Statin derivatives and methods using the same

Abstract

This application relates to compounds of formula (I') or formula (II'), as well as pharmaceutically acceptable salts thereof, pharmaceutical compositions, methods of use, and methods for preparing them. The compounds disclosed herein are useful for modulating stasmin-2 (STMN2) activity and may be used in the treatment of diseases in which STMN2 activity is involved, such as neurodegenerative diseases and disorders or axonal damage. TIFF2026521511000416.tif48128

Description

[Technical Field]

[0001] Related applications This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 472,434, filed on 12 June 2023, and U.S. Provisional Patent Application No. 63 / 611,822, filed on 19 December 2023, the entire contents of said application incorporated herein by reference. [Background technology]

[0002] background This disclosure relates to statin derivatives and their use as modifiers of statin (e.g., statin-2) for the treatment of diseases or disorders (e.g., neurodegenerative diseases).

[0003] Approximately 97% of cases of amyotrophic lateral sclerosis (ALS) and nearly half of patients with frontotemporal dementia (FTD) are pathologically associated with the mislocalization and aggregation of the RNA-binding protein TDP-43 in the cytoplasm of neurons and glial cells (ALS-TDP and FTD-TDP). Furthermore, mutations in the gene encoding it, TARDBP, have been a rare cause of both ALS and FTD, suggesting that TDP-43 may be central to the pathogenesis of ALS / FTD. Human mRNAs, such as the nerve growth-related protein stasmin-2 (STMN2; also known as SCG10), have been shown to be affected by a decrease in TDP-43. Abnormal splicing of STMN2 (inclusion of an abnormal "latent" exon 2a) and premature polyadenylation cause a decrease in STMN2 protein levels in cultured neurons in response to TDP-43 nuclear loss, and this latent exon feature is also detected in tissues from patients with sporadic and familial ALS and FTD, as well as from patients with Alzheimer's disease associated with TDP-43 pathology. STMN2 is a tubulin heterodimer binding partner, which is associated with neurite extension and axonal regeneration. Therefore, modulation of STMN2 is a therapeutic target applicable for the treatment of ALS.

[0004] Currently available therapies for ALS are non-target-driven and have limited efficacy. There is a need for effective therapies that target specific elements of the disease's pathophysiology, and STMN2 is a target whose usefulness for therapeutic modulation has been demonstrated. HMG-CoA reductase inhibitors (e.g., statins) are compounds that can increase STMN2. This disclosure arises from the need to provide further compounds for modulating STMN2 activity with enhanced therapeutic potential, particularly compounds with improved physicochemical, pharmacological, and / or pharmaceutical properties. [Overview of the project]

[0005] overview In some aspects, this disclosure relates to compounds of formula (I'): TIFF2026521511000002.tif31128 or a pharmaceutically acceptable salt thereof is provided, in the formula, TIFF2026521511000003.tif7128 is single or double bonded, as long as the valence allows; TIFF2026521511000004.tif7128 is a single or double bond, where the double bond is an (E) isomer; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 C6~C 10 An aryl or 5-10 membered heteroaryl, where the aryl or heteroaryl may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is a cycloalkyl; B1 is either H or -OH; B2 is H or -OH; Y is H, -C(O)OR3, -C(O)N(R3)2, each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 cycloalkyl; R A2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, or 5-10 member heteroaryl; and R A3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, 3-10 member heterocyclyl optionally substituted with one or more C1-C6 alkyl, C6-C 10 aryl, or 5-10 member heteroaryl optionally substituted with one or more C1-C6 alkyl, provided that (a) when R2 is cyclopropyl, X1 is N, A1 is CR A1 and A2 is CR A2 , at least one of R A1 and R A2 is not H; and (b) when R2 is cyclopropyl, X1 is N, A1 is CR A1 and A2 is CH, R A1 is not ethyl.

[0006] In some aspects, the disclosure provides a compound of formula (II'): TIFF2026521511000005.tif31128 or a pharmaceutically acceptable salt thereof is provided, in the formula, TIFF2026521511000006.tif9128 is a double bond, where the double bond is either an (E) or (Z) isomer; R1 C6~C 10 It is an aryl or 5-10 member heteroaryl, where the aryl or heteroaryl is one or more R 1a It may also be replaced with; Each R 1a These are independently halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is cycloalkyl or methyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 is H, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C3-C 10 Cycloalkyls are one or more C1-C6 alkoxys or -O(C3-C 10 It may also be substituted with a cycloalkyl group; or R5 and one R 1a It combines with intervening atoms to form a 3- to 10-membered heterocycline; m is either 0 or 1. however, (a) If R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl; and (b) If R1 is a monosubstituted C6 aryl substituted with one fluoropolymer, R2 is cyclopropyl, and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not cyclopropyl; and (c) If R2 is methyl, then R4 is not a C1-C6 alkyl group.

[0007] In some aspects, this disclosure provides methods for preparing the compounds described herein (for example, methods comprising one or more steps described in Schemes 1 to 7) or provides compounds obtained by such means.

[0008] In some aspects, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers, or a combination thereof.

[0009] In some respects, this disclosure provides intermediates described herein (for example, intermediates selected from the intermediates described in Examples 1 and 2) that are suitable for use in methods for preparing the compounds described herein.

[0010] In some aspects, the present disclosure provides methods for modulating stasmin-2 (STMN2) activity (e.g., in vitro or in vivo) with the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0011] In some aspects, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising the step of administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the Disclosure to a subject.

[0012] In some aspects, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is needed, the method comprising the step of administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the Disclosure to a subject.

[0013] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating STMN2 activity (e.g., in vitro or in vivo).

[0014] In some aspects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for use in treating or preventing diseases or disorders disclosed herein.

[0015] In some aspects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for use in treating diseases or disorders disclosed herein.

[0016] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating STMN2 activity (e.g., in vitro or in vivo).

[0017] In some aspects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0018] In some aspects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0019] In some aspects, the disease or disorder is a neurodegenerative disease (e.g., amyotrophic lateral sclerosis (ALS)).

[0020] In some aspects, the disease or disorder is associated with axonal degeneration, axonal injury, or axonal dysfunction.

[0021] In some aspects, neurodegenerative diseases are associated with axonal degeneration, axonal injury, or axonal dysfunction.

[0022] In some aspects, this disclosure provides methods for preparing the compounds of this disclosure.

[0023] In some aspects, this disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly interpreted by those skilled in the art in which this disclosure pertains. In the specification, singular forms also include plural forms unless explicitly stated otherwise in the context. Methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but preferred methods and materials are listed below. All publications, patent applications, patents and other references referenced herein are incorporated by reference. References cited herein are not considered prior art to the claimed inventions. In case of any conflict, this specification shall prevail, including definitions. In addition, materials, methods and examples are illustrative and not intended to limit. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0025] Other features and benefits of the disclosure will become apparent from the detailed description and claims below. [Brief explanation of the drawing]

[0026] [Figure 1-1] Figure 1 shows the activity of the compound in WT (left) and TDP-43 mutant (right) SH-SY5Y cells, with darker gray indicating a higher relative luminescence (RLU) per cell. [Figure 1-2] Please refer to the explanation in Figure 1-1. [Figure 1-3] Please refer to the explanation in Figure 1-1. [Figure 1-4] Please refer to the explanation in Figure 1-1. [Figure 1-5] Please refer to the explanation in Figure 1-1. [Figure 1-6] Please refer to the explanation in Figure 1-1. [Figure 2] Figure 2 shows the activity of the compounds disclosed herein across mutant TDP-43 cell lines compared to known controls. [Modes for carrying out the invention]

[0027] Detailed explanation This disclosure relates to statin derivatives, their prodrugs, and pharmaceutically acceptable salts, which can modulate the expression or activity of statmin-2 (STMN2) and are therefore useful in methods of treating the human or animal body. This disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of STMN2-related disorders, such as neurodegenerative diseases or disorders, or diseases or disorders associated with axonal damage.

[0028] definition Unless otherwise specified, the following terms used in the specification and claims have the meanings set forth below.

[0029] While we do not intend to limit ourselves by this statement, various options are described herein for each variable, but the disclosure is understood to be intended to encompass feasible embodiments having combinations of options. The disclosure may be interpreted as excluding feasible embodiments resulting from specific combinations of options. For example, while various options are described herein for each variable, the disclosure may be interpreted as excluding feasible compound structures resulting from specific combinations of variables.

[0030] As used herein, “alkyl,” “C1, C2, C3, C4, C5 or C6 alkyl,” or “C1-C6 alkyl” is intended to include C1, C2, C3, C4, C5 or C6 linear saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyls include moieties having 1 to 6 carbon atoms, and non-limitingly include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, the linear or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for linear groups, C3-C6 for branched groups), and in other embodiments, the linear or branched alkyl has 4 or fewer carbon atoms.

[0031] As used herein, the term “optionally substituted alkyl” refers to an unsubstituted alkyl or an alkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbons of the hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0032] As used herein, the term “alkenyl” includes unsaturated aliphatic groups of similar length that may be substituted for the alkyls listed above, but which contain at least one double bond. For example, the term “alkenyl” includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, linear or branched alkenyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0033] As used herein, the term “optionally substituted alkenyl” refers to an unsubstituted alkenyl or an alkenyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0034] As used herein, the term “alkynyl” includes unsaturated aliphatic groups of similar length that may be substituted for the alkyls listed above, but which contain at least one triple bond. For example, “alkynyl” includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In certain embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to contain C2, C3, C4, C5, or C6 chain (straight or branched) diunsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to contain C2, C3, C4, C5, and C6 alkenylene linker groups.

[0035] As used herein, the term “optionally substituted alkynyl” refers to an unsubstituted alkynyl or an alkynyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0036] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl moieties) include both an unsubstituted moiety and a moiety having one or more specified substituents. For example, substituted heterocyclyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0037] As used herein, the term "cycloalkyl" refers to a group of 3 to 30 carbon atoms (e.g., C3-C3). 12 , C3~C 10This refers to monocyclic or polycyclic (e.g., condensed, crosslinked, or spirocyclic) saturated or partially unsaturated hydrocarbon systems having C3-C8 rings. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the rings in the cycloalkyl must be non-aromatic.

[0038] As used herein, the term “heterocyclyl” means, unless otherwise specified, one or more heteroatoms (such as O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, one or one-to-two or one-to-three or one-to-four or one-to-five or one-to-six heteroatoms, or for example, a saturated or partially unsaturated 3-to-8 member monocycle, a 7-to-12 member dicycle (condensed, bridged, or spirocycle), or an 11-to-14 member tricycle (condensed, bridged, or spirocycle) having one, two, three, four, five, or six heteroatoms.Examples of heterocyclyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, and 1,4-oxazepanyl. , 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]yl, 7'H-spiro[cyclohexyl Xan-1,5'-Flo[3,4-b]pyridine]-yl, 3'H-Spiro[cyclohexane-1,1'-Flo[3,4-c]pyridine]-yl, 3-Azabicyclo[3.1.0]hexanyl, 3-Azabicyclo[3.1.0]hexane-3-yl, 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-Hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyrimidinyl, 5,6,7,8-Tetrahydro This includes, but is not limited to, lopirido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, etc. In the case of polycyclic heterocyclines, only one of the rings in the heterocycline must be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0039] If a variable has two bonds to the rest of the compound's formula, it is understood that the two bonds may be on the same atom or on different atoms of the variable. For example, if a variable (e.g., variable X) is a cycloalkyl or heterocyclyl and has two bonds to the rest of the compound's formula, the two bonds may be on the same atom or on different atoms of the cycloalkyl or heterocyclyl.

[0040] As used herein, the term “aryl” includes aromatic groups or polycyclic systems having one or more aromatic rings, including “conjugated” groups, and does not contain any heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like.

[0041] As used herein, the term “heteroaryl” is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic rings consisting of a carbon atom and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may be oxidized (i.e., N → O and S(O)). p(where p=1 or 2). Note that the total number of S and O atoms in an aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups may also be condensed or crosslinked with non-aromatic alicyclic or heterocyclic rings to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0042] Furthermore, the terms “aryl” and “heteroaryl” include polycyclic, e.g., tricyclic and bicyclic aryl and heteroaryl groups, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, or indoridine.

[0043] Cycloalkyl, heterocyclyl, aryl, or heteroaryl rings have substituents at one or more ring positions (e.g., ring-forming carbons or heteroatoms, e.g., N), such as those listed above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, They may be substituted with minocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The aryl and heteroaryl groups may also be condensed or crosslinked with non-aromatic alicyclic or heterocyclic rings to form a polycyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0044] As used herein, the term “approximately” refers to a quantity, value, or period that is within ±10% of the stated quantity, value, or period. In some embodiments, “approximately” refers to ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the stated quantity, value, or period. In other embodiments, “approximately” refers to ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the stated quantity, value, or period. In other embodiments, “approximately” refers to ±5% of the stated quantity, value, or period. In some embodiments, “approximately” refers to ±2% or ±1% of the enumerated quantity, value, or period. For example, in some embodiments, when the term “approximately” is used when describing a temperature or temperature range, these terms refer to the stated temperature or temperature range ±5°C, ±2°C, or ±1°C. In other embodiments, the term “approximately” refers to the stated temperature or temperature range ±2°C.

[0045] As used herein, the term “substituted” means that any one or more hydrogen atoms on a given atom are replaced with a group selected from those indicated, provided that the substitution does not exceed the normal valence of the given atom and the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. Keto substituents are not present in the aromatic moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). “Stable compound” and “stable structure” mean a compound that is robust enough to withstand isolation from a reaction mixture to a useful purity and formulation into an effective therapeutic agent.

[0046] When the attachment to a substituent is shown to cross a bond connecting two atoms within the ring, such a substituent may be attached to any atom within the ring. When a substituent is described without indicating the atom to which such a substituent is attached to the remainder of a compound of a given formula, such a substituent may be attached via any atom in such a formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0047] If any constituent of a compound or any variable (e.g., R) occurs more than once in a formula, its definition at each occurrence is independent of its definition at other occurrences. Thus, for example, if a group is shown to be substituted with 0 to 2 R moieties, such a group may be substituted with up to 2 R moieties, and each occurrence of R is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0048] As used herein, the term “hydroxy” or “hydroxyl” includes a group having -OH or -O - thereof.

[0049] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0050] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0051] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having a specified substituent that substitutes for one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0052] As used herein, the terms "alkoxy" or "alkoxyl" include substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, without limitation, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentyloxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. An alkoxy group may be substituted, for example, with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, without limitation, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0053] As used herein, expressions such as “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C,” and “selected from A, B, and C,” are used interchangeably unless otherwise specified, and all refer to something selected from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0054] This disclosure should be understood to provide methods for the synthesis of compounds of any of the formulas described herein. This disclosure also provides detailed methods for the synthesis of various disclosed compounds and those shown in the examples of this disclosure relating to the following schemes.

[0055] Throughout the specification, where a composition is described as having, including, or comprising a particular component, it should be understood that the composition is intended to be essentially composed of or consisting of the described component. Similarly, where a method or process is described as having, including, or comprising a particular process step, the process also essentially consists of or consists of the described process step. Furthermore, it should be understood that the order of the steps or the order in which a particular action is performed is not important, as long as the invention is implementable. In addition, two or more steps or actions may be performed simultaneously.

[0056] It should be understood that the disclosed synthesis process is tolerant of a variety of functional groups, and therefore various substituted starting materials can be used. The process generally provides the desired final compound at or near the end of the entire process, but in certain cases, it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0057] It should be understood that the compounds disclosed herein can be prepared in various ways using commercially available starting materials, compounds from literature-known or readily prepared intermediates, by employing standard synthetic methods and procedures that are known to those skilled in the art or that become apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups can be obtained from relevant scientific literature or standard textbooks in the field. Not limited to any one or more sources, but incorporated herein by reference, is Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd Classic textbooks such as John Wiley & Sons, New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are useful and well-known references to those skilled in the art of organic synthesis.

[0058] Those skilled in the art will see that the order of certain steps, such as the introduction and removal of protecting groups, may be altered during the reaction sequences and synthetic schemes described herein. Those skilled in the art will also recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups within a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3. rd This can be found in edition, John Wiley & Sons: New York, 1999.

[0059] Unless otherwise specified, any description of a treatment or preventive method should be understood to include the use of compounds to provide treatment or prevention as described herein. Unless otherwise specified, any description of a treatment or preventive method should be understood to include the use of compounds to prepare a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention in human or non-human animals, including rodents and other disease models.

[0060] Unless otherwise specified, any description of a treatment method should be understood to include the use of compounds to provide treatment as described herein. Unless otherwise specified, any description of a treatment method should be understood to include the use of compounds to prepare a medicament for treating such a condition. Treatments include treatment of human or non-human animals, including rodents and other disease models.

[0061] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. Mammals may be, for example, humans, or suitable non-human mammals such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. The subject may also be a bird or poultry. In some embodiments, the subject is human.

[0062] As used herein, the term “subject in need” refers to a subject who has a disease or is at high risk of developing a disease. In some embodiments, the subject in need is pathologically deficient in STMN2. The subject in need may be a subject that has been previously diagnosed or identified with one of the diseases or disorders disclosed herein. The subject in need may also be a subject affected by one of the diseases or disorders disclosed herein. Alternatively, the subject in need may be a subject at high risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject predisposed to developing such a disorder compared to the population as a whole). The subject in need may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond to or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need has received all known effective treatments for one of the diseases or disorders disclosed herein, and they have been unsuccessful. In some embodiments, the subject in need has received at least one prior treatment.

[0063] As used herein, the terms “to treat” or “to treat” describe the management and care of a patient aimed at combating a disease, condition, or disorder, and include the administration of the compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The terms “to treat” may also include the treatment of cells or animal models in vitro. References to “treating” or “to treat” should be understood to include the alleviation of established symptoms of the condition. "Treating" or "treating" a condition, disorder, or state means, therefore, (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or state in a person who is suffering from or may be predisposed to such a condition, disorder, or state but has not yet experienced or shown any clinical or preclinical symptoms of the condition, disorder, or state; (2) inhibiting the condition, disorder, or state, i.e., preventing, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance treatment) or at least one clinical or preclinical symptom of the disease; or (3) reducing or attenuating the disease, i.e., regressing at least one of the clinical or preclinical symptoms of the condition, disorder, or state.

[0064] It should be understood that the compounds disclosed herein, or any pharmaceutically acceptable salts, polymorphs, or solvates thereof, may be used or used to prevent related diseases, conditions, or disorders, or to identify suitable candidates for such purposes.

[0065] As used herein, the terms “prevent,” “prevent,” or “protect from” describe reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0066] Those skilled in the art should understand that for a detailed description of the known or equivalent technologies discussed herein, they can refer to general references. These references include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th This includes the 1990 edition. Naturally, these documents may be referenced when preparing or using the disclosure.

[0067] This disclosure should be understood to also provide pharmaceutical compositions comprising any compound described herein in combination with one or more pharmaceutically acceptable excipients, diluents, adjuvants, carriers, or combinations thereof.

[0068] As used herein, the term “pharmaceutical composition” refers to a formulation containing the compound of the Disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is a bulk or unit dosage form. A unit dosage form is any of various forms, including, for example, capsules, IV bags, tablets, a single pump on an aerosol inhaler, or a vial. The amount of the active ingredient (e.g., a formulation of the compound of the Disclosure or its salts, hydrates, solvates, or isomers) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that, in some cases, the dosage may need to be adjusted according to the patient’s age and condition. The dosage will also vary depending on the route of administration. Various routes are intended, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intraarachnoid, and intranasal. Dosage forms for topical or transdermal administration of the compound of the Disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants.

[0069] As used herein, the term “pharmaceutically acceptable” means a compound, anion, cation, substance, composition, carrier, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that has a reasonable benefit-to-risk ratio, within the bounds of sound medical judgment.

[0070] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, and useful for preparing a pharmaceutical composition that is not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary use and for pharmaceutically acceptable use in humans. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one and more such excipients.

[0071] It should be understood that the pharmaceutical compositions of this disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingested), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and isotonic adjusting agents such as sodium chloride or dextrose. pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be placed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0072] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to subjects by many of the well-known methods currently used for chemotherapeutic treatments. For example, the compounds of this disclosure may be injected into the bloodstream or body cavities, or ingested orally, or applied to the skin using a patch. The selected dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The condition of the patient (e.g., the disease or disorder disclosed herein) and the patient's health should preferably be closely monitored during and for a reasonable period after the treatment.

[0073] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent for treating, ameliorating, or preventing an identified disease, disorder, or condition, or for achieving a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will vary depending on the subject's weight, size, health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The dosage may vary within this range depending on the dosage form employed, the susceptibility of the patient, and the route of administration.

[0074] The dosage and regimen are adjusted to provide a sufficient level of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the condition, the overall health of the subject, the age, weight, and sex of the subject, diet, the time and frequency of administration, drug combinations, response susceptibility, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every three to four days, weekly, or once every two weeks depending on the half-life and clearance rate of the particular formulation.

[0075] Pharmaceutical compositions containing the active compounds of the present disclosure may be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, tabletting, pulverizing, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and / or auxiliaries that facilitate processing of the active compound into a pharmaceutically usable formulation. Of course, the appropriate formulation will vary depending on the selected route of administration.

[0076] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water-soluble) or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremofor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and preferably fluid enough to be easily filled / discharged from a syringe. It must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi. Carriers may be solvents or dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), cyclodextrin, and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Often, it is preferable to include isotonic agents in the composition, such as sugars, polyhydric alcohols like mannitol and sorbitol, and sodium chloride. The inclusion of absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition can lead to sustained absorption of the injectable composition.

[0077] Sterile injectable solutions can be prepared by filtration sterilization after incorporating the required amount of the active compound into a suitable solvent containing, as needed, one or a combination of the components listed above. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation method is vacuum drying and lyophilization, from which a powder of the active ingredient plus any additional desired components is obtained from a previously sterile filtered solution.

[0078] Oral compositions generally contain an inert diluent or an edible, pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound is incorporated with excipients and can be used in the form of tablets, lozenges, capsules, or pouches. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is applied orally, gargled with, and then spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0079] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gas like carbon dioxide, or via a nebulizer.

[0080] Systemic administration may also be by mucosal or percutaneous means. For mucosal or percutaneous administration, a penetrating agent suitable for the barrier to be penetrated is used in the formulation. Such penetrating agents are generally known in the art and, for example, for mucosal administration, include surfactants, bile salts, and fusidic acid derivatives. Mucosal administration can be achieved through the use of nasal drops, powders, or suppositories. For percutaneous administration, the active compound is formulated into an ointment, salve, gel, or cream, as is generally known in the art.

[0081] The active compound can be prepared using pharmaceutically acceptable carriers that protect the compound from rapid elimination from the body, such as controlled-release formulations including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. These substances are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (containing liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811.

[0082] Formulating oral or parenteral compositions in dosage unit form is particularly advantageous for ease of administration and uniformity of dosage. As used herein, a dosage unit form refers to a physically distinct unit suitable as a single dose for the target to be treated, each unit containing a predetermined amount of the active compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. The specifications for each dosage unit form disclosed depend on the specific properties of the active compound and the particular therapeutic effect to be achieved, and vary accordingly.

[0083] Please understand that pharmaceutical compositions may be included in a container, pack, or dispenser along with instructions for administration.

[0084] If the compounds of this disclosure can further form salts, it should be understood that any of these forms are intended to fall within the scope of the claimed disclosure.

[0085] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound of the disclosed compound in which the parent compound is modified to form an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, and alkali organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, dicarboxylic acid, carboxylic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethic acid This includes, but is not limited to, onic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannins, tartaric acid, toluenesulfone, and naturally occurring amine acids, such as glycine, alanine, phenylalanine, and arginine, which are derived from inorganic and organic acids selected from these.

[0086] In some embodiments, pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, trometamic acid salts, ammonia salts, arginine salts, or lysine salts.

[0087] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-octa-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The disclosure also includes salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine. In salt form, the ratio of the compound to the salt's cation or anion is understood to be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3.

