Statin derivatives and methods of use thereof

Abstract

The present disclosure relates to compounds of Formula (I ') or Formula (II'): (I ') or (II'), as well as their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation The compounds disclosed herein are useful for modulating stathmin-2 (STMN2) activity, and for treating disorders involving STMN2 activity, such as neurodegenerative diseases and disorders or axonal disorders.

Description

[0001] Related applications

[0002] This application claims priority and interest in U.S. Provisional Application No. 63 / 472,434, filed June 12, 2023; and priority in U.S. Provisional Application No. 63 / 611,822, filed December 19, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] This disclosure relates to statin derivatives and their use as stathmin (e.g., stathmin-2) modulators for the treatment of diseases or disorders (e.g., neurodegenerative diseases).

[0004] Approximately 97% of amyotrophic lateral sclerosis (ALS) cases and almost half of frontotemporal dementia (FTD) patients are pathologically associated with cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 in neurons and glial cells (ALS-TDP and FTD-TDP). Furthermore, mutations in its encoding gene, TARDBP, are a rare cause of both ALS and FTD, suggesting that TDP-43 may be central to the pathogenesis of ALS / FTD. Human mRNAs have been identified as being affected by reduced TDP-43, such as the neuronal growth-associated protein Stathmin-2 (STMN2; also known as SCG10). Aberrant splicing of STMN2 (including aberrantly “hidden” exon 2a) and premature polyadenylation lead to decreased STMN2 protein levels in response to nuclear loss of TDP-43 in cultured neurons. This hidden exon marker can also be 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 binding partner of tubulin heterodimers and is involved in neurite growth and axonal regeneration. Therefore, regulation of STMN2 is a potential therapeutic target for ALS treatment.

[0005] Currently available ALS therapies are non-target-driven and have limited efficacy. There is a need for effective therapies targeting specific factors of the disease's pathophysiology, with STMN2 being a target whose therapeutic modulation is proven manageable. HMG-CoA reductase inhibitors (e.g., statins) are compounds capable of increasing STMN2 activity. This disclosure stems from the need to provide other compounds with improved therapeutic potential for modulating STMN2 activity, particularly compounds with improved physicochemical, pharmacological, and / or pharmaceutical properties. Summary of the Invention

[0006] In some aspects, the present invention provides compounds of formula (I'):

[0007] (I'),

[0008] Or a pharmaceutically acceptable salt thereof, wherein:

[0009] It can be a single or double bond, as long as the valence key allows it;

[0010] It can be a single bond or a double bond, wherein the double bond is an (E) isomer;

[0011] X1 is CH or N;

[0012] A1 is CR A1 , N, O or S;

[0013] A2 is CR A2 , N, O or S;

[0014] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0015] R1 is C6-C 10 Aryl or 5 to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0016] R2 is C3-C 10 cycloalkyl;

[0017] B1 is H or -OH;

[0018] B2 is H or -OH;

[0019] Y represents H, -C(O)OR3, or -C(O)N(R3)2.

[0020] Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0021] R A1 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C 10 cycloalkyl;

[0022] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0023] R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, optional substituted 3- to 10-membered heterocyclic groups with one or more C1-C6 alkyl groups, C6-C 10 aryl, or optionally substituted with one or more C1-C6 alkyl groups, 5 to 10-membered heteroaryl groups.

[0024] The condition is:

[0025] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H; and

[0026] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

[0027] In some aspects, the present invention provides compounds of formula (II'):

[0028] (II'),

[0029] Or a pharmaceutically acceptable salt thereof, wherein:

[0030] It is a double bond, wherein the double bond is an (E) or (Z) isomer;

[0031] R1 is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. 1a ;

[0032] Each R 1a It is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0033] R2 is C3-C 10 cycloalkyl or methyl;

[0034] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0035] R4 is H, C3-C 10Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0036] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C6 alkoxy groups). 10 cycloalkyl); or

[0037] R5 and an R 1a Together with atoms in between, they form 3- to 10-membered heterocyclic groups; and

[0038] m is 0 or 1.

[0039] The condition is:

[0040] (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl; and

[0041] (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group, R2 is a cyclopropyl group, and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not a cyclopropyl group; and

[0042] (c) When R2 is methyl, then R4 is not a C1-C6 alkyl.

[0043] In some respects, this disclosure provides compounds that are obtainable or obtained by methods for preparing compounds as described herein (e.g., methods including one or more steps described in schemes 1-7).

[0044] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers or combinations thereof.

[0045] In some respects, this disclosure provides intermediates as described herein that are suitable for use in methods for preparing compounds as described herein (e.g., the intermediates are selected from those described in Examples 1-2).

[0046] In some respects, this disclosure provides a method (e.g., in vitro or in vivo) for modulating stathmin-2 (STMN2) activity using compounds of this disclosure or pharmaceutically acceptable salts thereof.

[0047] In some respects, this disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject in need of such treatment, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0048] In some respects, this disclosure provides a method for treating a disease or disorder disclosed herein in a subject in need of such treatment, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0049] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for modulating STMN2 activity (e.g., in vitro or in vivo).

[0050] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of the diseases or disorders disclosed herein.

[0051] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for the treatment of the diseases or disorders disclosed herein.

[0052] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for modulating STMN2 activity (e.g., in vitro or in vivo).

[0053] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of the diseases or disorders disclosed herein.

[0054] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of the diseases or disorders disclosed herein.

[0055] In some embodiments, the disease or disorder is a neurodegenerative disease (e.g., amyotrophic lateral sclerosis (ALS)).

[0056] In some implementations, the disease or disorder is associated with axonal degeneration, axonal injury, or axonopathy.

[0057] In some implementations, the neurodegenerative disease is associated with axonal degeneration, axonal injury, or axonopathy.

[0058] In some respects, this disclosure provides a method for preparing the compounds of this disclosure.

[0059] In some aspects, this disclosure provides a method for preparing a compound, the method comprising one or more steps described herein.

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, singular forms also include plural forms unless the context clearly indicates otherwise. Although similar or equivalent methods and materials to those described herein may be used in the practice or experimentation of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not recognized as prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described are merely exemplary and are not intended to be limiting. In case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structure shall prevail.

[0061] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. Brief description of the attached diagram

[0063] Figure 1 Compound activity in WT (left) and TDP-43 mutant (right) SH-SY5Y cells was depicted, with darker gray areas associated with higher relative light units (RLU) per cell.

[0064] Figure 2 The activity of the compounds of the present invention in the mutant TDP-43 cell line was described compared with known controls. Invention Details

[0066] This invention relates to statin derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which modulate the expression or activity of stathmin-2 (STMN2) and are therefore suitable for use in treatments in humans or animals. This disclosure also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating diseases involving STMN2, such as neurodegenerative diseases or disorders, or diseases or disorders associated with axonopathy.

[0067] definition

[0068] Unless otherwise stated, the following terms used in this specification and claims shall have the meanings set forth below.

[0069] Not wishing to be limited by this statement, it should be understood that while various options for variables are described herein, this disclosure is intended to cover feasible implementations with combinations of options. This disclosure can be interpreted as excluding infeasible implementations resulting from certain combinations of options. For example, while various options for variables are described herein, this disclosure can be interpreted as excluding structures of infeasible compounds resulting from certain combinations of variables.

[0070] As used herein, the terms "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" are intended to include C1, C2, C3, C4, C5, or C6 straight-chain (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 alkyl groups include portions having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, the straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in another embodiment, the straight-chain or branched alkyl group has four or fewer carbon atoms.

[0071] As used herein, the term "optionally substituted alkyl" means an unsubstituted alkyl group or an alkyl group having a specified substituent that replaces one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarbamate, sulfate, alkyl sulfinyl, sulfonato, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0072] As used herein, the term "alkenyl" includes unsaturated aliphatic groups that are similar in length and possible substitutions to the aforementioned alkyl groups but contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" includes alkenyl groups containing 2-6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3-6 carbon atoms.

[0073] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarbamate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0074] As used herein, the term "alkynyl" includes unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups described above, but contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, nonynyl, decanynyl) and branched-chain alkynyl groups. In some embodiments, the straight-chain or branched alkynyl group has six or fewer carbon atoms in its main chain (e.g., C2-C6 for straight chains and C3-C6 for branched chains). The term "C2-C6" includes alkynyl groups containing 2-6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3-6 carbon atoms. The terms "C2-C6 alkenyl linker" or "C2-C6 alkenyl linker" as used herein are intended to include C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6 sub-olefinic linkers are intended to include C2, C3, C4, C5 and C6 sub-olefinic linkers.

[0075] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl group or an alkynyl group having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarbamate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0076] Other optional substituted portions (such as optional substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include unsubstituted portions and portions having one or more specified substituents. For example, substituted heterocycloalkyl includes 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.

[0077] As used in this article, the term "cycloalkyl group" refers to a group having 3-30 carbon atoms (e.g., C3-C4). 12 C3-C 10 Cyclic hydrocarbons (or C3-C8) are monocyclic or polycyclic (e.g., fused rings, bridged rings, or spirocyclic) systems of saturated or partially unsaturated hydrocarbons. Examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cyclic hydrocarbon groups, only one ring in the cyclic hydrocarbon group needs to be non-aromatic.

[0078] As used herein, the term "heterocyclic hydrocarbon group" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic), or 11-14 membered tricyclic (fused, bridged, or spirocyclic) ring system having one or more heteroatoms (such as O, N, S, P, or Se), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms, said heteroatoms being independently selected from nitrogen, oxygen, and sulfur, unless otherwise stated. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazine, pyrrolyl, dioxane, tetrahydrofuranyl, isoindololinyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxacyclopropane, aziridine, oxacyclobutane, thiohexacyclobutane, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazacycloheptane, 1,4-oxazoloheptanyl, 2-oxacycloheptane, etc. -5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5 '-furano[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-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]pyridinyl, 5,6,7 ,8-Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, 5,6-dihydro-4H-cyclopentadien[b]thiophene, etc. In the case of polycyclic heterocyclic alkyl groups, only one ring in the heterocyclic alkyl group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0079] It should be understood that when a variable has two connections with the remainder of the formula of the compound, these two connections can be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is a cycloalkyl or heterocyclic group and has two connections with the remainder of the formula of the compound, these two connections can be at the same atom or different atoms of the cycloalkyl or heterocyclic group.

[0080] As used herein, the term "aryl" includes aromatic groups, including "conjugated" or polycyclic systems having one or more aromatic rings and containing no heteroatoms in the ring structure. The term aryl includes both monovalent and divalent types. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc.

[0081] 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 heterocycles, the ring consisting of a carbon atom and one or more heteroatoms, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms, said heteroatoms being independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p (where p = 1 or 2). It should be noted that the total number of S and O atoms in an aromatic heterocycle does not exceed one. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetraazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Heteroaryl groups can also fused or bridge with non-aromatic alicyclic or heterocyclic groups to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isooxazolyl).

[0082] In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl, such as tricyclic and bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazolium, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, denitropurine, or indazine.

[0083] The cyclic hydrocarbon group, heterocyclic group, aryl group, or heteroaryl ring may be substituted at one or more ring positions (e.g., the carbon or heteroatom forming the ring, such as N) with substituents such as those described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic ester, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, amino Carbonyl, alkylthiocarbonyl, phosphate ester, phosphonate alkyl, hypophosphonate alkyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarbamate, sulfate ester, alkylsulfinyl, sulfonate alkyl, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties. Aryyl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic groups to form polycyclic systems (e.g., tetrahydronaphthalene, methylenedioxyphenyl such as benzo[d][1,3]dioxacyclopentadien-5-yl).

[0084] As used herein, the term "about" means that the quantity, value, or duration is 10% or less of the quantity, value, or duration. In some embodiments, "about" means ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the quantity, value, or duration. In other embodiments, "about" means ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the quantity, value, or duration. In other embodiments, "about" means ±5% of the quantity, value, or duration. In other embodiments, "about" means ±2% or ±1% of the listed quantity, value, or duration. For example, in some embodiments, when the term "about" is used to describe a temperature or temperature range, these terms mean the described temperature or temperature range ±5°C, ±2°C, or ±1°C. In other embodiments, the term "about" means the described temperature or temperature range ±2°C.

[0085] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by an option of a specified group, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. When the substituent is an oxo or ketone (i.e., =O), then two hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Cyclic double bonds as used herein are double bonds formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are intended to mean a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic agent.

[0086] When the bond to a substituent is shown to be an intersecting bond with two atoms in the linking ring, then such a substituent can bond to any atom in the ring. When a substituent is listed without specifying which atom it bonds to the rest of the compound in the given formula, then such a substituent can bond to any atom in the formula. Combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound.

[0087] When any variable (e.g., R) appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for every other occurrence. Thus, for example, if a group is shown to be substituted by 0-2 R moieties, then that group may optionally be substituted by at most two R moieties, and R is independently selected from the definition of R each time it appears. Furthermore, combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound.

[0088] As used herein, the term "hydroxyl" or "hydroxyl" includes groups having -OH or -O-.

[0089] The term “halogenated” or “halogen” as used in this article refers to fluorine, chlorine, bromine, and iodine.

[0090] The terms “halogenated alkyl” or “halogenated alkoxy” refer to alkyl or alkoxy groups that are substituted with one or more halogen atoms.

[0091] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl or a haloalkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarbamate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety.

[0092] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently attached to an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, hypophosphonate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkyl thio, aryl thio, thiocarbamate, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0093] The expressions “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”, “choose from the group consisting of A, B and C”, “select from A, B and C”, etc., used interchangeably in this document, and all mean an option from the group consisting of A, B and / or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise indicated.

[0094] It should be understood that this disclosure provides methods for synthesizing compounds of any formula described herein. This disclosure also provides detailed methods for synthesizing the various disclosed compounds according to the following schemes and those shown in the examples.

[0095] It should be understood that throughout the specification, when a composition is described as having, including, or comprising specific components, it is assumed that the composition is also substantially composed of or consisting of the listed components. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process is also substantially composed of or consisting of the listed processing steps. Furthermore, it should be understood that the order of the steps or the sequence of certain actions is not important, as long as the invention remains feasible. Moreover, two or more steps or actions may be performed simultaneously.

[0096] It should be understood that the synthetic methods of this disclosure can allow for a variety of functional groups, and therefore a wide range of substituted starting materials can be used. The methods typically provide the desired final compound at or near the end of the process, although it may be desirable in some cases to further convert the compound into its pharmaceutically acceptable salt.

[0097] It should be understood that the compounds of this disclosure can be prepared in various ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates using standard synthetic methods and procedures known to those skilled in the art, or which will be apparent to those skilled in the art from the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as for functional group transformations and manipulations, are available from relevant scientific literature or standard textbooks in the art. Although not limited to any one or a few sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structures, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, 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) (incorporated herein by reference) are known and widely accepted reference textbooks on organic synthesis to those skilled in the art.

[0098] Those skilled in the art will notice that the order of certain steps, such as the introduction and removal of protecting groups, can be altered in the reaction sequence and synthetic scheme described herein. They will also recognize that certain groups may require protection from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove them can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999.

[0099] It should be understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of the said compound to provide the treatment or prevention as described herein. It should be further understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of the said compound to prepare a medicament for treating or preventing such a condition. The treatment or prevention includes treating or preventing human or non-human animals, including rodents and other disease models.

[0100] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of the said compound to provide the treatment as described herein. It should be further understood that, unless otherwise stated, any description of a treatment method includes the use of the said compound to prepare a drug for treating such a condition. The treatment includes treating human or non-human animals, including rodents and other disease models.

[0101] As used herein, the term "subject" includes humans and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

[0102] As used herein, the term "subject in need" refers to a subject with a disease or a subject with an increased risk of developing a disease. In some embodiments, the subject in need has a pathological defect in STMN2. The subject in need may be a subject who has been previously diagnosed or identified with a disease or disorder disclosed herein. The subject in need may also be a subject with a disease or disorder disclosed herein. Alternatively, the subject in need may be a subject with an increased risk of developing such a disease or disorder relative to the general population (i.e., a subject predisposed to developing such a disorder relative to the general population). The subject in need may have a treatment-resistant or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that is unresponsive to treatment 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 therapies for the disease or disorder disclosed herein and failed. In some embodiments, the subject in need has received at least one prior therapy.

