1.23 (m, 3H). MS (ESI+): m/z: 278.2 (M+H)⁺.

[0219] Example 23: (E)-l-Methylpyrrolidin-3-yl 3-(2-(thiophen-2-yl)vinyl)-lfl- pyrazole-l-carboxylate hydrochloride (I-38a·HCl) and (E)-l-Methylpyrrolidin-3-yl 5-(2- (thiophen-2-yl)vinyl)-LH-pyrazole-l<arboxylate hydrochloride (I-38b·HCl)

[0220] Step 1: Compound 23-2 was prepared by following the same procedure described in Ex. 19 Step 1. Compound 23-2 was obtained from (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1) and 1-methylpyrrolidin-3-ol (23-1) in 70% yield. MS (ESI⁺): m/z: 304.3 (M+H)⁺. [0221] Step 2: 1-Methylpyrrolidin-3-yl (E)-5-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carboxylate (23-2, 90 mg, 0.27 mmol) was dissolved in dioxane (5 mL) and a solution of 4 M HCl in dioxane (0.5 mL) was added. The mixture was stirred for 15 min. Solvent was evaporated and residue was dried under high vacuum to give (E)-1-methylpyrrolidin-3-yl 3-(2-(thiophen-2- yl)vinyl)-1H-pyrazole-1-carboxylate hydrochloride (I-38a·HCl) and (E)-1-methylpyrrolidin-3-yl 5-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carboxylate hydrochloride (I-38b·HCl), as a mixture of isomers in a ratio of 2.3:1 (100 mg, yield: 100 %). ¹H-NMR (300 MHz, CDCl₃): δ (ppm): 8.31-8.30 (m, 1H), 7.54 (d, J = 16.5 Hz, 1H), 7.48 (d, J = 5.1 Hz, 1H), 7.27 (d, J = 3.0 Hz, 1H), 7.07-7.04 (m, 1H), 6.90-6.85 (m, 2H), 5.76-5.66 (m, 1H), 4.18-3.86 (m, 2H), 3.74-3.66 (m, 1H), 3.55-3.46 (m, 1H), 3.09-3.05 (m, 3H), 2.81-2.69 (m, 1H), 2.47-2.37 (m, 1H). MS (ESI⁺): m/z: 304.3 (M+H)⁺. [0222] Example 24. 1,2-Bis((3-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethane (II-1a), 5-((E)-2-(thiophen-2-yl)vinyl)-1-((2-((3-((E)-2-(thiophen-2- yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethoxy)methyl)-1H-pyrazole (II-1b), and 1,2-bis((5-((E)- 2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethane (II-1c)

[0223] Step 1: A mixture of ethane-1,2-diol (24-1, 712 mg, 11.5 mmol), TMSCl (12.1 mL, 95.3 mmol), and paraformaldehyde (24-2, 724 mg, 24.1 mmol) was stirred at room temperature for 5 h, and then concentrated to dryness to give 1,2-bis(chloromethoxy)ethane (24-3) as a colorless oil. The crude product was used as such in the next step without purification. [0224] Step 2: A mixture of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 665 mg, 3.77 mmol) and t-BuOK (467 mg, 4.16 mmol) in THF (5 mL) was stirred at room temperature for 10 min, then 1,2-bis(chloromethoxy)ethane (24-3, 200 mg, 1.26 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, and then at 70 ºC for 2 h. The crude product was collected by concentration and then purified using an ISCO CombiFlash® (silica gel) to afford 1,2-bis((3-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)methoxy)ethane (II-1a), 5-((E)-2- (thiophen-2-yl)vinyl)-1-((2-((3-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)ethoxy)methyl)-1H-pyrazole (II-1b), and 1,2-bis((5-((E)-2-(thiophen-2-yl)vinyl)- 1H-pyrazol-1-yl)methoxy)ethane (II-1c), as a mixture of isomers, as a colorless gummy solid (224 mg, yield: 27.1%). ¹H-NMR (300 MHz, CD₃OD): δ (ppm): 7.74–7.63 (m, 1 H), 7.48-7.43 (m, 1 H), 7.34-7.25 (m,4 H), 7.17-7.09 (m, 2 H), 7.03-6.79 (m, 4 H), 6.64-6.50 (m, 2 H), 5.61- 5.38 (m, 4 H), 3.64-3.50 (m, 4 H). MS (ESI⁺): m/z : 439.33 (M+H)⁺. [0225] Example 25. 1,1',1''-((propane-1,2,3-triyltris(oxy))tris(methylene))tris(3-((E)-2- (thiophen-2-yl)vinyl)-1H-pyrazole) (II-3a), et al.