[0088] The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, percutaneously, transpulmonaryly, inhaled, transbuccal mucosa, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intraarachnoidally, and parenterally. In one embodiment, the compound is administered orally.

[0089] The administration regimen utilizing the compound is selected based on various factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salt to be employed.

[0090] The technologies for formulation and administration of the disclosed compounds are described in Remington: the Science and Practice of Pharmacy, 19. thThis can be found in edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such a pharmaceutical composition in an amount sufficient to provide the desired dosage within the range described herein.

[0091] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of this disclosure are evident from different examples. The examples provided illustrate different components and methodologies useful for carrying out this disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, a person skilled in the art could identify and adopt other components and methodologies useful for carrying out this disclosure.

[0092] In the synthetic schemes described herein, compounds may be illustrated in one particular configuration for simplification. Such particular configurations should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor do they exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers, however it should be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0093] All publications and patent documents referenced herein are incorporated herein by reference as if each such publication or document were specifically and individually indicated to be incorporated herein by reference. No reference to publications and patent documents is intended to ratify them as relevant prior art, nor does it ratify them in any way with respect to their content or date. As the present invention has been described in writing, those skilled in the art will recognize that the invention can be carried out in various embodiments, and that the above description and the following examples are illustrative and not limitations of the subsequent claims.

[0094] As used herein, the expression "compounds of the disclosure" refers, both conceptually and specifically, to the compounds disclosed herein.

[0095] Compounds of the Disclosure Equation (I') In some aspects, this disclosure relates to compounds of formula (I'): We provide TIFF2026521511000007.tif31128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000008.tif7128 is single or double bonded, as long as the valence allows; TIFF2026521511000009.tif7128 is a single or double bond, where the double bond is an (E) isomer; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 is C6~C 10The aryl or 5-10 membered heteroaryl is substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is a cycloalkyl; B1 is either H or -OH; B2 is either H or -OH; Y is H, -C(O)OR3, -C(O)N(R3)2, Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C6~C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocyclyl which may be substituted with one or more C1-C6 alkyl groups, C6-C 10 A 5-10 member heteroaryl which may be substituted with an aryl or one or more C1-C6 alkyl groups, however, (a) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 and R A2At least one of them is not H; and (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0096] In some aspects, this disclosure provides compounds of formula (I') or pharmaceutically acceptable salts thereof. During the ceremony, TIFF2026521511000010.tif7128 is single or double bonded, as long as the valence allows; TIFF2026521511000011.tif7128 is either a single or double bond, where the double bond is an (E) isomer; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 is C6~C 10 The aryl or 5-10 membered heteroaryl, where the aryl or heteroaryl may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is a cycloalkyl; B1 is either H or -OH; B2 is either H or -OH; Y is H, -C(O)OR3, -C(O)N(R3)2, Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C6~C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocyclyl which may be substituted with one or more C1-C6 alkyl groups, C6-C 10 A 5-10 member heteroaryl which may be substituted with an aryl or one or more C1-C6 alkyl groups, however, (a) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 and R A2 At least one of them is not H.

[0097] In some aspects, this disclosure provides compounds of formula (I') or pharmaceutically acceptable salts thereof. During the ceremony, TIFF2026521511000012.tif7128 is single or double bonded, as long as the valence allows; TIFF2026521511000013.tif7128 is a single or double bond, where the double bond is an (E) isomer; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3, N, O, or S, where at least one A1, A2, or A3 is S; R1 is C6~C 10 The aryl or 5-10 membered heteroaryl, where the aryl or heteroaryl may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is a cycloalkyl; B1 is either H or -OH; B2 is either H or -OH; Y is H, -C(O)OR3, -C(O)N(R3)2, Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C6~C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocyclyl which may be substituted with one or more C1-C6 alkyl groups, C6-C 10 A 5-10 member heteroaryl which may be substituted with an aryl or one or more C1-C6 alkyl groups, however, (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1and when A2 is CH, R A1 is not ethyl.

[0098] In some aspects, the present disclosure provides a compound of formula (I): TIFF2026521511000014.tif28128 or a pharmaceutically acceptable salt thereof, wherein TIFF2026521511000015.tif7128 is a single or double bond as valence permits; X1 is CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, wherein at least one of A1, A2, or A3 is S; R1 is C6 - C 10 aryl or 5 - 10 member heteroaryl optionally substituted with one or more halo, -CN, -OH, -NH2, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C[] R2 is C3 - C 10 [[]cycloalkyl; R3 is H, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxyl, or C1 - C6 haloalkyl; R A1 is H, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxyl, or C1 - C6 haloalkyl; R A2 is H, C1 - C6 alkyl, C[[] 10 2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxyl, C1 - C6 haloalkyl, C6 - C R A3The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. however, (a) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 and R A2 At least one of them is not H; and (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0099] In some embodiments, the compound of formula (I') is the compound of formula (I).

[0100] In some embodiments, the compound is of formula (I) or a pharmaceutically acceptable salt thereof. During the ceremony, TIFF2026521511000016.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. however, (a) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 and R A2 At least one of them is not H; and (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0101] In some aspects, this disclosure relates to compounds of formula (I): Provides TIFF2026521511000017.tif28128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000018.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. however, (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0102] In some aspects, this disclosure relates to compounds of formula (I): Provides TIFF2026521511000019.tif27128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000020.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. however, (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0103] In some aspects, this disclosure relates to compounds of formula (I): Provides TIFF2026521511000021.tif28128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000022.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1 or C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. however, (a) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 and R A2 At least one of them is not H.

[0104] In some aspects, this disclosure relates to compounds of formula (I): TIFF2026521511000023.tif28128 or a pharmaceutically acceptable salt thereof is provided, in the formula, TIFF2026521511000024.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 These are C1 or C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0105] In some aspects, this disclosure relates to compounds of formula (I): Provides TIFF2026521511000025.tif27128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000026.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1 or C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0106] In some aspects, this disclosure relates to compounds of formula (I''): Provides TIFF2026521511000027.tif31128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000028.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. however, (a) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If RA1 and R A2 At least one of them is not H; and (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0107] In some aspects, this disclosure relates to compounds of formula (I'''): Provides TIFF2026521511000029.tif31128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000030.tif7128 is single or double bonded, as long as the valence allows; X1 is either CH or N; A1 is CR A1 , N, O, or S; A2 is CR A2 , N, O, or S; A3 is CR A3 , N, O, or S, where at least one A1, A2, or A3 is S; R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10It is an aryl or a 5- to 10-membered heteroaryl; and R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. however, (a) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 and R A2 At least one of them is not H; and (b) R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0108] For the compounds disclosed herein, the variables Y, X1, A1, A2, A3, B1, B2, R1, R2, R3, R A1 , R A2 , and R A3 Each of these may be selected from the groups described herein, where applicable, and the variables Y, X1, A1, A2, A3, B1, B2, R1, R2, R3, R A1 , R A2 , and R A3 Any of the groups described herein, where applicable, the remaining variables Y, X1, A1, A2, A3, B1, B2, R1, R2, R3, R A1 , R A2 , and R A3 It is understood that one or more of these can be combined with any of the groups described herein.

[0109] In some cases, TIFF2026521511000031.tif7128 has single bonds as far as the valence allows.

[0110] In some cases, TIFF2026521511000032.tif7128 has a double bond as far as its valence allows.

[0111] In some cases, TIFF2026521511000033.tif7128 is a single bond.

[0112] In some cases, TIFF2026521511000034.tif7128 has a double bond, where the double bond is an (E) isomer.

[0113] In some embodiments, X1 is CH or N.

[0114] In some embodiments, X1 is CH. In some embodiments, X1 is N.

[0115] In some embodiments, A1 is CR A1 It is N, O, or S.

[0116] In some embodiments, A1 is CR A1 In some embodiments, A1 is CH.

[0117] In some embodiments, A1 is N. In some embodiments, A1 is O. In some embodiments, A1 is S.

[0118] In some embodiments, A2 is CR A2 It is N, O, or S.

[0119] In some embodiments, A2 is CR A2 In some embodiments, A2 is CH.

[0120] In some embodiments, A2 is N. In some embodiments, A2 is O. In some embodiments, A2 is S.

[0121] In some aspects, A3 is CR A3 It is N, O, or S.

[0122] In some aspects, A3 is CR A3 In some embodiments, A3 is CH.

[0123] In some embodiments, A3 is N. In some embodiments, A3 is O. In some embodiments, A3 is S.

[0124] In some embodiments, at least one A1, A2, or A3 is S.

[0125] In some embodiments, B1 is H.

[0126] In some embodiments, B1 is -OH.

[0127] In some embodiments, B2 is H.

[0128] In some embodiments, B2 is -OH.

[0129] In some embodiments, Y is H.

[0130] In some embodiments, Y is -C(O)OR3. In some embodiments, Y is -C(O)OH. In some embodiments, Y is -C(O)OMe.

[0131] In some embodiments, Y is -C(O)N(R3)2. In some embodiments, Y is -C(O)NH2. In some embodiments, Y is -C(O)NH(Me). In some embodiments, Y is -C(O)N(Me)2.

[0132] In some embodiments, R1 is C6~C 10 They are aryl or 5-10 member heteroaryl.

[0133] In some embodiments, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, C6-C 10 They are aryl or 5-10 member heteroaryl.

[0134] In some embodiments, R1 is substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, C6-C 10 They are aryl or 5-10 member heteroaryl.

[0135] In some embodiments, R1 is replaced by one or more halos C6~C 10 They are aryl or 5-10 member heteroaryl.

[0136] In some embodiments, R1 is replaced by a single halo C6~C 10 They are aryl or 5-10 member heteroaryl.

[0137] In some embodiments, R1 is C6~C 10 It is Ariel.

[0138] In some embodiments, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is Ariel.

[0139] In some embodiments, R1 is a C6-C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl substituted with one or more C1-C6 haloalkyls. 10 It is Ariel.

[0140] In some embodiments, R1 is replaced by one or more halos C6~C 10 It is Ariel.

[0141] In some embodiments, R1 is replaced by a single halo C6~C 10 It is Ariel.

[0142] In some embodiments, R1 is a C6 aryl.

[0143] In some embodiments, R1 is a C6 aryl which may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0144] In some embodiments, R1 is a C6 aryl substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0145] In some embodiments, R1 is a C6 aryl substituted with one or more halos.

[0146] In some embodiments, R1 is a C6 aryl substituted with a single halo.

[0147] In some embodiments, R1 is a 5- to 10-membered heteroaryl.

[0148] In some embodiments, R1 is a 5-10 member heteroaryl which may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0149] In some embodiments, R1 is a 5-10 membered heteroaryl substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0150] In some embodiments, R1 is a 5-10 member heteroaryl substituted with one or more halos.

[0151] In some embodiments, R1 is a 5- to 10-membered heteroaryl substituted with one halo.

[0152] In some embodiments, R1 is a 6-membered heteroaryl.

[0153] In some embodiments, R1 is a 6-membered heteroaryl which may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0154] In some embodiments, R1 is a six-membered heteroaryl substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0155] In some embodiments, R1 is a six-membered heteroaryl substituted with one or more halos.

[0156] In some embodiments, R1 is a six-membered heteroaryl substituted with one halo.

[0157] In some embodiments, R1 is a six-membered heteroaryl substituted with two halos.

[0158] In some embodiments, R1 is a six-membered heteroaryl substituted with one halo and one methyl.

[0159] In some embodiments, R1 The filename is TIFF2026521511000035.tif26129.

[0160] In some embodiments, R1 The filename is TIFF2026521511000036.tif29128.

[0161] In some embodiments, R1 The filename is TIFF2026521511000037.tif27128.

[0162] In some embodiments, R1 is substituted at least two positions.

[0163] In some embodiments, R1 is substituted at least three positions.

[0164] In some embodiments, R1 is substituted at least four positions.

[0165] In some embodiments, R2 is C3~C 10 It is a cycloalkyl group.

[0166] In some embodiments, R2 is a C3 cycloalkyl (cyclopropyl) group.

[0167] In some embodiments, R2 is a C4 cycloalkyl (cyclobutyl) group.

[0168] In some embodiments, R2 is a C5 cycloalkyl group. In some embodiments, R2 is a C6 cycloalkyl group. In some embodiments, R2 is a C7 cycloalkyl group. In some embodiments, R2 is a C8 cycloalkyl group. In some embodiments, R2 is a C9 cycloalkyl group. In some embodiments, R2 is a C 10 It is a cycloalkyl group.

[0169] In some embodiments, R2 is C5~C 10It is a cycloalkyl. In some embodiments, R2 is a crosslinked C5-C 10 It is a cycloalkyl compound. In some embodiments, R2 is a bicyclic C5-C compound. 10 It is a cycloalkyl group.

[0170] In some embodiments, R2 The filename is TIFF2026521511000038.tif18128.

[0171] In some embodiments, R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0172] In some embodiments, R3 is H.

[0173] In some embodiments, R3 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0174] In some embodiments, R3 is a C1-C6 alkyl group.

[0175] In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is butyl. In some embodiments, R3 is pentyl. In some embodiments, R3 is hexyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is isobutyl. In some embodiments, R3 is isopentyl. In some embodiments, R3 is isohexyl. In some embodiments, R3 is sec-butyl. In some embodiments, R3 is sec-pentyl. In some embodiments, R3 is sec-hexyl. In some embodiments, R3 is tert-butyl.

[0176] In some embodiments, R3 is a C2-C6 alkenyl (e.g., ethenyl, propenyl, butenyl).

[0177] In some embodiments, R3 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl).

[0178] In some embodiments, R3 is a C1-C6 alkoxyl.

[0179] In some embodiments, R3 is methoxyl. In some embodiments, R3 is ethoxyl. In some embodiments, R3 is propoxyl. In some embodiments, R3 is butoxyl. In some embodiments, R3 is pentoxyl. In some embodiments, R3 is hexoxyl.

[0180] In some embodiments, R3 is a C1-C6 haloalkyl group.

[0181] In some embodiments, R3 is halomethyl. In some embodiments, R3 is haloethyl. In some embodiments, R3 is halopropyl. In some embodiments, R3 is halobutyl. In some embodiments, R3 is halopentyl. In some embodiments, R3 is halohexyl.

[0182] In some embodiments, at least one R3 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0183] In some embodiments, at least one R3 is a C1-C6 alkyl group.

[0184] In some embodiments, at least one R3 is methyl. In some embodiments, at least one R3 is ethyl. In some embodiments, at least one R3 is propyl. In some embodiments, at least one R3 is butyl. In some embodiments, at least one R3 is pentyl. In some embodiments, at least one R3 is hexyl. In some embodiments, at least one R3 is isopropyl. In some embodiments, at least one R3 is isobutyl. In some embodiments, at least one R3 is isopentyl. In some embodiments, at least one R3 is isohexyl. In some embodiments, at least one R3 is sec-butyl. In some embodiments, at least one R3 is sec-pentyl. In some embodiments, at least one R3 is sec-hexyl. In some embodiments, at least one R3 is tert-butyl.

[0185] In some embodiments, at least one R3 is a C2-C6 alkenyl (e.g., ethenyl, propenyl, butenyl).

[0186] In some embodiments, at least one R3 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl).

[0187] In some embodiments, at least one R3 is a C1-C6 alkoxyl.

[0188] In some embodiments, at least one R3 is methoxyl. In some embodiments, at least one R3 is ethoxyl. In some embodiments, at least one R3 is propoxyl. In some embodiments, at least one R3 is butoxyl. In some embodiments, at least one R3 is pentoxyl. In some embodiments, at least one R3 is hexoxyl.

[0189] In some embodiments, at least one R3 is a C1-C6 haloalkyl group.

[0190] In some embodiments, at least one R3 is halomethyl. In some embodiments, at least one R3 is haloethyl. In some embodiments, at least one R3 is halopropyl. In some embodiments, at least one R3 is halobutyl. In some embodiments, at least one R3 is halopentyl. In some embodiments, at least one R3 is halohexyl.

[0191] In some embodiments, R3 is H or methyl.

[0192] In some embodiments, R A1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl group.

[0193] In some embodiments, R A1 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0194] In some embodiments, R A1 H is H.

[0195] In some embodiments, R A1 These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0196] In some embodiments, R A1 These are C1-C6 alkyl groups.

[0197] In some embodiments, R A1 is methyl. In some embodiments, R A1 is ethyl. In some embodiments, R A1 is propyl. In some embodiments, R A1is butyl. In some embodiments, R A1 is pentyl. In some embodiments, R A1 is hexyl. In some embodiments, R A1 is isopropyl. In some embodiments, R A1 is isobutyl. In some embodiments, R A1 is isopentyl. In some embodiments, R A1 is isohexyl. In some embodiments, R A1 is sec-butyl. In some embodiments, R A1 is sec-pentyl. In some embodiments, R A1 is sec-hexyl. In some embodiments, R A1 It is tert-butyl.

[0198] In some embodiments, R A1 These are C2-C6 alkenyls (e.g., ethenyl, propenyl, butenyl).

[0199] In some embodiments, R A1 These are C2-C6 alkynyl compounds (e.g., ethynyl, propynyl, butynyl).

[0200] In some embodiments, R A1 These are C1-C6 alkoxyls.

[0201] In some embodiments, R A1 is a methoxyl. In some embodiments, R A1 is ethoxyl. In some embodiments, R A1 It is propoxyl. In some embodiments, R A1 is butoxyl. In some embodiments, R A1 is pentoxyl. In some embodiments, R A1 It is hexoxyl.

[0202] In some embodiments, R A1 These are C1-C6 haloalkyl groups.

[0203] In some embodiments, R A1 is a halomethyl. In some embodiments, R A1 is haloethyl. In some embodiments, R A1 is a halopropyl. In some embodiments, R A1 is halobutyl. In some embodiments, R A1 is halopentyl. In some embodiments, R A1 It is a halohexyl.

[0204] In some embodiments, R A1 is C3~C 10 It is a cycloalkyl group.

[0205] In some embodiments, R A1 It is a C3 cycloalkyl (cyclopropyl) group.

[0206] In some embodiments, R A1 It is a C4 cycloalkyl (cyclobutyl) group.

[0207] In some embodiments, R A1 R is a C5 cycloalkyl. In some embodiments, R A1 is a C6 cycloalkyl. In some embodiments, R A1 R is a C7 cycloalkyl. In some embodiments, R A1 is a C8 cycloalkyl. In some embodiments, R A1 is a C9 cycloalkyl. In some embodiments, R A1 is C 10 It is a cycloalkyl group.

[0208] In some embodiments, R A1 is C5~C 10 It is a cycloalkyl. In some embodiments, R A1 Bridge C5~C 10 It is a cycloalkyl. In some embodiments, R A1 The double ring type C5~C 10 It is a cycloalkyl group.

[0209] In some embodiments, R A1 It is H, methyl, or cyclopropyl.

[0210] In some embodiments, R A1 It is either H or methyl.

[0211] In some embodiments, R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C6~C 10 They are aryl or 5- to 10-membered heteroaryl compounds.

[0212] In some embodiments, R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 They are aryl or 5- to 10-membered heteroaryl compounds.

[0213] In some embodiments, R A2 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0214] In some embodiments, R A2 H is H.

[0215] In some embodiments, R A2 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C6-C 10 They are aryl or 5- to 10-membered heteroaryl compounds.

[0216] In some embodiments, R A2 These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0217] In some embodiments, R A2 is C6~C 10 It is Ariel.

[0218] In some embodiments, R A2 This is a C6 aryl compound.

[0219] In some embodiments, R A2 is a C8 aryl. In some embodiments, R A2 is C 10 It is Ariel.

[0220] In some embodiments, R A2 These are 5-10 member heteroaryls.

[0221] In some embodiments, R A2 R is a 5-membered heteroaryl. In some embodiments, R A2 is a 6-membered heteroaryl. In some embodiments, R A2 is a 7-membered heteroaryl. In some embodiments, R A2 is an 8-membered heteroaryl. In some embodiments, R A2 is a 9-membered heteroaryl. In some embodiments, R A2 It is a 10-membered heteroaryl.

[0222] In some embodiments, R A2 These are C1-C6 alkyl groups.

[0223] In some embodiments, R A2 is methyl. In some embodiments, R A2 is ethyl. In some embodiments, R A2 is propyl. In some embodiments, R A2 is butyl. In some embodiments, R A2 is pentyl. In some embodiments, R A2 is hexyl. In some embodiments, R A2 is isopropyl. In some embodiments, R A2 is isobutyl. In some embodiments, R A2is isopentyl. In some embodiments, R A2 is isohexyl. In some embodiments, R A2 is sec-butyl. In some embodiments, R A2 is sec-pentyl. In some embodiments, R A2 is sec-hexyl. In some embodiments, R A2 It is tert-butyl.

[0224] In some embodiments, R A2 These are C2-C6 alkenyls (e.g., ethenyl, propenyl, butenyl).

[0225] In some embodiments, R A2 These are C2-C6 alkynyl compounds (e.g., ethynyl, propynyl, butynyl).

[0226] In some embodiments, R A2 These are C1-C6 alkoxyls.

[0227] In some embodiments, R A2 is a methoxyl. In some embodiments, R A2 is ethoxyl. In some embodiments, R A2 It is propoxyl. In some embodiments, R A2 is butoxyl. In some embodiments, R A2 is pentoxyl. In some embodiments, R A2 It is hexoxyl.

[0228] In some embodiments, R A2 These are C1-C6 haloalkyl groups.

[0229] In some embodiments, R A2 is a halomethyl. In some embodiments, R A2 is haloethyl. In some embodiments, R A2 is a halopropyl. In some embodiments, R A2 is halobutyl. In some embodiments, R A2is halopentyl. In some embodiments, R A2 It is a halohexyl.

[0230] In some embodiments, R A2 is C3~C 10 It is a cycloalkyl group.

[0231] In some embodiments, R A2 It is a C3 cycloalkyl (cyclopropyl) group.

[0232] In some embodiments, R A2 It is a C4 cycloalkyl (cyclobutyl) group.

[0233] In some embodiments, R A2 R is a C5 cycloalkyl. In some embodiments, R A2 is a C6 cycloalkyl. In some embodiments, R A2 R is a C7 cycloalkyl. In some embodiments, R A2 is a C8 cycloalkyl. In some embodiments, R A2 is a C9 cycloalkyl. In some embodiments, R A2 is C 10 It is a cycloalkyl group.

[0234] In some embodiments, R A2 is C5~C 10 It is a cycloalkyl. In some embodiments, R A2 Bridge C5~C 10 It is a cycloalkyl. In some embodiments, R A2 The double ring type C5~C 10 It is a cycloalkyl group.

[0235] In some embodiments, R A2 It is H, methyl, or cyclopropyl.

[0236] In some embodiments, R A2 It is either H or methyl.

[0237] In some embodiments, RA3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocyclyl which may be substituted with one or more C1-C6 alkyl groups, C6-C 10 It is an aryl, or a 5-10 member heteroaryl which may be substituted with one or more C1-C6 alkyl groups.

[0238] In some embodiments, R A3 The elements are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0239] In some embodiments, R A3 H is H.

[0240] In some embodiments, R A3 These are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0241] In some embodiments, R A3 These are C1-C6 alkyl groups.

[0242] In some embodiments, R A3 is methyl. In some embodiments, R A3 is ethyl. In some embodiments, R A3 is propyl. In some embodiments, R A3 is butyl. In some embodiments, R A3 is pentyl. In some embodiments, R A3 is hexyl. In some embodiments, R A3 is isopropyl. In some embodiments, R A3 is isobutyl. In some embodiments, R A3 is isopentyl. In some embodiments, R A3 is isohexyl. In some embodiments, RA3 is sec-butyl. In some embodiments, R A3 is sec-pentyl. In some embodiments, R A3 is sec-hexyl. In some embodiments, R A3 It is tert-butyl.

[0243] In some embodiments, R A3 These are C2-C6 alkenyls (e.g., ethenyl, propenyl, butenyl).