[0103] As used herein, the term “treatment” describes the management and care of a patient in order to combat a disease, condition, or disorder, and includes the administration of compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of the disease, condition, or disorder. The term “treatment” may also include treatment of in vitro cell or animal models. It should be understood that references to “treatment” include the relief of existing symptoms of a condition. Thus, “treatment” for a state, disorder, or disorder includes: (1) preventing or delaying the onset of clinical symptoms of a state, disorder, or disorder in a person who may have or is susceptible to the state, disorder, or disorder but has not yet experienced or displayed clinical or subclinical symptoms of the state, disorder, or disorder; (2) suppressing the state, disorder, or disorder, i.e., preventing, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e., causing the disappearance of at least one of the state, disorder, or disorder or its clinical or subclinical symptoms.

[0104] It should be understood that the compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs or solvates may or may not be used for the prevention of related diseases, symptoms or disorders, or for the identification of suitable candidates for such purposes.

[0105] The terms “prevention,” “stopping,” or “protection from” used in this article describe reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0106] It should be understood that those skilled in the art may refer to general reference texts for a detailed description of the known or equivalent techniques discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd 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, 18th Edition (1990). Of course, these texts may also be referenced when making or using any aspect of this disclosure.

[0107] It should be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein and at least one or more pharmaceutically acceptable excipients, diluents, adjuvants, carriers, or combinations thereof.

[0108] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds disclosed herein, in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage form can be any of a variety of forms, including, for example, capsules, intravenous infusion bags, tablets, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates, or isomers) in a unit dosage composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that, depending on the patient's age and condition, it may sometimes be necessary to make routine variations in dosage. Dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, sublingual, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal application of the compounds used in this 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 with any desired preservatives, buffers, or propellants.

[0109] As used herein, the term "pharmaceutically acceptable" means a compound, anion, cation, material, composition, carrier, and / or dosage form that, to a reasonable extent of medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0110] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for both veterinary and human pharmaceutical applications. As used in this specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

[0111] 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, such as intravenous, intradermal, subcutaneous, oral (e.g., oral ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial 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 agents for adjusting the pH such as sodium chloride or dextran. The pH may be adjusted with an acid or base (such as hydrochloric acid or sodium hydroxide). Parenteral preparations may be packaged in ampoules, disposable syringes, or multiple-dose tubular bottles made of glass or plastic.

[0112] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to a subject by many well-known methods currently used for chemotherapeutic treatment. For example, the compounds of this disclosure can be injected into the bloodstream or body cavity, administered orally, or applied through the skin as a patch. The selected dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. The condition (e.g., the disease or disorder disclosed herein) and the patient's health should preferably be closely monitored during treatment and for a reasonable period after treatment.

[0113] As used herein, the term "therapeutic effective amount" refers to the amount of a pharmaceutical agent used to treat, improve, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents chosen for administration. A therapeutically effective amount for a given situation can be determined through routine experiments within the skill and judgment of a clinician. Dosage can vary within this range depending on the dosage form used, patient sensitivity, and route of administration.

[0114] Adjust the dosage and administration to provide adequate levels of active agent or maintain the desired effect. Factors to consider include the severity of the condition, the subject's general health, age, weight and sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to the therapy. Depending on the half-life and clearance rate of the specific formulation, long-acting drug combinations may be administered every 3 to 4 days, weekly, or bi-weekly.

[0115] Pharmaceutical compositions containing the active compounds of this disclosure can be prepared in ways commonly known, such as by means of conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, embedding, or lyophilization processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of the active compound into articles suitable for pharmaceutical use. Of course, appropriate formulations depend on the chosen route of administration.

[0116] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in the water-soluble case) or dispersions, and sterile powders for immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, and Cremophor EL. TM (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid enough to be easily injected. It must be stable under the conditions of preparation and storage and must be preserved from contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size (in the case of dispersions), and by using surfactants. Inhibition of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include an isotonic agent in the composition, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride. The absorption of the injectable composition can be prolonged by including an absorption-delaying agent in the composition, such as aluminum monostearate and gelatin.

[0117] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound, along with one or more of the components listed above, into a suitable solvent, followed by filtration and sterilization. Dispersions are typically prepared by incorporating the active compound into a sterile medium containing a base dispersion medium and any other desired components from those listed above. For sterile powders used to prepare sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, which produce a powder containing the active ingredient plus any other desired components from its previously sterile filtered solution.

[0118] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be mixed with excipients and administered in the form of tablets, lozenges, capsules, or sacs. Oral compositions may also be prepared using a liquid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and by rinsing and spitting or swallowing. Pharmaceutically compatible binders and / or excipients may be included as part of the composition. The tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0119] 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 such as carbon dioxide) or a sprayer.

[0120] Systemic application can also be via transmucosal or transdermal routes. For transmucosal or transdermal application, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal application. Transmucosal application can be accomplished by using nasal sprays, powders, or suppositories. For transdermal application, the active compound is formulated into ointments, creams, gels, or lotions generally known in the art.

[0121] Active compounds can be prepared together with pharmaceutically acceptable carriers that protect the compounds 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, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be understood by those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including 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 U.S. Patent No. 4,522,811.

[0122] Of particular advantage is that, for ease of administration and uniform dosage, oral or parenteral compositions are formulated in dose units. The dose unit form used herein refers to a physically discrete unit suitable as a unit dose for a subject to be treated; each unit contains a predetermined amount of active compound, calculated to produce the desired therapeutic effect, in combination with the desired pharmaceutical carrier. The specifications of the dose unit form of this disclosure depend on and are directly dependent on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0123] It should be understood that the pharmaceutical composition may be included in a container, packet or dispenser together with the instructions for use.

[0124] It should be understood that all these forms are also considered within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

[0125] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the compounds of this disclosure, wherein the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and basic 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 or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, hydroxyacetaminophen, hexylresorcinic acid, hydrobamic acid, etc. Hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthenic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, primordial acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, hypoacetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0126] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, N,N′-dibenzylethylenediamine salt (benzathine salt), tromethamine salt, ammonium salt, arginine salt, or lysine salt.

[0127] Other pharmaceutically acceptable examples of 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]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also includes salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or salts formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. In salt form, it should be understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0128] The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, transdermally, pulmonaryly, by inhalation, sublingually, sublingually, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In one embodiment, the compound is administered orally.

[0129] The dosing regimen using the compound is selected based on a number of factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salt used.

[0130] Techniques for formulating and administering the disclosed compounds of this disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, are combined with a pharmaceutically acceptable carrier or diluent for use in a pharmaceutical article. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dose within the range described herein.

[0131] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will become apparent from the various embodiments. The provided embodiments illustrate different components and methods that can be used to practice this disclosure. The embodiments do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods that can be used to practice this disclosure.

[0132] In the synthetic schemes described herein, compounds may be drawn using a specific configuration for simplicity. Such a specific configuration should not be construed as limiting the disclosure to one or more isomers, tautomers, positional isomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0133] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were expressly and individually identified as incorporated herein by reference. The citation of publications and patent documents is not intended to acknowledge that any of them is prior art, nor does it constitute any admission of their content or date. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and the following examples are for illustrative purposes and not for limiting the scope of the following claims.

[0134] As used herein, the phrase "compounds of this disclosure" refers to those compounds disclosed herein, both generally and specifically.

[0135] The compounds disclosed herein

[0136] Formula (I')

[0137] In some aspects, the present invention provides compounds of formula (I'):

[0138] (I'),

[0139] Or a pharmaceutically acceptable salt thereof, wherein:

[0140] It can be a single or double bond, as long as the valence key allows it;

[0141] It can be a single bond or a double bond, wherein the double bond is an (E) isomer;

[0142] X1 is CH or N;

[0143] A1 is CR A1 , N, O or S;

[0144] A2 is CR A2 , N, O or S;

[0145] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0146] R1 is C6-C10 Aryl or 5 to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0147] R2 is C3-C 10 cycloalkyl;

[0148] B1 is H or -OH;

[0149] B2 is H or -OH;

[0150] Y represents H, -C(O)OR3, or -C(O)N(R3)2.

[0151] Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0152] R A1 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C 10 cycloalkyl;

[0153] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0154] R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, optional substituted 3- to 10-membered heterocyclic groups with one or more C1-C6 alkyl groups, C6-C 10 aryl, or optionally substituted with one or more C1-C6 alkyl groups, 5 to 10-membered heteroaryl groups.

[0155] The condition is:

[0156] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H; and

[0157] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then RA1 It is not ethyl.

[0158] In some aspects, the present invention provides compounds of formula (I'), or pharmaceutically acceptable salts thereof, wherein:

[0159] It can be a single or double bond, as long as the valence key allows it;

[0160] It can be a single bond or a double bond, wherein the double bond is an (E) isomer;

[0161] X1 is CH or N;

[0162] A1 is CR A1 , N, O or S;

[0163] A2 is CR A2 , N, O or S;

[0164] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0165] R1 is C6-C 10 Aryl or 5 to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0166] R2 is C3-C 10 cycloalkyl;

[0167] B1 is H or -OH;

[0168] B2 is H or -OH;

[0169] Y represents H, -C(O)OR3, or -C(O)N(R3)2.

[0170] Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0171] R A1 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C 10 cycloalkyl;

[0172] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C10 aryl or 5- to 10-membered heteroaryl; and

[0173] R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, optional substituted 3- to 10-membered heterocyclic groups with one or more C1-C6 alkyl groups, C6-C 10 aryl, or optionally substituted with one or more C1-C6 alkyl groups, 5 to 10-membered heteroaryl groups.

[0174] The condition is:

[0175] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H.

[0176] In some aspects, the present invention provides compounds of formula (I'), or pharmaceutically acceptable salts thereof, wherein:

[0177] It can be a single or double bond, as long as the valence key allows it;

[0178] It can be a single bond or a double bond, wherein the double bond is an (E) isomer;

[0179] X1 is CH or N;

[0180] A1 is CR A1 , N, O or S;

[0181] A2 is CR A2 , N, O or S;

[0182] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0183] R1 is C6-C 10 Aryl or 5 to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0184] R2 is C3-C 10 cycloalkyl;

[0185] B1 is H or -OH;

[0186] B2 is H or -OH;

[0187] Y represents H, -C(O)OR3, or -C(O)N(R3)2.

[0188] Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0189] R A1 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C 10 cycloalkyl;

[0190] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0191] R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, optional substituted 3- to 10-membered heterocyclic groups with one or more C1-C6 alkyl groups, C6-C 10 aryl, or optionally substituted with one or more C1-C6 alkyl groups, 5 to 10-membered heteroaryl groups.

[0192] The condition is:

[0193] (b) When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

[0194] In some aspects, the present invention provides compounds of formula (I):

[0195] (I),

[0196] Or a pharmaceutically acceptable salt thereof, wherein:

[0197] It can be a single or double bond, as long as the valence key allows it;

[0198] X1 is CH or N;

[0199] A1 is CR A1 , N, O or S;

[0200] A2 is CR A2 , N, O or S;

[0201] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0202] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0203] R2 is C3-C 10 cycloalkyl;

[0204] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0205] R A1 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0206] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0207] R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0208] The condition is:

[0209] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H; and

[0210] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

[0211] In some embodiments, the compound of formula (I') is a compound of formula (I).

[0212] In some embodiments, the compound is of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0213] It can be a single or double bond, as long as the valence key allows it;

[0214] X1 is CH or N;

[0215] A1 is CR A1 , N, O or S;

[0216] A2 is CR A2 , N, O or S;

[0217] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0218] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0219] R2 is C3-C 10 cycloalkyl;

[0220] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0221] R A1 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0222] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; and

[0223] R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0224] The condition is:

[0225] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H; and

[0226] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

[0227] In some aspects, the present invention provides compounds of formula (I):

[0228] (I),

[0229] Or a pharmaceutically acceptable salt thereof, wherein:

[0230] It can be a single or double bond, as long as the valence key allows it;

[0231] X1 is CH or N;

[0232] A1 is CR A1 , N, O or S;

[0233] A2 is CR A2 , N, O or S;

[0234] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0235] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0236] R2 is C3-C 10 cycloalkyl;

[0237] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0238] R A1 It is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0239] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0240] R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0241] The condition is:

[0242] (b) When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

[0243] In some aspects, the present invention provides compounds of formula (I):

[0244] (I),

[0245] Or a pharmaceutically acceptable salt thereof, wherein:

[0246] It can be a single or double bond, as long as the valence key allows it;

[0247] X1 is CH or N;

[0248] A1 is CR A1 , N, O or S;

[0249] A2 is CR A2 , N, O or S;

[0250] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0251] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0252] R2 is C3-C 10 cycloalkyl;

[0253] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0254] R A1 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0255] R A2 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0256] R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0257] The condition is:

[0258] (b) When R2 is cyclopropyl, X1 is N, and A1 is CRA1 And when A2 is CH, then R A1 It is not ethyl.

[0259] In some aspects, the present invention provides compounds of formula (I):

[0260] (I),

[0261] Or a pharmaceutically acceptable salt thereof, wherein:

[0262] It can be a single or double bond, as long as the valence key allows it;

[0263] X1 is CH or N;

[0264] A1 is CR A1 , N, O or S;

[0265] A2 is CR A2 , N, O or S;

[0266] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0267] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0268] R2 is C3-C 10 cycloalkyl;

[0269] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0270] R A1 It is H, C1 or C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0271] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0272] R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0273] The condition is:

[0274] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H.

[0275] In some aspects, the present invention provides compounds of formula (I):

[0276] (I),

[0277] Or a pharmaceutically acceptable salt thereof, wherein:

[0278] It can be a single or double bond, as long as the valence key allows it;

[0279] X1 is CH or N;

[0280] A1 is CR A1 , N, O or S;

[0281] A2 is CR A2 , N, O or S;

[0282] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0283] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0284] R2 is C3-C 10 cycloalkyl;

[0285] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0286] R A1 It is a C1 or C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0287] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0288] R A3It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0289] In some aspects, the present invention provides compounds of formula (I):

[0290] (I),

[0291] Or a pharmaceutically acceptable salt thereof, wherein:

[0292] It can be a single or double bond, as long as the valence key allows it;

[0293] X1 is CH or N;

[0294] A1 is CR A1 , N, O or S;

[0295] A2 is CR A2 , N, O or S;

[0296] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0297] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0298] R2 is C3-C 10 cycloalkyl;

[0299] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0300] R A1 It is H, C1 or C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0301] R A2 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0302] R A3 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0303] In some aspects, the present invention provides compounds of formula (I”):

[0304] (I”)

[0305] Or a pharmaceutically acceptable salt thereof, wherein:

[0306] It can be a single or double bond, as long as the valence key allows it;

[0307] X1 is CH or N;

[0308] A1 is CR A1 , N, O or S;

[0309] A2 is CR A2 , N, O or S;

[0310] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0311] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0312] R2 is C3-C 10 cycloalkyl;

[0313] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0314] R A1 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0315] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0316] R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0317] The condition is:

[0318] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CRA2 When, then R A1 and R A2 At least one of them is not H; and

[0319] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

[0320] In some aspects, the present invention provides compounds of formula (I”'):

[0321] (I”')

[0322] Or a pharmaceutically acceptable salt thereof, wherein:

[0323] It can be a single or double bond, as long as the valence key allows it;

[0324] X1 is CH or N;

[0325] A1 is CR A1 , N, O or S;

[0326] A2 is CR A2 , N, O or S;

[0327] A3 is CR A3 , N, O or S, wherein at least one of A1, A2 or A3 is S;

[0328] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0329] R2 is C3-C 10 cycloalkyl;

[0330] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0331] R A1 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0332] R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; and

[0333] R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0334] The condition is:

[0335] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H; and

[0336] When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

[0337] It should be understood that, 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 can be selected from the groups described herein where applicable, and for 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 may, where applicable, interact with the remaining variables Y, X1, A1, A2, A3, B1, B2, R1, R2, R3, R A1 R A2 and R A3 Any combination of one or more of the groups described herein.