[0226] Step 1: A mixture of propane-1,2,3-triol (25-1, 500 mg, 5.43 mmol), TMSCl (8.3 mL, 65.2 mmol), and paraformaldehyde (24-2, 505 mg, 16.8 mmol) was stirred at room temperature for 7 h, and then concentrated to dryness to give 1,2,3-tris(chloromethoxy)propane (25-3) as a colorless oil. The crude product was used as such in the next step without purification. [0227] Step 2: A mixture of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 519 mg, 2.95 mmol) and t-BuOK (350 mg, 3.12 mmol) in THF (10 mL) was stirred at room temperature for 10 min, then 1,2,3-tris(chloromethoxy)propane (25-3, 200 mg, 0.842 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then at 70 ºC for 4 h. The reaction mixture was concentrated and then purified using an ISCO CombiFlash® (silica gel) to afford a mixture of regioisomers including 1,1',1''-((propane-1,2,3-triyltris(oxy))tris(methylene))tris(3- ((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazole) (II-3a) and/or 1,1'-(((3-((5-((E)-2-(thiophen-2- yl)vinyl)-1H-pyrazol-1-yl)methoxy)propane-1,2-diyl)bis(oxy))bis(methylene))bis(3-((E)-2- (thiophen-2-yl)vinyl)-1H-pyrazole) (II-3b) and/or 1,1'-(((2-((3-((E)-2-(thiophen-2-yl)vinyl)-1H- pyrazol-1-yl)methoxy)propane-1,3-diyl)bis(oxy))bis(methylene))bis(5-((E)-2-(thiophen-2- yl)vinyl)-1H-pyrazole) (II-3c) and/or 1,1'-(((2-((5-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)propane-1,3-diyl)bis(oxy))bis(methylene))bis(3-((E)-2-(thiophen-2-yl)vinyl)-1H- pyrazole) (II-3d) and/or 1,1'-(((3-((3-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)propane-1,2-diyl)bis(oxy))bis(methylene))bis(5-((E)-2-(thiophen-2-yl)vinyl)-1H- pyrazole) (II-3e) and/or 1,1',1''-((propane-1,2,3-triyltris(oxy))tris(methylene))tris(5-((E)-2- (thiophen-2-yl)vinyl)-1H-pyrazole) (II-3f) (12.9 mg, yield: 2%) as a colorless gummy solid.¹H- NMR (300 MHz, CD₃OD): δ (ppm): 7.72-7.58 (m, 2 H), 7.48-7.43 (m, 1 H), 7.36-7.22 (m, 6 H), 7.20-7.14 (m, 1 H), 7.13-7.06 (m, 2 H), 7.05-6.96 (m, 3 H), 6.95-6.77 (m, 3 H), 6.66-6.47 (m, 3H), 5.64-5.26 (m, 6 H), 3.62-3.37 (m, 5 H). MS (ESI⁺): m/z : 657.51 (M+H)⁺. [0228] Example 26: 1,1'-(((2-(((3-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(3-((E)-2-(thiophen-2- yl)vinyl)-1H-pyrazole) (II-4a), et al.

[0229] Step 1: A mixture of 2-(hydroxymethyl)propane-1,3-diol (26-1, 576 mg, 5.43 mmol), TMSCl (8.3 mL, 65.2 mmol), and paraformaldehyde (24-2, 505 mg, 16.8 mmol) was stirred at room temperature for 6 h, and then concentrated to dryness to give 1,3-bis(chloromethoxy)-2- ((chloromethoxy)methyl)propane (26-3) as a colorless oil. The crude product was used in the next step without purification. [0230] Step 2: A mixture of (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 700 mg, 3.976 mmol) and t-BuOK (562 mg, 5.01 mmol) in THF (10 mL) was stirred at room temperature for 10 min, then 1,3-bis(chloromethoxy)-2-((chloromethoxy)methyl)propane (26-3, 200 mg, 0.795 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then at 70 ºC for 4 h. The reaction mixture was concentrated, and then purified using an ISCO CombiFlash® (silica gel) to afford a mixture of regioisomers including 1,1'-(((2-(((3-((E)-2-(thiophen-2- yl)vinyl)-1H-pyrazol-1-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(3-((E)- 2-(thiophen-2-yl)vinyl)-1H-pyrazole) (II-4a) and/or 1,1'-(((2-(((5-((E)-2-(thiophen-2-yl)vinyl)- 1H-pyrazol-1-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(3-((E)-2- (thiophen-2-yl)vinyl)-1H-pyrazole) (II-4b) and/or 1,1'-(((2-(((3-((E)-2-(thiophen-2-yl)vinyl)-1H- pyrazol-1-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(5-((E)-2-(thiophen- 2-yl)vinyl)-1H-pyrazole) (II-4c) and/or 1,1'-(((2-(((5-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(5-((E)-2-(thiophen-2- yl)vinyl)-1H-pyrazole) (II-4d) (26.7 mg, yield: 3%) as a colorless gummy solid. ¹H-NMR (300 MHz, CD₃OD): δ (ppm): 7.74-7.56 (m, 2 H), 7.52-7.39 (m, 1H), 7.37-7.22 (m, 6 H), 7.21-7.13 (m, 1 H), 7.12-7.06 (m, 2 H), 7.05-6.94 (m, 3 H), 6.92-6.74 (m, 3 H), 6.62-6.48 (m, 3 H), 5.52- 5.16 (m, 6 H), 3.55-3.34 (m, 6 H), 2.06-1.86 (m, 1 H). MS (ESI⁺): m/z : 671.11 (M+H)⁺. [0231] Example 27: (E)-4-((6-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1-yl)tetrahydro- 2H-pyran-2-yl)methyl)morpholine (I-27a)

[0232] Compound 1-1 is contacted with compound 27-1 under suitable acidic conditions (e.g., in the presence of PPTS) to afford compound 27-2. Compound 27-2 is subjected to suitable reductive amination conditions (e.g., comprising NaBH(OAc)₃ or NaBH₃CN) in the presence of morpholine to afford compound I-27a. [0233] Example 28: (E)-2-(hydroxymethyl)-6-(3-(2-(thiophen-2-yl)vinyl)-1H-pyrazol-1- yl)tetrahydro-2H-pyran-3,4-diol (I-30a)

1^{-1 28-2 I-30a} [0234] Compound 1-1 is contacted with compound 28-1 under suitable acidic conditions (e.g., in the presence of PPTS) to afford compound 28-2. Compound 28-2 is subjected to suitable saponification conditions (e.g., comprising sodium hydroxide) to afford compound I- 30a. [0235] Example 29: (E)-N-(2-(dimethylamino)ethyl)-6-(3-(2-(thiophen-2-yl)vinyl)-1H- pyrazol-1-yl)tetrahydro-2H-pyran-2-carboxamide (I-33a)

[0236] Compound 1-1 is contacted with compound 29-1 under suitable acidic conditions (e.g., in the presence of PPTS) to afford compound 29-2. Compound 29-2 is subjected to suitable coupling conditions (e.g., comprising HATU or EDC and DIPEA) in the presence of compound 29-3 to afford compound I-33a. [0237] Example 30: Piperidin-4-yl (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carboxylate hydrochloride (I-39a·HCl)