[0244] In some embodiments, R A3 These are C2-C6 alkynyl compounds (e.g., ethynyl, propynyl, butynyl).

[0245] In some embodiments, R A3 These are C1-C6 alkoxyls.

[0246] In some embodiments, R A3 is a methoxyl. In some embodiments, R A3 is ethoxyl. In some embodiments, R A3 It is propoxyl. In some embodiments, R A3 is butoxyl. In some embodiments, R A3 is pentoxyl. In some embodiments, R A3 It is hexoxyl.

[0247] In some embodiments, R A3 These are C1-C6 haloalkyl groups.

[0248] In some embodiments, R A3 is a halomethyl. In some embodiments, R A3 is haloethyl. In some embodiments, R A3 is a halopropyl. In some embodiments, R A3 is halobutyl. In some embodiments, R A3 is halopentyl. In some embodiments, R A3 It is a halohexyl.

[0249] In some embodiments, R A3 is C3~C 10 It is a cycloalkyl group.

[0250] In some embodiments, R A3 It is a C3 cycloalkyl (cyclopropyl) group.

[0251] In some embodiments, R A3 It is a C4 cycloalkyl (cyclobutyl) group.

[0252] In some embodiments, R A3 R is a C5 cycloalkyl. In some embodiments, R A3 is a C6 cycloalkyl. In some embodiments, R A3 R is a C7 cycloalkyl. In some embodiments, R A3 is a C8 cycloalkyl. In some embodiments, R A3 is a C9 cycloalkyl. In some embodiments, R A3 is C 10 It is a cycloalkyl group.

[0253] In some embodiments, R A3 is C5~C 10 It is a cycloalkyl. In some embodiments, R A3 Bridge C5~C 10 It is a cycloalkyl. In some embodiments, R A3 The double ring type C5~C 10 It is a cycloalkyl group.

[0254] In some embodiments, R A3 These are 3-10 member heterocyclines.

[0255] In some embodiments, R A3 It is a 3-membered heterocycline. In some embodiments, R A3 It is a 4-membered heterocycline. In some embodiments, R A3 It is a 5-membered heterocycline. In some embodiments, R A3It is a 6-membered heterocycline. In some embodiments, R A3 It is a 7-membered heterocycline. In some embodiments, R A3 It is an 8-membered heterocycline. In some embodiments, R A3 It is a 9-membered heterocycline. In some embodiments, R A3 It is a 10-membered heterocycline.

[0256] In some embodiments, R A3 It is a 3-10 member heterocycline which may be substituted with one or more C1-C6 alkyl groups.

[0257] In some embodiments, R A3 It is a 3-10 membered heterocycline substituted with one or more C1-C6 alkyl groups.

[0258] In some embodiments, R A3 is C6~C 10 It is Ariel.

[0259] In some embodiments, R A3 This is a C6 aryl compound.

[0260] In some embodiments, R A3 These are 5-10 member heteroaryls.

[0261] In some embodiments, R A3 It is a 5-10 member heteroaryl which may be substituted with one or more C1-C6 alkyl groups.

[0262] In some embodiments, R A3 It is a 5-10 member heteroaryl substituted with one or more C1-C6 alkyl groups.

[0263] In some embodiments, R A3 It is a 5-6 member heteroaryl compound.

[0264] In some embodiments, R A3It is a 5-6 member heteroaryl which may be substituted with one or more C1-C6 alkyl groups.

[0265] In some embodiments, R A3 It is a 5-6 member heteroaryl substituted with one or more C1-C6 alkyl groups.

[0266] In some embodiments, R A3 H, methyl, phenyl, cyclopropyl, cyclobutyl, cyclohexyl, The filename is TIFF2026521511000039.tif24128.

[0267] In some embodiments, R A3 It is either H or methyl.

[0268] In some embodiments, R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 and R A2 At least one of them is not H.

[0269] In some embodiments, R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A1 It is not H.

[0270] In some embodiments, R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 If R A2 It is not H.

[0271] In some embodiments, R2 is cyclopropyl, X1 is N, and A1 is CR A1 And if A2 is CH, then R A1 It is not ethyl.

[0272] In some embodiments, a compound of formula (I) or formula (I') is defined as formula (I'): It is the substance specified in TIFF2026521511000040.tif31128 or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the compound of formula (I) or formula (I') is formula (Ia), (Ib), (Ic), or (Id): It is the substance specified in TIFF2026521511000041.tif138128 or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the compound of formula (I) or formula (I') is (I'-a), (I'-b), (I'-c), or (I'-d): It is the substance specified in TIFF2026521511000042.tif136128 or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the compound of formula (I) or formula (I') is formula (Id), (Ie), (If), or (Ig): It is the substance specified in TIFF2026521511000043.tif150128 or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the compound of formula (I) or formula (I') is (I'-d), (I'-e), (I'-f), or (I'-g): It is the substance specified in TIFF2026521511000044.tif149128 or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the compound of formula (I) or formula (I') is formula (Ih), (Ii), (Ij), or (Ik): TIFF2026521511000045.tif230121 or a pharmaceutically acceptable salt thereof, where R 1an is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0278] In some embodiments, compounds of formula (I) or formula (I') are (I'-h), (I'-i), (I'-j), or (I'-k): TIFF2026521511000046.tif222120 or a pharmaceutically acceptable salt thereof, in the formula R 1a n is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0279] In some embodiments, the compound of formula (I) or formula (I') is (Il), (Im), (In), or (Io): TIFF2026521511000047.tif230119 or a pharmaceutically acceptable salt thereof, in the formula R 1a n is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0280] In some embodiments, a compound of formula (I) or formula (I') is a compound of formula (I'-l), (I'-m), (I'-n), or (I'-o): TIFF2026521511000048.tif236121 or a pharmaceutically acceptable salt thereof, where R 1a n is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0281] Formula (II') In some aspects, this disclosure relates to compounds of formula (II'): Provides TIFF2026521511000049.tif31128 or a pharmaceutically acceptable salt thereof, in the formula, TIFF2026521511000050.tif9128 is a double bond, where the double bond is either an (E) or (Z) isomer; R1 C6~C 10 It is an aryl or 5-10 member heteroaryl, where the aryl or heteroaryl is one or more R 1a It may also be replaced with; Each R 1a These are independently halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is cycloalkyl or methyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 is H, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C3-C 10 Cycloalkyls are one or more C1-C6 alkoxys or -O(C3-C 10 It may be substituted with a cycloalkyl group, or R5 and one R 1a It combines with intervening atoms to form a 3- to 10-membered heterocycline; m is either 0 or 1. however, (a) If R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl; and (b) If R1 is a monosubstituted C6 aryl substituted with one fluoropolymer, R2 is cyclopropyl, and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not cyclopropyl; and (c) If R2 is methyl, then R4 is not a C1-C6 alkyl group.

[0282] In some aspects, this disclosure provides compounds of formula (II') or pharmaceutically acceptable salts thereof. During the ceremony, TIFF2026521511000051.tif9128 has a double bond, where the double bond is either an (E) or (Z) isomer; R1 C6~C 10 It is an aryl or 5-10 member heteroaryl, where the aryl or heteroaryl is one or more R 1a It may also be replaced with; Each R 1a These are independently halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is cycloalkyl or methyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 is H, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10It is a cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C3-C 10 Cycloalkyls are one or more C1-C6 alkoxys or -O(C3-C 10 It may be substituted with a cycloalkyl group, or R5 and one R 1a It combines with intervening atoms to form a 3- to 10-membered heterocycline; m is either 0 or 1. however, (a) If R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl; and (b) If R1 is a monosubstituted C6 aryl with one fluoropolymer, R2 is cyclopropyl, and R5 is a C1 alkyl with a C1 alkoxypolymer, then R4 is not cyclopropyl.

[0283] In some aspects, this disclosure provides compounds of formula (II') or pharmaceutically acceptable salts thereof. During the ceremony, TIFF2026521511000052.tif9128 is a double bond, where the double bond is either an (E) or (Z) isomer; R1 C6~C 10 It is an aryl or 5-10 member heteroaryl, where the aryl or heteroaryl is one or more R 1a It may also be replaced with; Each R 1a These are independently halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is cycloalkyl or methyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 is H, C3~C 10They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C3-C 10 Cycloalkyls are one or more C1-C6 alkoxys or -O(C3-C 10 It may be substituted with a cycloalkyl group, or R5 and one R 1a It combines with intervening atoms to form a 3- to 10-membered heterocycline; m is either 0 or 1. however, (a) If R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl.

[0284] In some aspects, this disclosure provides compounds of formula (II') or pharmaceutically acceptable salts thereof. During the ceremony, TIFF2026521511000053.tif9128 is a double bond, where the double bond is either an (E) or (Z) isomer; R1 C6~C 10 It is an aryl or 5-10 member heteroaryl, where the aryl or heteroaryl is one or more R 1a It may also be replaced with; Each R 1a These are independently halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R2 is C3~C 10 It is cycloalkyl or methyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 is H, C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C3-C 10 Cycloalkyls are one or more C1-C6 alkoxys or -O(C3-C 10 It may be substituted with a cycloalkyl group, or R5 and one R 1a It combines with intervening atoms to form a 3- to 10-membered heterocycline; m is either 0 or 1. however, (b) If R1 is a monosubstituted C6 aryl with one fluoropolymer, then R2 is cyclopropyl.

[0285] In some aspects, this disclosure relates to compounds of formula (II): Provides TIFF2026521511000054.tif29128 or a pharmaceutically acceptable salt thereof, in the formula, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is cycloalkyl or methyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl is one or more C1-C6 alkoxy or -O(C3-C 10 It may be substituted with a cycloalkyl group, however, (a) If R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl; and (b) If R1 is a monosubstituted C6 aryl substituted with one fluoropolymer, R2 is cyclopropyl, and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not cyclopropyl; and (c) If R2 is methyl, then R4 is not a C1-C6 alkyl group.

[0286] In some embodiments, the compound of formula (II') is the compound of formula (II).

[0287] In some aspects, this disclosure relates to compounds of formula (II): TIFF2026521511000055.tif29128 or a pharmaceutically acceptable salt thereof is provided, in the formula, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where the alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl may be substituted with one or more C1-C6 alkoxys. however, (a) If R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl; and (b) If R1 is a monosubstituted C6 aryl with one fluoropolymer, R2 is cyclopropyl, and R5 is a C1 alkyl with a C1 alkoxypolymer, then R4 is not cyclopropyl.

[0288] In some aspects, this disclosure relates to compounds of formula (II): Provides TIFF2026521511000056.tif29128 or a pharmaceutically acceptable salt thereof, in the formula, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 is C4~C 10They are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where the alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl may be substituted with one or more C1-C6 alkoxys. however, (a) If R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl.

[0289] In some aspects, this disclosure relates to compounds of formula (II): Provides TIFF2026521511000057.tif29128 or a pharmaceutically acceptable salt thereof, in the formula, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 C3~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C2 or C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where the alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl may be substituted with one or more C1-C6 alkoxys. however, (b) If R1 is a monosubstituted C6 aryl with one fluoropolymer, R2 is cyclopropyl, and R5 is a C1 alkyl with a C1 alkoxypolymer, then R4 is not cyclopropyl.

[0290] In some aspects, this disclosure relates to compounds of formula (II): We provide TIFF2026521511000058.tif29128 or a pharmaceutically acceptable salt thereof, in the formula, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is an aryl or a 5- to 10-membered heteroaryl; R2 is C3~C 10 It is a cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R4 is C4~C 10 They are cycloalkyl, 3-10 membered heterocyclyl, C1-C2 or C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where the alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl may be substituted with one or more C1-C6 alkoxys.

[0291] For the compounds disclosed herein, the variables R1 and R 1a R2, R3, R4, and R5 may be selected from the groups described herein, where applicable, and the variables R1, R 1a For any of R2, R3, R4, and R5, any group described herein, where applicable, the remaining variables R1, R1a It is understood that one or more of R2, R3, R4, and R5 can be combined with any of the groups described herein.

[0292] In some cases, TIFF2026521511000059.tif7128 has a double bond, and here the double bond is an (E) isomer.

[0293] In some cases, TIFF2026521511000060.tif7128 has a double bond, and here the double bond is a (Z) isomer.

[0294] In some embodiments, R1 is C6~C 10 They are aryl or 5-10 member heteroaryl.

[0295] In some embodiments, R1 is C6~C 10 It is an aryl or 5-10 member heteroaryl, where the aryl or heteroaryl is one or more R 1a It may be replaced with .

[0296] In some embodiments, R1 is C6~C 10 It is an aryl or 5-10 member heteroaryl, where the aryl or heteroaryl is one or more R 1a It has been replaced with.

[0297] In some embodiments, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 They are aryl or 5-10 member heteroaryl.

[0298] In some embodiments, R1 is a C6-C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl substituted with one or more C1-C6 haloalkyls. 10 They are aryl or 5-10 member heteroaryl.

[0299] In some embodiments, R1 may be substituted with one or more halos, -CN, -OH, or -NH2 C6~C 10 They are aryl or 5-10 member heteroaryl.

[0300] In some embodiments, R1 is a C6-C6 substituted with one or more halos, -CN, -OH, or -NH2. 10 They are aryl or 5-10 member heteroaryl.

[0301] In some embodiments, R1 is replaced by one or more halos C6~C 10 They are aryl or 5-10 member heteroaryl.

[0302] In some embodiments, R1 is replaced by a single halo C6~C 10 They are aryl or 5-10 member heteroaryl.

[0303] In some embodiments, R1 is C6~C 10 It is Ariel.

[0304] In some embodiments, R1 may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl. 10 It is Ariel.

[0305] In some embodiments, R1 is a C6-C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl substituted with one or more C1-C6 haloalkyls.10 It is Ariel.

[0306] In some embodiments, R1 is replaced by one or more halos C6~C 10 It is Ariel.

[0307] In some embodiments, R1 is replaced by a single halo C6~C 10 It is Ariel.

[0308] In some embodiments, R1 is a C6 aryl.

[0309] In some embodiments, R1 is a C6 aryl which may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0310] In some embodiments, R1 is a C6 aryl substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0311] In some embodiments, R1 is a C6 aryl which may be substituted with one or more halos, -CN, -OH, or -NH2.

[0312] In some embodiments, R1 is a C6 aryl substituted with one or more halo, -CN, -OH, or -NH2.

[0313] In some embodiments, R1 is a C6 aryl substituted with one or more halos.

[0314] In some embodiments, R1 is a C6 aryl substituted with a single halo.

[0315] In some embodiments, R1 is a 5- to 10-membered heteroaryl.

[0316] In some embodiments, R1 is a 5-10 member heteroaryl which may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0317] In some embodiments, R1 is a 5-10 membered heteroaryl substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0318] In some embodiments, R1 is a 5-10 member heteroaryl substituted with one or more halos.

[0319] In some embodiments, R1 is a 5- to 10-membered heteroaryl substituted with one halo.

[0320] In some embodiments, R1 is a 6-membered heteroaryl.

[0321] In some embodiments, R1 is a 6-membered heteroaryl which may be substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0322] In some embodiments, R1 is a six-membered heteroaryl substituted with one or more halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0323] In some embodiments, R1 is a six-membered heteroaryl substituted with one or more halos.

[0324] In some embodiments, R1 is a six-membered heteroaryl substituted with one halo.

[0325] In some embodiments, R1 The filename is TIFF2026521511000061.tif67153.

[0326] In some embodiments, R1 The filename is TIFF2026521511000062.tif47150.

[0327] In some embodiments, R1 The filename is TIFF2026521511000063.tif35128.

[0328] In some embodiments, R1 is substituted at least two positions.

[0329] In some embodiments, R1 is substituted at least three positions.

[0330] In some embodiments, R1 is substituted at least four positions.

[0331] In some embodiments, each R 1a These are independently halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0332] In some embodiments, at least one R 1a These are halos (for example, Cl, F, I, Br).

[0333] In some embodiments, at least one R 1a is -CN.

[0334] In some embodiments, at least one R 1a It is -OH.

[0335] In some embodiments, at least one R1a It is -NH2.

[0336] In some embodiments, at least one R 1a These are C1-C6 alkyl groups.

[0337] In some embodiments, R 1a is methyl. In some embodiments, R 1a is ethyl. In some embodiments, R 1a is propyl. In some embodiments, R 1a is butyl. In some embodiments, R 1a is pentyl. In some embodiments, R 1a is hexyl. In some embodiments, R 1a is isopropyl. In some embodiments, R 1a is isobutyl. In some embodiments, R 1a is isopentyl. In some embodiments, R 1a is isohexyl. In some embodiments, R 1a is sec-butyl. In some embodiments, R 1a is sec-pentyl. In some embodiments, R 1a is sec-hexyl. In some embodiments, R 1a It is tert-butyl.

[0338] In some embodiments, R 1a These are C2-C6 alkenyls (e.g., ethenyl, propenyl, butenyl).

[0339] In some embodiments, R 1a These are C2-C6 alkynyl compounds (e.g., ethynyl, propynyl, butynyl).

[0340] In some embodiments, R 1a These are C1-C6 alkoxyls.

[0341] In some embodiments, R 1a is a methoxyl. In some embodiments, R 1ais ethoxyl. In some embodiments, R 1a It is propoxyl. In some embodiments, R 1a is butoxyl. In some embodiments, R 1a is pentoxyl. In some embodiments, R 1a It is hexoxyl.

[0342] In some embodiments, R 1a These are C1-C6 haloalkyl groups.

[0343] In some embodiments, R 1a is a halomethyl. In some embodiments, R 1a is haloethyl. In some embodiments, R 1a is a halopropyl. In some embodiments, R 1a is halobutyl. In some embodiments, R 1a is halopentyl. In some embodiments, R 1a It is a halohexyl.

[0344] In some embodiments, R2 is methyl.

[0345] In some embodiments, R2 is C3~C 10 It is a cycloalkyl group.

[0346] In some embodiments, R2 is a C3 cycloalkyl (cyclopropyl) group.

[0347] In some embodiments, R2 is a C4 cycloalkyl (cyclobutyl) group.

[0348] In some embodiments, R2 is a C5 cycloalkyl group. In some embodiments, R2 is a C6 cycloalkyl group. In some embodiments, R2 is a C7 cycloalkyl group. In some embodiments, R2 is a C8 cycloalkyl group. In some embodiments, R2 is a C9 cycloalkyl group. In some embodiments, R2 is a C 10 It is a cycloalkyl group.

[0349] In some embodiments, R2 is C5~C 10 It is a cycloalkyl. In some embodiments, R2 is a crosslinked C5-C 10 It is a cycloalkyl compound. In some embodiments, R2 is a bicyclic C5-C compound. 10 It is a cycloalkyl group.

[0350] In some embodiments, R2 is methyl, The filename is TIFF2026521511000064.tif16128.

[0351] In some embodiments, R2 The filename is TIFF2026521511000065.tif17128.

[0352] In some embodiments, R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0353] In some embodiments, R3 is H.

[0354] In some embodiments, R3 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0355] In some embodiments, R3 is a C1-C6 alkyl group.

[0356] In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is butyl. In some embodiments, R3 is pentyl. In some embodiments, R3 is hexyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is isobutyl. In some embodiments, R3 is isopentyl. In some embodiments, R3 is isohexyl. In some embodiments, R3 is sec-butyl. In some embodiments, R3 is sec-pentyl. In some embodiments, R3 is sec-hexyl. In some embodiments, R3 is tert-butyl.

[0357] In some embodiments, R3 is a C2-C6 alkenyl (e.g., ethenyl, propenyl, butenyl).

[0358] In some embodiments, R3 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl).

[0359] In some embodiments, R3 is a C1-C6 alkoxyl.

[0360] In some embodiments, R3 is methoxyl. In some embodiments, R3 is ethoxyl. In some embodiments, R3 is propoxyl. In some embodiments, R3 is butoxyl. In some embodiments, R3 is pentoxyl. In some embodiments, R3 is hexoxyl.

[0361] In some embodiments, R3 is a C1-C6 haloalkyl group.

[0362] In some embodiments, R3 is halomethyl. In some embodiments, R3 is haloethyl. In some embodiments, R3 is halopropyl. In some embodiments, R3 is halobutyl. In some embodiments, R3 is halopentyl. In some embodiments, R3 is halohexyl.

[0363] In some embodiments, R4 is H, C3~C 10 These are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0364] In some embodiments, R4 is H.

[0365] In some embodiments, R4 is C3~C 10 These are cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0366] In some embodiments, R4 is C3~C 10 These are cycloalkyl, 3-10 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0367] In some embodiments, R4 is C3~C 10 It is a cycloalkyl group.

[0368] In some embodiments, R4 is a C3 cycloalkyl (cyclopropyl) group.

[0369] In some embodiments, R4 is a C4 cycloalkyl (cyclobutyl) group.

[0370] In some embodiments, R4 is a C5 cycloalkyl group. In some embodiments, R4 is a C6 cycloalkyl group. In some embodiments, R4 is a C7 cycloalkyl group. In some embodiments, R4 is a C8 cycloalkyl group. In some embodiments, R4 is a C9 cycloalkyl group. In some embodiments, R4 is a C 10 It is a cycloalkyl group.

[0371] In some embodiments, R4 is C5~C 10It is a cycloalkyl. In some embodiments, R4 is a crosslinked C5~C 10 It is a cycloalkyl compound. In some embodiments, R4 is a bicyclic C5-C compound. 10 It is a cycloalkyl group.

[0372] In some embodiments, R4 is a 3- to 10-membered heterocycline.

[0373] In some embodiments, R4 is a 3-membered heterocycline. In some embodiments, R4 is a 4-membered heterocycline. In some embodiments, R4 is a 5-membered heterocycline. In some embodiments, R4 is a 6-membered heterocycline. In some embodiments, R4 is a 7-membered heterocycline. In some embodiments, R4 is an 8-membered heterocycline. In some embodiments, R4 is a 9-membered heterocycline. In some embodiments, R4 is a 10-membered heterocycline.

[0374] In some embodiments, R4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0375] In some embodiments, R4 is a C1-C6 alkyl group.

[0376] In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is propyl. In some embodiments, R4 is butyl. In some embodiments, R4 is pentyl. In some embodiments, R4 is hexyl. In some embodiments, R4 is isopropyl. In some embodiments, R4 is isobutyl. In some embodiments, R4 is isopentyl. In some embodiments, R4 is isohexyl. In some embodiments, R4 is sec-butyl. In some embodiments, R4 is sec-pentyl. In some embodiments, R4 is sec-hexyl. In some embodiments, R4 is tert-butyl.

[0377] In some embodiments, R4 is a C2-C6 alkenyl (e.g., ethenyl, propenyl, butenyl).

[0378] In some embodiments, R4 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl).

[0379] In some embodiments, R4 is a C1-C6 alkoxyl.

[0380] In some embodiments, R4 is methoxyl. In some embodiments, R4 is ethoxyl. In some embodiments, R4 is propoxyl. In some embodiments, R4 is butoxyl. In some embodiments, R4 is pentoxyl. In some embodiments, R4 is hexoxyl.

[0381] In some embodiments, R4 is a C1-C6 haloalkyl group.

[0382] In some embodiments, R4 is halomethyl. In some embodiments, R4 is haloethyl. In some embodiments, R4 is halopropyl. In some embodiments, R4 is halobutyl. In some embodiments, R4 is halopentyl. In some embodiments, R4 is halohexyl.

[0383] In some embodiments, R4 is H, The filename is TIFF2026521511000066.tif16128.

[0384] In some embodiments, R4 The filename is TIFF2026521511000067.tif17128.

[0385] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl group.

[0386] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C3-C 10 Cycloalkyls are one or more C1-C6 alkoxys or -O(C3-C 10 It may be substituted with a cycloalkyl group.

[0387] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C3-C 10 It is a cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C3-C 10 Cycloalkyls are one or more C1-C6 alkoxys or -O(C3-C 10 It is substituted with a cycloalkyl group.

[0388] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.

[0389] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where the alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl may be substituted with one or more C1-C6 alkoxys.