[0338] In some implementation schemes, It is a single key, provided that the valence key is allowed.

[0339] In some implementation schemes, It is a double bond, provided the valence bond is allowed.

[0340] In some implementation schemes, It is a single key.

[0341] In some implementation schemes, It is a double bond, wherein the double bond is an (E) isomer.

[0342] In some implementations, X1 is CH or N.

[0343] In some implementations, X1 is CH. In some implementations, X1 is N.

[0344] In some implementations, A1 is CR A1 , N, O or S.

[0345] In some implementations, A1 is CR A1 In some implementations, A1 is CH.

[0346] In some implementations, A1 is N. In some implementations, A1 is O. In some implementations, A1 is S.

[0347] In some implementations, A2 is CR A2 , N, O or S.

[0348] In some implementations, A2 is CR A2 In some implementations, A2 is CH.

[0349] In some implementations, A2 is N. In some implementations, A2 is O. In some implementations, A2 is S.

[0350] In some implementations, A3 is CR A3 , N, O or S.

[0351] In some implementations, A3 is CR A3 In some implementations, A3 is CH.

[0352] In some implementations, A3 is N. In some implementations, A3 is O. In some implementations, A3 is S.

[0353] In some implementations, at least one of A1, A2, or A3 is S.

[0354] In some implementations, B1 is H.

[0355] In some implementations, B1 is -OH.

[0356] In some implementations, B2 is H.

[0357] In some implementations, B2 is -OH.

[0358] In some implementations, Y is H.

[0359] In some embodiments, Y is -C(O)OR3. In some embodiments, Y is -C(O)OH. In some embodiments, Y is -C(O)OMe.

[0360] 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.

[0361] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl compounds.

[0362] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0363] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, which are substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0364] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, which are substituted with one or more halogens.

[0365] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, which are substituted with a halogen.

[0366] In some implementations, R1 is C6-C 10 Aryl.

[0367] In some implementations, R1 is C6-C 10 Aryl group, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0368] In some implementations, R1 is C6-C 10 Aryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0369] In some implementations, R1 is C6-C 10 Aryl groups are substituted with one or more halogens.

[0370] In some implementations, R1 is C6-C 10 Aryl groups are substituted with one halogen.

[0371] In some implementations, R1 is a C6 aryl group.

[0372] In some embodiments, R1 is a C6 aryl group, which may optionally be substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0373] In some embodiments, R1 is a C6 aryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0374] In some implementations, R1 is a C6 aryl group, which is substituted with one or more halogens.

[0375] In some implementations, R1 is a C6 aryl group, which is substituted with a halogen.

[0376] In some implementations, R1 is a 5- to 10-membered heteroaryl group.

[0377] In some embodiments, R1 is a 5- to 10-membered heteroaryl group, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0378] In some embodiments, R1 is a 5- to 10-membered heteroaryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0379] In some implementations, R1 is a 5- to 10-membered heteroaryl group, which is substituted with one or more halogens.

[0380] In some implementations, R1 is a 5- to 10-membered heteroaryl group, which is substituted with a halogen.

[0381] In some implementations, R1 is a 6-membered heteroaryl group.

[0382] In some embodiments, R1 is a 6-membered heteroaryl group, which may be optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0383] In some embodiments, R1 is a 6-membered heteroaryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0384] In some implementations, R1 is a 6-membered heteroaryl group, which is substituted with one or more halogens.

[0385] In some implementations, R1 is a 6-membered heteroaryl group, which is substituted with a halogen.

[0386] In some implementations, R1 is a 6-membered heteroaryl group, which is substituted with two halogens.

[0387] In some implementations, R1 is a 6-membered heteroaryl group, which is substituted with a halogen and a methyl group.

[0388] In some implementations, R1 is , , , , , , ,or .

[0389] In some implementations, R1 is , ,or .

[0390] In some implementations, R1 is .

[0391] In some implementations, R1 is replaced in at least two positions.

[0392] In some implementations, R1 is replaced in at least 3 bits.

[0393] In some implementations, R1 is replaced in at least 4 bits.

[0394] In some implementations, R2 is C3-C 10 Cycloalkyl.

[0395] In some implementations, R2 is a C3 cycloalkyl (cyclopropyl).

[0396] In some implementations, R2 is a C4 cycloalkyl (cyclobutyl).

[0397] 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 Cycloalkyl.

[0398] In some implementations, R2 is C5-C 10 Cycloalkyl. In some embodiments, R2 is a bridging C5-C group. 10 Cycloalkyl. In some embodiments, R2 is a bicyclic C5-C64. 10 Cycloalkyl.

[0399] In some implementations, R2 is .

[0400] In some embodiments, R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0401] In some implementations, R3 is H.

[0402] In some embodiments, R3 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0403] In some implementations, R3 is a C1-C6 alkyl group.

[0404] 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.

[0405] In some embodiments, R3 is a C2-C6 alkenyl group (e.g., vinyl, propenyl, butenyl).

[0406] In some implementations, R3 is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0407] In some implementations, R3 is a C1-C6 alkoxy group.

[0408] In some embodiments, R3 is methoxy. In some embodiments, R3 is ethoxy. In some embodiments, R3 is propoxy. In some embodiments, R3 is butoxy. In some embodiments, R3 is pentoxy. In some embodiments, R3 is hexoxy.

[0409] In some implementations, R3 is a C1-C6 haloalkyl group.

[0410] In some embodiments, R3 is a halomethyl group. In some embodiments, R3 is a haloethyl group. In some embodiments, R3 is a halopropyl group. In some embodiments, R3 is a halobutyl group. In some embodiments, R3 is a halopentyl group. In some embodiments, R3 is a halohexyl group.

[0411] In some embodiments, at least one R3 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0412] In some embodiments, at least one R3 is a C1-C6 alkyl group.

[0413] 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.

[0414] In some embodiments, at least one R3 is a C2-C6 alkenyl group (e.g., vinyl, propenyl, butenyl).

[0415] In some embodiments, at least one R3 is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0416] In some embodiments, at least one R3 is a C1-C6 alkoxy group.

[0417] In some embodiments, at least one R3 is methoxy. In some embodiments, at least one R3 is ethoxy. In some embodiments, at least one R3 is propoxy. In some embodiments, at least one R3 is butoxy. In some embodiments, at least one R3 is pentoxy. In some embodiments, at least one R3 is hexoxy.

[0418] In some embodiments, at least one R3 is a C1-C6 haloalkyl group.

[0419] In some embodiments, at least one R3 is a halomethyl group. In some embodiments, at least one R3 is a haloethyl group. In some embodiments, at least one R3 is a halopropyl group. In some embodiments, at least one R3 is a halobutyl group. In some embodiments, at least one R3 is a halopentyl group. In some embodiments, at least one R3 is a halohexyl group.

[0420] In some implementations, R3 is H or methyl.

[0421] In some implementation schemes, R A1 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C 10 Cycloalkyl.

[0422] In some implementation schemes, R A1 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0423] In some implementation schemes, R A1 For H.

[0424] In some implementation schemes, R A1 It is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0425] In some implementation schemes, R A1 It is a C1-C6 alkyl group.

[0426] In some implementation schemes, R A1 It is methyl. In some embodiments, R A1 It is ethyl. In some embodiments, R A1 It is propyl. In some embodiments, R A1 For butyl. In some implementations, R A1 It is pentyl. In some implementations, R A1 For its own foundation. In some implementation schemes, R A1It is isopropyl. In some embodiments, R A1 It is isobutyl. In some embodiments, R A1 It is isopentyl. In some embodiments, R A1 It is an allohexyl group. In some implementations, R A1 It is sec-butyl. In some implementations, R A1 It is sec-amyl. In some implementations, R A1 For Zhongjiji. In some implementations, R A1 It is tert-butyl.

[0427] In some implementation schemes, R A1 It is C2-C6 alkenyl (e.g., vinyl, propenyl, butenyl).

[0428] In some implementation schemes, R A1 It is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0429] In some implementation schemes, R A1 It is a C1-C6 alkoxy group.

[0430] In some implementation schemes, R A1 It is methoxylated. In some embodiments, R A1 It is ethoxylated. In some embodiments, R A1 It is propoxylated. In some embodiments, R A1 It is butoxylated. In some embodiments, R A1 It is pentoxygenated. In some embodiments, R A1 It is an hexoxy group.

[0431] In some implementation schemes, R A1 It is a C1-C6 haloalkyl group.

[0432] In some implementation schemes, R A1 It is a halomethyl group. In some embodiments, R A1 It is a haloethyl. In some embodiments, R A1 It is a halogenated propyl group. In some embodiments, R A1 It is a halogenated butyl. In some embodiments, R A1 It is a halopentyl group. In some embodiments, R A1 It is a halogenated hexyl group.

[0433] In some implementation schemes, R A1 For C3-C 10 Cycloalkyl.

[0434] In some implementation schemes, R A1 It is a C3 cycloalkyl (cyclopropyl).

[0435] In some implementation schemes, R A1 It is a C4 cycloalkyl (cyclobutyl).

[0436] In some implementation schemes, R A1 It is a C5 cycloalkyl group. In some embodiments, R A1 It is a C6 cycloalkyl group. In some embodiments, R A1 It is a C7 cycloalkyl group. In some embodiments, R A1 It is a C8 cycloalkyl group. In some embodiments, R A1 It is a C9 cycloalkyl group. In some embodiments, R A1 C 10 Cycloalkyl.

[0437] In some implementation schemes, R A1 C5-C 10 Cycloalkyl. In some embodiments, R A1 For bridging C5-C 10 Cycloalkyl. In some embodiments, R A1 For dual-ring C5-C 10 Cycloalkyl.

[0438] In some implementation schemes, R A1 It can be H, methyl, or cyclopropyl.

[0439] In some implementation schemes, R A1 It is H or methyl.

[0440] In some implementation schemes, R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl compounds.

[0441] In some implementation schemes, R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl compounds.

[0442] In some implementation schemes, R A2 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0443] In some implementation schemes, R A2 For H.

[0444] In some implementation schemes, R A2 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl compounds.

[0445] In some implementation schemes, R A2 It is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0446] In some implementation schemes, R A2 For C6-C 10 Aryl.

[0447] In some implementation schemes, R A2 It is a C6 aryl group.

[0448] In some implementation schemes, R A2 It is C8 aryl. In some embodiments, R A2 C 10 Aryl.

[0449] In some implementation schemes, R A2 It consists of 5 to 10 heteroaryl groups.

[0450] In some implementation schemes, R A2 It is a 5-membered heteroaryl group. In some embodiments, R A2 It is a 6-membered heteroaryl group. In some embodiments, R A2 It is a 7-membered heteroaryl group. In some embodiments, R A2 It is an 8-membered heteroaryl group. In some embodiments, R A2 It is a 9-membered heteroaryl group. In some embodiments, R A2 It is a 10-membered heteroaryl group.

[0451] In some implementation schemes, R A2 It is a C1-C6 alkyl group.

[0452] In some implementation schemes, R A2 It is methyl. In some embodiments, R A2 It is ethyl. In some embodiments, R A2 It is propyl. In some embodiments, R A2 For butyl. In some implementations, R A2 It is pentyl. In some implementations, R A2 For its own foundation. In some implementation schemes, R A2 It is isopropyl. In some embodiments, R A2 It is isobutyl. In some embodiments, RA2 It is isopentyl. In some embodiments, R A2 It is an allohexyl group. In some implementations, R A2 It is sec-butyl. In some implementations, R A2 It is sec-amyl. In some implementations, R A2 For Zhongjiji. In some implementations, R A2 It is tert-butyl.

[0453] In some implementation schemes, R A2 It is C2-C6 alkenyl (e.g., vinyl, propenyl, butenyl).

[0454] In some implementation schemes, R A2 It is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0455] In some implementation schemes, R A2 It is a C1-C6 alkoxy group.

[0456] In some implementation schemes, R A2 It is methoxylated. In some embodiments, R A2 It is ethoxylated. In some embodiments, R A2 It is propoxylated. In some embodiments, R A2 It is butoxylated. In some embodiments, R A2 It is pentoxygenated. In some embodiments, R A2 It is an hexoxy group.

[0457] In some implementation schemes, R A2 It is a C1-C6 haloalkyl group.

[0458] In some implementation schemes, R A2 It is a halomethyl group. In some embodiments, R A2 It is a haloethyl. In some embodiments, R A2 It is a halogenated propyl group. In some embodiments, R A2 It is a halogenated butyl. In some embodiments, R A2 It is a halopentyl group. In some embodiments, R A2 It is a halogenated hexyl group.

[0459] In some implementation schemes, R A2 For C3-C 10 Cycloalkyl.

[0460] In some implementation schemes, R A2 It is a C3 cycloalkyl (cyclopropyl).

[0461] In some implementation schemes, R A2It is a C4 cycloalkyl (cyclobutyl).

[0462] In some implementation schemes, R A2 It is a C5 cycloalkyl group. In some embodiments, R A2 It is a C6 cycloalkyl group. In some embodiments, R A2 It is a C7 cycloalkyl group. In some embodiments, R A2 It is a C8 cycloalkyl group. In some embodiments, R A2 It is a C9 cycloalkyl group. In some embodiments, R A2 C 10 Cycloalkyl.

[0463] In some implementation schemes, R A2 C5-C 10 Cycloalkyl. In some embodiments, R A2 For bridging C5-C 10 Cycloalkyl. In some embodiments, R A2 For dual-ring C5-C 10 Cycloalkyl.

[0464] In some implementation schemes, R A2 It can be H, methyl, or cyclopropyl.

[0465] In some implementation schemes, R A2 It is H or methyl.

[0466] In some implementation schemes, R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, optional substituted 3- to 10-membered heterocyclic groups with one or more C1-C6 alkyl groups, C6-C 10 Aryl, or optionally substituted with one or more C1-C6 alkyl groups, comprising 5 to 10 heteroaryl groups.

[0467] In some implementation schemes, R A3 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0468] In some implementation schemes, R A3 For H.

[0469] In some implementation schemes, R A3 It is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0470] In some implementation schemes, R A3 It is a C1-C6 alkyl group.

[0471] In some implementation schemes, R A3 It is methyl. In some embodiments, R A3 It is ethyl. In some embodiments, R A3 It is propyl. In some embodiments, R A3 For butyl. In some implementations, R A3 It is pentyl. In some implementations, R A3 For its own foundation. In some implementation schemes, R A3 It is isopropyl. In some embodiments, R A3 It is isobutyl. In some embodiments, R A3 It is isopentyl. In some embodiments, R A3 It is an allohexyl group. In some implementations, R A3 It is sec-butyl. In some implementations, R A3 It is sec-amyl. In some implementations, R A3 For Zhongjiji. In some implementations, R A3 It is tert-butyl.

[0472] In some implementation schemes, R A3 It is C2-C6 alkenyl (e.g., vinyl, propenyl, butenyl).

[0473] In some implementation schemes, R A3 It is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0474] In some implementation schemes, R A3 It is a C1-C6 alkoxy group.

[0475] In some implementation schemes, R A3 It is methoxylated. In some embodiments, R A3 It is ethoxylated. In some embodiments, R A3 It is propoxylated. In some embodiments, R A3 It is butoxylated. In some embodiments, R A3 It is pentoxygenated. In some embodiments, R A3 It is an hexoxy group.

[0476] In some implementation schemes, R A3 It is a C1-C6 haloalkyl group.

[0477] In some implementation schemes, R A3 It is a halomethyl group. In some embodiments, R A3 It is a haloethyl. In some embodiments, R A3 It is a halogenated propyl group. In some embodiments, RA3 It is a halogenated butyl. In some embodiments, R A3 It is a halopentyl group. In some embodiments, R A3 It is a halogenated hexyl group.