I^-39a∙HCl [0238] (E)-5-(2-(thiophen-2-yl)vinyl)-1H-pyrazole (1-1, 1g, 5.7 mmol) was treated with phosgene (20% in toluene, 14 mL) at 0 °C. The reaction mixture was stirred at rt for 1 hr. The solvent was removed under reduced pressure, and the crude carbamoyl chloride was dissolved in anhydrous DCM (15 mL). tert-Butyl 4-hydroxypiperidine-1-carboxylate (30-2, 1.06g, 5.7 mmol) and triethylamine (1.2 mL, 7.5 mmol) were dissolved in DCM (20 mL) and cooled at 0 °C. The crude carbamoyl chloride was added dropwise and the reaction mixture was stirred at rt for 16 hr. The solution was washed with saturated sodium bicarbonate (20 mL), organic layers were separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified using silica gel column chromatography to give tert-butyl (E)-4-((3-(2-(thiophen-2-yl)vinyl)-1H- pyrazole-1-carbonyl)oxy)piperidine-1-carboxylate (30-2, 660 mg, 28% yield). MS (ESI+): m/z: 404.5 (M+H)⁺. [0239] tert-Butyl (E)-4-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carbonyl)oxy)piperidine- 1-carboxylate (30-2, 310 mg, 0.77 mmol) was dissolved in 4M HCl solution in dioxane (5 mL) and allowed to stir at rt for 20 minute. The mixture was evaporated to dryness and dried further under high vacuum to give piperidin-4-yl (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carboxylate hydrogen chloride as an off white solid (I-39a·HCl, 256 mg, yield 98 %).¹H-NMR (300 MHz, CDCl₃): δ (ppm): 9.20 (s, 2H), 8.40 (d, J = 3.0 Hz, 1H), 7.59-7.53 (m, 2H), 7.36 (d, J = 3.0 Hz, 1H), 7.09-7.07 (m, 1H), 6.95-6.88 (m, 2H), 5.18 (hept, J = 3.6 Hz, 1H), 3.23-3.12 (m, 4H), 2.19-2.0 (m, 4H). MS (ESI+): m/z: 304.3 (M+H)⁺. [0240] Example 31: 1-methylpiperidin-4-yl (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole- 1-carboxylate hydrochloride (I-40a·HCl)

[0241] The title compound was prepared according to the general procedure described in Example 30: I-40a·HCl, 20 mg, 37% yield as white solid. ¹H-NMR (300 MHz, CDCl₃): δ (ppm): 8.38 (d, J = 3.0 Hz, 1H), 7.61-7.54 (m, 2H), 7.38 (d, J = 3.0 Hz, 1H), 7.09-7.07 (m, 1H), 6.97-6.90 (m, 2H), 5.19-5.17 (m, 1H), 3.23-3.12 (m, 4H), 3.1 (s, 3H), 2.19-2.0 (m, 4H). MS (ESI+): m/z: 318.4 (M+H)⁺. [0242] Example 32: (E)-N,N,N-trimethyl-2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carbonyl)oxy)ethan-1-aminium chloride (I-41a·Cl)

[0243] Under N₂, to a suspension of 32-1 (1.0 g, 7.162 mmol) and 32-2 (0.85 g, 2.865 mmol) in DCM (20 mL) at 0 °C was added pyridine (0.643 mL, 7.95 mmol, in DCM), and stirred at 0 °C for 10 min. The mixture was stirred for 20 h at room temperature. Then, terevalefim (1.26 g, 7.162 mmol) in DCM (20 mL, with pyridine (854.3 mg, 10.8 mmol)) was added to the reaction mixture at room temperature, and stirred for 1 h. Then, the mixture was filtered and the solid was thoroughly washed with DCM (2 x 30 mL) and CHCl₃ (2 x 20 mL). After preliminary drying, the absence of Py.HCl was confirmed via ¹HNMR, and the filtered solid was further dried under high vacuum to give I-41a·Cl (1.3 g, yield: 53%) as off-white solid. ¹H-NMR (300 MHz, DMSO-d₆): δ (ppm) 8.36 (d, J = 3.0 Hz, 1H), 7.63–7.56 (m, 2H), 7.31 (d, J = 3.0 Hz, 1H), 7.12–7.09 (dd, J = 6.0 Hz, 3.0 Hz, 2H), 7.00 (d, J = 3.0 Hz, 1 H), 6.90 (d, J = 15.0 Hz, 1H), 4.84–4.80 (m, 2H), 3.88–4.84 (m, 2H), 3.20 (s, 9H). MS (ESI⁺): m/z: 306.31 (M+H)⁺. [0244] Example 33: (S)-2-amino-3-methoxy-3-oxopropyl (E)-3-(2-(thiophen-2-yl)vinyl)- 1H-pyrazole-1-carboxylate hydrochloride (I-42a-i·HCl)

[0245] The title compound was prepared according to the general procedure described in Example 30: (I-42a-i·HCl, 35 mg, 29% yield) as off white solid. δ (ppm): 9.0 (s, 3H), 8.46 (d, J = 3.0 Hz, 1H), 7.60-7.54 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 7.09-7.07 (m, 1H), 6.97-6.86 (m, 2H), 4.85-4.64 (m, 3H), 3.77 (s, 3H), 3.69-3.63 (m, 1H), 3.49-3.42 (m, 1H), 3.23-3.12 (m, 4H), 2.19-2.0 (m, 4H). MS (ESI+): m/z: 304.3 (M+H)⁺. [0246] Example 34: (3S)-5-(methoxycarbonyl)pyrrolidin-3-yl 3-((E)-2-(thiophen-2- yl)vinyl)-1H-pyrazole-1-carboxylate hydrochloride (I-43a-i/ii·HCl)