[0390] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl is one or more C1-C6 alkoxy or -O(C3-C 10 It is substituted with a cycloalkyl group.

[0391] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, where the alkyl, alkenyl, alkynyl, alkoxyl, or haloalkyl is substituted with one or more C1-C6 alkoxys.

[0392] In some embodiments, R5 is H.

[0393] In some embodiments, R5 is a C1-C6 alkyl group.

[0394] In some embodiments, R5 is one or more C1-C6 alkoxys or -O(C3-C 10 It is a C1-C6 alkyl group that may be substituted with a cycloalkyl group.

[0395] In some embodiments, R5 is one or more C1-C6 alkoxys or -O(C3-C 10 These are C1-C6 alkyl groups substituted with cycloalkyl groups.

[0396] In some embodiments, R5 is a C1-C6 alkyl which may be substituted with one or more C1-C6 alkoxys.

[0397] In some embodiments, R5 is a C1-C6 alkyl group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is propyl. In some embodiments, R5 is butyl. In some embodiments, R5 is pentyl. In some embodiments, R5 is hexyl. In some embodiments, R5 is isopropyl. In some embodiments, R5 is isobutyl. In some embodiments, R5 is isopentyl. In some embodiments, R5 is isohexyl. In some embodiments, R5 is sec-butyl. In some embodiments, R5 is sec-pentyl. In some embodiments, R5 is sec-hexyl. In some embodiments, R5 is tert-butyl.

[0398] In some embodiments, R5 is methyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is ethyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is propyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is butyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is pentyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is hexyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isopropyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isobutyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isopentyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isohexyl which may be substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is sec-butyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is sec-pentyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is sec-hexyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is tert-butyl which may be substituted with one or more C1-C6 alkoxys.

[0399] In some embodiments, R5 is methyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is ethyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is propyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is butyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is pentyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is hexyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isopropyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isobutyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isopentyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isohexyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is sec-butyl substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is sec-pentyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is sec-hexyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is tert-butyl substituted with one or more C1-C6 alkoxys.

[0400] In some embodiments, R5 is one or more -O(C3~C 10 It is a methyl group which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is ethyl which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is a propyl that may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is a butyl molecule which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10Pentyl may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is a hexyl which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is an isopropyl which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is an isobutyl which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is an isopentyl which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is an isohexyl which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is sec-butyl which may be substituted with cycloalkyl. In some embodiments, R5 is one or more -O(C3~C 10 It is sec-pentyl which may be substituted with cycloalkyl. In some embodiments, R5 is one or more -O(C3~C 10 It is a sec-hexyl which may be substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is tert-butyl which may be substituted with a cycloalkyl group.

[0401] In some embodiments, R5 is one or more -O(C3~C 10 It is a methyl molecule substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C) 10 It is ethyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is a propyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is a butyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10It is a pentyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is a hexyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is isopropyl substituted with cycloalkyl. In some embodiments, R5 is one or more -O(C3~C 10 It is isobutyl substituted with cycloalkyl groups. In some embodiments, R5 is one or more -O(C3~C 10 It is an isopentyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is an isohexyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is sec-butyl substituted with cycloalkyl. In some embodiments, R5 is one or more -O(C3~C 10 It is sec-pentyl substituted with cycloalkyl. In some embodiments, R5 is one or more -O(C3~C 10 It is a sec-hexyl substituted with a cycloalkyl group. In some embodiments, R5 is one or more -O(C3~C 10 It is tert-butyl substituted with cycloalkyl groups.

[0402] In some embodiments, R5 is a C2-C6 alkenyl (e.g., ethenyl, propenyl, butenyl).

[0403] In some embodiments, R5 is a C2-C6 alkenyl which may be substituted with one or more C1-C6 alkoxys.

[0404] In some embodiments, R5 is a C2-C6 alkenyl substituted with one or more C1-C6 alkoxys.

[0405] In some embodiments, R5 is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl).

[0406] In some embodiments, R5 is a C2-C6 alkynyl which may be substituted with one or more C1-C6 alkoxys.

[0407] In some embodiments, R5 is a C2-C6 alkynyl substituted with one or more C1-C6 alkoxys.

[0408] In some embodiments, R5 is a C1-C6 alkoxyl.

[0409] In some embodiments, R5 is a C1-C6 alkoxyl which may be substituted with one or more C1-C6 alkoxys.

[0410] In some embodiments, R5 is a C1-C6 alkoxyl substituted with one or more C1-C6 alkoxys.

[0411] In some embodiments, R5 is methoxyl. In some embodiments, R5 is ethoxyl. In some embodiments, R5 is propoxyl. In some embodiments, R5 is butoxyl. In some embodiments, R5 is pentoxyl. In some embodiments, R5 is hexoxyl.

[0412] In some embodiments, R5 is a methoxyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is an ethoxyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a propoxyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a butoxyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a pentoxyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a hexoxyl which may be substituted with one or more C1-C6 alkoxys.

[0413] In some embodiments, R5 is a methoxyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is an ethoxyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a propoxyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a butoxyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a pentoxyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a hexoxyl substituted with one or more C1-C6 alkoxys.

[0414] In some embodiments, R5 is a C1-C6 haloalkyl group.

[0415] In some embodiments, R5 is a C1-C6 haloalkyl which may be substituted with one or more C1-C6 alkoxys.

[0416] In some embodiments, R5 is a C1-C6 haloalkyl substituted with one or more C1-C6 alkoxys.

[0417] In some embodiments, R5 is halomethyl. In some embodiments, R5 is haloethyl. In some embodiments, R5 is halopropyl. In some embodiments, R5 is halobutyl. In some embodiments, R5 is halopentyl. In some embodiments, R5 is halohexyl.

[0418] In some embodiments, R5 is a halomethyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a haloethyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halopropyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halobutyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halopentyl which may be substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halohexyl which may be substituted with one or more C1-C6 alkoxys.

[0419] In some embodiments, R5 is a halomethyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a haloethyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halopropyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halobutyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halopentyl substituted with one or more C1-C6 alkoxys. In some embodiments, R5 is a halohexyl substituted with one or more C1-C6 alkoxys.

[0420] In some embodiments, R5 and one R 1a These atoms combine with intervening atoms to form 3- to 10-membered heterocyclines.

[0421] In some embodiments, R5 and one R 1a It combines with intervening atoms to form tetrahydropyranyl.

[0422] In some embodiments, R5 is -(CH2)-OCH3, -(CH2)-O-cyclopropyl, cyclopropyl, or H.

[0423] In some embodiments, R5 is -(CH2)-OCH3, -(CH2)-O-cyclopropyl, or H.

[0424] In some embodiments, R5 is -(CH2)-OCH3 or H.

[0425] In some embodiments, if R2 is cyclopropyl and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not isopropyl.

[0426] In some embodiments, if R1 is a monosubstituted C6 aryl substituted with one fluoropolymer, R2 is cyclopropyl, and R5 is a C1 alkyl substituted with a C1 alkoxy, then R4 is not cyclopropyl.

[0427] In some embodiments, if R2 is methyl, then R4 is not a C1-C6 alkyl group.

[0428] In some embodiments, the compound of formula (II) or formula (II') is formula (II-a) or (II-b): It is the substance specified in TIFF2026521511000068.tif69128 or a pharmaceutically acceptable salt thereof.

[0429] In some embodiments, the compound of formula (II) or formula (II') is formula (II-c): TIFF2026521511000069.tif50128 or a pharmaceutically acceptable salt thereof, where R 1a n is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0430] In some embodiments, the compound of formula (II) or formula (II') is formula (II-d) or (II-e): TIFF2026521511000070.tif110128 or a pharmaceutically acceptable salt thereof, where R 1a n is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0431] In some embodiments, the compound of formula (II) or formula (II') is formula (II-f) or (II-g): It is the substance specified in TIFF2026521511000071.tif69128 or a pharmaceutically acceptable salt thereof.

[0432] In some embodiments, the compound of formula (II) or formula (II') is formula (II-h): TIFF2026521511000072.tif47128 or a pharmaceutically acceptable salt thereof, in the formula R 1a n is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0433] In some embodiments, the compound of formula (II) or formula (II') is formula (II-i) or (II-j): TIFF2026521511000073.tif110128 or a pharmaceutically acceptable salt thereof, where R 1a n is a halo, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl, and n is 0, 1, 2, 3, or 4.

[0434] compound In some embodiments, the compound is selected from the compounds listed in Table 1 or their prodrugs or pharmaceutically acceptable salts.

[0435] In some embodiments, the compound is selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

[0436] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

[0437] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0438] In some embodiments, the compound is selected from the compounds listed in Table 1A or their prodrugs or pharmaceutically acceptable salts.

[0439] In some embodiments, the compound is selected from the compounds listed in Table 1A or pharmaceutically acceptable salts thereof.

[0440] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 1A or pharmaceutically acceptable salts thereof.

[0441] In some embodiments, the compound is selected from the compounds listed in Table 1A.

[0442] In some embodiments, the compound is selected from the compounds listed in Table 2 or their prodrugs or pharmaceutically acceptable salts.

[0443] In some embodiments, the compound is selected from the compounds listed in Table 2 or pharmaceutically acceptable salts thereof.

[0444] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 2 or their pharmaceutically acceptable salts.

[0445] In some embodiments, the compound is selected from the compounds listed in Table 2.

[0446] In some embodiments, the compound is selected from the compounds listed in Table 2A or their prodrugs or pharmaceutically acceptable salts.

[0447] In some embodiments, the compound is selected from the compounds listed in Table 2A or pharmaceutically acceptable salts thereof.

[0448] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 2A or pharmaceutically acceptable salts thereof.

[0449] In some embodiments, the compound is selected from the compounds listed in Table 2A.

[0450] In some embodiments, the compound is selected from the compounds listed in Table 3 or their prodrugs or pharmaceutically acceptable salts.

[0451] In some embodiments, the compound is selected from the compounds listed in Table 3 or pharmaceutically acceptable salts thereof.

[0452] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 3 or pharmaceutically acceptable salts thereof.

[0453] In some embodiments, the compound is selected from the compounds listed in Table 3.

[0454] [Table 1] TIFF2026521511000075.tif218137TIFF2026521511000076.tif150137

[0455] [Table 1A] TIFF2026521511000078.tif223145TIFF2026521511000079.tif222145TIFF202 6521511000080.tif219145TIFF2026521511000081.tif194145TIFF2026521511 000082.tif186145TIFF2026521511000083.tif183145TIFF2026521511000084. tif187145TIFF2026521511000085.tif185145TIFF2026521511000086.tif54145

[0456] [Table 2] TIFF2026521511000088.tif152146

[0457] [Table 2A] TIFF2026521511000090.tif208139TIFF2026521511000091.tif203139TIFF2026521511000092.tif213139TIFF2026521511000093.tif96139

[0458] [Table 3]

[0459] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 1.

[0460] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 1A.

[0461] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 2.

[0462] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 2A.

[0463] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 3.

[0464] In some aspects, this disclosure provides compounds (e.g., isotope-labeled compounds) that are isotope derivatives of any one of the compounds of the formulas disclosed herein.

[0465] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0466] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1 or a pharmaceutically acceptable salt thereof.

[0467] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs listed in Table 1 or a pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0469] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1A, or a prodrug or pharmaceutically acceptable salt thereof.

[0470] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1A, or a pharmaceutically acceptable salt thereof.

[0471] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs listed in Table 1A or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1A.

[0473] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0474] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2 or a pharmaceutically acceptable salt thereof.

[0475] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs listed in Table 2 or a pharmaceutically acceptable salt thereof.

[0476] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2.

[0477] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2A, or a prodrug or pharmaceutically acceptable salt thereof.

[0478] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2A or a pharmaceutically acceptable salt thereof.

[0479] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs listed in Table 2A or a pharmaceutically acceptable salt thereof.

[0480] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2A.

[0481] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0482] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3 or a pharmaceutically acceptable salt thereof.

[0483] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs listed in Table 3 or a pharmaceutically acceptable salt thereof.

[0484] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3.

[0485] In some embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0486] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by substituting non-isotopic labeling reagents with isotopic labeling reagents.

[0487] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0488] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0489] As used herein, the term “isotope derivative” refers to a derivative of a compound in which one or more atoms are isotope-enriched or labeled. For example, an isotope derivative of a compound of formula (I) or formula (II) is isotope-enriched with respect to one or more isotopes or labeled with them compared to the corresponding compound of formula (I) or formula (II). In some embodiments, the isotope derivative is 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34The isotope derivative is enriched with respect to or labeled with respect to one or more atoms selected from S. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., with respect to one or more atoms). 2 (It is concentrated with H). In some embodiments, the compound 18 It is a fluorine-labeled compound. In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 The compound is labeled with I, or any combination thereof. In some embodiments, the compound is labeled with I. 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 This is an S-labeled compound, or any combination thereof.

[0490] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It is understood that S-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared using non-isotope labeling reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 By substituting with an S-labeled reagent, it can be prepared by performing the procedures disclosed in the scheme and / or examples described herein.

[0491] The aforementioned 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 Compounds of the invention containing one or more S atoms, or their pharmaceutically acceptable salts or solvates, are within the scope of the invention. Furthermore, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 Substitution with S) may yield certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or a reduction in the required dose.

[0492] To avoid misunderstanding, it should be noted that when a base satisfies the requirement of "as described herein" in this specification, that base should be understood to encompass all of the broadest definitions initially described and all of the specific definitions of that base.

[0493] The various functional groups and substituents constituting the compounds of formula (I) or formula (II) are typically selected so that the molecular weight of the compound does not exceed 1,000 doltons. Typically, the molecular weight of the compound will be less than 900 doltons, for example, less than 800, or less than 750, or less than 700, or less than 650. More simply, the molecular weight will be less than 600 doltons, for example, 550 doltons or less.

[0494] Suitable pharmaceutically acceptable salts of the compounds of this disclosure are, for example, acid addition salts of the compounds of this disclosure with sufficiently basic acids, such as inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methanesulfonic citrate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure with sufficiently acidic acids are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or organic bases that produce pharmaceutically acceptable cations, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0495] Compounds of any one of the formulas disclosed herein and any pharmaceutically acceptable salts thereof will be understood to include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compound.

[0496] It will be understood that the compounds disclosed herein may be shown in a particular configuration. Such a particular configuration should not be construed as limiting this disclosure to one or other isomers, tautomers, regioisomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. In some embodiments, showing a compound herein in a particular configuration is intended to encompass and refer to each or any mixture thereof of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, but the presentation is further intended to refer to the specific configuration of the compound.

[0497] It will be understood that compounds disclosed herein may be presented without specifying their configuration (e.g., without specifying their stereochemistry). Such presentations are intended to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound without specifying its configuration herein is intended to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0498] As used herein, the term “isomer” refers to compounds that have the same molecular formula but differ in the order of their atomic bonding or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of atoms are called “stereoisomers.” Stereoiomers that are not mirror images of each other are called “diastereoisomers,” and stereoisomers that are mirror images of each other but cannot be superimposed are called “enantiomers” or sometimes “optical isomers.” A mixture containing equal amounts of individual enantiomer forms with opposite chiralities is called a “racemic mixture.”

[0499] As used herein, the term “chiral center” refers to an atom bonded to four non-identical substituents.

[0500] As used herein, the term “chiral isomer” refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist either as individual diastereomers or as a mixture of diastereomers called a “diastereomer mixture.” If a single chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Kahn, Ingold, and Preloge priority rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0501] As used herein, the term “geometric isomer” refers to diastereomers that exist as a result of the rotation being hindered around a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans or Z and E, which indicate that the groups are on the same side or opposite side of the double bond within the molecule, according to the Kahn-Ingold-Prelogue rule.

[0502] Please understand that the compounds in this disclosure may be illustrated as different chiral or geometric isomers. If a compound has chiral or geometric isomeric forms, please understand that all isomeric forms are intended to be included within the scope of this disclosure, and that the names of the compounds do not exclude any isomeric form, and that not all isomers necessarily have the same level of activity.

[0503] The structures and other compounds discussed in this disclosure should be understood to include all of their atropic isomers. It should also be understood that not all atropic isomers have the same level of activity.

[0504] As used herein, the term “atropic isomer” refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The existence of atropic isomers is due to restricted rotation caused by the obstruction of the rotation of a large group around a central bond. Such atropic isomers typically exist as a mixture, but as a result of recent advances in chromatography techniques, it has become possible in certain cases to separate a mixture of two atropic isomers.

[0505] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal transfer of hydrogen atoms, involving the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of sets of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers varies depending on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic (ring-shaped) form, as exemplified by glucose.

[0506] It should be understood that the compounds of this disclosure may be illustrated as different tautomers. Where a compound has tautomer forms, all isomers are intended to be included within the scope of this disclosure, and the names of the compounds do not exclude any tautomer form. It will be understood that certain tautomers may have higher levels of activity than others.

[0507] Compounds with the same molecular formula but different atomic bonding properties or order, or different arrangements of atoms in space, are called "isomers." Isomers with different arrangements of atoms in space are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," while those that are mirror images that cannot be superimposed on each other are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center, either by the Kahn-Prelogue R and S order rules, or by the rotation of the plane of polarization of the molecule, which is designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0508] The compounds of this disclosure may have one or more chiral centers, and such compounds may therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise specified, the descriptions or names of specific compounds in the specification and claims are intended to include both individual enantiomers and mixtures such as racemates. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by separation of racemic forms. Some of the compounds of this disclosure may have geometric isomers (E- and Z-isomers). This disclosure should be understood to encompass all optical, diastereoisomers and geometric isomers, as well as mixtures thereof, that have STMN2 regulatory activity.

[0509] This disclosure also includes compounds of the disclosure as defined herein, which include one or more isotopic substitutions.

[0510] Compounds of any formula described herein should be understood to include the compounds themselves and, where applicable, their salts and solvates. For example, salts can be formed between a positively charged group (e.g., amino) on a substituted compound disclosed herein and an anion. Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucuronates, glutarates, maleates, maleates, succinates, fumarates, tartarates, tosylates, salicylates, lactates, naphthalene sulfonates, and acetates (e.g., trifluoroacetate).

[0511] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a negatively charged group (e.g., a carboxylate) on a substituted compound disclosed herein and a cation. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions or diethylamine ions. Substituted compounds disclosed herein also include those containing a quaternary nitrogen atom.

[0512] It should be understood that the compounds of this disclosure, for example, salts of the compounds, may exist in either a hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Unlimited examples of hydrates include monohydrates, dihydrates, etc. Unlimited examples of solvates include ethanol solvate, acetone solvate, etc.

[0513] As used herein, the term “solvate” refers to a solvation form containing either stoichiometric or nonstoichiometric amounts of solvent. Some compounds tend to trap solvent molecules in a certain molar ratio in their crystalline solid state, thereby forming solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more water molecules and one molecule of a substance, where water retains its molecular state as H2O.

[0514] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but has a slightly different composition (for example, when one atom is replaced by an atom of another element, or when a particular functional group is present, or when one functional group is replaced by another). Thus, an analog is a compound that is similar or equivalent in function and appearance but not similar or equivalent in structure or origin to the reference compound.

[0515] As used herein, the term “derivative” refers to a compound having a common core structure and substituted with any of the groups described herein.

[0516] As used herein, the term “biological equivalent” refers to a compound resulting from the exchange of an atom or group of atoms with another broadly similar atom or group of atoms. The purpose of substitution with a biological equivalent is to create a novel compound with similar biological properties to the parent compound. Substitution with a biological equivalent may be based on physicochemical or morphological criteria. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0517] It should be understood that any one particular compound of the formulas disclosed herein may exist in solvated and non-solvated forms, for example, hydrated forms. Preferred pharmaceutically acceptable solvates are hydrates, such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that the disclosure encompasses all such solvated forms having STMN2 activity.

[0518] It should be understood that any one particular compound among the formulas disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms or mixtures thereof that have STMN2 activity. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0519] Compounds of any one of the formulas disclosed herein may exist in a number of different tautomerized forms, and references to compounds of formula (I) or formula (II) include all such forms. To avoid misunderstanding, if a compound may exist in one of several tautomerized forms and only one is specifically described or shown, then formula (I) or formula (II) still encompasses all the others. Examples of tautomerized forms include, for example, the following tautomer pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro, including keto, enol, and enolate forms. TIFF2026521511000095.tif19128

[0520] Compounds of any one of the formulas disclosed herein that contain an amine functional group may also form an N-oxide. References herein to compounds of formula (I) or formula (II) containing an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of nitrogen atoms in tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0521] Any compound of any of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound disclosed herein. The prodrug may be used to modify the physical and / or pharmacokinetic properties of the compound disclosed herein. A prodrug can be formed if the compound disclosed contains a suitable group or substituent to which the property-modifying group can be attached. Examples of prodrugs include derivatives of any compound of any of the formulas disclosed herein that contain an alkyl or acyl substituent on the ester or amide group that is cleavable in vivo.

[0522] Accordingly, this disclosure includes compounds of any one of the formulas disclosed herein as defined above, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, this disclosure includes compounds of any one of the formulas disclosed herein produced by organic synthesis means, and compounds produced in the body of a human or animal by metabolism of precursor compounds, that is, any one of the formulas disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0523] The preferred pharmaceutically acceptable prodrugs of any one of the compounds of the formulas disclosed herein are based on reasonable medical judgment that they are suitable for administration to the human or animal body without undesirable pharmacological activity and without excessive toxicity. Various forms of prodrugs are described in the following documents, for example: a) Methods in Enzymology, Vol. 42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0524] A suitable pharmaceutically acceptable prodrug for any compound of any of the formulas disclosed herein that contains a hydroxyl group is, for example, its ester or ether which is cleavable in vivo. A suitable pharmaceutically acceptable ester or ether for any compound of any of the formulas disclosed herein that contains a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce a hydroxyl-parent compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). Furthermore, suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include C1-C such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C6 alkyl groups such as alkanoyl groups, ethoxycarbonyl groups, N,N-(C1-C6 alkyl)2-carbamoyl groups, 2-dialkylaminoacetyl groups, and 2-carboxyacetyl groups. 10 It contains an alkoxycarbonyl group. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include acetoxymethyl and α-acyloxyalkyl groups such as pivaloyloxymethyl.

[0525] Suitable pharmaceutically acceptable prodrugs of any compound of any of the formulas disclosed herein having a carboxyl group include, for example, amides formed by amines that can be cleaved in vivo, such as ammonia; C1-C4 alkylamines such as methylamine; (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines such as benzylamine; and amino acids or esters thereof such as glycine.

[0526] A suitable pharmaceutically acceptable prodrug of any compound of any of the formulas disclosed herein having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, C1-C such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 The amides are formed by an alkanoyl group. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0527] The in vivo effect of any compound of any of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the human or animal body after administration of any compound of any of the formulas disclosed herein. As stated above, the in vivo effect of any compound of any of the formulas disclosed herein may also be exerted via the metabolism of a precursor compound (prodrug).

[0528] Preferably, this disclosure excludes any individual compounds that do not have the biological activity as defined herein.

[0529] Synthesis method In some aspects, this disclosure provides methods for preparing the compounds of this disclosure.

[0530] In some aspects, this disclosure provides a method for compounding a compound, comprising one or more steps described herein.

[0531] In some aspects, this disclosure provides compounds that can, can, or can be obtained directly by methods for preparing the compounds described herein.

[0532] In some aspects, this disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein.

[0533] The compounds of this disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the attached examples.

[0534] In the descriptions of the synthesis methods described herein, and in any referenced synthesis methods used to prepare the starting materials, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and post-treatment procedures, can be selected by those skilled in the art.

[0535] Those skilled in the field of organic synthesis will understand that the functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0536] It will be recognized that in the synthesis of the compounds of this disclosure in the processes specified herein, or in the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. Experienced chemists will know when such protection is necessary and how such protecting groups can be positioned and subsequently removed. For examples of protecting groups, see one of the many general documents on this subject, e.g., "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to experienced chemists as appropriate for the removal of the protecting group in question, and such method is chosen to result in the removal of the protecting group while minimizing disruption of the group at other positions in the molecule. Thus, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the groups in some of the reactions described herein.