[0478] In some implementation schemes, R A3 For C3-C 10 Cycloalkyl.

[0479] In some implementation schemes, R A3 It is a C3 cycloalkyl (cyclopropyl).

[0480] In some implementation schemes, R A3 It is a C4 cycloalkyl (cyclobutyl).

[0481] In some implementation schemes, R A3 It is a C5 cycloalkyl group. In some embodiments, R A3 It is a C6 cycloalkyl group. In some embodiments, R A3 It is a C7 cycloalkyl group. In some embodiments, R A3 It is a C8 cycloalkyl group. In some embodiments, R A3 It is a C9 cycloalkyl group. In some embodiments, R A3 C 10 Cycloalkyl.

[0482] In some implementation schemes, R A3 C5-C 10 Cycloalkyl. In some embodiments, R A3 For bridging C5-C 10 Cycloalkyl. In some embodiments, R A3 For dual-ring C5-C 10 Cycloalkyl.

[0483] In some implementation schemes, R A3 It consists of 3 to 10-membered heterocyclic groups.

[0484] In some implementation schemes, R A3 It is a 3-membered heterocyclic group. In some embodiments, R A3 It is a 4-membered heterocyclic group. In some embodiments, R A3 It is a 5-membered heterocyclic group. In some embodiments, R A3 It is a 6-membered heterocyclic group. In some embodiments, R A3 It is a 7-membered heterocyclic group. In some embodiments, R A3 It is an 8-membered heterocyclic group. In some implementations, R A3 It is a 9-membered heterocyclic group. In some embodiments, R A3 It is a 10-membered heterocyclic group.

[0485] In some implementation schemes, R A3 The substituted group is a 3- to 10-membered heterocyclic group with one or more C1-C6 alkyl groups.

[0486] In some implementation schemes, R A3 To replace 3- to 10-membered heterocyclic groups having one or more C1-C6 alkyl groups.

[0487] In some implementation schemes, R A3 For C6-C 10 Aryl.

[0488] In some implementation schemes, R A3 It is a C6 aryl group.

[0489] In some implementation schemes, R A3 It consists of 5 to 10 heteroaryl groups.

[0490] In some implementation schemes, R A3 It is a 5- to 10-membered heteroaryl group optionally substituted with one or more C1-C6 alkyl groups.

[0491] In some implementation schemes, R A3 To replace 5- to 10-membered heteroaryl groups having one or more C1-C6 alkyl groups.

[0492] In some implementation schemes, R A3 It is a 5- to 6-membered heteroaryl group.

[0493] In some implementation schemes, R A3 It is a 5- to 6-membered heteroaryl group, which may optionally be substituted with one or more C1-C6 alkyl groups.

[0494] In some implementation schemes, R A3 It is a 5- to 6-membered heteroaryl group, which is substituted with one or more C1-C6 alkyl groups.

[0495] In some implementation schemes, R A3 H, methyl, phenyl, cyclopropyl, cyclobutyl, cyclohexyl , , ,or .

[0496] In some implementation schemes, R A3 It is H or methyl.

[0497] In some implementations, R2 is cyclopropyl, X1 is N, and A1 is CR. A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H.

[0498] In some implementations, R2 is cyclopropyl, X1 is N, and A1 is CR. A1 And A2 is CR A2 When, then R A1 Not H.

[0499] In some implementations, R2 is cyclopropyl, X1 is N, and A1 is CR. A1 And A2 is CR A2 When, then R A2 Not H.

[0500] In some implementations, R2 is cyclopropyl, X1 is N, and A1 is CR. A1 And when A2 is CH, then R A1 It is not ethyl.

[0501] In some embodiments, the compound of formula (I) or formula (I') is of formula (I'):

[0502] (I'),

[0503] Or its pharmaceutically acceptable salt.

[0504] In some embodiments, the compounds of formula (I) or formula (I') are of formula (Ia), (Ib), (Ic), or (Id):

[0505] (Ia),

[0506] (Ib),

[0507] (Ic), or

[0508] (Id),

[0509] Or its pharmaceutically acceptable salt.

[0510] In some embodiments, the compound of formula (I) or formula (I') is of formula (I'-a), (I'-b), (I'-c), or (I'-d):

[0511] (I'-a),

[0512] (I'-b),

[0513] (I'-c), or

[0514] (I'-d),

[0515] Or its pharmaceutically acceptable salt.

[0516] In some embodiments, the compound of formula (I) or formula (I') is of formula (Id), (Ie), (If), or (Ig):

[0517] (Id),

[0518] (Ie),

[0519] (If), or

[0520] (Ig),

[0521] Or its pharmaceutically acceptable salt.

[0522] In some embodiments, the compound of formula (I) or formula (I') is of formula (I'-d), (I'-e), (I'-f), or (I'-g):

[0523] (I'-d),

[0524] (I'-e),

[0525] (I'-f), or

[0526] (I'-g),

[0527] Or its pharmaceutically acceptable salt.

[0528] In some embodiments, the compounds of formula (I) or formula (I') are of formula (Ih), (Ii), (Ij), or (Ik):

[0529] (Ih),

[0530] (Ii),

[0531] (Ij), or

[0532] (Ik),

[0533] Or a pharmaceutically acceptable salt thereof, wherein R 1aIt is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0534] In some embodiments, the compound of formula (I) or formula (I') is of formula (I'-h), (I'-i), (I'-j), or (I'-k):

[0535] (I'-h),

[0536] (I'-i),

[0537] (I'-j), or

[0538] (I'-k),

[0539] Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0540] In some embodiments, the compound of formula (I) or formula (I') is of formula (Il), (Im), (In), or (Io):

[0541] (Il),

[0542] (Im),

[0543] (In), or

[0544] (Io),

[0545] Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0546] In some embodiments, the compound of formula (I) or formula (I') is of formula (I'-l), (I'-m), (I'-n), or (I'-o):

[0547] (I'-l),

[0548] (I'-m),

[0549] (I'-n), or

[0550] (I'-o),

[0551] Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0552] Formula (II')

[0553] In some aspects, the present invention provides compounds of formula (II'):

[0554] (II'),

[0555] Or a pharmaceutically acceptable salt thereof, wherein:

[0556] It is a double bond, wherein the double bond is an (E) or (Z) isomer;

[0557] R1 is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. 1a ;

[0558] Each R 1a It is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0559] R2 is C3-C 10 cycloalkyl or methyl;

[0560] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0561] R4 is H, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0562] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C6 alkoxy groups). 10 cycloalkyl), or

[0563] R5 and an R 1a Together with atoms in between, they form 3- to 10-membered heterocyclic groups; and

[0564] m is 0 or 1.

[0565] The condition is:

[0566] (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl; and

[0567] (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group, R2 is a cyclopropyl group, and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not a cyclopropyl group; and

[0568] (c) When R2 is methyl, then R4 is not a C1-C6 alkyl.

[0569] In some aspects, the present invention provides compounds of formula (II'), or pharmaceutically acceptable salts thereof, wherein:

[0570] It is a double bond, wherein the double bond is an (E) or (Z) isomer;

[0571] R1 is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. 1a ;

[0572] Each R 1a It is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0573] R2 is C3-C 10 cycloalkyl or methyl;

[0574] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0575] R4 is H, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0576] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C6 alkoxy groups). 10 cycloalkyl), or

[0577] R5 and an R 1a Together with atoms in between, they form 3- to 10-membered heterocyclic groups; and

[0578] m is 0 or 1.

[0579] The condition is:

[0580] (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl; and

[0581] (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group, R2 is a cyclopropyl group, and R5 is a C1 alkyl group with a C1 alkoxy substituted group, then R4 is not a cyclopropyl group.

[0582] In some aspects, the present invention provides compounds of formula (II'), or pharmaceutically acceptable salts thereof, wherein:

[0583] It is a double bond, wherein the double bond is an (E) or (Z) isomer;

[0584] R1 is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. 1a ;

[0585] Each R 1a It is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0586] R2 is C3-C 10 cycloalkyl or methyl;

[0587] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0588] R4 is H, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0589] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C6 alkoxy groups). 10 cycloalkyl), or

[0590] R5 and an R 1a Together with atoms in between, they form 3- to 10-membered heterocyclic groups; and

[0591] m is 0 or 1.

[0592] The condition is:

[0593] (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl.

[0594] In some aspects, the present invention provides compounds of formula (II'), or pharmaceutically acceptable salts thereof, wherein:

[0595] It is a double bond, wherein the double bond is an (E) or (Z) isomer;

[0596] R1 is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. 1a ;

[0597] Each R 1a It is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0598] R2 is C3-C 10 cycloalkyl or methyl;

[0599] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0600] R4 is H, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0601] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C6 alkoxy groups). 10 cycloalkyl), or

[0602] R5 and an R 1a Together with atoms in between, they form 3- to 10-membered heterocyclic groups; and

[0603] m is 0 or 1.

[0604] The condition is:

[0605] (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group and R2 is a cyclopropyl group.

[0606] In some respects, the present invention provides compounds of formula (II):

[0607] (II),

[0608] Or a pharmaceutically acceptable salt thereof, wherein:

[0609] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0610] R2 is C3-C 10 cycloalkyl or methyl;

[0611] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0612] R4 is C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; and

[0613] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C4). 10 cycloalkyl),

[0614] The condition is:

[0615] (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl; and

[0616] (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group, R2 is a cyclopropyl group, and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not a cyclopropyl group; and

[0617] (c) When R2 is methyl, then R4 is not a C1-C6 alkyl.

[0618] In some embodiments, the compound of formula (II') is a compound of formula (II).

[0619] In some respects, the present invention provides compounds of formula (II):

[0620] (II),

[0621] Or a pharmaceutically acceptable salt thereof, wherein:

[0622] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0623] R2 is C3-C 10 cycloalkyl;

[0624] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0625] R4 is C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; and

[0626] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups.

[0627] The condition is:

[0628] (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl; and

[0629] (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group, R2 is a cyclopropyl group, and R5 is a C1 alkyl group with a C1 substituted alkoxy group, then R4 is not a cyclopropyl group.

[0630] In some respects, the present invention provides compounds of formula (II):

[0631] (II),

[0632] Or a pharmaceutically acceptable salt thereof, wherein:

[0633] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0634] R2 is C3-C 10 cycloalkyl;

[0635] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0636] R4 is C4-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; and

[0637] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups.

[0638] The condition is:

[0639] (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl.

[0640] In some respects, the present invention provides compounds of formula (II):

[0641] (II),

[0642] Or a pharmaceutically acceptable salt thereof, wherein:

[0643] R1 is C6-C 10aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0644] R2 is C3-C 10 cycloalkyl;

[0645] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0646] R4 is C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C2 or C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl; and

[0647] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups.

[0648] The condition is:

[0649] (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group, R2 is a cyclopropyl group, and R5 is a C1 alkyl group with a C1 alkoxy substituted group, then R4 is not a cyclopropyl group.

[0650] In some respects, the present invention provides compounds of formula (II):

[0651] (II),

[0652] Or a pharmaceutically acceptable salt thereof, wherein:

[0653] R1 is C6-C 10 aryl or 5 to 10 heteroaryl, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0654] R2 is C3-C 10 cycloalkyl;

[0655] R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0656] R4 is C4-C 10Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C2 or C4-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl; and

[0657] R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl is optionally substituted with one or more C1-C6 alkoxy groups.

[0658] It should be understood that, for the compounds disclosed herein, variables R1 and R2 are... 1a R1, R2, R3, R4, and R5 may each be selected from the groups described herein where applicable, and for the variables R1, R2, R3, R4, and R5, the groups may be selected from the groups described herein. 1a Any of the groups described in R1, R2, R3, R4, and R5 may, where applicable, be combined with the remaining variables R1, R2, R3, R4, and R5. 1a Any combination of one or more of the groups described above, R2, R3, R4, and R5.

[0659] In some implementation schemes, It is a double bond, wherein the double bond is an (E) isomer.

[0660] In some implementation schemes, It is a double bond, wherein the double bond is a (Z) isomer.

[0661] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl compounds.

[0662] In some implementations, R1 is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. 1a .

[0663] In some implementations, R1 is C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the aryl or heteroaryl is substituted with one or more R 1a .

[0664] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0665] In some implementations, R1 is C6-C 10Aryl or 5 to 10 heteroaryl groups, which are substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0666] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, optionally substituted with one or more halogens, -CN, -OH or -NH2.

[0667] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, which are substituted with one or more halogens, -CN, -OH or -NH2.

[0668] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, which are substituted with one or more halogens.

[0669] In some implementations, R1 is C6-C 10 Aryl or 5 to 10 heteroaryl groups, which are substituted with a halogen.

[0670] In some implementations, R1 is C6-C 10 Aryl.

[0671] In some implementations, R1 is C6-C 10 Aryl group, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0672] In some implementations, R1 is C6-C 10 Aryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0673] In some implementations, R1 is C6-C 10 Aryl groups are substituted with one or more halogens.

[0674] In some implementations, R1 is C6-C 10 Aryl groups are substituted with one halogen.

[0675] In some implementations, R1 is a C6 aryl group.

[0676] In some embodiments, R1 is a C6 aryl group, which may optionally be substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0677] In some embodiments, R1 is a C6 aryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0678] In some embodiments, R1 is a C6 aryl group, which may optionally be substituted with one or more halogens, -CN, -OH, or -NH2.

[0679] In some embodiments, R1 is a C6 aryl group, which is substituted with one or more halogens, -CN, -OH, or -NH2.

[0680] In some implementations, R1 is a C6 aryl group, which is substituted with one or more halogens.

[0681] In some implementations, R1 is a C6 aryl group, which is substituted with a halogen.

[0682] In some implementations, R1 is a 5- to 10-membered heteroaryl group.

[0683] In some embodiments, R1 is a 5- to 10-membered heteroaryl group, optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0684] In some embodiments, R1 is a 5- to 10-membered heteroaryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0685] In some implementations, R1 is a 5- to 10-membered heteroaryl group, which is substituted with one or more halogens.

[0686] In some implementations, R1 is a 5- to 10-membered heteroaryl group, which is substituted with a halogen.

[0687] In some implementations, R1 is a 6-membered heteroaryl group.

[0688] In some embodiments, R1 is a 6-membered heteroaryl group, which may be optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0689] In some embodiments, R1 is a 6-membered heteroaryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0690] In some implementations, R1 is a 6-membered heteroaryl group, which is substituted with one or more halogens.

[0691] In some implementations, R1 is a 6-membered heteroaryl group, which is substituted with a halogen.

[0692] In some implementations, R1 is , , , , , , , , , , , ,or .

[0693] In some implementations, R1 is , , , , , , , , , , ,or .

[0694] In some implementations, R1 is or .

[0695] In some implementations, R1 is replaced in at least two positions.

[0696] In some implementations, R1 is replaced in at least 3 bits.

[0697] In some implementations, R1 is replaced in at least 4 bits.

[0698] In some implementation schemes, each R 1a It is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0699] In some implementations, at least one R 1a Halogenated (e.g., Cl, F, I, Br).

[0700] In some implementations, at least one R 1a For -CN.

[0701] In some implementations, at least one R 1a It is -OH.

[0702] In some implementations, at least one R 1a It is -NH2.

[0703] In some implementations, at least one R 1a It is a C1-C6 alkyl group.

[0704] In some implementation schemes, R 1a It is methyl. In some embodiments, R 1a It is ethyl. In some embodiments, R 1a It is propyl. In some embodiments, R 1a For butyl. In some implementations, R 1a It is pentyl. In some implementations, R 1a For its own foundation. In some implementation schemes, R 1a It is isopropyl. In some embodiments, R 1a It is isobutyl. In some embodiments, R 1a It is isopentyl. In some embodiments, R 1a It is an allohexyl group. In some implementations, R 1a It is sec-butyl. In some implementations, R 1a It is sec-amyl. In some implementations, R 1a For Zhongjiji. In some implementations, R 1a It is tert-butyl.

[0705] In some implementation schemes, R 1a It is C2-C6 alkenyl (e.g., vinyl, propenyl, butenyl).