[0247] Under N₂, to a solution of 32-2 (484.0 mg, 1.631 mmol) in DCM (10 mL) at 0 °C was added pyridine (0.366 mL, 4.525 mmol) and stirred at 0 °C for 10 min. A solution of 34-1 (1.0 g, 4.077 mmol) in DCM (10 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred for 3.5 h at room temperature and concentrated. Ethyl acetate (10 mL) was added to the resulting residue and filtered to remove solids. The filtrate was concentrated and THF (5 mL) was added, followed by terevalefim (359.3 mg, 2.04 mmol, in Py (0.495 mL, 6.115 mmol) in THF (10 mL)) at room temperature. The reaction mixture was stirred for 10 min at room temperature. Completion of the reaction was confirmed by UPLC- MS. Then, solvent was evaporated, and the crude material was washed with aq. NaHCO₃ (15 mL) and DCM (2 x 25 mL). The combined organic layer was dried over Na₂SO₄, concentrated and the crude compound was triturated with diethyl ether (2 x 10 mL) to give 34-2 (580 mg, yield: 32%) as off-white solid. MS (ESI⁺): m/z: 448.38 (M+H)⁺. [0248] A solution of 34-2 (100 mg, 0.224 mmol) in 1,4-dioxane (2 mL) was added 4 N HCl in 1,4-dioxane (1 mL) and stirred at room temperature for 2 h. Completion of the reaction was confirmed by UPLC-MS analysis. After completion, the solvent was evaporated under reduced pressure. The residue was purified by trituration in ether (2 x 5 mL). The solid was filtered and dried under high vacuum to give I-43a-i/ii·HCl as pale-yellow solid (61 mg, yield: 78.4%). ¹H- NMR (300 MHz, DMSO-d₆): δ (ppm) 10.51 (brs, 1H), 9.64 (brs, 1H), 8.55 (d, J = 3.0 Hz, 1H), 7.59 (d, J = 12.0 Hz, 1H), 7.55 (s, 1H), 7.31 (d, J = 3.0 Hz, 1H), 7.12–7.09 (dd, J = 6.0 Hz, 3.0 Hz, 2H), 6.96 (d, J = 3.0 Hz, 1 H), 6.90 (d, J = 15.0 Hz, 1H), 5.60 (brs, 1 H), 4.73–4.66 (dd, J = 12.0 Hz, 9.0 Hz, 1H), 3.79 (s, 3H), 3.65–3.54 (m, 2H), 2.72–2.64 (m, 1H), 2.45–2.42 (m, 1H). MS (ESI⁺): m/z: 348.33 (M+H)⁺. [0249] Example 35: (4S)-4-((3-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carbonyl)oxy)pyrrolidine-2-carboxylic acid-hydrochloride (I-44a-i/ii·HCl)

[0250] Under N₂, to a solution of 32-2 (82.6 mg, 0.278 mmol) in DCM (5 mL) at 0 °C, was added pyridine (63.0 µL, 0.773 mmol) and stirred at 0 °C for 10 min. A solution of 35-1 (200.0 mg, 0.696 mmol) in DCM (5 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred for 3.5 h at room temperature and concentrated. Ethyl acetate (5 mL) was added to the resulting residue and filtered to remove solids. The filtrate was concentrated and THF (5 mL) was added, followed by terevalefim (61.3 mg, 0.35 mmol, in Py (84.4 µL, 1.04 mmol) in THF (5 mL)) at room temperature. The reaction mixture was stirred for 10 min at room temperature. Completion of the reaction was confirmed by UPLC-MS. Then, THF was evaporated, and the crude mass was washed with aq. NaHCO₃ (15 mL) and DCM (2 x 25 mL). The combined organic layer was dried over Na₂SO₄, concentrated and the crude compound was triturated with diethyl ether (2 x 10 mL) to give 35-2 (102.8 mg, yield: 60%) as off-white solid. MS (ESI⁺): m/z: 490.6 (M+H)⁺. [0251] To a solution of 35-2 (100 mg, 0.2042 mmol) was added 4N HCl in 1,4-dioxane (3 mL) and stirred at room temperature for 24 h. Completion of the reaction was confirmed by UPLC-MS analysis. After completion, evaporated the solvent under reduced pressure. The residue was purified by trituration in ether (2 x 5 mL). Filtered the solid and dried under high vacuum to give I-44a-i/ii·HCl as pale-yellow solid (52.9 mg, yield: 60%). ¹H-NMR (300 MHz, DMSO-d₆): δ (ppm) 10.04 (brs, 2H), 9.16 (brs, 1H), 8.49 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 12.0 Hz, 1H), 7.55 (s, 1H), 7.31 (d, J = 3.0 Hz, 1H), 7.12–7.09 (dd, J = 6.0 Hz, 3.0 Hz, 2H), 6.97 (d, J = 3.0 Hz, 1 H), 6.90 (d, J = 15.0 Hz, 1H), 5.59 (brs, 1 H), 4.64–4.58 (dd, J = 12.0 Hz, 9.0 Hz, 1H), 3.65–3.60 (m, 2H), 2.72–2.64 (m, 1H), 2.46–2.39 (m, 1H). MS (ESI⁺): m/z: 334.27 (M+H)⁺. [0252] Example 36: Sodium (4S)-4-((3-((E)-2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carbonyl)oxy)pyrrolidine-2-carboxylate (I-44a-i/ii·Na)

[0253] To a suspension of I-44a-i/ii·HCl (50 mg, 0.135 mmol) in minimum amount of water (0.1 mL) was added aq. NaHCO₃ (24.9 mg, 0.297 mmol) and stirred at room temperature for 30 min. The precipitated solid was filtered and dried under high vacuum to give I-44a-i/ii·Na as off- white solid (18.0 mg, yield: 37%).¹H-NMR (300 MHz, DMSO-d₆): δ (ppm) 8.39 (d, J = 3.0 Hz, 1H), 7.58 (d, J = 12.0 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J = 3.0 Hz, 1H), 7.11–7.08 (dd, J = 6.0 Hz, 3.0 Hz, 2H), 6.96 (d, J = 3.0 Hz, 1 H), 6.90 (d, J = 15.0 Hz, 1H), 5.48 (brs, 1 H), 3.93 (t, J = 9.0 Hz, 1H), 3.52–3.42 (m, 2H), 2.47–2.42 (m, 1H), 2.25–2.15 (m, 1H). MS (ESI⁺): m/z: 334.27 (M+H)⁺. [0254] Example 37: (E)-1,1-dimethyl-3-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carbonyl)oxy)pyrrolidin-1-ium iodide (I-45a·I)