[0537] For example, suitable protecting groups for amino or alkylamino groups include acyl groups, such as alkanoyl groups like acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; or aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups will inevitably differ depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl, or alkoxycarbonyl or aroyl groups may be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups may be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups may be removed by hydrogenation on a catalyst such as palladium carbon or by treatment with a Lewis acid such as borontris (trifluoroacetate). Suitable alternative protecting groups for primary amino groups are phthaloyl groups, which can be removed by treatment with alkylamines such as dimethylaminopropylamine or hydrazine.

[0538] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups like acetyl, alloyl groups, such as benzoyl, or arylmethyl groups, such as benzyl. The deprotection conditions for the above protecting groups will inevitably differ depending on the choice of protecting group. For example, acyl groups such as alkanoyl or alloyl groups may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups may be removed by hydrogenation on a catalyst such as palladium-carbon.

[0539] Suitable protecting groups for the carboxyl group include, for example, esterifying groups such as methyl or ethyl groups, which may be removed by hydrolysis with a base such as sodium hydroxide; or, for example, tert-butyl groups, which may be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid; or, for example, benzyl groups, which may be removed by hydrogenation on a catalyst such as palladium-carbon.

[0540] After a compound of formula (I) or formula (II) is synthesized by any one of the processes specified herein, the process may further include the following additional steps: (i) removing all existing protecting groups; (ii) converting the compound of formula (I) or formula (II) into another compound of formula (I) or formula (II); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0541] The resulting compounds of formula (I) or formula (II) can be isolated and purified using techniques well known in the art.

[0542] In some embodiments, the reaction of the compounds is preferably carried out in the presence of a suitable solvent that is inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; and ethylene. Glycol ethers such as glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of such solvents or mixtures with water, are included without limitation.

[0543] The reaction temperature is preferably between approximately -100°C and 300°C, depending on the reaction process and conditions used.

[0544] The reaction time generally ranges from a few minutes to several days, depending on the reactivity of each compound and the reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the above reaction temperature, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0545] Furthermore, by utilizing the procedures described herein, in conjunction with the usual art, additional compounds of this disclosure can be readily prepared. Those skilled in the art will readily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation procedures.

[0546] As will be understood by those skilled in the art of organic synthesis, the compounds of this disclosure are readily accessible through various synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions should be used to obtain the compounds of this disclosure, and how they should be applied and adapted, if necessary or useful, in any particular case. Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting them with other compounds of this disclosure under suitable conditions, for example, by converting a particular functional group present in the compound of this disclosure or a suitable precursor molecule to another by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions; these methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthesized protecting (or protective) groups, if necessary or useful; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis, and are described in more detail, for example, PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0547] A general route for preparing the compound of the application is described in Schemes 1 to 7 herein.

[0548] In some embodiments, the compounds described in schemes 1 to 7 are sodium salts of the compounds.

[0549] Scheme 1 In Scheme 1, amines can be acylated (e.g., by ethylmalonyl chloride) in an anhydrous solvent (e.g., DCM) at room temperature under standard conditions (e.g., by a tertiary amine base such as Et3N, DIPEA, or pyridine). Ring closure (i.e., step 2) can occur under both basic conditions (e.g., NaOEt in EtOH) and an amine base (e.g., DBU). Alternatively, neutralization with a base following aqueous acidic solution (e.g., HCl) under reflux may yield the desired product. Chlorination of 1-C (step 3) may yield 1-D. Reduction of the ester following sequential Suzuki coupling conditions (step 4) may provide 1-E. Conversion to a halide (1-G, step 6) may occur via mesylation and Finkelstein reaction. The halogen is then treated with a phosphine source (e.g., PPh3, POR) to provide the corresponding phosphine or phosphonate (step 7). Olefination of a commercially available aldehyde with 1-H may occur (step 8), followed by overall deprotection of 1-J to produce 1-K.

[0550] Scheme 2 Reactions 1, 2, 3, and 6 to intermediate A, starting from commercially available thiophenaniline, are described in Scheme 1. Furthermore, processing intermediate A to a desired analog is also described in Scheme 1.

[0551] Commercially available substituted benzoylacetonitrile and 1,4-dithian-2,5-diol can be stirred in an alcohol solvent in the presence of an amine (e.g., DIPEA) (step 4). Under acidic conditions, aniline can be treated with a ketone to introduce R1 and R2, thereby providing intermediate A, which is a cyclization product.

[0552] Scheme 3 Starting from anilino-bromide, aniline can be protected (e.g., Boc protection) (Step 1). Suzuki coupling conditions of the bromide with a boronic acid or boronic acid ester used in the presence of a Pd catalyst and an aqueous solution of a base (carbonate) can be used in a mixed solvent system (Step 2). Deprotection (Step 3) followed by thiazole formation (Step 4) may produce a thiazole ring. A Suzuki reaction following Sandmeyer reduction of aniline may produce 3-F (Step 5). Bromination and deprotection (Step 6) followed by Suzuki coupling (Step 7) may provide 3-H. Conversion of phenol to triflate may provide 3-I (Step 8). The following combinations: palladium salt / base (e.g., K2CO3, triethylamine, or N,N-dicyclohexylmethylamine), can be used to couple a commercially available olefin with a triflate in a solvent in the presence of a phosphine ligand to produce 3-J. Overall deprotection can yield 3-K (step 10).

[0553] Scheme 4 TIFF2026521511000099.tif107150 Thiazole formation (step 1) followed by Sandmeyer reduction of aniline and Suzuki reaction (step 2) may provide 4-C. Alternatively, the Sandmeyer intermediate can be reduced to R A2 A scaffold in which is -H may be provided. A subsequent Suzuki reaction may be completed to introduce R1 (step 3). A Suzuki reaction (step 5) following halogenation (X=I or Br) (step 4) provides 4-F. Deprotection of phenol (step 6) and conversion of phenol to triflate (step 7) provides 4-H. Coupling a commercially available olefin with triflate, followed by overall deprotection, may yield 4-J (step 9).

[0554] Scheme 5 Under Suzuki coupling conditions, the introduction of R2 may proceed (Step 1). Oxidation of pyridine (Step 2) and subsequent halogenation (Step 3) may provide 5-D. Suzuki coupling with a desired boronic ester or boronic acid (Reaction 5) (Step 4), followed by halogenation and coupling with a commercially available olefin (Step 6) may provide 5-G. Overall deprotection may yield 5-H (Step 7).

[0555] Scheme 6 TIFF2026521511000101.tif161141 Keto-esterification with an aldehyde in the presence of a secondary amine base may provide 6-C (Step 1). Cyclization with an amine-mediated olefin (6-D) may provide a dihydropyridine ring (Step 2). The ring system is then oxidized (Step 3), followed by selective reduction (Step 4) and methylation of one ester to provide a methyl ether (6-h; Step 5). There is conversion to a halide (6-J, Step 7) and Finkelstein reaction following reduction of the ester (Step 6). The halide is then treated with a phosphine source to provide the corresponding phosphine or phosphonate (Step 8). Olefination of 6-K with a commercially available aldehyde (Step 9) and overall deprotection of 6-L may yield 6-M (Step 10).

[0556] Scheme 7 TIFF2026521511000102.tif161150 Protection of phenol (step 1) and a series of Suzuki reactions (step 2) may provide 7-C. Halogenation of pyridine (step 3) and carbonylation of the pyridine ring may provide an ester (7-E; step 4). Deprotection of the benzyl group may yield a phenol (step 5). Conversion of phenol to triflate (step 6) followed by Suzuki coupling of the triflate to introduce R1 (step 7) may yield intermediate A. Treatment of intermediate A with a phosphine source, following esterification (step 12) and conversion to a halide (7-O, step 13), may yield the corresponding phosphine or phosphonate (step 14). Overall deprotection of 7-Q following olefination with a commercially available aldehyde (step 15) may yield 7-R.

[0557] Alternatively, the preparation of intermediate A may begin with the condensation of an aldehyde and a ketone in the presence of a basic aqueous solution (step 8), followed by a Michael reaction with a ketoester (step 10), and then cyclization to produce intermediate A.

[0558] Biological assays Compounds designed, selected, and / or optimized by the methods described above can be characterized after production using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including, but not limited to, the assays described below, to determine whether they have predicted activity, binding activity, and / or binding specificity.

[0559] Furthermore, high-throughput screening can be used to accelerate analysis using such assays. As a result, it becomes possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and US Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, not limited to those described below.

[0560] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of this disclosure. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, gel shift assays, reporter gene assays, in vitro cell survival assays, and assays described herein.

[0561] In some embodiments, biological assays are described in the examples herein.

[0562] STMN2 has been shown to be involved not only in axonal regeneration but also in the maintenance of the neuromuscular junction. Constitutive knockout of Stmn2 in mice causes motor and sensory axonal dysfunction, and long-term suppression of Stmn2 in the central nervous system of otherwise wild-type adult mice leads to progressive muscle denervation and structural breakdown of motor axons. Reduced Stmn2 levels cause axonal diameter reduction and myelin layer transection in motor axons. In vitro, STMN2 supplementation using lentiviral technology can restore axonal regrowth after axonal transection in TDP-43-deficient iPSC neurons, demonstrating that axonal regeneration may be induced by supplementing STMN2 levels despite the missplicing of thousands of other genes caused by the loss of TDP-43 function.

[0563] In some embodiments, the compounds of the present disclosure inhibit HMG-CoA reductase.

[0564] In some embodiments, inhibition of HMG-CoA reductase correlates with increased STMN2 expression.

[0565] In some embodiments, the compounds of the present disclosure can be screened and validated using a nanoluciferase assay.

[0566] In some embodiments, cells (e.g., TDP-mut STMN2-NLuc SH-SY5Y cells) may be used to screen for compounds of formula (I'), formula (I), formula (II'), or formula (II).

[0567] In some embodiments, the compounds of the present disclosure may be screened using a neurite outgrowth assay (e.g., in SH-SY5Y cells).

[0568] Pharmaceutical composition In some aspects, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure as active ingredients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or combinations thereof. In some embodiments, the Disclosure provides pharmaceutical compositions comprising compounds listed in Table 1, Table 1A, Table 2, Table 2A, or Table 3. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1, Table 1A, Table 2, Table 2A, or Table 3.

[0569] As used herein, the term “composition” is intended to encompass products containing specific components in specific amounts, as well as any products resulting directly or indirectly from specific combinations of specific components in specific amounts.

[0570] The compounds of this disclosure can be formulated for oral administration in the form of tablets, capsules (including sustained-release or sustained-release formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all in forms familiar to those skilled in the pharmaceutical art.

[0571] The formulations of this disclosure may be in the form of aqueous solutions containing an aqueous vehicle. The aqueous vehicle component may contain water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonic agents, viscosity / suspensioning agents, buffering agents, and pH adjusters, as well as mixtures thereof.

[0572] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, as well as mixtures thereof.

[0573] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0574] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as mixtures thereof.

[0575] Aqueous vehicles may also contain isotonic agents to adjust their isotonicity (osmotic pressure). Isotonic agents can be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof.

[0576] The aqueous vehicle may also contain a viscosity / suspensioning agent. Suitable viscosity / suspensioning agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, and hydroxyethylcellulose; crosslinked acrylic acid polymers (carbomers) such as polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400); carboxymethylcellulose; hydroxypropylmethylcellulose; and acrylic acid polymers crosslinked with polyalkenyl ethers or divinyl glycol (e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P); and mixtures thereof.

[0577] To adjust the formulation to an acceptable pH range (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to an acceptable pH range for the target. Therefore, depending on the formulation, it may not be necessary to use both an acid and a base, and the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0578] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or salts thereof including disodium tetraborate), citrate buffers (such as citric acid or salts thereof including sodium citrate), and ε-aminocaproic acid, as well as mixtures thereof.

[0579] The formulation may further contain a wetting agent. A preferred class of wetting agents is selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated castor oil ethers, polyoxyethylene-sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyroxapole), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, as well as mixtures thereof.

[0580] Oral compositions generally contain an inert diluent or an edible, pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is applied orally, gargled with, and then spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0581] Further aspects of the disclosure provide pharmaceutical compositions comprising the compounds of the Disclosure as defined above or pharmaceutically acceptable salts, hydrates, or solvates thereof in combination with pharmaceutically acceptable diluents or carriers.

[0582] The compositions disclosed may be in forms suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely ground powder or liquid aerosol), administration by blowing (e.g., as finely ground powder), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0583] The disclosed compositions may be obtained by conventional procedures using conventional pharmaceutically acceptable excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0584] An effective amount of the compounds of this disclosure for use in therapeutic purposes is sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with the STMN2-related conditions referred to herein.

[0585] An effective amount of the compounds of this disclosure for use in therapeutics is sufficient to treat the STMN2-related conditions referred herein, to slow their progression, and / or to reduce the symptoms associated with the conditions.

[0586] The size of the dose of a compound of formula (I) or formula (II) for therapeutic or prophylactic purposes will naturally vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0587] How to use In some aspects, the present disclosure provides methods for modulating STMN2 expression with the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0588] In some aspects, the present disclosure provides a method for modulating STMN2 expression (e.g., in vitro or in vivo) with an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0589] In some aspects, the present disclosure provides methods for modulating STMN2 expression (e.g., in vitro or in vivo) with the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0590] In some aspects, the present disclosure provides methods for modulating STMN2 expression (e.g., in vitro or in vivo) with an effective amount of a pharmaceutical composition comprising the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0591] In some aspects, the present disclosure provides methods for modulating STMN2 expression (e.g., in vitro or in vivo) with a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0592] In some aspects, the present disclosure provides a method for increasing neurite extension in a subject where such effect is needed, comprising the step of administering a therapeutically effective dose to the subject of the compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0593] In some aspects, the present disclosure provides a method for increasing neurite extension in a subject where such increase is needed, the method comprising the step of administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject.

[0594] In some aspects, the present disclosure provides a method for increasing axonal growth in a subject where such growth is needed, comprising the step of administering a therapeutically effective dose to the subject of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0595] In some aspects, the present disclosure provides a method for increasing axonal growth in a subject where such growth is needed, the method comprising the step of administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject.

[0596] In some aspects, the present disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising the step of administering a therapeutically effective dose to a subject of the present disclosure or a pharmaceutically acceptable salt thereof.

[0597] In some aspects, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is necessary, comprising the step of administering a therapeutically effective dose to a subject of the Compounds Disclosed or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the Pharmaceuticals Disclosed.

[0598] In some aspects, the present disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising the step of administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject.

[0599] In some aspects, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is needed, the method comprising the step of administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the Disclosure to a subject.

[0600] In some embodiments, the disease or disorder is associated with the STMN2 expression involved. In some embodiments, the disease or disorder is a disease or disorder in which STMN2 expression is involved.

[0601] In some embodiments, regulation of expression is regulation of activity.

[0602] In some aspects, the disease or disorder is a neurodegenerative disease or disorder.

[0603] In some aspects, the disease or disorder is associated with axonal degeneration, axonal injury, or axonal dysfunction.

[0604] In some embodiments, the disease or disorder is axonal degeneration, axonal injury, or axonal disorder.

[0605] In some aspects, the disease or disorder is axonal degeneration.

[0606] In some embodiments, the disease or disorder is axonal injury.

[0607] In some aspects, the disease or disorder is an axonal disorder.

[0608] In some aspects, neurodegenerative diseases are associated with axonal degeneration, axonal injury, or axonal dysfunction.

[0609] In some aspects, neurodegenerative diseases are associated with axonal degeneration.

[0610] In some aspects, neurodegenerative diseases are associated with axonal injury.

[0611] In some aspects, neurodegenerative diseases are associated with axonal damage.

[0612] In some aspects, the Disclosure provides a method for treating or preventing a neurodegenerative disease or disorder in a subject where such treatment is needed, comprising the step of administering a therapeutically effective dose to a subject of the Disclosure compound or a pharmaceutically acceptable salt thereof or a pharmaceutically effective composition of the Disclosure.

[0613] In some aspects, the present disclosure provides a method for treating a neurodegenerative disease or disorder in a subject where such treatment is needed, comprising the step of administering a therapeutically effective dose to a subject of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically effective composition thereof.

[0614] In some aspects, the present disclosure provides a method for treating or preventing a neurodegenerative disease or disorder in a subject in need, the method comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the present disclosure to the subject.

[0615] In some aspects, the present disclosure provides a method for treating a neurodegenerative disease or disorder in a subject where such treatment is needed, the method comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the present disclosure to the subject.

[0616] In some aspects, the present disclosure provides a method for treating or preventing axonal damage in a subject where such treatment is needed, comprising the step of administering a therapeutically effective dose to a subject of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically effective composition thereof.

[0617] In some aspects, the present disclosure provides a method for treating axonal damage in a subject where such treatment is needed, comprising the step of administering a therapeutically effective dose to a subject of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically effective dose of the pharmaceutically acceptable composition thereof.

[0618] In some aspects, the present disclosure provides a method for treating or preventing axonal damage in a subject in need, the method comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the present disclosure to the subject.

[0619] In some aspects, the Disclosure provides a method for treating axonal damage in a subject where such treatment is needed, comprising the step of administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the Disclosure to the subject.

[0620] In some aspects, the present disclosure provides compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions of the present disclosure for use in modulating STMN2 expression.

[0621] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating STMN2 expression (e.g., in vitro or in vivo).

[0622] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating STMN2 expression (e.g., in vitro or in vivo).

[0623] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment and / or prevention of a disease in a patient characterized by loss of STMN2 expression.

[0624] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutically acceptable compositions of the present disclosure for use in increasing neurite extension.

[0625] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in increasing neurite extension.

[0626] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutically acceptable compositions of the present disclosure for use in increasing axonal growth.

[0627] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in increasing axonal growth.

[0628] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutically acceptable compositions of the present disclosure for use in treating or preventing diseases or disorders.

[0629] In some aspects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for use in treating or preventing diseases or disorders disclosed herein.

[0630] In some aspects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for use in treating diseases or disorders disclosed herein.

[0631] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in treating or preventing neurodegenerative diseases or disorders in subjects where such treatment is needed.

[0632] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in treating neurodegenerative diseases or disorders in subjects where such treatment is necessary.

[0633] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in treating or preventing axonal damage in subjects where such treatment is necessary.

[0634] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in treating axonal damage in subjects where such treatment is necessary.

[0635] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating STMN2 expression (e.g., in vitro or in vivo).

[0636] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for increasing neurite extension.

[0637] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for increasing axonal growth.

[0638] In some aspects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0639] In some aspects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0640] In some aspects, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing neurodegenerative diseases or disorders in subjects where such treatment is needed.

[0641] In some aspects, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for treating neurodegenerative diseases or disorders in subjects where such treatment is needed.

[0642] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing axonal damage in subjects where such treatment is needed.

[0643] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical for treating axonal damage in subjects where such treatment is needed.

[0644] In some embodiments, the present disclosure provides compounds that function as modifiers of STMN2 activity.

[0645] In some embodiments, the regulation results in increased STMN2 expression.

[0646] In some embodiments, the regulation results in increased STMN2 expression via inhibition of HMG-CoA reductase.

[0647] In some embodiments, the present disclosure provides compounds that function as inhibitors of HMG-CoA reductase.

[0648] The efficacy of the compounds disclosed herein can be determined by industry-accepted assays / disease models in accordance with standard methods for elucidating efficacy described in the art and found in current general knowledge.

[0649] The disclosure also provides a method for treating a disease or disorder involving STMN2 activity in a subject requiring such treatment, the method comprising the step of administering a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof to the subject.

[0650] In some embodiments, the disease or disorder is associated with TDP43-induced STMN2 deficiency.

[0651] In some embodiments, the disease or disorder is a neurodegenerative disease or disorder associated with TDP43-induced STMN2 deficiency.

[0652] In some aspects, the disease or disorder is associated with phenotypic axonal dysfunction.

[0653] In some aspects, phenotypic axonal dysfunction is caused by injury, invasiveness, or aging.

[0654] In some embodiments, phenotypic axonal dysfunction is caused by brain injury or brain trauma.

[0655] In some aspects, the disease or disorder is associated with reduced axonal growth.

[0656] In some aspects, disease or disorder is associated with reduced neurite outgrowth.

[0657] In some aspects, the disease or disorder is a synaptic disorder.

[0658] In some aspects, synaptic dysfunction is associated with synaptic defects.

[0659] In some aspects, synaptic defects are associated with neurological disorders or disabilities.

[0660] In some embodiments, a disease or disorder involves a deficiency in synaptic function.

[0661] In some cases, the disability is a spinal cord injury.

[0662] In some aspects, the disorder is nerve damage.

[0663] In some embodiments, neurodegenerative diseases or disorders are selected from amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Rett syndrome, Alexander syndrome, Perry syndrome, limbic-dominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), Lewy body dementia (LBD), peripheral neuropathy (chemotherapy-induced neuropathy, trauma-induced), and autism spectrum disorder.

[0664] In some aspects, axonal damage is associated with amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Rett syndrome, Alexander syndrome, Perry syndrome, limbic-dominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), Lewy body dementia (LBD), peripheral neuropathy (chemotherapy-induced neuropathy, trauma-induced), and autism spectrum disorder.

[0665] In some aspects, the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS).

[0666] In some aspects, the neurodegenerative disease or disorder is Parkinson's disease (PD).

[0667] In some aspects, the neurodegenerative disease or disorder is Alzheimer's disease (AD).

[0668] In some aspects, the neurodegenerative disease or disorder is frontotemporal dementia (FTD).

[0669] In some aspects, neurodegenerative diseases or disorders are inclusion body myopathy (IBM).

[0670] In some aspects, a neurodegenerative disease or disorder is Rett syndrome.

[0671] In some aspects, a neurodegenerative disease or disorder is Alexander syndrome.

[0672] In some aspects, a neurodegenerative disease or disorder is Perry syndrome.

[0673] In some aspects, the neurodegenerative disease or disorder is limbic-dominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC).

[0674] In some aspects, the neurodegenerative disease or disorder is Lewy body dementia (LBD).

[0675] In some aspects, neurodegenerative diseases or disorders are peripheral neuropathy (chemotherapy-induced neuropathy, trauma-induced neuropathy).

[0676] In some aspects, a neurodegenerative disease or disorder is autism spectrum disorder.

[0677] Route of administration The compounds of this disclosure or pharmaceutically acceptable salts thereof may be administered alone as sole therapeutic agents, or in combination with one or more other substances and / or treatments. Such co-treatments may be achieved by simultaneous, sequential, or separate administrations of the individual components of the treatment.

[0678] For example, the therapeutic effect may be enhanced by the administration of an adjuvant (i.e., the adjuvant itself may have only a minimal therapeutic effect, but when combined with other therapeutic agents, it may improve the overall therapeutic effect on the individual). Alternatively, and this is merely an example, the benefits experienced by the individual may be increased by administering the compound of formula (I'), formula (I), formula (II'), or formula (II) together with another therapeutic agent (including a therapeutic regimen) that also has therapeutic benefits.

[0679] When the compounds of the disclosed herein are administered in combination with other therapeutic agents, the compounds of the disclosed herein do not need to be administered via the same route as the other therapeutic agents, and may be administered via different routes due to their different physical and chemical properties. For example, the compounds of the disclosed herein may be administered orally to produce and maintain their good blood concentrations, while the other therapeutic agents may be administered intravenously. The initial administration may be carried out according to established protocols known in the art, and the dosage, mode of administration, and timing of administration may then be modified by a skilled clinician based on the observed effects.

[0680] The specific selection of other therapeutic agents will depend on the attending physician's diagnosis and their judgment of the individual's condition and appropriate treatment protocol. According to this aspect of the disclosure, combinations for use in the treatment of diseases involving STMN2 activity are provided, comprising the previously defined compounds of this disclosure or their pharmaceutically acceptable salts and other suitable agents.