[0706] In some implementation schemes, R 1a It is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0707] In some implementation schemes, R 1a It is a C1-C6 alkoxy group.

[0708] In some implementation schemes, R 1a It is methoxylated. In some embodiments, R 1a It is ethoxylated. In some embodiments, R1a It is propoxylated. In some embodiments, R 1a It is butoxylated. In some embodiments, R 1a It is pentoxygenated. In some embodiments, R 1a It is an hexoxy group.

[0709] In some implementation schemes, R 1a It is a C1-C6 haloalkyl group.

[0710] In some implementation schemes, R 1a It is a halomethyl group. In some embodiments, R 1a It is a haloethyl. In some embodiments, R 1a It is a halogenated propyl group. In some embodiments, R 1a It is a halogenated butyl. In some embodiments, R 1a It is a halopentyl group. In some embodiments, R 1a It is a halogenated hexyl group.

[0711] In some implementations, R2 is methyl.

[0712] In some implementations, R2 is C3-C 10 Cycloalkyl.

[0713] In some implementations, R2 is a C3 cycloalkyl (cyclopropyl).

[0714] In some implementations, R2 is a C4 cycloalkyl (cyclobutyl).

[0715] 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 Cycloalkyl.

[0716] In some implementations, R2 is C5-C 10 Cycloalkyl. In some embodiments, R2 is a bridging C5-C group. 10 Cycloalkyl. In some embodiments, R2 is a bicyclic C5-C64. 10 Cycloalkyl.

[0717] In some implementations, R2 is methyl. ,or .

[0718] In some implementations, R2 is or .

[0719] In some embodiments, R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0720] In some implementations, R3 is H.

[0721] In some embodiments, R3 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0722] In some implementations, R3 is a C1-C6 alkyl group.

[0723] 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.

[0724] In some embodiments, R3 is a C2-C6 alkenyl group (e.g., vinyl, propenyl, butenyl).

[0725] In some implementations, R3 is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0726] In some implementations, R3 is a C1-C6 alkoxy group.

[0727] In some embodiments, R3 is methoxy. In some embodiments, R3 is ethoxy. In some embodiments, R3 is propoxy. In some embodiments, R3 is butoxy. In some embodiments, R3 is pentoxy. In some embodiments, R3 is hexoxy.

[0728] In some implementations, R3 is a C1-C6 haloalkyl group.

[0729] In some embodiments, R3 is a halomethyl group. In some embodiments, R3 is a haloethyl group. In some embodiments, R3 is a halopropyl group. In some embodiments, R3 is a halobutyl group. In some embodiments, R3 is a halopentyl group. In some embodiments, R3 is a halohexyl group.

[0730] In some implementations, R4 is H, C3-C 10Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0731] In some implementations, R4 is H.

[0732] In some implementations, R4 is C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0733] In some implementations, R4 is C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0734] In some implementations, R4 is C3-C 10 Cycloalkyl.

[0735] In some implementations, R4 is a C3 cycloalkyl (cyclopropyl).

[0736] In some implementations, R4 is a C4 cycloalkyl (cyclobutyl).

[0737] 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 Cycloalkyl.

[0738] In some implementations, R4 is C5-C 10 Cycloalkyl. In some embodiments, R4 is a bridging C5-C group. 10 Cycloalkyl. In some embodiments, R4 is a bicyclic C5-C64. 10 Cycloalkyl.

[0739] In some implementations, R4 is a 3- to 10-membered heterocyclic group.

[0740] In some embodiments, R4 is a 3-membered heterocyclic group. In some embodiments, R4 is a 4-membered heterocyclic group. In some embodiments, R4 is a 5-membered heterocyclic group. In some embodiments, R4 is a 6-membered heterocyclic group. In some embodiments, R4 is a 7-membered heterocyclic group. In some embodiments, R4 is an 8-membered heterocyclic group. In some embodiments, R4 is a 9-membered heterocyclic group. In some embodiments, R4 is a 10-membered heterocyclic group.

[0741] In some embodiments, R4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0742] In some implementations, R4 is a C1-C6 alkyl group.

[0743] 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.

[0744] In some embodiments, R4 is a C2-C6 alkenyl group (e.g., vinyl, propenyl, butenyl).

[0745] In some implementations, R4 is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0746] In some implementations, R4 is a C1-C6 alkoxy group.

[0747] In some embodiments, R4 is methoxy. In some embodiments, R4 is ethoxy. In some embodiments, R4 is propoxy. In some embodiments, R4 is butoxy. In some embodiments, R4 is pentoxy. In some embodiments, R4 is hexoxy.

[0748] In some implementations, R4 is a C1-C6 haloalkyl group.

[0749] In some embodiments, R4 is a halomethyl group. In some embodiments, R4 is a haloethyl group. In some embodiments, R4 is a halopropyl group. In some embodiments, R4 is a halobutyl group. In some embodiments, R4 is a halopentyl group. In some embodiments, R4 is a halohexyl group.

[0750] In some implementations, R4 is H, , ,or .

[0751] In some implementations, R4 is , ,or .

[0752] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl.

[0753] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C6 alkoxy groups). 10 (cycloalkyl).

[0754] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 Cycloalkyl substitution with one or more C1-C6 alkoxy groups or -O (C3-C6) 10 (cycloalkyl).

[0755] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0756] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl is optionally substituted with one or more C1-C6 alkoxy groups.

[0757] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl is substituted with one or more C1-C6 alkoxy groups or -O (C3-C4). 10 (cycloalkyl).

[0758] In some embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkoxy, or haloalkyl is substituted with one or more C1-C6 alkoxy groups.

[0759] In some implementations, R5 is H.

[0760] In some implementations, R5 is a C1-C6 alkyl group.

[0761] In some embodiments, R5 is a C1-C6 alkyl group, optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C4). 10 (cycloalkyl).

[0762] In some embodiments, R5 is a C1-C6 alkyl group substituted with one or more C1-C6 alkoxy groups or -O (C3-C4) alkyl groups. 10 (cycloalkyl).

[0763] In some embodiments, R5 is a C1-C6 alkyl group, which is optionally substituted with one or more C1-C6 alkoxy groups.

[0764] 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.

[0765] In some embodiments, R5 is methyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is ethyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is propyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is butyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is pentyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is hexyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isopropyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isobutyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isopentyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is isohexyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is sec-butyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is sec-pentyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is sec-hexyl, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is tert-butyl, optionally substituted with one or more C1-C6 alkoxy groups.

[0766] 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 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 alkoxy groups. In some embodiments, R5 is sec-hexyl, substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is tert-butyl, substituted with one or more C1-C6 alkoxy groups.

[0767] In some embodiments, R5 is methyl, which is optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is ethyl, optionally substituted with one or more -O (C3-C4) groups. 10 (Cycloalkyl). In some embodiments, R5 is propyl, which is optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is butyl, which is optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is pentyl, optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is hexyl, optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isopropyl, optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isobutyl, which is optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isopentyl, which is optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isohexyl, optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is sec-butyl, which is optionally substituted with one or more -O (C3-C4) groups. 10 (Cycloalkyl). In some embodiments, R5 is secondary pentyl, which is optionally substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is secondary hexyl, which is optionally substituted with one or more -O (C3-C4) groups. 10 (Cycloalkyl). In some embodiments, R5 is tert-butyl, which is optionally substituted with one or more -O (C3-C) groups. 10 (cycloalkyl).

[0768] In some embodiments, R5 is a methyl group, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is ethyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is propyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is butyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is pentyl, which is substituted with one or more -O (C3-C) groups.10 (Cycloalkyl). In some embodiments, R5 is hexyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isopropyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isobutyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isopentyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is isohexyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is sec-butyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is secondary pentyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is secondary hexyl, which is substituted with one or more -O (C3-C) groups. 10 (Cycloalkyl). In some embodiments, R5 is tert-butyl, which is substituted with one or more -O (C3-C) groups. 10 (cycloalkyl).

[0769] In some implementations, R5 is a C2-C6 alkenyl group (e.g., vinyl, propenyl, butenyl).

[0770] In some embodiments, R5 is a C2-C6 alkenyl group, which is optionally substituted with one or more C1-C6 alkoxy groups.

[0771] In some embodiments, R5 is a C2-C6 alkenyl group, which is substituted with one or more C1-C6 alkoxy groups.

[0772] In some implementations, R5 is a C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0773] In some embodiments, R5 is a C2-C6 alkynyl group, which is optionally substituted with one or more C1-C6 alkoxy groups.

[0774] In some embodiments, R5 is a C2-C6 alkynyl group, which is substituted with one or more C1-C6 alkoxy groups.

[0775] In some implementations, R5 is a C1-C6 alkoxy group.

[0776] In some embodiments, R5 is a C1-C6 alkoxy group, which may optionally be substituted with one or more C1-C6 alkoxy groups.

[0777] In some embodiments, R5 is a C1-C6 alkoxy group, which is substituted with one or more C1-C6 alkoxy groups.

[0778] In some embodiments, R5 is methoxy. In some embodiments, R5 is ethoxy. In some embodiments, R5 is propoxy. In some embodiments, R5 is butoxy. In some embodiments, R5 is pentoxy. In some embodiments, R5 is hexoxy.

[0779] In some embodiments, R5 is a methoxy group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is an ethoxy group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a propoxy group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a butoxy group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is an pentoxy group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a hexoxy group, optionally substituted with one or more C1-C6 alkoxy groups.

[0780] In some embodiments, R5 is a methoxy group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is an ethoxy group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a propoxy group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a butoxy group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is an pentoxy group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a hexoxy group substituted with one or more C1-C6 alkoxy groups.

[0781] In some implementations, R5 is a C1-C6 haloalkyl group.

[0782] In some embodiments, R5 is a C1-C6 haloalkyl group, which is optionally substituted with one or more C1-C6 alkoxy groups.

[0783] In some embodiments, R5 is a C1-C6 haloalkyl group substituted with one or more C1-C6 alkoxy groups.

[0784] In some embodiments, R5 is a halomethyl group. In some embodiments, R5 is a haloethyl group. In some embodiments, R5 is a halopropyl group. In some embodiments, R5 is a halobutyl group. In some embodiments, R5 is a halopentyl group. In some embodiments, R5 is a halohexyl group.

[0785] In some embodiments, R5 is a halomethyl group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a haloethyl group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a halopropyl group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a halobutyl group, optionally substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a halopentyl group, optionally substituted with one or more C1-C6 alkoxy groups.

[0786] In some embodiments, R5 is a halomethyl group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a haloethyl group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a halopropyl group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a halobutyl group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a halopentyl group substituted with one or more C1-C6 alkoxy groups. In some embodiments, R5 is a halohexyl group substituted with one or more C1-C6 alkoxy groups.

[0787] In some implementations, R5 and an R 1a Together with the atoms in between, they form 3 to 10-membered heterocyclic groups.

[0788] In some implementations, R5 and an R 1a Together with the atoms in between, they form a tetrahydropyranyl group.

[0789] In some implementations, R5 is –(CH2)-OCH3, –(CH2)-O-cyclopropyl, cyclopropyl, or H.

[0790] In some implementations, R5 is –(CH2)-OCH3, –(CH2)-O-cyclopropyl, or H.

[0791] In some implementations, R5 is –(CH2)-OCH3 or H.

[0792] In some embodiments, when R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl.

[0793] In some embodiments, R4 is not cyclopropyl when R1 is a monosubstituted C6 aryl group with a fluorine substituted group, R2 is cyclopropyl, and R5 is a C1 alkyl group with a C1 alkoxy substituted group.

[0794] In some implementations, when R2 is methyl, then R4 is not a C1-C6 alkyl.

[0795] In some embodiments, the compound of formula (II) or (II') is of formula (II-a) or (II-b):

[0796] (II-a) or

[0797] (II-b),

[0798] Or its pharmaceutically acceptable salt.

[0799] In some embodiments, the compound of formula (II) or formula (II') is of formula (II-c):

[0800] (II-c),

[0801] Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0802] In some embodiments, the compound of formula (II) or formula (II') is of formula (II-d) or (II-e):

[0803] (II-d) or

[0804] (II-e),

[0805] Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0806] In some embodiments, the compound of formula (II) or formula (II') is of formula (II-f) or (II-g):

[0807] (II-f) or

[0808] (II-g),

[0809] Or its pharmaceutically acceptable salt.

[0810] In some embodiments, the compound of formula (II) or formula (II') is of formula (II-h):

[0811] (II-h),

[0812] Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0813] In some embodiments, the compounds of formula (II) or (II') are of formula (II-i) or (II-j):

[0814] (II-i) or

[0815] (II-j),

[0816] Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

[0817] compound

[0818] In some embodiments, the compound is selected from the compounds described in Table 1, or their prodrugs or pharmaceutically acceptable salts.

[0819] In some embodiments, the compound is selected from the compounds described in Table 1, or pharmaceutically acceptable salts thereof.

[0820] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1, or pharmaceutically acceptable salts thereof.

[0821] In some embodiments, the compound is selected from the compounds described in Table 1.

[0822] In some embodiments, the compound is selected from the compounds described in Table 1A, or their prodrugs or pharmaceutically acceptable salts.

[0823] In some embodiments, the compound is selected from the compounds described in Table 1A, or pharmaceutically acceptable salts thereof.

[0824] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1A, or pharmaceutically acceptable salts thereof.

[0825] In some embodiments, the compound is selected from the compounds described in Table 1A.

[0826] In some embodiments, the compound is selected from the compounds described in Table 2, or their prodrugs or pharmaceutically acceptable salts.

[0827] In some embodiments, the compound is selected from the compounds described in Table 2, or pharmaceutically acceptable salts thereof.

[0828] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 2, or pharmaceutically acceptable salts thereof.

[0829] In some embodiments, the compound is selected from the compounds described in Table 2.

[0830] In some embodiments, the compound is selected from the compounds described in Table 2A, or their prodrugs or pharmaceutically acceptable salts.

[0831] In some embodiments, the compound is selected from the compounds described in Table 2A, or pharmaceutically acceptable salts thereof.

[0832] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 2A, or pharmaceutically acceptable salts thereof.

[0833] In some embodiments, the compound is selected from the compounds described in Table 2A.

[0834] In some embodiments, the compound is selected from the compounds described in Table 3, or their prodrugs or pharmaceutically acceptable salts.

[0835] In some embodiments, the compound is selected from the compounds described in Table 3, or pharmaceutically acceptable salts thereof.

[0836] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 3, or pharmaceutically acceptable salts thereof.

[0837] In some embodiments, the compound is selected from the compounds described in Table 3.

[0838] Table 1.

[0839]

[0840]

[0841]

[0842] Table 1A.

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852] Table 2.

[0853]

[0854]

[0855] Table 2A.

[0856]

[0857]

[0858]

[0859]

[0860] Table 3.

[0861]

[0862] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds listed in Table 1.

[0863] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds listed in Table 1A.

[0864] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds listed in Table 2.

[0865] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds listed in Table 2A.

[0866] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds listed in Table 3.

[0867] In some aspects, the present invention provides compounds that are isotopic derivatives of any of the compounds of the formula disclosed herein (e.g., isotopically labeled compounds).

[0868] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1, or a prodrug or a pharmaceutically acceptable salt thereof.

[0869] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0870] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0871] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1.

[0872] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1A, or a prodrug or a pharmaceutically acceptable salt thereof.

[0873] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1A, or a pharmaceutically acceptable salt thereof.

[0874] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds listed in Table 1A, or a pharmaceutically acceptable salt thereof.

[0875] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 1A.

[0876] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 2, or a prodrug or a pharmaceutically acceptable salt thereof.

[0877] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0878] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0879] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 2.

[0880] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 2A, or a prodrug or a pharmaceutically acceptable salt thereof.

[0881] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 2A, or a pharmaceutically acceptable salt thereof.

[0882] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Table 2A, or a pharmaceutically acceptable salt thereof.

[0883] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 2A.

[0884] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 3, or a prodrug or a pharmaceutically acceptable salt thereof.