37-1 I-45a∙I [0255] 1-methylpyrrolidin-3-yl (E)-3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1-carboxylate (37-1, 50 mg, 0.16 mmol) was dissolved in acetone.2.0 M MeI in MTBE (0.4 mL, 0.8 mml) was added dropwise to reaction mixture and allowed to stir for 1 h. Solvent was evaporated and the solid was washed with fresh MTBE to give (E)-1,1-dimethyl-3-((3-(2-(thiophen-2-yl)vinyl)-1H- pyrazole-1-carbonyl)oxy)pyrrolidin-1-ium iodide as white solid (I-45a·I, yield 98%, 69 mg). δ (ppm): 8.40 (d, J = 3.0 Hz, 1H), 7.60-7.54 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 7.10-7.08 (m, 1H), 6.99-6.86 (m, 2H), 5.66-5.61 (m, 1H), 4.03-3.95 (m, 2H), 3.83-3.74 (m, 1H), 3.64-3.55 (m, 1H), 3.25 (s, 3H), 3.19 (s, 3H), 2.82-2.69 (m, 2H). MS (ESI+): m/z: 319.4 (M+H)⁺. [0256] Example 38: (E)-N,N,N-trimethyl-2-((3-(2-(thiophen-2-yl)vinyl)-1H-pyrazole-1- carbonyl)oxy)ethan-1-aminium iodide (I-41a·I)

[0257] I-41a·I was prepared by following the general procedure described in Example 37 (32 mg, 98% yield, white solid). δ (ppm): 8.35 (d, J = 3.0 Hz, 1H), 7.61-7.54 (m, 2H), 7.30 (d, J = 3.0 Hz, 1H), 7.10-7.07 (m, 1H), 6.99 (d, J = 2.7 Hz, 1H), 6.89-6.84 (m, 1H), 4.80-4.78 (m, 2H), 3.84-3.81 (m, 2H), 3.18 (s, 9H). MS (ESI+): m/z: 307.4 (M+H)⁺. Pharmacokinetic Analysis [0258] Male C57BL/6 mice at 6 to 8 weeks age (body weight, 20-22 g), were used to perform pharmacokinetic (PK) studies on provided compounds in comparison to terevalefim. All compounds were prepared in 50% PEG-300 + 40% PBS + 10% Tween-80 formulation. Doses of provided compounds were adjusted to provide a molar equivalent dose of terevalefim based on each compound’s molecular weight. Compounds were administered once orally, intravenously, or intramuscularly at the indicated doses in 100 µL or 200 µL volume. [0259] For oral and intramuscular administration, blood was collected into BD Microtainer^® tubes using a 1 cc syringe by retro orbital eye bleeding at 0 min (baseline-control), 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr and 8 hr time points. For each time point, n=3 mice were used. [0260] For intravenous administration, blood was drawn from the vena cava using a 1 cc syringe at 0 min (baseline-control), 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr and 8 hr time points. For each time point, n=3 mice were used. The animals were then sacrificed. [0261] All the blood samples for each time point were spun for 5 min at 12000 g in a microcentrifuge. Serum samples were transferred to Eppendorf tubes and stored in the freezer. [0262] Serum concentrations of terevalefim were determined from each sample using LC- MS/MS according to the following method. After spiking in propranolol as the internal standard, mouse serum samples were purified by protein precipitation with acetonitrile. Terevalefim was analyzed by LC-MS/MS. Chromatographic separation was performed with a Shimadzu Prominence system on a Phenomenex Synergi Polar-RP column (4 µm, 80Å, 2x150 mm) with a gradient elution (0.1% acetic acid 1 mM ammonium acetate in water as mobile phase A and 50 mM acetic acid in acetonitrile as mobile phase B). MRM detection (177.03 to 144.07 for terevalefim and 260.15 to 116.1 for propranolol) was carried out with AB Sciex API-4000 triple quadrupole mass spectrometer. Oral Administration [0263] Results of oral PK studies are summarized in Table 3. Table 3.

^*

Dose adjusted to be molar equivalent of a 10 mg/kg dose of terevalefim; ^†Concentration of terevalefim relative to amount observed at same time point when terevalefim is administered; ^aMixture of I-7a and I-7b, prepared according to Example 7; ^bMixture of I-8a·Na and I-8b·Na, prepared according to Example 8; ^cMixture of I-14a and I-14b, prepared according to Example 14; ^dMixture of I-9a·Na₂ and I-9b·Na₂, prepared according to Example 9; ^eMixture of I-16a and I-16b, prepared according to Example 16; ^fMixture of I-17a and I-17b, prepared according to Example 17; ^gMixture of I-15a and I-15b, prepared according to Example 15; ^hMixture of I-18a and I-18b, prepared according to Example 18. Intravenous Administration [0264] Results of intravenous PK studies are summarized in Table 4. Table 4. ^*

Dose that is molar equivalent of a 2 mg/kg dose of terevalefim. Some compounds were administered at a dose equivalent to a 5 mg/kg or 10 mg/kg dose of terevalefim, and then concentration values were normalized to an equivalent 2 mg/kg dose of terevalefim for comparison; ^†Concentration of terevalefim relative to amount observed at same time point when terevalefim is administered; ^††AUC relative to AUC observed when terevalefim is administered; aMixture of I-14a and I-14b, prepared according to Example 14; ^bMixture of I-9a·Na₂ and I- 9b·Na₂, prepared according to Example 9; ^cMixture of I-18a and I-18b, prepared according to Example 18. [0265] Intravenous PK data for compound I-41a·Cl are shown in FIG.1. [0266] Additional intravenous PK data were collected for compound I-41a·Cl in rats. Results are shown in FIG.2. PK data in rats were collected using a protocol similar to the one described above for mice. [0267] Intravenous and intramuscular PK data for compound I-41a·Cl are shown in FIG.3. [0268] A comparison of intramuscular PK data for compound I-41a·Cl with intramuscular and intravenous PK data for terevalefim is shown in FIG.4. Intramuscular Administration [0269] Results of intramuscular PK studies are summarized in Table 5. Table 5.