[0681] Further aspects of the disclosure provide pharmaceutical compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0682] In addition to their use in therapeutic medicine, compounds of formula (I'), formula (I), formula (II'), or formula (II) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo testing systems for evaluating the effects of modulating STMN2 activity in experimental animals such as dogs, rabbits, monkeys, miniature pigs, rats, and mice, as part of the search for novel therapeutic agents.

[0683] Any of the above-described pharmaceutical compositions, processes, methods, uses, drugs, and manufacturing characteristics of this disclosure may also apply to any of the alternative embodiments of the polymers of this disclosure described herein.

[0684] The compounds of this disclosure, or pharmaceutical compositions containing these compounds, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or topical (i.e., at the desired site of action).

[0685] Routes of administration include oral (e.g., by taking); oral cavity; sublingual; transdermal (e.g., by patches, ointments, etc.); transmucosal (e.g., by patches, ointments, etc.); intranasal (e.g., by nasal sprays or powders); ocular (e.g., by eye drops); lung (e.g., through the mouth or nose, e.g., by aerosol, e.g., by inhalation or inhalation therapy); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; and non-limitingly, subcutaneous or intramuscular implantation of depots or reservoirs. [Examples]

[0686] For illustrative purposes, neutral compounds of formula (I'), formula (I), formula (II'), or formula (II) are synthesized and tested in the examples. It is understood that the neutral compounds of formula (I) or formula (II) can be converted to the corresponding pharmaceutically acceptable salts of the compound by means of the ordinary art (e.g., by saponification of the ester to a carboxylate salt, or by hydrolysis of the amide to form the corresponding carboxylic acid, and then conversion of the carboxylic acid to a carboxylate salt).

[0687] In some embodiments, the compounds of formula (I'), formula (I), formula (II'), or formula (II) are sodium salts of the compound.

[0688] Abbreviation ACN Acetonitrile CDCl3 chloroform-d DCM Dichloromethane DMSO-d6 Dimethyl sulfoxide-d6 eq. equivalent amount ESI Electrospray Ionization EtOH Ethanol hr time HPLC (High-Performance Liquid Chromatography) LCMS (Liquid Chromatography and Mass Spectrometry) MeOH-d4 Deuterated methanol MeOH methanol min NMR nuclear magnetic resonance RP inverse phase RT retention time TLC (Thin-Layer Chromatography)

[0689] Example 1. Synthesis of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-3-methylthieno[3,2-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid Step 1. Compound 1A (15.83 g, 105.13 mmol, 13.23 mL, 1.2 eq) was added to a solution of Compound 1 (15 g, 87.61 mmol, 1 eq) and Et3N (26.60 g, 262.83 mmol, 36.58 mL, 3 eq) in CH2Cl2 (150 mL), and the mixture was stirred at 25°C for 2 hours. LC-MS showed that the starting material was completely consumed and the desired product was observed. Water (200 mL) was added to the mixture, and the mixture was extracted with CH2Cl2 (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-25%) to obtain compound 2 (10.73 g, yield 42.93%) as a yellow solid. LCMS (ESI+): m / z = 307.9 (M+23), RT: 0.331 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, setting the flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, setting the flow rate to 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes, setting the flow rate to 2.0 mL / min.

[0690] Step 2. NaOEt (2.56 g, 37.61 mmol, 1 eq) was added to a solution of compound 2 (10.73 g, 37.61 mmol, 1 eq) in EtOH (100 mL), and the mixture was stirred at 80°C for 2 hours. LC-MS showed that the desired product was observed. The mixture was cooled to 25°C and filtered. The filtered cake was dried under reduced pressure to obtain compound 3 (11.76 g, crude) as a white solid. LC-MS (ESI+): m / z = 254.0 (M+1), RT: 0.353 min.

[0691] Step 3. Add POCl3 (19 mL) to a solution of compound 3 (5 g, 19.74 mmol, 1 eq) in toluene (19 mL), and stir the mixture at 100°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired product was observed. The mixture was poured into saturated NaHCO3 aqueous solution (500 mL) and extracted with ELISA (500 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was combined with a parallel batch (using 5 g of compound 3) and purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-5%) to obtain compound 4 (3.7 g, yield 32.30%) as a white solid. LC-MS (ESI+): m / z = 290.0 (M+1), RT: 0.503 min.

[0692] Step 4. Compound 4 (2.17 g, 7.48 mmol, 1 eq), compound 5A (941.75 mg, 6.73 mmol, 0.9 eq), Cs2CO3 (4.87 g, 14.96 mmol, 2 eq), and Pd(dppf)Cl2.CH2Cl2 (610.72 mg, 747.85 μmol, 0.1 eq) were mixed in dioxane (20 mL) and H2O (2 mL). The mixture was degassed and purged three times with N2, and the mixture was stirred at 100°C for 2 hours under N2. LC-MS showed that the starting materials were completely consumed and the desired MS was observed. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-5%) to obtain compound 5C (1.38 g, yield 52.75%) as a colorless oil. LCMS (ESI+): m / z = 350.0 (M+1), RT: 0.526 min.

[0693] Step 5. Compound 5C (480.00 mg, 1.37 mmol, 1 eq), compound 4A (471.47 mg, 5.49 mmol, 4 eq), Cs2CO3 (894.17 mg, 2.74 mmol, 2 eq), and Pd(dppf)Cl2.CH2Cl2 (112.06 mg, 137.22 μmol, 0.1 eq) were mixed in dioxane (5 mL) and H2O (0.5 mL). The mixture was degassed and purged three times with N2, and the mixture was stirred at 100°C for 2 hours under N2. LC-MS showed that the starting materials were completely consumed and the desired product was observed. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-5%) to obtain compound 6 (135 mg, yield 27.68%) as a colorless oil. TIFF2026521511000108.tif24146

[0694] Step 6. To a solution of compound 6 (890 mg, 2.50 mmol, 1 eq) in THF (10 mL), LiAlH4 (2.5 M, 1.50 mL, 1.5 eq) was added at 0°C, and the mixture was stirred under N2 at 25°C for 1 hour. TLC showed that the starting material was completely consumed and new, more polar spots were observed. Water (50 mL) was added to stop the reaction, and the mixture was extracted with siRNA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain compound 7 (714 mg, yield 90.99%) as a white solid, which was used directly in the next step.

[0695] Step 7. A solution of compound 7 (714 mg, 2.28 mmol, 1 eq) and PPh3 (1.20 g, 4.56 mmol, 2 eq) in DCM (10 mL) was cooled to 0°C under N2. CBr4 (1.13 g, 3.42 mmol, 1.5 eq) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired product was observed. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-5%) to obtain compound 8 (646 mg, yield 75.35%) as a white solid. LC-MS (ESI+): m / z = 376.0 (M+1), RT: 0.593 min.

[0696] Step 8. To a solution of compound 8 (646 mg, 1.72 mmol, 1 eq) in toluene (5 mL), PPh3 (675.43 mg, 2.58 mmol, 1.5 eq) was added, and the mixture was stirred at 110°C for 2 hours. LC-MS showed that the starting material was completely consumed and the desired MS was observed. The mixture was concentrated under reduced pressure to obtain compound 9 (1.09 g, yield 99.43%) as a white solid, which was used directly in the next step. LC-MS (ESI+): m / z = 558.2 (M-Br), RT: 0.450 min.

[0697] Step 9. To a solution of compound 9 (1.09 g, 1.71 mmol, 1 eq) in THF (20 mL), NaH (102.41 mg, 2.56 mmol, 60% purity, 1.5 eq) and compound 9A (661.38 mg, 2.56 mmol, 1.5 eq) were added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired product was observed. The mixture was stopped by adding water (3 mL) and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-10%) to obtain compound 10 (595 mg, yield 32.41%) as a white solid. LC-MS (ESI+): m / z = 538.2 (M+1), RT: 0.623 min.

[0698] TIFF2026521511000113.tif40134 Step 10. TFA (2 mL) was added to a solution of compound 10 (595 mg, 1.11 mmol, 1 eq) in DCM (6 mL), and the mixture was stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired product was observed. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC: column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: B 55%~85% over 10 minutes to obtain the crude product, which was further purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0~50%) to obtain (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-3-methylthieno[3,2-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid (87.3 mg, yield 17.87%) as a white solid. TIFF2026521511000114.tif38146

[0699] Example 2. (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thieno[3,2-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid Step 1. To a solution of compound 1 (15 g, 95.43 mmol, 1 eq) in DCM (150 mL), Et3N (28.97 g, 286.28 mmol, 39.85 mL, 3 eq) and compound 1A (17.24 g, 114.51 mmol, 14.42 mL, 1.2 eq) were added. The mixture was stirred at 25°C for 2 hours. TLC showed that the starting material had been completely consumed and large new spots were detected. Water (200 mL) was added to the reaction mixture. The mixture was extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-9%) to obtain compound 2 (14.22 g, yield 54.93%) as a yellow oil. LCMS (ESI+): m / z = 272.0 (M+1), RT: 0.375 min.

[0700] Step 2. EtONa (5.35 g, 78.62 mmol, 1.5 eq) was added to a solution of compound 2 (14.22 g, 52.42 mmol, 1 eq) in EtOH (143 mL). The mixture was stirred at 80°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The reaction mixture was filtered, and the solid was dried under reduced pressure to obtain compound 3 (12.51 g, yield 99.76%) as a yellow solid. LC-MS (ESI+): m / z = 240.1 (M+1), RT: 0.328 min.

[0701] Step 3. POCl3 (19 mL) was added to a solution of compound 3 (4 g, 16.72 mmol, 1 eq) in toluene (19 mL). The mixture was stirred at 100 °C for 16 hours. TLC showed that the starting material had been completely consumed and large new spots were detected. After cooling to room temperature, the reaction mixture was added to saturated sodium bicarbonate aqueous solution (500 mL) at 25 °C, and then extracted with ethyl acetate (500 mL x 3). The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-2%) to obtain compound 4 (1.51 g, yield 32.71%) as a white solid. LCMS (ESI+): m / z = 275.9 (M+1), RT: 0.455 min.

[0702] Step 4. To a solution of compound 4 (520 mg, 1.88 mmol, 1 eq) and compound 4A (129.40 mg, 1.51 mmol, 0.8 eq) in dioxane (5 mL) and H2O (0.5 mL), Pd(dppf)Cl2.CH2Cl2 (153.78 mg, 188.31 μmol, 0.1 eq) and Cs2CO3 (1.23 g, 3.77 mmol, 2 eq) were added. The mixture was stirred under N2 at 100°C for 16 hours. TLC showed that some compound 4 remained and two large new spots were detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-2%) to obtain compound 5 (100 mg, yield 17.72%) as a colorless oil. TIFF2026521511000119.tif18146

[0703] Step 5. Compound 5 (300 mg, 1.06 mmol, 1 eq) and Compound 5B (446.94 mg, 3.19 mmol, 3 eq) were dissolved in dioxane (2 mL) and H2O (0.2 mL) to which Pd(dppf)Cl2.CH2Cl2 (86.95 mg, 106.47 μmol, 0.1 eq) and Cs2CO3 (693.83 mg, 2.13 mmol, 2 eq) were added. The mixture was stirred at 100°C for 16 hours under N2. TLC showed that the starting material was completely consumed and large new spots were detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-5%) to obtain Compound 6 (262 mg, yield 68.47%) as a brown oil. LCMS (ESI+): m / z=342.1 (M+1), RT: 0.500 min.

[0704] Step 6. To a solution of compound 6 (466 mg, 1.36 mmol, 1 eq) in THF (5 mL), LAH (2.5 M, 818.98 μL, 1.5 eq) was added at 0°C. The mixture was stirred under N2 at 25°C for 2 hours. LC-MS showed that the starting material was completely consumed and the product was detected. The reaction mixture was cooled to -10 to 0°C, and water (0.1 mL), followed by 15% NaOH aqueous solution (0.1 mL) and water (0.3 mL) were slowly added dropwise to the reaction mixture. The mixture was warmed to room temperature and stirred for 15 minutes. Anhydrous Na2SO4 was then added, and the mixture was filtered. The filtered cake was washed with ethyl acetate (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain compound 7 (414 mg, 1.31 mmol, yield 96.25%) as a yellow oil. LCMS (ESI+): m / z=300 (M+1), RT: 0.313 min.

[0705] Step 7. To a solution of compound 7 (200 mg, 668.09 μmol, 1 eq) in DCM (3 mL), PPh3 (350.46 mg, 1.34 mmol, 2 eq) and CBr4 (332.33 mg, 1.00 mmol, 1.5 eq) were added at 0°C. The mixture was stirred under N2 at 25°C for 1 hour. LC-MS showed that the starting materials were completely consumed and the product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-5%) to obtain compound 8 (111 mg, yield 45.86%) as a yellow oil. LC-MS (ESI+): m / z = 362.0 (M+1), RT: 0.500 min.

[0706] Step 8. PPh3 (123.08 mg, 469.28 μmol, 1 eq) was added to a solution of compound 8 (170 mg, 469.28 μmol, 1 eq) in toluene (2 mL). The mixture was stirred under N2 at 110 °C for 0.5 hours. LC-MS showed that the starting material was completely consumed and the product was detected. The reaction mixture was concentrated under reduced pressure to obtain compound 9 (300 mg, crude) as a white solid. LC-MS (ESI+): m / z = 544.1 (M-Br), RT: 0.427 min.

[0707] Step 9. K2CO3 (129.68 mg, 938.29 μmol, 2 eq) was added to a solution of compound 9 (293 mg, 469.14 μmol, 1 eq) and compound 9A (181.78 mg, 703.71 μmol, 1.5 eq) in THF (3 mL). The mixture was stirred under N2 at 25°C for 16 hours. LC-MS showed that the starting materials were completely consumed and the product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-7%) to obtain compound 10 (107 mg, yield 43.12%) as a white solid. TIFF2026521511000125.tif31146

[0708] In some embodiments, compound 10 is the sodium salt of compound 10.

[0709] Step 10. TFA (0.5 mL) was added to a solution of compound 10 (107 mg, 204.33 μmol, 1 eq) in DCM (1.5 mL). The mixture was stirred under N2 at 25°C for 0.5 hours. LC-MS showed that the starting material was completely consumed and the product was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: B 36%~66% over 10 minutes) to obtain the crude product, which was dissolved in THF / H2O (1:1, 1 mL) and adjusted to pH=9. This was then further purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH3.H2O)-ACN]; gradient: B 8%~28% over 10 minutes) to obtain (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thieno[3,2-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid (20.10 mg, yield 17.83%) as a white solid. TIFF2026521511000127.tif31146LCMS(ESI+):m / z=428.2(M-17), RT:1.573 min. LC / MS:HALO C18 90A 2.7um 3.0×30mm. Detection method: Diode array detector (DAD). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.018% TFA) in water (0.037% TFA) to 95% ACN over 3.0 minutes, set flow rate to 1.0 mL / min; then hold at 95% ACN for 0.60 minutes; set flow rate from 1.0 mL / min to 1.5 mL / min; return to 5% ACN in water and hold for 0.40 minutes; set flow rate to 1.5 mL / min.

[0710] Example 3. Synthesis of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thiazolo[5,4-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid Step 1. A solution of formic acid (23.63 g, 513.38 mmol, 3 eq) and Ac2O (19.22 g, 188.24 mmol, 1.1 eq) in THF (100 mL) was stirred at 70°C for 3 hours. Compound 1 (22 g, 171.13 mmol, 1 eq) was added at 25°C. The mixture was stirred under N2 at 70°C for 3 hours. LC-MS showed that 96% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was triturated with PE / siRNA = 3:1 (20 mL) at 25°C for 30 minutes and filtered. The filtered cake was dried under reduced pressure to obtain Compound 2 (21.5 g, yield 80.24%) as a yellow solid. TIFF2026521511000129.tif18146

[0711] Step 2. 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (25.83 g, 63.87 mmol, 1 eq) was added to a solution of compound 2 (10.0 g, 63.87 mmol, 1 eq) in THF (400 mL). The mixture was stirred under N2 at 70°C for 16 hours. LC-MS showed that 32% of the desired compound was detected. The reaction mixture was added to an aqueous solution of NaHCO3 (100 mL), and the mixture was extracted with siRNA (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was combined with five batches (using 10 g x 4 and 5 g of compound 2) and purified by flash column chromatography on silica gel (0-9% ethyl acetate in PE) to obtain compound 3 (34.4 g, yield 79.10%) as a yellow solid. LC / MS (ESI+): m / z = 137.1 (M+1), RT: 0.204 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50-1050. Mobile phase: The mixture was increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; then returned to 5% ACN in water and held for 0.02 minutes, with a flow rate of 2.0 mL / min.

[0712] Step 3. To a solution of compound 3 (10.0 g, 73.44 mmol, 1 eq) in DCM (190 mL), m-CPBA (29.82 g, 146.87 mmol, 85% purity, 2 eq) was added. The mixture was stirred under N2 at 25°C for 16 hours. LC-MS showed that 52% of the desired compound was detected. The reaction mixture was added to an aqueous solution of Na2SO3 (200 mL). The quenching liquid was tested using moistened potassium iodide test paper. The test paper remained white even in the acidic system. The reaction mixture was adjusted to pH=8 with an aqueous solution of NaHCO3 and extracted with DCM (300 mL x 4). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was combined with a parallel batch (using 10 g of compound 3), tritulated with PE / siRNA = 3:1 (10 mL) at 25°C for 30 minutes, and filtered. The filtered cake was concentrated under reduced pressure to obtain compound 4 (2.80 g, yield 12.52%) as a brown solid. TIFF2026521511000132.tif11128

[0713] Step 4. The solution of compound 4 (2.80 g, 18.40 mmol, 1 eq) in POCl3 (10 mL) was stirred at 100°C for 1 hour. LC-MS showed that 31% of the desired compound was detected. The reaction mixture was added to saturated sodium bicarbonate solution (500 mL) at 25°C and then extracted with siRNA (500 mL × 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: Daisogel C18 250*70 mm*10 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; gradient: B 16%~46% over 23 minutes) to obtain compound 5 (1.20 g, yield 38.22%) as a white solid. TIFF2026521511000134.tif4150

[0714] Step 5. To a solution of compound 5 (1.20 g, 7.03 mmol, 1 eq) and compound 5A (1.48 g, 10.55 mmol, 1.5 eq) in dioxane (10 mL) and H2O (1 mL), Cs2CO3 (4.58 g, 14.07 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (574.36 mg, 703.32 μmol, 0.1 eq) were added. The mixture was stirred at 100°C for 2 hours under N2. LCMS showed that 48% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% siRNA in PE) to obtain compound 6 (1.50 g, yield 77.80%) as a yellow solid. LCMS (ESI+): m / z = 231.0 (M+1), RT: 0.397 min. 5~95AB_0.8 min: LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 min, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min, with a flow rate of 2.0 mL / min; returned to 5% ACN in water and held for 0.02 min, with a flow rate of 2.0 mL / min.

[0715] Step 6. To a solution of compound 6 (1.4 g, 6.08 mmol, 1 eq) in DCM (14 mL), m-CPBA (2.47 g, 12.16 mmol, 85% purity, 2 eq) was added. The mixture was stirred under N2 at 25°C for 8 hours. LC-MS showed that 91% of the desired compound was detected. The reaction mixture was added to an aqueous solution of Na2SO3 (150 mL). The quench solution was tested using moistened potassium iodide test paper. The test paper remained white even in the acidic system. The reaction mixture was adjusted to pH=8 with an aqueous solution of NaHCO3 and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-6% MeOH in DCM) on silica gel to obtain compound 7 (1.31 g, yield 43.75%) as a pale yellow solid. LC / MS (ESI+): m / z = 246.9 (M+1), RT: 0.445 min. LC / MS: Gemini@5umNX-C18 110A 2*30 mm, 5um. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50-1050. Mobile phase: Increased from 5% ACN in water (0.025% NH3·H2O) to 95% ACN in water over 0.70 min, with a flow rate of 1.7 mL / min, then held at 95% ACN for 0.20 min. The flow rate was then set to 1.7 mL / min; returned to 5% ACN in water and held for 0.10 min. The flow rate was set to 1.7 mL / min.

[0716] Step 7 of TIFF2026521511000137.tif40128 involved stirring a solution of compound 7 (1.31 g, 5.32 mmol, 1 eq) in POCl3 (6 mL) at 100°C for 2 hours. LC-MS showed detection of 94% of the desired compound. The reaction mixture was added to saturated sodium bicarbonate solution (500 mL) at 25°C and then extracted with siRNA (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 8 (1.28, yield 90.90%) as a white solid. LC-MS (ESI+): m / z = 265.0 (M+1), RT: 0.464 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 minutes with a flow rate of 2.0 mL / min; returned to 5% ACN in water and held for 0.02 minutes, with a flow rate of 2.0 mL / min.)

[0717] Step 8. To a solution of compound 8 (1.28 g, 4.84 mmol, 1 eq) and compound 8A (1.66 g, 19.34 mmol, 4 eq) in dioxane (12 mL) and H2O (1.2 mL), Cs2CO3 (3.15 g, 9.67 mmol, 2 eq) and Pd(dppf)Cl2 (353.82 mg, 483.56 μmol, 0.1 eq) were added. The mixture was stirred at 100°C for 2 hours under N2. LCMS showed that 82% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-5% siRNA in PE) on silica gel to obtain compound 9 (1.45 g, 99.83% yield) as a white solid. LCMS (ESI+): m / z = 271.0 (M+1), RT: 0.483 min. 5~95AB_0.8 min: LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 min, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min, with a flow rate of 2.0 mL / min; returned to 5% ACN in water and held for 0.02 min, with a flow rate of 2.0 mL / min.

[0718] Step 9. TBCA (2.83 g, 6.10 mmol, 2.2 eq) was added to a solution of compound 9 (750 mg, 2.77 mmol, 1 eq) in AcOH (10 mL). The mixture was stirred at 30°C for 1 hour under N2. LC-MS showed that 83% of the desired compound was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-5% siRNA in PE) to obtain compound 10 (600 mg, yield 61.93%) as a yellow oil. TIFF2026521511000140.tif18146

[0719] In some embodiments, compound 10 is the sodium salt of compound 10.

[0720] Step 10. Compound 10 (600 mg, 1.72 mmol, 1 eq) and compound 10A (660.62 mg, 2.58 mmol, 1.5 eq) in ACN (3 mL) were mixed with tBu3P Pd G2 (88.04 mg, 171.81 μmol, 0.1 eq) and N-cyclohexyl-N-methyl-cyclohexaneamine (2.52 g, 12.89 mmol, 7.5 eq). The mixture was stirred under N2 at 90°C for 16 hours. LC-MS showed that 58% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% siRNA in PE) on silica gel to obtain the crude product. The crude product was purified by preparative TLC (PE / DCM = 1:3) to obtain compound 11 (100 mg, yield 11.09%) as a white solid. TIFF2026521511000142.tif24146

[0721] In some embodiments, compound 11 is the sodium salt of compound 11.

[0722] Step 11. HCl (1M, 1.5eq) was added to a solution of compound 11 (100 mg, 190.60 μmol, 1eq) in MeCN (1 mL). The mixture was stirred at 45°C for 16 hours. LC-MS showed that 88% of the desired compound was detected. The reaction mixture was adjusted to pH=9 with 1N NaOH aqueous solution and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: CDO2-Waters Xbridge BEH C18 150*25*10um; mobile phase: [water (NH3.H2O)-ACN]; gradient: B from 0% to 29% over 12 minutes) to obtain (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thiazolo[5,4-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid (12.34 mg, yield 14.34%) as a white solid. TIFF2026521511000144.tif31146LCMS(ESI+):m / z=429.2(M+1), RT:1.635 min. LC / MS:Kinetex(registered trademark) EVO C18 3.0×50mm 2.6um. Detection method was photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 3.40 minutes, flow rate set to 0.9 mL / min; then held at 95% ACN for 0.30 minutes, flow rate set to 0.9 mL / min; returned to 5% ACN in water, held for 0.30 minutes, flow rate set to 1.2 mL / min.