[0885] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 3, or a pharmaceutically acceptable salt thereof.

[0886] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds listed in Table 3, or a pharmaceutically acceptable salt thereof.

[0887] In some embodiments, the compound is an isotopic derivative of any of the compounds listed in Table 3.

[0888] In some implementations, the pharmaceutically acceptable salt is a sodium salt.

[0889] It should be understood that isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotope derivatives can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents and by performing the operations disclosed in the schemes described herein and / or in the examples.

[0890] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0891] In some embodiments, the isotope derivative is a deuterium-labeled compound of any of the various compounds disclosed herein.

[0892] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are enriched or labeled with an isotope. For example, compared to the corresponding compound of formula (I) or formula (II), the isotope derivative of the compound is enriched or labeled with one or more isotopes. In some embodiments, the isotope derivative is enriched or labeled with one or more atoms selected from... 2 H, 13 C, 14 C,15 N, 18 O, 29 Si, 31 P and 34 S. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., deuterium-labeled with respect to one or more atoms). 2 H enrichment). In some embodiments, the compound is 18 An F-labeled compound. In some embodiments, the compound is... 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compounds, or any combination thereof. In some embodiments, the compound is... 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds or any combination thereof.

[0893] It should be understood that any of a variety of techniques recognized in the art can be used for preparation. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S-labeled compounds. For example, by performing the operations disclosed in the schemes described herein and / or in the examples, by using... 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 Deuterium-labeled compounds can be prepared largely by using S-labeled reagents instead of non-isotope-labeled reagents.

[0894] Containing the aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I,135 I, 32 S, 34 S, 35 S and 36 One or more of the compounds of the present invention, or their pharmaceutically acceptable salts or solvates, containing the S atom are within the scope of the present 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 S) replacement may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0895] To avoid confusion, it should be understood that when a group is defined in this specification as “described herein”, the group includes the first and broadest definition and each and all of the specific definitions within that group.

[0896] The various functional groups and substituents constituting compounds of formula (I) or (II) are generally chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More typically, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600, and, for example, 550 Daltons or less.

[0897] Suitable pharmaceutically acceptable salts of the compounds disclosed herein are, for example, acid addition salts of the compounds of this disclosure that are sufficiently basic, such as acid addition salts formed with, for example, inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid). Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

[0898] It should be understood that any compound of any of the formulas disclosed herein and any pharmaceutically acceptable salt thereof comprises stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compound.

[0899] It should be understood that while the compounds disclosed herein may exist in a particular configuration, such particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers. In some embodiments, the presentation of compounds in a particular configuration herein is intended to cover and refer to each of the available isomers, tautomers, positional isomers, and stereoisomers of the compound, or any mixture thereof; although the presentation is further intended to refer to a specific configuration of the compound.

[0900] It should be understood that while compounds disclosed herein may be presented without a specified configuration (e.g., without a specified stereochemistry), such presentation is intended to cover all available isomers, tautomers, positional isomers, and stereoisomers of the compounds. In some embodiments, the presentation of compounds herein without a specified configuration is intended to refer to each or any mixture of the available isomers, tautomers, positional isomers, and stereoisomers of the compounds.

[0901] As used in this article, "isomerism" refers to compounds with the same molecular formula but different atomic bonding sequences or spatial arrangements. Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of enantiomers with opposite chirality is called a "racemic mixture."

[0902] The term "chiral center" as used in this article refers to a carbon atom bonded to four different substituents.

[0903] 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 as individual diastereomers or as mixtures of diastereomers, referred to as "diastereomer mixtures." When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration indicates the spatial arrangement of substituents attached to the chiral center. Substituents connected to the chiral center under consideration were ordered according to the order rules of Cahn, Ingold, and Prelog (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).

[0904] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation around a double bond or a cyclic hydrocarbon linker (e.g., 1,3-cyclobutyl). According to the Cahn-Ingold-Prelog rule, these configurations are distinguished by the prefixes cis and trans, or Z and E, indicating that the groups are located on the same or opposite sides of the double bond in the molecule.

[0905] It should be understood that the compounds of this disclosure may be described as different chiral or geometric isomers. It should also be understood that when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any isomer. It should be understood that not all isomers may have the same level of activity.

[0906] It should be understood that the structures and other compounds discussed in this disclosure include all their transisomers. It should also be understood that not all transisomers possess the same level of activity.

[0907] The term "trans-isomer" as used in this article refers to a class of stereoisomers in which the atoms of the two isomers are arranged differently in space. The existence of trans-isomers is attributed to restricted rotation caused by the impeded rotation of the large group around the central bond. Such trans-isomers usually exist as mixtures, but due to recent advances in chromatographic techniques, mixtures of two trans-isomers can now be separated under certain conditions.

[0908] As used in this article, a "tautomer" is one of two or more structural isomers existing in equilibrium, and which readily transforms from one isomer to another. This transformation results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer combinations in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, simultaneous shifts of electrons and hydrogen atoms occur. Ring-chain tautomerism arises because the aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to produce a cyclic (ring-like) form, as exhibited by glucose.

[0909] It should be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer form. It should be understood that some tautomers may have higher activity levels than others.

[0910] Compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R- and S-ordering rules of Cahn and Prelog, or by rotating the molecular polarization plane and specifying them as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as single enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0911] The compounds of this disclosure may have one or more asymmetric centers; therefore, such compounds can be prepared as individual (R)- or (S)- stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its single enantiomer and racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see 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 resolving the racemic form. Some compounds of this disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that this disclosure covers all optical diastereomers and geometric isomers and mixtures thereof with STMN2 modulating activity.

[0912] This disclosure also includes compounds as defined herein that contain one or more isotope substitutions.

[0913] It should be understood that any compound of any kind described herein includes the compound itself, as well as, where applicable, their salts and their solvates. For example, salts can be formed between anion and a positively charged group (e.g., amino group) on the substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0914] 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 cation and a negatively charged group (e.g., a carboxyl group) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include those salts containing a quaternary nitrogen atom.

[0915] It should be understood that the compounds of this disclosure, such as salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0916] As used herein, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in their crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcohol. A hydrate is formed by the combination of one or more water molecules with a substance molecule, wherein the water retains its molecular state as H₂O.

[0917] As used herein, the term "analogue" refers to a compound that is structurally similar to another but has a slightly different composition (e.g., by substitution of an atom with an atom of a different element, or in the presence of a specific functional group, or by the substitution of one functional group by another). Therefore, an analogue is a compound that is functionally similar or equivalent in appearance but differs from the reference compound in structure or origin.

[0918] As used in this article, the term "derivative" refers to compounds that share a common core structure and are substituted by various groups as described herein.

[0919] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another substantially similar atom or group of atoms. The aim of bioisostere substitution is to create a new compound with biological properties similar to the parent compound. Bioisostere substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0920] It should also be understood that certain compounds of any of the formulas disclosed herein may exist in both solvated and unsolvated forms, such as, for example, hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure includes all such solvated forms having STMN2 activity.

[0921] It should also be understood that certain compounds of any of the formulas disclosed herein may exhibit polymorphism, and this disclosure includes 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 analysis, 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.

[0922] Compounds of any formula disclosed herein may exist in many different tautomeric forms, and references to compounds of formula (I) or (II) include all such forms. For the avoidance of confusion, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other forms are still included in formula (I) or (II). Examples of tautomeric forms include ketone-, enol-, and enolide- forms, such as in, for example, the following tautomeric pairs: ketone / enol (exemplified below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0923]

[0924] Ketone enol enols

[0925] Compounds containing any of the formulas disclosed herein, which contain amine functional groups, can also form N-oxides. Compounds of formula (I) or (II) containing amine functional groups mentioned herein also include N-oxides. In the case of compounds containing several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in 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., peroxycarboxylic acid), see, for example, Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, p. More specifically, N-oxides can be prepared by the LW Deady operation (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example in an inert solvent such as dichloromethane.

[0926] Compounds of any of the formulas disclosed herein can be administered as prodrugs, which decompose in humans or animals to release the compounds of this disclosure. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of this disclosure. Prodrugs can be formed when the compounds of this disclosure contain suitable groups or substituents (to which modifying groups may be attached). Examples of prodrugs include derivatives of any of the formulas disclosed herein containing in vivo cleavable alkyl or acyl substituents at the ester or amide group.

[0927] Therefore, this disclosure includes compounds of any of the formulas disclosed herein as defined above, whether obtained by organic synthesis or obtained in humans or animals by cleavage of their prodrugs. Thus, this disclosure includes compounds of any of the formulas disclosed herein produced by organic synthesis, and compounds produced in humans or animals by the metabolism of prodrug compounds, i.e., compounds of any of the formulas disclosed herein can be synthetically produced or metabolically produced compounds.

[0928] A suitable pharmaceutically acceptable prodrug for any of the compounds disclosed herein is one that, based on reasonable medical judgment, is suitable for administration to humans or animals without undesirable pharmacological activity and without inappropriate toxicity. Various forms of prodrugs have been described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309–396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Prodrugs, 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 Prodrugs,” H. Bundgaard, pp. 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, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0929] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxyl group in any of the formulas disclosed herein are, for example, esters or ethers that are cleavable in vivo. Suitable pharmaceutically acceptable ester-forming groups of compounds containing a hydroxyl group in any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleavable in vivo in a human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups of the hydroxyl group include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of the hydroxyl group include C1-C1 esters. 10 Alkyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C1-C 10 Alkoxycarbonyl groups include ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic 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. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl groups such as acetoxymethyl and neopentyloxymethyl.

[0930] Suitable pharmaceutically acceptable prodrugs of compounds having a carboxyl group of any of the formulas disclosed herein are, for example, amides that are cleavable in vivo, such as those with amines such as ammonia, C 1-4 Alkylamines such as methylamine, (C1-C4 alkyl)2amines 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 amides formed from amino acids such as glycine or their esters.

[0931] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group of any of the formulas disclosed herein are, for example, amide derivatives that are cleavable in vivo. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, those with C1-C2 groups. 10 Alkyl groups include acetyl, benzoyl, phenylacetyl, and amides formed by substituted benzoyl and phenylacetyl groups. Examples of cyclic 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.

[0932] The in vivo effects of any compound of any formula disclosed herein may be exerted in part by one or more metabolites formed in a human or animal following administration of any compound of any formula disclosed herein. As described above, the in vivo effects of any compound of any formula disclosed herein may also be exerted through the metabolism of a prodrug.

[0933] As appropriate, this disclosure excludes any individual compound that does not have the biological activity defined herein.

[0934] Synthesis method

[0935] In some respects, this disclosure provides a method for preparing the compounds of this disclosure.

[0936] In some respects, this disclosure provides a method for preparing a compound, comprising one or more steps as described herein.

[0937] In some respects, this disclosure provides compounds that are obtainable, acquired, or directly obtained by methods used to prepare compounds as described herein.

[0938] In some respects, this disclosure provides intermediates as described herein, which are suitable for use in methods for preparing compounds as described herein.

[0939] The compounds of this disclosure can be prepared using any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[0940] In the description of the synthetic methods described herein and any reference synthetic methods used to prepare the starting materials, it should be understood that all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and post-treatment procedures, can be selected by those skilled in the art.

[0941] Those skilled in the field of organic synthesis will understand that the functional groups present on various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0942] It should be understood that in the process of synthesizing the compounds disclosed herein using the methods defined herein, or in the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. A skilled chemist will understand 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 texts on the subject, such as Theodora Green's "Protective Groups in Organic Synthesis" (published by John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist suitable for removing the protecting groups in question, choosing such a method to achieve the removal of the protecting groups with minimal interference to groups elsewhere in the molecule. Therefore, if the reactants include, for example, groups such as amino, carboxyl, or hydroxyl, it may be necessary to protect these groups in some of the reactions mentioned herein.

[0943] As examples, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups like acetyl groups, alkoxycarbonyl groups like methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl groups, arylmethoxycarbonyl groups like benzyloxycarbonyl groups, or aromatic acyl groups like benzoyl groups. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups can be removed by hydrolysis, for example, 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 can be removed, for example, by treatment with a suitable acid (such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid), and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation with a catalyst (such as carbon-supported palladium) or by treatment with a Lewis acid such as tri(trifluoroacetic acid)boron. Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[0944] Suitable protecting groups for the hydroxyl group are, for example, acyl groups, such as alkanoyl groups like acetyl, aromatic acyl groups like benzoyl, or arylmethyl groups like benzyl. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aromatic acyl groups can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl can be removed by hydrogenation, for example, via a catalyst (e.g., palladium supported on carbon).

[0945] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl, which can be removed by, for example, hydrolysis with a base (such as sodium hydroxide), or by, for example, tert-butyl, which can be removed by, for example, treatment with an acid (such as an organic acid such as trifluoroacetic acid), or by, for example, benzyl, which can be removed by, for example, hydrogenation with a catalyst (such as palladium supported on carbon).

[0946] Once a compound of formula (I) or formula (II) has been synthesized by any of the methods defined herein, the method may further include the following additional steps: (i) removing any protecting groups present; (ii) converting a 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.

[0947] The obtained compounds of formula (I) or formula (II) can be isolated and purified using techniques well known in the art.

[0948] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, 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, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; ethylene glycol ethers, Such as ethylene glycol monomethyl ether or monoethyl ether or ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (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 said solvents or mixtures with water.

[0949] The reaction temperature is appropriately between about -100°C and 300°C, depending on the reaction steps and the conditions used.

[0950] Reaction times typically range from less than a minute to several days, depending on the reactivity of the various compounds and the reaction conditions. Suitable reaction times can be readily determined using methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally range from 10 minutes to 48 hours.

[0951] Furthermore, other compounds of this disclosure can be readily prepared using the procedures described herein in conjunction with common techniques in the art. Those skilled in the art will readily understand that these compounds can be prepared using known modifications to the conditions and methods of the following preparation procedures.

[0952] As those skilled in the art of organic synthesis will understand, the compounds of this disclosure can be readily obtained by a variety of synthetic routes, some of which are illustrated by way of example in the accompanying examples. Those skilled in the art will readily recognize which reagents and reaction conditions to use and how to apply and modify them in any particular case (whenever necessary or useful) to obtain the compounds of this disclosure. Furthermore, some compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, to convert a particular functional group present in a compound of this disclosure or a suitable precursor molecule into another; these methods are well known to those skilled in the art. Likewise, those skilled in the art will apply (whenever necessary or useful) synthetic protecting (or protective) groups; 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, in PGM Wuts, TW Greene, “Greene's Protective Groups in Organic Synthesis,” 4th edition (2006) (John Wiley & Sons).

[0953] The general route for preparing the compounds of this application is described in Schemes 1-7 herein.

[0954] In some embodiments, the compounds described in schemes 1-7 are sodium salts of the compounds.

[0955] Option 1

[0956]

[0957] In Scheme 1, the amine can be acylated (e.g., with ethylmalonyl chloride) at room temperature in an anhydrous solvent (e.g., DCM) under standard conditions (e.g., with a tertiary amine base such as Et3N, DIPEA, or pyridine). Ring closure (i.e., step 2) can be carried out under alkaline conditions (e.g., NaOH in EtOH) and with an amine base (e.g., DBU). Alternatively, reflux with an aqueous acid (e.g., HCl) followed by neutralization with a base yields the desired product. Chlorination of 1-C (step 3) can provide 1-D. Continuous Suzuki coupling conditions followed by ester reduction (step 4) can provide 1-E. Conversion to a halide (1-G, step 6) can be carried out by methanesulfonation and a Finkelstein reaction. The halide can then be treated with a phosphine source (e.g., PPh3, POR) to provide the corresponding phosphine or phosphonate (step 7). Alkenylation with a commercial aldehyde and 1-H (step 8), followed by overall deprotection of 1-J, yields 1-K.

[0958] Option 2

[0959]

[0960] Starting with commercially available thiophene-aniline, reactions 1, 2, 3, and 6 form intermediate A, as described in Scheme 1. Furthermore, Scheme 1 also describes the processing of intermediate A into the desired analogue.