*Dose adjusted to be molar equivalent of a 5 mg/kg dose of terevalefim; ^†Concentration of terevalefim relative to amount observed at same time point when terevalefim is administered; †^†AUC relative to AUC observed when terevalefim is administered; ^aMixture of I-38a·HCl and I- 38b·HCl, prepared according to Example 23. Stability Studies [0270] Stability of compound I-19a·HCl was evaluated in various aqueous solutions and showed stability for up to 3 hours. Decomposition under various conditions was assessed using LCMS. Results are summarized in Table 6. Table 6.

Acute and Chronic Lung Injury Models with Chlorine [0271] C57Bl/6 mice or FVB mice (~20 g) were exposed to Cl₂ gas in environmental chambers and then returned to cages. Cl₂-exposed mice were randomized after exposure to vehicle or I-41a·Cl compound groups and administered the corresponding treatment. At the end of the study, mice were evaluated for body mass, BALF turbidity and BALF protein, as well as histological signs of airway thickening/airway remodeling, bronchial and/or alveolar epithelial cellular apoptosis (TUNEL), cellular infiltration (F4/80), and myeloperoxidase level. For chronic lung fibrosis models, histological analysis with Trichrome and IHC staining was also performed. The chlorine model studies are summarized in Table 7. Table 7.

Kidney Ischemia/Reperfusion Models [0272] In a rat model of transient unilateral renal artery occlusion, male Sprague Dawley rats (~250 g) were anesthetized and the left renal artery occluded with a microvascular clamp. After 30-45 minutes, the clamp was removed and the kidney allowed to reperfuse. Approx. ten minutes into reperfusion, the nonischemic contralateral kidney was excised. Animals were treated with vehicle or test compound as described below until the day of sacrifice. Urine output volume was used to determine the ability of a test compound to restore function to injured kidneys. Results are summarized in Table 8. Table 8.

HgCl₂-Induced Renal Injury Model [0273] Mice were injected with a high dose of HgCl₂ (e.g., 7 mg/kg, s.c.) and divided into treatment groups. Animals received vehicle or a test compound on the day of HgCl₂ injection and daily thereafter for 2 days, and then were euthanized. Blood samples (e.g., collected before and during administration) were analyzed for, e.g., serum creatinine. Results are summarized in Table 9. Table 9.

Other Biological Assays Unilateral Ureteral Obstruction (UUO) Renal Injury Model [0274] A UUO mouse model is used as a model for renal injury secondary to ureteral obstruction. Mice are subjected to unilateral ureteral obstruction. Animals receive vehicle or a test compound starting on the day of surgery and continuing for, e.g., 7-10 days. After sacrifice, kidneys from the mice are examined for histological evidence of injury and extent of protection by a test compound. For example, immuno-histochemical staining is performed for fibronectin, proliferating cell nuclear antigen (PCNA), and TUNEL (for an assessment of apoptosis). Trichrome staining is performed to assess the extent of collagen formation as an indication of interstitial fibrosis. 5/6 Nephrectomy Model of Chronic Kidney Disease [0275] A 5/6 nephrectomy rat model is used as a model for chronic kidney disease. Rats are subjected to a 5/6 left nephrectomy (ligation of 2 of the 3 branches of the left renal artery) and excision of the right kidney. After ablation, blood samples are obtained and serum creatinine (SCr) is determined. Rats with SCr values indicating adequate and sustained renal ablation (e.g., between 0.8 and 1.2 mg/dL) are entered into the study. Following surgery (e.g., one week after surgery), animals are randomized to vehicle or test compound and are administered treatment regularly (e.g., for 5 weeks). Animals are then sacrificed. Urine and kidney samples are obtained for evaluation of proteinuria, histopathology and pharmacodynamic markers of kidney function. Bleomycin Model of Pulmonary Fibrosis [0276] A bleomycin mouse model is used as a model for pulmonary fibrosis. Male C57BL/6 mice are treated with bleomycin or saline via intratracheal administration. Bleomycin-treated mice are divided into 2 groups. A vehicle or test compound is administered (e.g., daily) until sacrifice (e.g., on day 12 or day 21 or day 28). Lung samples from the mice are then harvested for analysis. Tissues are sectioned and, for example, stained with modified Masson’s Trichrome and analyzed for interstitial fibrosis; and/or stained with picrosirius red (PSR) and analyzed for collagen content; and/or stained with hematoxylin-eosin (H&E) and analyzed for lung fibrosis; and/or stained with IHC and analyzed for TGFβ1. Lung weight and hydroxyproline content are also measured in order to assess the extent of fibrosis. Inducible TGFβ1 Model of Lung Fibrosis [0277] Transgenic mice are used that expresses TGFβ1 in the lung via an externally regulatable, triple transgenic system using a doxycycline-inducible promoter. (See Lee, C. G., et al. Proc. Am. Thorac. Soc. 2006 Jul;3(5):418-23; Lee C. G., et al. J. Exp. Med. 2004 Aug 2;200(3)377-89). Eight-to-ten week old TGFβ1 positive female mice are induced (fed) with doxycycline (dox) for, e.g., 4 weeks. In addition, age and gender matched TGFβ1 negative mice from the transgenic mouse breeding colony not fed with dox are included as control mice (sham). Dox fed mice are randomized to vehicle and test compound, e.g., for 4 weeks, with continued dox feeding. All mice are then sacrificed, and body weights and lung weights taken. Lung hydroxyproline (HYP), picrosirius red (PSR) staining, and histopathological observations from (H&E) slides and IHC staining are evaluated to assess extent of fibrosis. Models of Liver Fibrosis [0278] In one experiment, serum starved (activated) LX2 cells (an immortalized human hepatic stellate cell line) are treated with a test compound. A decrease in collagen I mRNA expression, as well as expression of other fibrotic marker genes, indicates antifibrotic activity. [0279] In another experiment, rats are treated with thioacetamide (TAA), e.g., three times a week for 6 weeks, at which point they are sacrificed. Test compound or vehicle is administered during the 6 week period. After sacrifice, a panel of functional and histological tests are performed, such as gross morphology, body mass, kidney mass, portal pressure, presence of ascites, enzymes (AST, ALT), collagen content, interstitial fibrosis by performing tissue hydroxyproline and histological picrosirius red staining and immunohistochemical staining for fibrotic markers of alpha-smooth muscle actin and MMP-2, Collagen-1, TGFβ1 and fibronectin. [0280] In another experiment, rats are subjected to bile duct ligation for 4 weeks and sacrificed. Test compound or vehicle is administered during the 4 week period. After sacrifice, a panel of functional and histological tests are performed, such as gross morphology, body mass, kidney mass, portal pressure, presence of ascites, enzymes (AST, ALT), collagen content, interstitial fibrosis by performing tissue hydroxyproline and histological picrosirius red staining and immunohistochemical staining for fibrotic markers of alpha-smooth muscle actin and MMP- 2, Collagen-1, TGFβ1 and fibronectin. Middle Cerebral Artery Occlusion (MCAO) Model of Cerebral Infarction [0281] Cerebral infarction is induced in rats by middle cerebral artery occlusion (MCAO) for 24 hr. Test compound or vehicle is administered. Sections of the brain are then examined for cell death by staining with 2,3,5-triphenyl-2H-tetrazolium chloride (TTC). Bleomycin Model of Systemic Sclerosis [0282] A bleomycin mouse model is used as a model for systemic sclerosis and skin fibrosis. Female C57BL/6 mice are administered bleomycin subcutaneously repeatedly, e.g., 5 times a week for 4 weeks. Then, bleomycin-treated mice are randomized to vehicle and test compound treatment groups. Treatment is administered, e.g., twice daily, and subcutaneous bleomycin administrations are continued, e.g., 3 days per week. After a period of treatment (e.g., 5 weeks), mice are sacrificed and body weight and lung weight are recorded. Tissue samples from the left lung and left kidney are snap frozen. A skin biopsy is taken from the bleomycin injected site and fixed in formalin. The right lung and right kidney are also fixed in formalin for histopathological evaluation. Dermal thickness measurements are made from H&E-stained tissue sections by measuring the distance from the epidermis to the dermal junction using Bioquant planimetric software. Lung and kidney hydroxyproline (HYP) assays are performed to determine tissue collagen content. Skin, lung and kidney histopathological fibrotic scores are determined. Picrosirius red (PSR) staining of kidney sections is also performed to determine renal collagen deposition. [0283] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS 1. A compound of Formula I: (