[0723] Example 4. Synthesis of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid Step 1. Et3N (49.16 g, 485.85 mmol, 67.62 mL, 2 eq) was added to a solution of compound 1 (31.23 g, 242.92 mmol, 1 eq) in Ac2O (125 mL). The mixture was stirred at 100°C for 2 hours. LC-MS showed that 93% of the desired compound was detected. Water (300 mL) was added to the reaction mixture, and then extracted with SiO (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 2 (55.3 g, crude) as a yellow oil. LC-MS (ESI+): m / z = 213.1 (M+1), RT: 0.241 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 minutes, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.)

[0724] Step 2. NaOH (1M, 0.25eq) was added to a solution of compound 2 (55g, 258.66 mmol, 1eq) in MeOH (500mL). The mixture was stirred at 25°C for 0.5 hours. LCMS showed that 100% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (400mL), adjusted to pH=8 with 1N HCl, and extracted with ELISA (500mL x 3). The combined organic layers were washed with brine (500mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 3 (46.46g, crude) as a brown solid. LCMS (ESI+): m / z=171.1 (M+1), RT: 0.169 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 minutes, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.)

[0725] Step 3. 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (96.92 g, 239.63 mmol, 0.8 eq) was added to a solution of compound 3 (51.1 g, 299.54 mmol, 1 eq) in THF (500 mL). The mixture was stirred under N2 at 25°C for 16 hours. LC-MS showed that 45% of the desired compound was detected. The reaction mixture was added to an aqueous solution of NaHCO3 (500 mL), and the mixture was extracted with siRNA (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-16% ethyl acetate in PE) to obtain compound 4 (42.47 g, yield 57.58%) as a yellow oil. LCMS (ESI+): m / z = 151.1 (M+1), RT: 0.249 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 minutes, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.)

[0726] Step 4. To a solution of compound 4 (13.3 g, 88.55 mmol, 1 eq) in DCM (140 mL), m-CPBA (35.95 g, 177.10 mmol, 85% purity, 2 eq) was added. The mixture was stirred under N2 at 25°C for 16 hours. LC-MS showed that 86% of the desired compound was detected. The reaction mixture was added to an aqueous solution of Na2SO3 (100 mL). The quench solution was tested using moistened potassium iodide test paper. The test paper remained white even in the acidic system. The reaction mixture was adjusted to pH=8 with an aqueous solution of NaHCO3 and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-6% MeOH in DCM) on silica gel to obtain compound 5 (5.99 mg, yield 40.70%) as a yellow oil. TIFF2026521511000149.tif11128

[0727] Step 5. The solution of compound 5 (6.48 g, 38.99 mmol, 1 eq) in POCl3 (19 mL) was stirred at 100 °C for 2 hours. LC-MS showed that 65% of the product was detected. The reaction mixture was added to saturated sodium bicarbonate solution (500 mL) at 25 °C and extracted with  (500 mL × 3). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: Daisogel C18 250*70 mm*10 μm; mobile phase: [water (NH3.H2O)-ACN]; gradient: B 10%~40% over 25 minutes) to obtain compound 6 (7.28 g, yield 50.56%) as a white solid. TIFF2026521511000151.tif4149LCMS(ESI+): m / z=184.9(M+1), RT: 0.292 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 minutes, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.)

[0728] Step 6. To a solution of compound 6 (7.28 g, 39.43 mmol, 1 eq) and compound 6B (8.27 g, 59.14 mmol, 1.5 eq) in dioxane (70 mL) and H2O (7 mL), Cs2CO3 (25.69 g, 78.85 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (3.22 g, 3.94 mmol, 0.1 eq) were added. The mixture was stirred at 100°C for 2 hours under N2. LCMS showed that 66% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-5% siRNA in PE) on silica gel to obtain compound 7 (10.7 g, 99.98% yield) as a white solid. LCMS (ESI+): m / z = 245.1 (M+1), RT: 0.421 min. 5~95AB_0.8 min: LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 min, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 min, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 min, with a flow rate of 2.0 mL / min.

[0729] Step 7. To a solution of compound 7 (10.7 g, 43.80 mmol, 1 eq) in DCM (100 mL), m-CPBA (15.12 g, 87.60 mmol, 2 eq) was added. The mixture was stirred under N2 at 25°C for 10 hours. LC-MS showed that 95% of the desired compound was detected. The reaction mixture was added to an aqueous solution of Na2SO3 (150 mL). The quench solution was tested using moistened potassium iodide test paper. The test paper remained white even in the acidic system. The reaction mixture was adjusted to pH=8 with an aqueous solution of NaHCO3 and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-6% MeOH in DCM) on silica gel to obtain compound 8 (9.54 g, yield 83.68%) as a pale yellow solid. LC / MS (ESI+): m / z = 260.9 (M+1), RT: 0.635 min. LC / MS: Gemini@5umNX-C18 110A 2*30 mm, 5um. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50-1050. Mobile phase: Increased from 0% ACN in water (0.025% NH3·H2O) to 60% ACN in water over 0.70 minutes, with a flow rate of 1.7 mL / min; then held at 60% ACN for 0.20 minutes, with a flow rate of 1.7 mL / min; returned to 0% ACN in water and held for 0.10 minutes. The flow rate was set to 1.7 mL / min.

[0730] Step 8 of TIFF2026521511000154.tif40128 involved stirring a solution of compound 8 (4.77 g, 18.33 mmol, 1 eq) in POCl3 (19 mL) at 100°C for 2 hours. LC-MS showed detection of 96% of the desired compound. The reaction mixture was added to saturated sodium bicarbonate solution (1500 mL) at 25°C and extracted with siRNA (1500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 9 (9.67 g, yield 94.65%) as a white solid. LC-MS (ESI+): m / z = 279.0 (M+1), RT: 0.488 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 minutes, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.)

[0731] Step 9. To a solution of compound 9 (9.67 g, 34.69 mmol, 1 eq) and compound 9A (9.54 g, 111.02 mmol, 3.2 eq) in dioxane (90 mL) and H2O (9 mL), Cs2CO3 (22.61 g, 69.39 mmol, 2 eq) and Pd(dppf)Cl2 (2.54 g, 3.47 mmol, 0.1 eq) were added. The mixture was stirred at 100°C for 2 hours under N2. LCMS showed that 80% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-5% siRNA in PE) on silica gel to obtain compound 10 (8.8 g, yield 89.20%) as a white solid. LCMS (ESI+): m / z = 285.1 (M+1), RT: 0.503 min. 5~95AB_0.8 min: LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 min, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 min, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 min, with a flow rate of 2.0 mL / min.

[0732] Step 10. To a solution of compound 10 (2.80 g, 9.85 mmol, 1 eq) in DMA (30 mL) and H2O (20 mL), NBS (2.10 g, 11.82 mmol, 1.2 eq) and TsOH.H2O (187.31 mg, 984.70 μmol, 0.1 eq) were added. The mixture was stirred under N2 at 120°C for 0.5 hours. LC-MS showed detection of 44% compound 10 and approximately 15% of the desired compound. The reaction mixture was concentrated under reduced pressure. The residue was combined with two batches (using 3g x 2 of compound 10) and purified by reverse-phase HPLC (column: Phenomenex luna C18 (250*70mm, 10um); mobile phase: [water (FA)-ACN]; gradient: B 60%~90% over 5 minutes) to obtain compound 11 (1.52g, yield 13.57%) as a black oil. LCMS (ESI+): m / z = 363.0 (M+1), RT: 0.549 min. 5~95AB_0.8 min:LC / MS (The column used for chromatography was Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient for B was 5%~95% over 0.60 minutes, with a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.)

[0733] Step 11. Compound 11 (400 mg, 1.10 mmol, 1 eq) and compound 11A (423.41 mg, 1.65 mmol, 1.5 eq) in ACN (8 mL) were mixed with tBu3P Pd G2 (56.42 mg, 110.12 μmol, 0.1 eq) and N-cyclohexyl-N-methyl-cyclohexaneamine (1.61 g, 8.26 mmol, 7.5 eq). The mixture was stirred under N2 at 90°C for 16 hours. LC-MS showed that 54% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was combined with a parallel batch (using 200 mg of compound 11) and purified by flash silica gel chromatography (100% siRNA) to obtain the crude product. The crude product was purified by reverse-phase HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: B 80%~100% over 10 minutes) and preparative TLC (PE / Â=5:1) to obtain compound 12 (100 mg, yield 16.86%) as a white solid. TIFF2026521511000158.tif31146

[0734] In some embodiments, compound 12 is the sodium salt of compound 12.

[0735] TIFF2026521511000159.tif31144 Step 12. HCl (1.5M, 1.5eq) was added to a solution of compound 12 (90 mg, 167.08 μmol, 1 eq) in ACN (1 mL). The mixture was stirred at 45°C for 16 hours. LC-MS showed that 79% of the desired compound was detected. The reaction mixture was adjusted to pH=9 with 1N NaOH aqueous solution, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH3,H2O)-ACN]; gradient: B 4%~34% over 10 minutes) to obtain the sodium salt of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthiazolo[5,4-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid (35.3 mg, yield 47.75%) as a white solid. TIFF2026521511000160.tif31146LCMS(ESI+):m / z=443.2(M+1), RT:1.610 min. LC / MS:Kinetex(registered trademark) XBridge C18 3.0*50mm, 5um. Detection method was photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increased from 0% ACN to 60% ACN in water (0.025% NH3·H2O) for 3.00 min, flow rate set to 0.9 mL / min; then held at 60% ACN for 0.70 min, flow rate set to 0.9 mL / min; returned to 0% ACN in water, held for 0.30 min, flow rate set to 1.2 mL / min.

[0736] Example 5. Synthesis of (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-2-methylthieno[2,3-b]pyridine-5-yl)-3,5-dihydroxyhepta-6-enoic acid Step 1: Compound 1A (7.12 g, 122.59 mmol, 8.92 mL, 2 eq), S (3.93 g, 122.59 mmol, 2 eq), and diethylamine (13.45 g, 183.88 mmol, 18.94 mL, 3 eq) were added to a solution of compound 1 (100 mL, 61.29 mmol, 1 eq) in EtOH (100 mL). The mixture was degassed and purged three times with N2 and stirred at 70°C for 2 hours under an N2 atmosphere. LCMS showed that the reactants were completely consumed and one peak with 58% of the desired mass was detected. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (30 mL x 3), and washed with brine (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (PE / Â=1 / 0~10 / 1) to obtain compound 2 (5.3 g, yield 26.75%) as a yellow solid. LCMS (ESI+): m / z=236.0 (M+1), RT: 0.423 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set to a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set to a flow rate of 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes, set to a flow rate of 2.0 mL / min.

[0737] Step 2: To a solution of compound 2 (4.3 g, 13.30 mmol, 1 eq) in AcOH (20 mL), 3-cyclopropyl-3-oxo-propanenitrile (2.90 g, 26.61 mmol, 2 eq) and H2SO4 (2.61 g, 26.61 mmol, 1.42 mL, 2 eq) were added. The mixture was stirred at 100°C for 1 hour. LC-MS showed that the reactants were completely consumed and one peak with 56% of the desired mass was detected. The reaction was stopped by adding 50 mL of water at 25°C. The mixture was extracted with ethyl acetate (50 mL x 3), washed with brine (50 mL x 3), then the organic layer was evaporated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (FA)-ACN]; gradient: B 60%~90% over 22 minutes), and concentrated under vacuum to obtain compound 3 (4 g, yield 75.09%) as a yellow solid. TIFF2026521511000163.tif18146LCMS(ESI+):m / z=309.0(M+1), RT:0.466 min. LC / MS:Kinetex(registered trademark) EVO C18 2.1×30mm 5um. Detection method is photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, set flow rate to 2.0 mL / min.

[0738] Step 3: The mixture of compound 3 (2 g, 6.24 mmol, 1 eq) in DCM (20 mL) was degassed and purged three times with N2, and then DIBAL-H (1 M, 12.49 mL, 2 eq) was slowly added to the solution at 0°C. The mixture was stirred at 25°C for 1 hour under an N2 atmosphere. LCMS showed that the reactants were completely consumed and one peak with the desired mass of 36% was detected. The reaction was stopped by slowly adding 10 mL of MeOH and 5 mL of 15% NaOH solution at 0°C. The mixture was stirred at 25°C for 15 minutes under an N2 atmosphere, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â=1 / 0~10 / 1) on silica gel to obtain compound 4 (0.8 g, yield 19.21%) as a yellow solid. LC / MS (ESI+): m / z=311.9 (M+1), RT: 0.618 min. LC / MS: HALO C18 90A 2.1×30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 min, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min, with a flow rate of 2.0 mL / min; returned to 5% ACN in water and held for 0.02 min. Set the flow rate to 2.0 mL / min.

[0739] Step 4: To a solution of compound 4 (0.8 g, 2.40 mmol, 1 eq) in MeOH (8 mL), NaBH4 (136.12 mg, 3.60 mmol, 1.5 eq) was added at 0°C under an N2 atmosphere. The mixture was degassed and purged three times with N2 and stirred at 25°C for 1 hour under an N2 atmosphere. LCMS showed that the reactants were completely consumed and one peak with 89% of the desired mass was detected. The reaction was stopped by slowly adding 20 mL of H2O at 0°C. The mixture was extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL x 3), and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / Â=1 / 0~10 / 1) to obtain compound 5 (0.6 g, yield 78.55%) as a white solid. TIFF2026521511000166.tif18146LCMS(ESI+):m / z=314.0(M+1), RT:0.465 min. LC / MS:Kinetex(registered trademark) EVO C18 2.1×30mm 5um. Detection method is photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, set flow rate to 2.0 mL / min.

[0740] Step 5: To a solution of compound 5 (0.3 g, 942.06 μmol, 1 eq) in DCM (3 mL), PPh3 (494.18 mg, 1.88 mmol, 2 eq) and CBr4 (468.62 mg, 1.41 mmol, 1.5 eq) were added at 0°C. The mixture was stirred at 25°C for 1 hour. LC-MS indicated that the reactants were completely consumed and that one peak with the desired mass of 24% was detected. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE / siRNA = 1 / 0 to 10 / 1) on silica gel to obtain compound 6 (0.65 g, yield 90.23%) as a white solid. LC-MS (ESI+): m / z = 375.9 (M+1), RT: 0.588 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set to a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set to a flow rate of 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes, set to a flow rate of 2.0 mL / min.

[0741] Step 6: The mixture of compound 6 (0.65 g, 1.70 mmol, 1 eq) and PPh3 (668.88 mg, 2.55 mmol, 1.5 eq) in toluene (6 mL) was degassed and purged three times with N2, and the mixture was then stirred at 110°C for 1 hour under an N2 atmosphere. LCMS showed that the reactants were completely consumed and one peak with the desired mass of 11% was detected. The mixture was concentrated under reduced pressure to obtain compound 7 (1.09 g, yield 100.00%) as a white solid. LCMS (ESI+): m / z = 558.1 (M-79), RT: 0.458 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. Detection method: photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50 to 1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, set flow rate to 2.0 mL / min.

[0742] Step 7: LC-MS showed that the reactants were completely consumed and one peak with the desired mass of 18% was detected. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / siRNA = 1 / 0 to 10 / 1) to obtain the crude product. The crude product was purified by preparative TLC (PE / siRNA = 10 / 1) to obtain compound 8 (0.2 g, yield 21.53%) as a colorless oil. TIFF2026521511000170.tif31146LCMS(ESI+):m / z=538.2(M+1), RT:2.402 min. LC / MS:Kinetex(registered trademark) EVO C18 3.0×50mm 2.6um. Detection method: PDA. MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 2.40 minutes, flow rate set to 1.2 mL / min; then held at 95% ACN for 0.30 minutes, flow rate set to 1.2 mL / min; returned to 5% ACN in water, held for 0.30 minutes, flow rate set to 1.2 mL / min.

[0743] Step 8: To a solution of compound 8 (200 mg, 367.43 μmol, 1 eq) in MeCN (2 mL), HCl (1 M, 734.86 μL, 2 eq) was added. The mixture was stirred at 45°C for 12 hours. Then NaOH (1.5 M, 1.22 mL, 5 eq) was added to the solution. The mixture was stirred at 45°C for 1 hour. LC-MS showed that the reactants were completely consumed and one peak with 100% of the desired mass was detected. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: CDO2-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water (NH3H2O)-ACN]; gradient: B 15%~35% over 10 minutes), and directly lyophilized to obtain (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-2-methylthieno[2,3-b]pyridine-5-yl)-3,5-dihydroxyhepta-6-enoic acid (68.22 mg, yield 37.44%) as a white solid. TIFF2026521511000172.tif24146LCMS(ESI+):m / z=442.0(M+1), RT:1.403 min. LC / MS:Kinetex(registered trademark) XBridge C18 3.0*50mm, 5um. Detection method: PDA. MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increased from 5% ACN to 95% ACN in water (0.025% NH3·H2O) for 3.00 min, flow rate set to 0.9 mL / min; then held at 95% ACN for 0.70 min, flow rate set to 0.9 mL / min; returned to 5% ACN in water, held for 0.30 min, flow rate set to 1.2 mL / min.

[0744] Example 6. Synthesis of the sodium salt of (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-3-methylthieno[2,3-b]pyridine-5-yl)-3,5-dihydroxyhepta-6-enoic acid Step 1: Compound 1 (10.0 g, 61.29 mmol, 1 eq), Compound 1A (11.05 g, 61.29 mmol, 1 eq), and DIEA (7.92 g, 61.29 mmol, 10.68 mL, 1 eq) in EtOH (100 mL) were degassed and purged three times with N2, and the mixture was stirred at 50°C for 15 hours under an N2 atmosphere. LCMS showed that 63% of the desired compounds were detected. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was tritulated with PE / Â=10:1 (50 mL) and filtered. The cake was dried under reduced pressure to obtain compound 2 (6.8 g, yield 44.80%) as a yellow solid. LC / MS (ESI+): m / z = 235.9.0 (M+23), RT: 0.446 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50 to 1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, setting the flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, setting the flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, setting the flow rate to 2.0 mL / min.

[0745] Step 2: Compound 2 (1.6 g, 6.80 mmol, 1 eq) and Compound 2A (1.48 g, 13.60 mmol, 2 eq) were dissolved in AcOH (15 mL) and concentrated H2SO4 (1.33 g, 13.60 mmol, 724.98 μL, 2 eq) was added, and the mixture was stirred at 100 °C for 2 hours. LC-MS showed that the reactants were completely consumed and 58% of the desired product was observed. The mixture was poured into saturated Na2CO3 aqueous solution (200 mL) and extracted with siRNA (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (0-5% siRNA in PE) to obtain Compound 3 (1.25 g, yield 59.61%) as a yellow solid. LC / MS (ESI+): m / z = 309.1 (M+1), RT: 0.529 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. Detection method: photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50 to 1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.

[0746] In some embodiments, compound 2 is the sodium salt of compound 2.

[0747] In some embodiments, compound 3 is the sodium salt of compound 3.

[0748] Step 3: Add DIBAL-H (1M, 8.11mL, 2eq) to a solution of compound 3 (1.25g, 4.05 mmol, 1eq) in toluene (10mL) at -78°C, and stir the mixture under N2 at -78°C for 0.5 hours. Warm the mixture to 25°C and stir under N2 for 2 hours. LCMS showed that the reactants were completely consumed and 58% of the desired product was observed. The reaction was stopped with MeOH (10mL) at 0°C, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (0-5% ethyl acetate in PE) to obtain compound 4 (400mg, yield 31.69%) as a yellow solid. LC / MS (ESI+): m / z = 312.1 (M+1), RT: 0.531 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. Detection method: photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50 to 1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, set flow rate to 2.0 mL / min.

[0749] In some embodiments, compound 4 is the sodium salt of compound 4.

[0750] Step 4: To a solution of compound 4 (400 mg, 1.28 mmol, 1 eq) in MeOH (4 mL), NaBH4 (72.90 mg, 1.93 mmol, 1.5 eq) was added, and the mixture was stirred under N2 at 25°C for 2 hours. LC-MS showed that the reactants were completely consumed and 92% of the desired product was observed. The reaction was stopped with saturated NH4Cl aqueous solution (20 mL), and the mixture was extracted with HCl (30 mL x 3). The combined organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (0-10% HCl in PE) to obtain compound 5 (355 mg, yield 88.18%) as a yellow oil. LC-MS (ESI+): m / z = 314.1 (M+1), RT: 0.453 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.

[0751] In some embodiments, compound 5 is the sodium salt of compound 5.

[0752] Step 5: To a solution of compound 5 (355 mg, 1.13 mmol, 1 eq) in DCM (5 mL), PPh3 (594.22 mg, 2.27 mmol, 2 eq) and CBr4 (563.49 mg, 1.70 mmol, 1.5 eq) were added at 0°C, and the mixture was stirred at 25°C for 1 hour. LC-MS showed that the reactants were completely consumed and 80% of the desired product was observed. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (0-5% ethyl acetate in PE) on silica gel to obtain compound 6 (256 mg, yield 60.06%) as a white solid. LC-MS (ESI+): m / z = 376.0 (M+1), RT: 0.570 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, with a flow rate of 2.0 mL / min.

[0753] In some embodiments, compound 6 is the sodium salt of compound 6.

[0754] Step 6: To a solution of compound 6 (256 mg, 680.34 μmol, 1 eq) in toluene (3 mL), PPh3 (267.66 mg, 1.02 mmol, 1.5 eq) was added, and the mixture was stirred at 100°C for 1 hour. LC-MS showed that the reactants were completely consumed and 66% of the desired product was observed. The mixture was concentrated under reduced pressure to obtain compound 7 (434 mg, crude) as a white solid. LC-MS (ESI+): m / z = 558.2 (M-79), RT: 0.455 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50 to 1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, setting the flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, setting the flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, setting the flow rate to 2.0 mL / min.

[0755] In some embodiments, compound 7 is the sodium salt of compound 7.

[0756] Step 7: To a solution of compound 7 (434 mg, 679.64 μmol, 1 eq) and compound 7A (263.34 mg, 1.02 mmol, 1.5 eq) in THF (3 mL), Cs2CO3 (664.32 mg, 2.04 mmol, 3 eq) was added, and the mixture was stirred at 25°C for 5 hours. LC-MS showed that the reactants were completely consumed and 55% of the desired product was observed. The reaction was stopped with water (20 mL), and extracted with siRNA (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (0-5% siRNA in PE) to obtain compound 8 (177 mg, yield 48.44%) as a colorless oil. LC / MS (ESI+): m / z = 538.3 (M+1), RT: 0.623 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. Detection method: photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50 to 1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then held at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; returned to 5% ACN in water, held for 0.02 minutes, set flow rate to 2.0 mL / min. TIFF2026521511000180.tif31146

[0757] In some embodiments, compound 8 is the sodium salt of compound 8.

[0758] Step 8: To a solution of compound 8 (177 mg, 329.19 μmol, 1 eq) in ACN (2 mL), HCl (1 M, 658.38 μL, 2 eq) was added, and the mixture was stirred at 45°C for 16 hours. NaOH aqueous solution (193.11 mg, 724.22 μmol, 15% purity, 2.2 eq) was added, and the mixture was stirred at 45°C for 0.5 hours. LC-MS showed that the reactants were completely consumed and 99% of the desired product was observed. The mixture was purified by preparative HPLC (column: CD02-Waters Xbidge BEH C18 150*25*10um, mobile phase: [water (NH3.H2O)-ACN]; gradient: B 11%~41% over 10 minutes) to obtain the sodium salt of (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-3-methylthieno[2,3-b]pyridine-5-yl)-3,5-dihydroxyhepta-6-enoic acid (104.80 mg, yield 72.11%) as a white solid. TIFF2026521511000182.tif24146LCMS(ESI+):m / z=442.1(M+1), RT:1.365 min. LC / MS:Kinetex(registered trademark) EVO C18 3.0×50mm 2.6um. Detection method is photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN over 3.40 minutes, flow rate set to 0.9 mL / min; then held at 95% ACN for 0.30 minutes, flow rate set to 0.9 mL / min; returned to 5% ACN in water, held for 0.30 minutes, flow rate set to 1.2 mL / min.