[0961] Commercially available substituted benzoylacetonitrile and 1,4-dithiane-2,5-diol can be stirred in an alcohol solvent in the presence of an amine (e.g., DIPEA) (step 4). Aniline can be treated with a ketone to install R1 and R2 under acidic conditions to give the cyclized product—intermediate A.

[0962] Option 3

[0963]

[0964] Starting with aniline bromide, aniline can be protected (e.g., Boc protection) (step 1). Under Suzuki coupling conditions with boric acid or borate esters in the presence of a Pd catalyst, an aqueous (carbonate) form can be used in a mixed solvent system (step 2). Deprotection (step 3), followed by the formation of a thiazole (step 4), can generate a thiazole ring. Sandmeyer reduction of aniline, followed by a Suzuki reaction, can produce 3-F (step 5). Bromination and deprotection (step 6), followed by Suzuki coupling (step 7), can provide 3-H. Conversion of phenol to trifluoromethanesulfonate can provide 3-I (step 8). Coupling trifluoromethanesulfonate with a commercially available olefin in a solvent in the presence of a combination of palladium salts / bases (e.g., K₂CO₃, triethylamine, or N,N-dicyclohexylmethylamine) and phosphine ligands can produce 3-J. Complete deprotection yields 3-K (step 10).

[0965] Option 4

[0966]

[0967] Thiazole formation (step 1), followed by Sandmeyer reduction and Suzuki reaction of aniline (step 2), provides 4-C. Alternatively, the Sandmeyer intermediate can be reduced to provide the skeleton, wherein R... A2 Yes -H. The subsequent Suzuki reaction can be completed to install R1 (step 3). Halogenation (X = I or Br) (step 4), followed by a Suzuki reaction (step 5) provides 4-F. Deprotection of phenol (step 6) and conversion of phenol to trifluoromethanesulfonate (step 7) provide 4-H. Coupling the trifluoromethanesulfonate with a commercially available olefin, followed by complete deprotection, provides 4-J (step 9).

[0968] Option 5

[0969]

[0970] Under Suzuki coupling conditions, R2 can be installed (step 1). Oxidation of pyridine (step 2) and subsequent halogenation (step 3) can provide 5-D. Suzuki coupling with the desired boronic ester or boric acid (reaction 5) (step 4), followed by halogenation and coupling with a commercially available olefin (step 6) can provide 5-G. Complete deprotection can provide 5-H (step 7).

[0971] Option 6

[0972]

[0973] Ketoester condensation with an aldehyde in the presence of a secondary amine base provides a 6-C ring (step 1). Amine-mediated cyclization with an alkene (6-D) provides a dihydropyridine ring (step 2). The ring system can then be oxidized (step 3), followed by selective reduction of an ester (step 4), and methylation can provide a methyl ether (6-h; step 5). Esters are reduced (step 6), subsequently converted to halides (6-J, step 7), and subjected to a Finkelstein reaction. The halides can then be treated with a phosphine source to provide the corresponding phosphine or phosphonate ester (step 8). 6-M can be obtained by 6-K olefination with a commercially available aldehyde (step 9) and overall deprotection of 6-L (step 10).

[0974] Option 7

[0975]

[0976] Phenol protection (step 1) and a series of successive Suzuki reactions (step 2) provide 7-C. Halogenation of pyridine (step 3) and carbonylation of the pyridine ring provide an ester (7-E; step 4). Deprotection of the benzyl group yields phenol (step 5). Phenol is converted to trifluoromethanesulfonate (step 6), followed by Suzuki coupling of the trifluoromethanesulfonate to mount R1 (step 7), which produces intermediate A. From intermediate A, ester reduction (step 12) and conversion to a halide (7-O, step 13) are followed by treatment with a phosphine source to provide the corresponding phosphine or phosphonate ester (step 14). Alkenylation with a commercially available aldehyde (step 15), followed by overall deprotection of 7-Q, yields 7-R.

[0977] Alternatively, intermediate A can be prepared by starting with an aqueous base-mediated condensation of an aldehyde and a ketone (step 8), followed by a Michael reaction with a ketone ester (step 10), and then cyclization to produce intermediate A.

[0978] Biological assay

[0979] Once compounds designed, selected, and / or optimized using the methods described above are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, the molecules can be characterized by conventional assays, including, but not limited to, those described below, to determine whether they possess predicted activity, binding activity, and / or binding specificity.

[0980] Furthermore, high-throughput screening can be used to accelerate analyses using such assays. Therefore, the activity of molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can be performed using one or more different assay techniques, including, but not limited to, those described below.

[0981] Various in vitro or in vivo biological assays can be applied to detect the effects of the compounds disclosed herein. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility variation assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0982] In some implementations, the biological test is described in the embodiments herein.

[0983] It has been shown that STMN2 is involved not only in axonal regeneration but also in the maintenance of the neuromuscular junction. Constitutive knockout of Stmn2 in mice leads to motor and sensory axonopathy, and chronic inhibition of Stmn2 in the central nervous system of other wild-type adult mice results in progressive muscle denervation and structural collapse of motor axons. Decreased Stmn2 levels lead to axonal diameter contraction and myelin sheath transection in motor axons. In vitro, STMN2 substitution in lentivirus-mediated TDP-43-deficient iPSC neurons can restore axonal regeneration after axonal transection, suggesting that despite TDP-43 loss of function leading to missplicing of thousands of other genes, supplementing STMN2 levels may still lead to axonal regeneration.

[0984] In some embodiments, the compounds disclosed herein inhibit HMG-CoA reductase.

[0985] In some implementations, inhibition of HMG-CoA reductase is associated with increased STMN2 expression.

[0986] In some implementations, nano-luciferase assays can be used to screen and validate the compounds of the present invention.

[0987] In some implementations, cells (e.g., TDP-mut STMN2-NLuc SH-SY5Y cells) can be used to screen compounds of formula (I'), formula (I), formula (II'), or formula (II).

[0988] In some embodiments, a neural spur extension assay (e.g., in SH-SY5Y cells) can be used to screen the compounds of the present invention.

[0989] Pharmaceutical Composition

[0990] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound of the various types 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 present invention provides a pharmaceutical composition comprising a compound described in Table 1, Table 1A, Table 2, Table 2A, or Table 3. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound selected from Table 1, Table 1A, Table 2, Table 2A, or Table 3.

[0991] The term “composition” as used herein is intended to include products containing specified amounts of specified ingredients, and any products directly or indirectly produced from combinations of specified amounts of specified ingredients.

[0992] The compounds of this disclosure can be formulated for oral administration in forms such as tablets, capsules (each including sustained-release or time-release formulations), 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 well known to those skilled in the pharmaceutical art.

[0993] The formulations disclosed herein may be in the form of an aqueous solution comprising an aqueous medium. The aqueous medium component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from: solubilizers, chelating agents, preservatives, tensioning agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0994] Any suitable solubilizer can be used. Examples of solubilizers include cyclodextrins, such as those selected from: hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, fully acetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched-chain β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0995] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the following: ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate and tetrasodium edetate and mixtures thereof.

[0996] Any suitable preservative may be used. Examples of preservatives include those selected from the following: quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben and sorbic acid, and mixtures thereof.

[0997] The aqueous medium may also include a tensioning agent to adjust the tension (osmotic pressure). The tensioning agent may be selected from glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0998] The aqueous medium may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from: cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose, and crosslinked acrylic polymers (carbomers), such as acrylic polymers crosslinked with polyolefin ethers or divinyl glycol (carbomers—such as carbomer 934, carbomer 934P, carbomer 971, carbomer 974 and carbomer 974P) and mixtures thereof.

[0999] To adjust the formulation to an acceptable pH (typically a pH range of 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 an inorganic acid or a metal hydroxide base selected from potassium hydroxide, sodium hydroxide, and 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 target pH range. Therefore, it may not be necessary to use both an acid and a base simultaneously—depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[1000] The aqueous medium may also contain a buffer to stabilize the pH. When used, the buffer is selected from the following: phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[1001] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from: polyoxypropylene-polyoxyethylene block copolymers (poloxam), polyethoxylated ethers of castor oil, polyoxyethylene-modified sorbitol esters (polysorbates), oxyethylated octylphenol polymers (teroxam), polyoxyethylene 40 stearate, ethylene glycol esters of fatty acids, glyceryl esters of fatty acids, sucrose fatty acid esters and polyoxyethylene fatty acid esters, and mixtures thereof.

[1002] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be blended with excipients and used in tablet, lozenge, or capsule form. Oral compositions may also be prepared using a liquid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and by rinsing and spitting or swallowing. Pharmaceutically compatible binders and / or excipients may be included as part of the composition. The tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[1003] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[1004] The compositions disclosed herein may be in forms suitable for use as follows: oral administration (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical administration (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely pulverized powders or liquid aerosols), administration by blowing (e.g., as finely pulverized powders), 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).

[1005] The compositions of this disclosure can be obtained through conventional procedures using conventional pharmaceutical excipients, as is well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[1006] An effective amount of the compound of this disclosure for use in therapy is sufficient to treat or prevent the STMN2-related conditions mentioned herein, slow their progression, and / or alleviate symptoms associated with said conditions.

[1007] An effective amount of the compound of this disclosure for use in therapy is sufficient to treat the STMN2-related conditions mentioned herein, slow their progression, and / or alleviate symptoms associated with the conditions.

[1008] The dosage of compounds of formula (I) or (II) used for therapeutic or preventative purposes will naturally vary according to well-known medical principles, the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[1009] How to use

[1010] In some aspects, the present invention provides a method for regulating STMN2 expression using compounds of the present invention or pharmaceutically acceptable salts thereof.

[1011] In some aspects, the present invention provides a method (e.g., in vitro or in vivo) for regulating STMN2 expression using an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[1012] In some aspects, the present invention provides a method (e.g., in vitro or in vivo) for regulating STMN2 expression using compounds of the present invention or pharmaceutically acceptable salts thereof.

[1013] In some aspects, the present invention provides a method (e.g., in vitro or in vivo) for regulating STMN2 expression using an effective amount of a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[1014] In some aspects, the present invention provides a method (e.g., in vitro or in vivo) for regulating STMN2 expression using a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[1015] In some aspects, the present invention provides a method for increasing neurite growth in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[1016] In some aspects, the present invention provides a method for increasing neurite growth in a subject in need, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

[1017] In some aspects, the present invention provides a method for increasing axonal growth in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[1018] In some aspects, the present invention provides a method for increasing axonal growth in a subject in need, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

[1019] In some aspects, the present invention provides methods for treating or preventing diseases or disorders disclosed herein in a subject in need, including administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject.

[1020] In some aspects, the present invention provides methods for treating the diseases or disorders disclosed herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1021] In some aspects, the present invention provides methods for treating or preventing the diseases or disorders disclosed herein in a subject in need, including administering a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject.

[1022] In some aspects, the present invention provides methods for treating the diseases or disorders disclosed herein in a subject in need, including administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1023] In some embodiments, the disease or disorder is associated with STMN2 expression. In some embodiments, the disease or disorder is a disease or disorder involving STMN2 expression.

[1024] In some implementations, regulatory expression is referred to as regulatory activity.

[1025] In some implementations, the disease or disorder is a neurodegenerative disease or disorder.

[1026] In some implementations, the disease or disorder is associated with axonal degeneration, axonal injury, or axonal lesion.

[1027] In some implementations, the disease or disorder is axonal degeneration, axonal injury, or axonal lesion.

[1028] In some implementations, the disease or disorder is an axonal mutation.

[1029] In some implementations, the disease or disorder is axonal injury.

[1030] In some implementations, the disease or disorder is an axonal lesion.

[1031] In some implementations, the neurodegenerative disease is associated with axonal degeneration, axonal injury, or axonal lesion.

[1032] In some implementations, the neurodegenerative disease is associated with axonal degeneration.

[1033] In some implementations, the neurodegenerative disease is associated with axonal injury.

[1034] In some implementations, the neurodegenerative disease is associated with axonal lesions.

[1035] In some aspects, the present invention provides methods for treating or preventing neurodegenerative diseases or disorders in subjects in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1036] In some aspects, the present invention provides a method for treating neurodegenerative diseases or disorders in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1037] In some aspects, the present invention provides methods for treating or preventing neurodegenerative diseases or disorders in subjects in need, including administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1038] In some aspects, the present invention provides a method for treating neurodegenerative diseases or disorders in a subject in need, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1039] In some aspects, the present invention provides a method for treating or preventing axonal lesions in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1040] In some aspects, the present invention provides a method for treating axonal lesions in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1041] In some aspects, the present invention provides a method for treating or preventing axonal lesions in a subject in need, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1042] In some aspects, the present invention provides a method for treating axonal lesions in a subject in need, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

[1043] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for regulating STMN2 expression.

[1044] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for regulating STMN2 expression (e.g., in vitro or in vivo).

[1045] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for regulating STMN2 expression (e.g., in vitro or in vivo).

[1046] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use in treating and / or preventing diseases in patients, said diseases being characterized by loss of STMN2 expression.

[1047] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for increasing neurite growth.

[1048] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for increasing neurite growth.

[1049] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for increasing axonal growth.

[1050] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for increasing axonal growth.

[1051] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, for the treatment or prevention of diseases or disorders.

[1052] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment or prevention of the diseases or disorders disclosed herein.

[1053] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of the diseases or disorders disclosed herein.

[1054] In some aspects, the present invention provides compounds of the invention or pharmaceutically acceptable salts thereof for use in treating or preventing neurodegenerative diseases or disorders in subjects in need.

[1055] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use in treating neurodegenerative diseases or disorders in subjects in need.

[1056] In some aspects, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use in treating or preventing axonal lesions in subjects in need.

[1057] In some aspects, the present invention provides compounds of the invention or pharmaceutically acceptable salts thereof for use in treating axonal lesions in subjects in need.

[1058] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for regulating STMN2 expression (e.g., in vitro or in vivo).

[1059] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of a medicament for increasing neurite growth.

[1060] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for increasing axonal growth.

[1061] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of the diseases or disorders disclosed herein.

[1062] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of the diseases or disorders disclosed herein.

[1063] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of neurodegenerative diseases or disorders in subjects in need.

[1064] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of neurodegenerative diseases or disorders in subjects in need.

[1065] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of axonal lesions in subjects in need.

[1066] In some aspects, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of a medicament for the treatment of axonal lesions in subjects in need.

[1067] In some embodiments, the present invention provides compounds that act as modulators of STMN2 activity.

[1068] In some implementations, the regulation leads to increased STMN2 expression.

[1069] In some implementations, the regulation leads to increased STMN2 expression by inhibiting HMG-CoA-reductase.

[1070] In some embodiments, the present invention provides compounds that function as HMG-CoA-reductase inhibitors.

[1071] The effectiveness of the compounds disclosed herein can be determined using industry-accepted assays / disease models and standard practices that elucidate them, as described in the art and found in current general knowledge.

[1072] This disclosure also provides a method for treating a disease or disorder involving STMN2 activity in a subject requiring such treatment, the method comprising administering to the subject a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1073] In some implementations, the disease or disorder is associated with TDP43-induced STMN2 deficiency.

[1074] In some embodiments, the disease or disorder is a neurodegenerative disease or disorder associated with TDP43-induced STMN2 deficiency.

[1075] In some implementations, the disease or disorder is associated with phenotypic axonal lesions.

[1076] In some implementations, the phenotypic axonal lesions are caused by injury, trauma, or aging.

[1077] In some implementations, the phenotypic axonal lesions are caused by brain injury or brain trauma.

[1078] In some implementations, the disease or disorder is associated with reduced axonal growth.

[1079] In some implementations, the disease or disorder is associated with reduced neurite growth.

[1080] In some implementations, the disease or disorder is a synaptic disorder.

[1081] In some implementations, the synaptic barrier is associated with synaptic defects.

[1082] In some implementations, the synaptic defect is associated with neurological diseases or disorders.