or a pharmaceutically acceptable salt thereof, wherein: L is –N(R)-, -O-, -S-, -S(O)-, -SO₂-, -OC(O)-, -SC(O)-, -OC(O)O-, -OC(S)O-, -OC(O)N(R)-, - N(R)C(O)O-, –OP(O)(OR)O-, -OP(S)(OR)O-, -OP(O)(R)O-, -OP(O)(OR)-, - OP(O)(OR)N(R)-, -N(R)P(O)(OR)O-, -OSO₂O-, -OSO₂N(R)-, or -N(R)SO₂O-; R¹ is hydrogen or an optionally substituted group selected from C_1-6 aliphatic, a 3- to 7- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and a 5- to 6-membered heteroaryl ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur; R² and R³ are each independently hydrogen or optionally substituted C_1-6 aliphatic; or R² and R³ are taken together to form an oxo; or R² and R³ are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur; each R^a is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 aliphatic; each R^b is independently halogen, -CN, -CO₂R, -C(O)N(R)₂, -NO₂, -N(R)₂, -OR, -SR, or optionally substituted C_1-6 aliphatic; each R is independently hydrogen or optionally substituted C_1-6 aliphatic; n is 0, 1, 2, or 3; and m is 0, 1, or 2.

2. The compound of claim 1, wherein R² and R³ are each hydrogen.

3. The compound of claim 1, wherein R² and R³ are taken together to form an oxo.

4. The compound of any one of the preceding claims, wherein m is 0.

5. The compound of any one of the preceding claims, wherein n is 0.

6. The compound of any one of the preceding claims, wherein L is –N(R)-, –O-, -OC(O)-, or –OP(O)(OR)O-.

7. The compound of any one of the preceding claims, wherein L is –OC(O)-.

8. The compound of any one of the preceding claims, wherein L is –N(R)- or –O-.

9. The compound of any one of the preceding claims, wherein L is –O-.

10. The compound of any one of the preceding claims, wherein R¹ is hydrogen, optionally substituted C_1-6 aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of any one of the preceding claims, wherein R¹ is optionally substituted C_1-6 alkyl.

12. The compound of any one of the preceding claims, wherein R¹ is C_1-6 alkyl optionally substituted with one or more of –NH₂, -N(C_1-6 alkyl)₂, -N(C_1-6 alkyl)₃ ⁺, –OH, –O(C_1-6 alkyl), - OC(O)(C_1-6 alkyl), -C(O)OH, -C(O)(O-C_1-6 alkyl), -OC(O)(O-C_1-6 alkyl), -OP(O)(OH)₂, and a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

13. The compound of any one of claims 1-10, wherein R¹ is optionally substituted 5- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

14. The compound of any one of the preceding claims, wherein R¹ and R² are taken together with the atoms to which they are attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having, in addition to L, 0-1 heteroatoms selected from nitrogen, oxygen, and sulfur.

15. The compound of any one of the preceding claims, wherein each R is independently hydrogen or optionally substituted C_1-6 alkyl.

16. The compound of any one of the preceding claims, wherein the compound is of Formula IA:

IA or a pharmaceutically acceptable salt thereof.

17. The compound of any one of the preceding claims, wherein the compound is of Formula IB: (

IB or a pharmaceutically acceptable salt thereof.