[0759] Example 7. Synthesis of the sodium salt of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthieno[3,2-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid. Step 1: The mixture of compound 1 (28 g, 79.98 mmol, 1 eq) in DCM (140 mL) and TFA (140 mL) was degassed and purged three times with N2, and the mixture was stirred at 40°C for 1 hour under an N2 atmosphere. LC / MS showed that the starting material was completely consumed and the desired MS was observed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-20% ethyl acetate in PE) on silica gel to obtain compound 2 (12 g, yield 64.74%) as a yellow solid. LC / MS (ESI+): m / z = 236.0 (M+1), RT: 0.417 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50-1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, set flow rate to 2.0 mL / min.

[0760] In some embodiments, compound 1 is the sodium salt of compound 1.

[0761] In some embodiments, compound 2 is the sodium salt of compound 2.

[0762] Step 2: Compound 2 (6.6 g, 28.06 mmol, 1 eq), Compound 2B (6.12 g, 56.10 mmol, 2 eq), and H2SO4 (5.50 g, 56.10 mmol, 2 eq) in AcOH (80 mL) were degassed and purged three times with N2, and the mixture was then stirred at 100°C for 1 hour under an N2 atmosphere. LC-MS showed the desired MS. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL) and extracted with SiO (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% Â in PE) on silica gel to obtain compound 3 (4.4 g, 50.86%) as a yellow solid. LC / MS (ESI+): m / z = 309.1 (M+1), RT: 0.517 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. Detection method was photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50-1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 min, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min, with a flow rate of 2.0 mL / min; returned to 5% ACN in water and held for 0.02 min. Set the flow rate to 2.0 mL / min.

[0763] In some embodiments, compound 3 is the sodium salt of compound 3.

[0764] Step 3: Add DIBAL-H (1M, 11.67mL, 2eq) to a solution of compound 3 (1.8g, 5.84 mmol, 1eq) in toluene (20mL) at -78°C, and stir the mixture under N2 at -78°C for 0.5 hours. Warm the mixture to 25°C and stir under N2 for 2 hours. LCMS showed the desired MS. The reaction was stopped by adding CH3OH (20mL) at 0°C, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-6% ethyl acetate in PE) to obtain compound 4 (760mg, yield 41.82%) as a yellow solid. LCMS (ESI+): m / z = 312.0 (M+1), RT: 0.487 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 minutes with a flow rate of 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes with a flow rate of 2.0 mL / min.

[0765] In some embodiments, compound 4 is the sodium salt of compound 4.

[0766] Step 4: To a solution of compound 4 (760 mg, 2.44 mmol, 1 eq) in MeOH (8 mL), NaBH4 (138.51 mg, 3.66 mmol, 1.5 eq) was added, and the mixture was stirred under N2 at 25°C for 2 hours. LC-MS showed that the starting material was completely consumed and the desired MS was observed. The reaction was stopped by adding saturated NH4Cl (20 mL), and the mixture was extracted with siRNA (20 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-20% siRNA in PE) to obtain compound 5 (610 mg, yield 79.75%) as a white solid. LC-MS (ESI+): m / z = 314.5 (M+1), RT: 0.322 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 minutes with a flow rate of 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes with a flow rate of 2.0 mL / min.

[0767] In some embodiments, compound 5 is the sodium salt of compound 5.

[0768] Step 5: To a solution of compound 5 (0.61 g, 1.95 mmol, 1 eq) in DCM (8 mL), CBr4 (968.25 mg, 2.92 mmol, 1.5 eq) and PPh3 (1.02 g, 3.89 mmol, 2 eq) were added at 0°C. The resulting mixture was stirred at 25°C for 1 hour under an N2 atmosphere. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-5% ethyl acetate in PE) to obtain compound 6 (770 mg, purity 50%, yield 52.57%) as a white solid. LC-MS (ESI+): m / z = 376.0 (M+1), RT: 0.483 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 minutes with a flow rate of 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes with a flow rate of 2.0 mL / min.

[0769] In some embodiments, compound 6 is the sodium salt of compound 6.

[0770] Step 6: To a solution of compound 6 (0.77 g, 1.02 mmol, 1 eq) in toluene (10 mL), PPh3 (268.36 mg, 1.02 mmol, 1 eq) was added, and the mixture was stirred at 110°C for 1 hour under an N2 atmosphere. LC-MS showed that the starting material was completely consumed and the desired product was observed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain compound 7 (655 mg, crude) as a colorless liquid. LC-MS (ESI+): m / z = 558.2 (M-Br), RT: 0.433 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50 to 1050. Mobile phase: Increase the flow rate from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, setting the flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, setting the flow rate to 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes, setting the flow rate to 2.0 mL / min.

[0771] In some embodiments, compound 7 is the sodium salt of compound 7.

[0772] Step 7: To a solution of compound 7 (655 mg, 1.03 mmol, 1 eq) and compound 7A (397.43 mg, 1.54 mmol, 1.5 eq) in THF (10 mL), Cs2CO3 (668.40 mg, 2.05 mmol, 2 eq) was added, and the mixture was stirred at 25°C for 16 hours under an N2 atmosphere. LC-MS showed that the starting material was completely consumed and the desired MS was observed. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-6% siRNA in PE) to obtain compound 8 (210 mg, yield 37.70%) as a white solid. TIFF2026521511000190.tif24146LCMS(ESI+):m / z=538.4(M+1), RT:0.506 min. LC / MS:Kinetex(registered trademark) EVO C18 2.1×30mm 5um. Detection method is photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, set flow rate to 2.0 mL / min.

[0773] In some embodiments, compound 8 is the sodium salt of compound 8.

[0774] Step 8: To a solution of compound 8 (130 mg, 241.78 μmol, 1 eq) in ACN (2 mL), HCl (1.5 M, 1.5 eq) was added, and the mixture was stirred at 45°C for 14 hours under an N2 atmosphere. NaOH (1 M, 2 eq) was added, and the mixture was stirred at 45°C for 2 hours under an N2 atmosphere. LC-MS showed that the starting material was completely consumed and the desired MS was observed. The reaction mixture was purified by preparative HPLC (column: CDO2-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water (NH3H2O)-ACN]; gradient: B 12%~32% over 10 minutes) to obtain the sodium salt of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthieno[3,2-b]pyridine-6-yl)-3,5-dihydroxyhepta-6-enoic acid (50.30 mg, yield 46.65%) as a white solid. TIFF2026521511000192.tif31151LCMS(ESI+):m / z=442.2(M+1), RT:1.358 min. LC / MS:Kinetex(registered trademark) EVO C18 3.0×50mm 2.6um. Detection method was photodiode array (PDA&ELSD). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 3.4 minutes, flow rate set to 0.9 mL / min; then held at 95% ACN for 0.3 minutes, flow rate set to 0.9 mL / min; returned to 5% ACN in water, held for 0.3 minutes, flow rate set to 1.2 mL / min.

[0775] Example 8. Synthesis of the sodium salt of (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-2-methylbenzo[d]thiazole-5-yl)-3,5-dihydroxyhepta-6-enoic acid Step 1: Add NBS (10.43 g, 58.58 mmol, 1.05 eq) to a solution of compound 1 (10 g, 55.79 mmol, 1 eq) in DCM (100 mL). Stir the mixture at 20°C for 12 hours. Combine the reaction mixture with a parallel batch (using 10 g of compound 1), stop the reaction by adding saturated Na2SO3 (100 mL), and extract with DCM (200 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / siRNA = 40 / 1~1 / 1) to obtain compound 2 (17.5 g, yield 60.15%) as a white solid. LCMS (ESI+): m / z = 258.0 (M+1), RT: 0.415 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 minutes with a flow rate of 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes with a flow rate of 2.0 mL / min.

[0776] Step 2: To a solution of compound 2 (5 g, 19.37 mmol, 1 eq) in dioxane (50 mL) and H2O (10 mL), K2CO3 (8.03 g, 58.11 mmol, 3 eq), compound 2A (6.45 g, 29.05 mmol, 1.5 eq), and Pd(dppf)Cl2 (1.42 g, 1.94 mmol, 0.1 eq) were added. The mixture was stirred at 100°C for 12 hours. The reaction mixture was combined with a parallel batch (using 5 g of compound 2), diluted with H2O (300 mL), and extracted with SiO2 (150 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â=1 / 0~4 / 1) on silica gel to obtain compound 3 (9g, yield 85.00%, purity 100%) as a white solid. LC / MS (ESI+): m / z=274.0 (M+1), RT: 0.486 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. Detection method was photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increase the flow rate from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, setting the flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, setting the flow rate to 2.0 mL / min; return to 5% ACN in water and hold for 0.02 minutes, setting the flow rate to 2.0 mL / min.

[0777] Step 3: Add NBS (7.81 g, 43.90 mmol, 4 eq) to a solution of compound 3 (3 g, 10.98 mmol, 1 eq) in DMF (30 mL), and stir the mixture at 50°C for 3 hours. Dilute the mixture with H2O (100 mL) and extract with siRNA (130 mL x 2). Wash the combined organic layer with brine (200 mL x 2), dry over Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by column chromatography on silica gel (PE / siRNA = 1 / 0 to 50 / 1) to obtain compound 4 (3.5 g, yield 89.63%) as a white solid. LCMS (ESI+): m / z = 351.9 (M+1), RT: 0.532 min. LC / MS: Kinetex® EVO C18 2.1×30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, with a flow rate of 2.0 mL / min.

[0778] Step 4: To a solution of compound 4 (3.5 g, 9.94 mmol, 1 eq) in dioxane (35 mL) and H2O (7 mL), K2CO3 (4.12 g, 29.81 mmol, 3 eq), compound 4A (2.21 g, 14.91 mmol, 1.5 eq), and Pd(dppf)Cl2 (727.10 mg, 993.69 μmol, 0.1 eq) were added. The mixture was stirred at 100°C for 5 hours. The mixture was diluted with H2O (200 mL) and extracted with SiO2 (150 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â=1 / 0~50 / 1) on silica gel to obtain compound 5 (2.4 g, yield 77%) as a white solid. LC / MS (ESI+): m / z=314.0 (M+1), RT: 0.533 min. LC / MS: Kinetex® EVO C18 2.1×30 mm 5 μm. Detection method was photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water and held for 0.02 minutes. Set the flow rate to 2.0 mL / min.

[0779] Step 5: To a solution of compound 5 (3.5 g, 11.17 mmol, 1 eq) in DCM (35 mL), BBr3 (13.99 g, 55.84 mmol, 5.38 mL, 5 eq) was added under N2 at -78°C. The mixture was stirred at -78°C for 0.25 hours. The reaction mixture was then warmed to 20°C and stirred for 1.75 hours. The reaction mixture was combined with a parallel batch (using 1.5 g of compound 5) and stopped by adding ice water (100 mL). The mixture was diluted with saturated NaHCO3 (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE / Â=1 / 0~35 / 1) to obtain compound 6 (2.3 g, yield 48%) as a yellow solid. LC / MS (ESI+): m / z=300.0 (M+1), RT: 0.478 min. LC / MS: Kinetex® EVO C18 2.1×30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive electrospray ionization. The MS range was 50~1050. Mobile phase: Increased from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, with a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 minutes, with a flow rate of 2.0 mL / min; returned to 5% ACN in water and held for 0.02 minutes. Set the flow rate to 2.0 mL / min.

[0780] Step 6: To a solution of compound 6 (2.03 g, 6.78 mmol, 1 eq) in DCM (20 mL), DIEA (2.63 g, 20.34 mmol, 3.54 mL, 3 eq) and Tf2O (2.87 g, 10.17 mmol, 1.68 mL, 1.5 eq) were added, and the mixture was stirred at -78 °C for 1 hour. The mixture was diluted with H2O (150 mL) and extracted with siRNA (200 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / siRNA = 1 / 0 to 80 / 1) to obtain compound 7 (2.7 g, yield 94.74%) as a yellow solid. LCMS (ESI+): m / z = 431.9 (M+1), RT: 0.568 min. LC / MS: Kinetex® EVO C18 2.1 × 30 mm 5 μm. Detection method: photodiode array (PDA). MS mode was positive electrospray ionization. MS range was 50 to 1050. Mobile phase: Increase from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water over 0.60 minutes, set flow rate to 2.0 mL / min; then hold at 95% ACN for 0.18 minutes, set flow rate to 2.0 mL / min; return to 5% ACN in water, hold for 0.02 minutes, set flow rate to 2.0 mL / min.

[0781] Step 7: Xphos Pd G4 (99.72 mg, 115.90 μmol, 0.1 eq) and N-cyclohexyl-N-methyl-cyclohexaneamine (1.70 g, 8.69 mmol, 1.84 mL, 7.5 eq) were added to a solution of compound 7 (0.5 g, 1.16 mmol, 1 eq) and compound 7A (1.19 g, 4.64 mmol, 4 eq) in DMF (5 mL). The mixture was stirred at 90 °C for 20 hours. The mixture was combined with a parallel batch (using 0.5 g of compound 7), diluted with H2O (60 mL), and extracted with SiO (60 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (0-10% siRNA in PE) on silica gel, and further pu...

Claims

1. Compound of formula (I'): or a pharmaceutically acceptable salt thereof: During the ceremony, It is a single or double bond, insofar as the valence allows; is a single or double bond, where the double bond is an (E) isomer; X 1 is CH or N; A 1 CR A1 , N, O, or S; A 2 CR A2 , N, O, or S; A 3 is CR A3 , N, O, or S, where at least one A 1 , A 2 , or A 3 is S; R 1 is C 6 ~C 10 The aryl or 5- to 10-membered heteroaryl is one or more halos, -CN, -OH, -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It may also be substituted with a haloalkyl; R 2 is C 3 ~C 10 It is a cycloalkyl; B 1 is H or -OH; B 2 is H or -OH; Y is H, -C(O)OR 3 ,-C(O)N(R 3 ) 2 And, Each R 3 H and C are independent of each other. 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl; R A1 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 10 It is a cycloalkyl; R A2 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, C 3 ~C 10 Cycloalkyl, C 6 ~C 10 It is an aryl or a 5- to 10-membered heteroaryl; and R A3 is H, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 1 to C 6 alkoxyl, C 1 to C 6 haloalkyl, C 3 to C 10 cycloalkyl, one or more C 1 to C 6 alkyl-substituted 3- to 10-member heterocyclyl, C 6 to C 10 aryl, or one or more C 1 to C 6 alkyl-substituted 5- to 10-member heteroaryl, and however, (a)R 2 is cyclopropyl, X 1 is N, A 1 is CR A1 and A 2 is CR A2 when, R A1 and R A2 at least one of which is not H; and (b)R 2 is cyclopropyl, and X 1 N is A 1 CR A1 and A 2 If CH, then R A1 It is not ethyl. Claim 2 is a single or double bond, insofar as its valence allows; X 1 is CH or N; A 1 CR A1 , N, O, or S; A 2 CR A2 , N, O, or S; A 3 CR A3 , N, O, or S, where at least one A 1 , A 2 , or A 3 is S; R 1 is C 6 ~C 10 The aryl or 5- to 10-membered heteroaryl is one or more halos, -CN, -OH, -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It may also be substituted with a haloalkyl; R 2 is C 3 ~C 10 It is a cycloalkyl; R 3 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl; R A1 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl; R A2 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl; and R A3 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl, however, (a)R 2 is cyclopropyl, and X 1 N is A 1 CR A1 and A 2 CR A2 If R A1 and R A2 At least one of them is not H; and (b)R 2 is cyclopropyl, and X 1 N is A 1 CR A1 and A 2 If CH, then R A1 It is not ethyl. The compound according to claim 1.

3. X 1 The compound according to claim 1 or claim 2, wherein is N.

4. A 1 CR A1 A compound according to any one of the preceding claims, wherein the compound is N or S.

5. A 2 CR A2 The compound according to any one of the preceding claims.

6. A 3 CR A3 A compound according to any one of the preceding claims, wherein the compound is N or S.

7. R 1 However, one or more halos, -CN, -OH, -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 C substituted with haloalkyl 6 A compound according to any one of the preceding claims, wherein the compound is aryl.

8. R 1 but The compound according to any one of the preceding claims.

9. R 2 but The compound according to any one of the preceding claims.

10. R 3 A compound according to any one of the preceding claims, wherein is H or methyl.

11. R A1 The compound according to any one of the preceding claims, wherein is H, methyl, or cyclopropyl.

12. R A2 The compound according to any one of the preceding claims, wherein is H, methyl, or cyclopropyl.

13. R A3 H, methyl, phenyl, cyclopropyl, cyclobutyl, cyclohexyl, The compound according to any one of the preceding claims.

14. The compound of formula (I') is: The compound according to any one of the preceding claims, which is the compound or a pharmaceutically acceptable salt thereof.

15. Compounds of formula (I') are also known as (Ia), (Ib), (Ic), or (Id): The compound according to any one of the preceding claims, which is the compound or a pharmaceutically acceptable salt thereof.

16. Compounds of formula (I') are (I'-a), (I'-b), (I'-c), or (I'-d): The compound according to any one of the preceding claims, which is the compound or a pharmaceutically acceptable salt thereof.

17. The compound of formula (I') is also known as formula (Id), (Ie), (If), or (Ig): The compound according to any one of claims 1 to 15, which is the compound or a pharmaceutically acceptable salt thereof.

18. Compounds of formula (I') are (I'-d), (I'-e), (I'-f), or (I'-g): The compound according to any one of the preceding claims, which is the compound or a pharmaceutically acceptable salt thereof.

19. Compounds of formula (I') are also known as (Ih), (Ii), (Ij), or (Ik): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 The compound according to any one of claims 1 to 15, wherein it is a haloalkyl compound and n is 0, 1, 2, 3, or 4.

20. Compounds of formula (I') are (I'-h), (I'-i), (I'-j), or (I'-k): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 A compound according to any one of the preceding claims, wherein it is a haloalkyl compound and n is 0, 1, 2, 3, or 4.

21. Compounds of formula (I') are also known as (Il), (Im), (In), or (Io): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 The compound according to any one of claims 1 to 15, wherein it is a haloalkyl compound and n is 0, 1, 2, 3, or 4.

22. Compounds of formula (I') are also known as (I'-l), (I'-m), (I'-n), or (I'-o): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 A compound according to any one of the preceding claims, wherein it is a haloalkyl compound and n is 0, 1, 2, 3, or 4.

23. Compound of formula (II'): or a pharmaceutically acceptable salt thereof: During the ceremony, is a double bond, where the double bond is an (E) or (Z) isomer; R 1 is C 6 ~C 10 An aryl or 5- to 10-membered heteroaryl, where the aryl or heteroaryl is one or more R 1a It is also fine if it is replaced with; Each R 1a These are independently called Hal, -CN, -OH, and -NH. 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl; R 2 is C 3 ~C 10 It is cycloalkyl or methyl; R 3 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl; R 4 H, C 3 ~C 10 Cycloalkyl, 3-10 membered heterocyclyl, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 It is a haloalkyl; R 5 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 10 It is a cycloalkyl, where the alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl or C 3 ~C 10 Cycloalkyl is one or more C 1 ~C 6 Alkoxy or -O(C 3 ~C 10 It may be substituted with a cycloalkyl group, or R 5 and one R 1a It, together with the intervening atom, forms a 3- to 10-membered heterocycline; and m is either 0 or 1. however, (a)R 2 is cyclopropyl and R 5 C 1 alkoxy-substituted C 1 If it is alkyl, R 4 is not isopropyl; and (b)R 1 monosubstituted C, which is substituted with one fluoropolymer. 6 It is aryl, R 2 is cyclopropyl and R 5 C 1 alkoxy-substituted C 1 If it is alkyl, R 4 is not cyclopropyl; and (c)R 2 If R is methyl, 4 is C 1 ~C 6 It is not alkyl.

24. R 1 However, one or more halos, -CN, -OH, -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 C substituted with haloalkyl 6 The compound according to claim 23, wherein it is an aryl compound.

25. R 1 but The compound according to claim 23 or claim 24.

26. R 2 is methyl, The compound according to any one of claims 23 to 25.

27. R 3 The compound according to any one of claims 23 to 26, wherein is H.

28. R 4 H, The compound according to any one of claims 23 to 27.

29. R 5 ga-(CH 2 )-OCH 3 ,-(CH 2 )-O-cyclopropyl, cyclopropyl, or H, or R 5 and one R 1a The compound according to any one of claims 23 to 28, wherein it combines with an intervening atom to form a tetrahydropyran.

30. The compound of formula (II') is either of formula (II-a) or (II-b): The compound according to any one of claims 23 to 29, which is the compound or a pharmaceutically acceptable salt thereof.

31. The compound of formula (II') is, formula (II-c): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 The compound according to any one of claims 23 to 30, wherein it is a haloalkyl compound and n is 0, 1, 2, 3, or 4.

32. The compound of formula (II') is either of formula (II-d) or (II-e): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 The compound according to any one of claims 23 to 31, wherein it is a haloalkyl compound and n is 0, 1, 2, 3, or 4.

33. The compound of formula (II') is either (II-f) or (II-g): The compound according to any one of claims 23 to 32, which is the compound or a pharmaceutically acceptable salt thereof.

34. In some embodiments, the compound of formula (II') is, as is the compound of formula (II-h): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 The compound according to any one of claims 23 to 33, wherein it is a haloalkyl compound and n is 0, 1, 2, 3, or 4.

35. In some embodiments, compounds of formula (II') are of formula (II-i) or (II-j): A salt of or a pharmaceutically acceptable salt thereof, where R 1a -NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Alkoxyl, or C 1 ~C 6 The compound according to any one of claims 23 to 34, wherein it is a haloalkyl and n is 0, 1, 2, 3, or 4.

36. A compound according to any one of the preceding claims, selected from the compounds listed in Table 1 or Table 1A or their pharmaceutically acceptable salts.

37. A compound according to any one of the preceding claims, selected from the compounds listed in Table 2 or Table 2A or their pharmaceutically acceptable salts.

38. A compound according to any one of the preceding claims, selected from the compounds listed in Table 3 or pharmaceutically acceptable salts thereof.

39. A compound that can be obtained or is obtained by the method described herein, optionally comprising one or more steps described in Schemes 1 to 7.

40. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

41. The pharmaceutical composition according to any one of claims 1 to 34, wherein the compound is selected from the compounds listed in Table 1, Table 1A, Table 2, Table 2A, or Table 3.

42. A method for modulating STMN2 activity using a compound according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 40 or claim 41.

43. A compound according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 40 or claim 41 for use in modulating STMN2 activity.

44. Use of a compound according to any one of claims 1 to 39 in the manufacture of a pharmaceutical product for modulating STMN2 activity.

45. A method for treating or preventing a disease or disorder in a person who needs it, A step of administering to the subject a compound according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 40 or claim 41. The method, including the method described above.

46. A compound according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 40 or claim 41 for use in treating or preventing a disease or disorder.

47. Use of a compound according to any one of claims 1 to 39 in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder.

48. The method, compound, pharmaceutical composition, or use according to any one of claims 45 to 47, wherein the disease or disorder is associated with the STMN2 activity involved.

49. The method, compound, pharmaceutical composition, or use according to any one of claims 45 to 48, wherein the disease or disorder is a neurodegenerative disease or disorder.

50. The method, compound, pharmaceutical composition, or use according to any one of claims 45 to 48, wherein the disease or disorder is an axonal disorder.

51. The method, compound, pharmaceutical composition, or use according to claim 49, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Rett syndrome, Alexander syndrome, Perry syndrome, limbic-dominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), Lewy body dementia (LBD), peripheral neuropathy (chemotherapy-induced neuropathy, trauma-induced), and autism spectrum disorder.

52. The method, compound, pharmaceutical composition, or use according to any one of claims 42 to 51, wherein the subject is a human.

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