18. The compound of any one of the preceding claims, wherein the compound is of Formula IC: (

IC or a pharmaceutically acceptable salt thereof.

19. The compound of any one of the preceding claims, wherein the compound is of Formula ID:

ID or a pharmaceutically acceptable salt thereof.

20. The compound of any one of the preceding claims, wherein the compound is of Formula IE: (

IE or a pharmaceutically acceptable salt thereof.

21. The compound of any one of the preceding claims, wherein the compound is of Formula IF: ⁽

or a pharmaceutically acceptable salt thereof.

22. The compound of any one of the preceding claims, wherein the compound is of Formula IG: (

IG or a pharmaceutically acceptable salt thereof.

23. The compound of any one of the preceding claims, wherein the compound is of Formula IH: (

or a pharmaceutically acceptable salt thereof.

24. The compound of any one of the preceding claims, wherein the compound is not:

.

25. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

26. A mixture comprising a compound of Formula IA, or a pharmaceutically acceptable salt thereof, and a compound of Formula IB, or a pharmaceutically acceptable salt thereof.

27. A mixture comprising a compound of Formula IC, or a pharmaceutically acceptable salt thereof, and a compound of Formula ID, or a pharmaceutically acceptable salt thereof.

28. A mixture comprising a compound of Formula IE, or a pharmaceutically acceptable salt thereof, and a compound of Formula IF, or a pharmaceutically acceptable salt thereof.

29. A mixture comprising a compound of Formula IG, or a pharmaceutically acceptable salt thereof, and a compound of Formula IH, or a pharmaceutically acceptable salt thereof.

30. A compound of Formula II:

II or a pharmaceutically acceptable salt thereof, wherein: Z is a covalent bond or a bivalent or trivalent linking moiety that is an optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R’)-, -C(O)-, - C(S)-, -C(NR’)-, -C(NOR’)-, -C(NN(R’)₂)-, -OC(O)-, -C(O)O-, -C(O)N(R’)-, -N(R’)C(O)-, - C(NR’)O-, -OC(NR’)-, -C(NR’)NR’-, -N(R’)C(NR’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, - OC(O)N(R’)-, -N(R’)C(O)S-, -SC(O)N(R’)-, -N(R’)C(NR’)N(R’)-, -SO2-, -SO2N(R’)-, - N(R’)SO₂-, -OP(O)(OH)O-, -OP(S)(OH)O-, -OP(S)(SH)O-, -OP(S)(COOH)O-, - OP(O)(COOH)O-, -OP(O)(NR₂)O-, -NP(O)(OH)O-, -OP(O)(OH)N-, or –Cy-; each Cy is independently an optionally substituted, mono- or bicyclic, 3- to 10-membered, bivalent or trivalent ring system, wherein the ring system is fully saturated, partially unsaturated, or aromatic, and wherein the ring system contains 0-5 heteroatoms selected from the group consisting of O, N, and S; each L² is independently –N(R’)-, -O-, -S-, -S(O)-, -SO₂-, -OC(O)-, -SC(O)-, -OC(O)O-, - OC(S)O-, -OC(O)N(R’)-, -N(R’)C(O)O-, –OP(O)(OR’)O-, -OP(S)(OR’)O-, -OP(O)(R’)O-, - OP(O)(OR’)-, -OP(O)(OR’)N(R’)-, -N(R’)P(O)(OR’)O-, -OSO₂O-, -OSO₂N(R’)-, or - N(R’)SO₂O-; each R⁴ and R⁵ are independently hydrogen or optionally substituted C_1-6 aliphatic; or R⁴ and R⁵ are taken together to form an oxo; or R⁴ and R⁵ are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur; each R^c is independently halogen, -CN, -CO₂R’, -C(O)N(R’)₂, -N(R’)₂, -OR’, -SR’, or optionally substituted C_1-6 aliphatic; each R^d is independently halogen, -CN, -CO₂R’, -C(O)N(R’)₂, -N(R’)₂, -OR’, -SR’, or optionally substituted C_1-6 aliphatic; each R’ is independently hydrogen or optionally substituted C_1-6 aliphatic; each p is independently 0, 1, 2, or 3; each q is independently 0, 1, or 2; and t is 2 or 3.

31. The compound of claim 30, wherein each R⁴ and R⁵ are hydrogen.

32. The compound of claim 30 or 31, wherein R⁴ and R⁵ are taken together to form an oxo.

33. The compound of any one of claims 30-32, wherein each p is 0.

34. The compound of any one of claims 30-33, wherein each q is 0.

35. The compound of any one of claims 30-34, wherein each L² is –O-.

36. The compound of any one of claims 30-35, wherein Z is a bivalent or trivalent linking moiety that is an optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-.

37. The compound of any one of claims 30-36, wherein t is 2.

38. The compound of any one of claims 30-37, wherein Z is a bivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –Cy-.

39. The compound of any one of claims 30-36, wherein t is 3.

40. The compound of any one of claims 30-36 and 39, wherein Z is a trivalent, optionally substituted, straight or branched, saturated or unsaturated C_1-8 hydrocarbon chain.

41. The compound of any one of claims 30-40, wherein each Cy is independently an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

42. The compound of any one of claims 30-41, wherein each R’ is independently hydrogen or optionally substituted C_1-6 alkyl.

43. The compound of any one of claims 30-42, wherein the compound is of Formula IIA:

IIA or a pharmaceutically acceptable salt thereof.

44. The compound of any one of claims 30-42, wherein the compound is of Formula IIB:

IIB or a pharmaceutically acceptable salt thereof.

45. A compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising a compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

47. A method comprising administering a compound of any one of claims 1-45 or the pharmaceutical composition of claim 46 to a subject in need thereof.

48. A method of treating a disease, disorder or condition selected from fibrotic liver disease, ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease and/or renal fibrosis, lung fibrosis, damaged and/or ischemic organs, transplants or grafts, stroke, and cerebrovascular disease, the method comprising administering a compound of any one of claims 1-45 or the pharmaceutical composition of claim 46 to a subject in need thereof.