[1083] In some implementations, the disease or disorder has a prominent functional deficit.

[1084] In some implementations, the obstacle is a spinal cord injury.

[1085] In some implementations, the obstacle is nerve damage.

[1086] In some implementations, the neurodegenerative disease or disorder is 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, age-related border-dominant TDP-43 encephalopathy neuropathology (LATE-NC), Lewy body dementia (LBD), peripheral neuropathy (chemotherapy-induced neuropathy, injury-induced neuropathy), and autism spectrum disorders.

[1087] In some implementations, axonal lesions are associated with the following: 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, age-related border-dominant TDP-43 encephalopathy neuropathology (LATE-NC), Lewy body dementia (LBD), peripheral neuropathy (chemotherapy-induced neuropathy, injury-induced neuropathy), and autism spectrum disorders.

[1088] In some implementations, the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS).

[1089] In some implementations, the neurodegenerative disease or disorder is Parkinson's disease (PD).

[1090] In some implementations, the neurodegenerative disease or disorder is Alzheimer's disease (AD).

[1091] In some implementations, the neurodegenerative disease or disorder is frontotemporal dementia (FTD).

[1092] In some implementations, the neurodegenerative disease or disorder is inclusion body myopathy (IBM).

[1093] In some implementations, the neurodegenerative disease or disorder is Rett syndrome.

[1094] In some implementations, the neurodegenerative disease or disorder is Alexander syndrome.

[1095] In some implementations, the neurodegenerative disease or disorder is Perry syndrome.

[1096] In some implementations, the neurodegenerative disease or disorder is age-related marginal-dominant TDP-43 encephalopathy neuropathological changes (LATE-NC).

[1097] In some implementations, the neurodegenerative disease or disorder is Lewy body dementia (LBD).

[1098] In some embodiments, the neurodegenerative disease or disorder is a peripheral neuropathy (e.g., chemotherapy-induced neuropathy or injury-induced neuropathy).

[1099] In some implementations, the neurodegenerative disease or disorder is autism spectrum disorder.

[1100] Application route

[1101] The compounds disclosed herein, or their pharmaceutically acceptable salts, may be administered alone as a sole therapy, or may be administered in combination with one or more other substances and / or treatments. Such combination therapy may be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

[1102] For example, the efficacy of treatment can be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual can be increased by administering a compound of formula (I), (II'), or (II) with another therapeutic agent (which also includes treatment regimens) that also has therapeutic benefits.

[1103] When the compounds of this disclosure are used in combination with other therapeutic agents, the compounds of this disclosure do not need to be administered via the same route as the other therapeutic agents, and can be administered via different routes due to their different physical and chemical characteristics. For example, the compounds of this disclosure can be administered orally to produce and maintain a good blood level, while other therapeutic agents can be administered intravenously. Initial administration can be performed according to established protocols known in the art, and then, based on observed effects, a skilled clinician can modify the dosage, administration mode, and frequency of administration.

[1104] The specific choice of other therapeutic agents will depend on the attending physician's diagnosis and their assessment of the individual's condition, as well as the appropriate treatment regimen. According to this aspect of the disclosure, combinations are provided for treating diseases involving STMN2 activity, said combinations comprising compounds of the disclosure as defined above or pharmaceutically acceptable salts thereof, and another suitable agent.

[1105] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of this disclosure or a pharmaceutically acceptable salt thereof, and a suitable, pharmaceutically acceptable diluent or carrier.

[1106] In addition to their use in therapeutics, compounds of formula (I), formula (II'), or formula (II) and their pharmaceutically acceptable salts can also be used as pharmacological tools in the development and standardization of in vitro and in vivo test systems to evaluate the modulatory effects of STMN2 receptor activity in experimental animals such as dogs, rabbits, monkeys, miniature pigs, rats, and mice as part of the search for new therapeutics.

[1107] In any of the pharmaceutical compositions, processes, methods, uses, pharmaceuticals, and preparation characteristics described in this disclosure, any alternative embodiments of the macromolecules of this disclosure described herein are also applicable.

[1108] The compounds of this disclosure or pharmaceutical compositions comprising such compounds may be administered to a subject via any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[1109] Routes of administration include, but are not limited to, oral (e.g., by ingestion); sublingual; sublingual; transdermal (e.g., by patches, plasters, etc.); transmucosal (e.g., by patches, plasters, etc.); intranasal (e.g., by nasal sprays or powders); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and implantation via a reservoir or pool, such as subcutaneous or intramuscular. Example

[1110] For illustrative purposes, neutral compounds of formula (I'), (I), (II'), or (II) were synthesized and tested in the examples. It should be understood that neutral compounds of formula (I) or (II) can be converted into their respective pharmaceutically acceptable salts using conventional techniques in the art (e.g., by saponifying esters to carboxylates, or by hydrolyzing amides to form the corresponding carboxylic acids, and then converting the carboxylic acids to carboxylates).

[1111] In some embodiments, the compound of formula (I'), formula (I), formula (II') or formula (II) is a sodium salt of the compound.

[1112] abbreviation

[1113]

[1114] Example 1. Synthesis of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-3-methylthiopheno[3,2-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoic acid

[1115]

[1116] 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 h. LCMS showed complete consumption of the starting material and the desired product was observed. Water (200 mL) was added to the mixture, and the mixture was extracted with CH2Cl2 (200 mL × 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 to 25%) to give compound 2 (10.73 g, 42.93% yield) as a yellow solid. LCMS (ESI+): m / z = 307.9 (M+23), RT: 0.331 min. 5-95AB_0.8MIN: LC / MS (Kinetex® EVOC18 2.1x30mm 5µm column used for chromatography. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1117]

[1118] Step 2. Add NaOEt (2.56 g, 37.61 mmol, 1 eq) to a solution of compound 2 (10.73 g, 37.61 mmol, 1 eq) in EtOH (100 mL) and stir the mixture at 80 °C for 2 h. LCMS showed the desired product. Cool the mixture to 25 °C and filter. Dry the filter cake under reduced pressure to give compound 3 (11.76 g, crude substance), which is a white solid. LCMS (ESI+): m / z = 254.0 (M+1), RT: 0.353 min.

[1119]

[1120] Step 3. POCl3 (19 mL) was added to a solution of compound 3 (5 g, 19.74 mmol, 1 eq) in toluene (19 mL), and the mixture was stirred at 100 °C for 16 h. LCMS showed complete consumption of the starting material and observation of the desired product. The mixture was poured into a saturated aqueous solution of NaHCO3 (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was combined with parallel batches (using 5 g of compound 3) and purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 5%) to give compound 4 (3.7 g, 32.30% yield) as a white solid. LCMS (ESI+): m / z = 290.0 (M+1), RT: 0.503 min.

[1121]

[1122] Step 4. A solution of 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) in dioxane (20 mL) and H₂O (2 mL) was degassed and purged three times with N₂. The mixture was then stirred at 100 °C under N₂ for 2 h. LC-MS showed complete consumption of the starting material and the desired MS was observed. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 5%) to give compound 5C (1.38 g, 52.75% yield), which was a colorless oil. LCMS (ESI+): m / z = 350.0 (M+1), RT: 0.526 minutes.

[1123]

[1124] Step 5. A solution of 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) in dioxane (5 mL) and H₂O (0.5 mL) was degassed and washed three times with N₂. The mixture was then stirred at 100 °C under N₂ for 2 h. LC-MS showed complete consumption of the starting material and observation of the desired product. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 5%) to give compound 6 (135 mg, 27.68% yield) as a colorless oil. 1 H NMR: (400 MHz, CDCl3)δ 1.10-0.90 (m, 5 H), 1.31 (br dd, J=4.4, 2.8 Hz, 2 H), 2.20 - 2.35 (m, 1 H), 2.47 (s, 3 H), 4.14 (q, J=7.2 Hz, 2 H), 7.18 (t, J=8.8 Hz, 2 H), 7.40 (s, 1 H), 7.50 (dd, J=8.4, 5.2 Hz, 2 H). LCMS (ESI+): m / z =356.1 (M+1), RT: 0.567 min.

[1125]

[1126] Step 6. LiAlH4 (2.5 M, 1.50 mL, 1.5 eq) was added to a solution of compound 6 (890 mg, 2.50 mmol, 1 eq) in THF (10 mL) at 0 °C, and the mixture was stirred at 25 °C under N2 for 1 h. TLC showed complete consumption of the starting material and new spots with high polarity were observed. The reaction was quenched by adding water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 7 (714 mg, 90.99% yield), a white solid, which was used directly for the next step.

[1127]

[1128] 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 h. LCMS showed complete consumption of the starting material and observation of the desired product. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 5%) to give compound 8 (646 mg, 75.35% yield) as a white solid. LCMS (ESI+): m / z = 376.0 (M+1), RT: 0.593 min.

[1129]

[1130] Step 8. PPh3 (675.43 mg, 2.58 mmol, 1 eq) was added to a solution of compound 8 (646 mg, 1.72 mmol, 1 eq) in toluene (5 mL), and the mixture was stirred at 110 °C for 2 h. LCMS showed complete consumption of the starting material and the desired MS was observed. The mixture was concentrated under reduced pressure to give compound 9 (1.09 g, 99.43% yield), a white solid, which was used directly for the next step. LCMS (ESI+): m / z = 558.2 (M-Br), RT: 0.450 min.

[1131]

[1132] Step 9. Add NaH (102.41 mg, 2.56 mmol, 60% purity, 1.5 eq) and compound 9A (661.38 mg, 2.56 mmol, 1.5 eq) to a solution of compound 9 (1.09 g, 1.71 mmol, 1 eq) in THF (20 mL). Stir the mixture at 20 °C for 1 hr. LCMS showed complete consumption of the starting material and observation of the desired product. Quench the mixture with water (3 mL) and concentrate under reduced pressure to give the crude product. Purify the crude product by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 10%) to give compound 10 (595 mg, 32.41% yield) as a white solid. LCMS (ESI+): m / z = 538.2 (M+1), RT: 0.623 min.

[1133]

[1134] 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. LCMS showed complete consumption of the starting material and the desired product was observed. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC: column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN]; gradient: 55%-85% B for 10 minutes to obtain the crude product, which was further purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 50%) to give (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-3-methylthieno[3,2-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoic acid (87.3 mg, 17.87% yield), as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 1.02 (dd, J=8.0, 2.4 Hz, 2H), 1.26 - 1.34 (m, 2 H), 1.60 - 1.67 (m, 1 H), 1.75 - 1.89 (m, 2 H), 2.28 - 2.40 (m, 1 H), 2.46 (s, 3 H), 2.56 - 2.66 (m, 1 H), 2.67 - 2.79 (m, 1 H), 4.18 - 4.35 (m, 1H), 5.12 - 5.28 (m, 1 H), 5.61 (dd, J=16.0, 6.4 Hz, 1 H), 6.80 (dd, J=16.0, 1.2 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2 H), 7.29 (d, J = 1.2 Hz, 1 H), 7.36 (dd, J = 8.8, 5.6 Hz, 2 H). LCMS (ESI+): m / z = 424.0 (M-17), RT: 2.232 minutes.

[1135] Example 2. (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thiopheno[3,2-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoic acid

[1136]

[1137] Step 1. Add 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) to a solution of Compound 1 (15 g, 95.43 mmol, 1 eq) in DCM (150 mL). Stir the mixture at 25 °C for 2 h. TLC showed complete consumption of the starting material and detection of major new spots. Add water (200 mL) to the reaction mixture. Extract the mixture with DCM (200 mL × 3). Wash the combined organic layers with brine (200 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 9%) to give Compound 2 (14.22 g, 54.93% yield) as a yellow oil. LCMS (ESI+): m / z = 272.0 (M+1), RT: 0.375 minutes.

[1138]

[1139] Step 2. Add EtONa (5.35 g, 78.62 mmol, 1.5 eq) to a solution of compound 2 (14.22 g, 52.42 mmol, 1 eq) in EtOH (143 mL). Stir the mixture at 80 °C for 16 h. LCMS showed that the starting material was consumed and the desired MS was detected. Filter the reaction mixture and dry the solid under reduced pressure to give compound 3 (12.51 g, 99.76% yield), which was a yellow solid. LCMS (ESI+): m / z = 240.1 (M+1), RT: 0.328 min.

[1140]

[1141] 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 h. TLC showed complete consumption of the starting material and detection of major new spots. After cooling to room temperature, the reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (500 mL) at 25 °C and then extracted with ethyl acetate (500 mL × 3). The combined organic layers were 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 to 2%) to give compound 4 (1.51 g, 32.71% yield) as a white solid. LCMS (ESI+): m / z = 275.9 (M+1), RT: 0.455 min.

[1142]

[1143] Step 4. 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 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). The mixture was stirred at 100 °C under nitrogen for 16 hrs. TLC showed a partial residue of compound 4, with two major new spots detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 2%) to give compound 5 (100 mg, 17.72% yield) as a colorless oil. 1 H NMR: (400 MHz, CDCl3) δ1.04 (dd, J=8.0, 2.8 Hz, 2 H) 1.24 (dd, J=4.4, 2.8 Hz, 2 H) 1.46 (t, J=7.2 Hz, 3 H) 2.10 - 2.17 (m, 1 H) 4.52 (q, J=7.2 Hz, 2 H) 7.45 (d, J=5.6 Hz, 1 H) 7.79 (d, J=5.6 Hz, 1 H).

[1144]

[1145] Step 5. 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 to a solution of compound 5 (300 mg, 1.06 mmol, 1 eq) and compound 5B (446.94 mg, 3.19 mmol, 3 eq) in dioxane (2 mL) and H2O (0.2 mL). The mixture was stirred at 100 °C under nitrogen for 16 hrs. TLC showed complete consumption of the starting material and detection of major new spots. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 5%) to give compound 6 (262 mg, 68.47% yield) as a brown oil. LCMS (ESI+): m / z = 342.1 (M+1), RT: 0.500 minutes.

[1146]

[1147] Step 6. LAH (2.5 M, 818.98 μL, 1.5 eq) was added to a solution of compound 6 (466 mg, 1.36 mmol, 1 eq) in THF (5 mL) at 0 °C. The mixture was stirred at 25 °C under nitrogen for 2 hrs. LCMS showed complete consumption of the starting material and detection of the product. The reaction was cooled to -10 to 0 °C, and water (0.1 mL) was slowly added dropwise to the reaction, followed by 0.1 mL of 15% NaOH aqueous solution and 0.3 mL of water. The mixture was warmed to room temperature and stirred for 15 min. Then, anhydrous Na2SO4 was added, and the mixture was filtered. The filter cake was washed with ethyl acetate (10 mL × 3), and the filtrate was concentrated under reduced pressure to give compound 7 (414 mg, 1.31 mmol, 96.25% yield) as a yellow oil. LCMS (ESI+): m / z = 300 (M+1), RT: 0.313 minutes.

[1148]

[1149] Step 7. PPh3 (350.46 mg, 1.34 mmol, 2 eq) and CBr4 (332.33 mg, 1.00 mmol, 1.5 eq) were added to a solution of compound 7 (200 mg, 668.09 μmol, 1 eq) in DCM (3 mL) at 0 °C. The mixture was stirred at 25 °C under nitrogen for 1 hr. LCMS showed complete consumption of the starting material and detection of the product. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 5%) to give compound 8 (111 mg, 45.86% yield) as a yellow oil. LCMS (ESI+): m / z = 362.0 (M+1), RT: 0.500 min.

[1150]

[1151] 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 at 110 °C under nitrogen for 0.5 hr. LCMS showed complete consumption of the starting material and detection of the product. The reaction mixture was concentrated under reduced pressure to give compound 9 (300 mg, crude substance) as a white solid. LCMS (ESI+): m / z = 544.1 (M-Br), RT: 0.427 min.

[1152]

[1153] 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 at 25 °C under nitrogen for 16 hrs. LCMS showed complete consumption of the starting material and detection of the product. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 to 7%) to give compound 10 (107 mg, 43.12% yield) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 1.01 - 1.04 (m, 2 H) 1.18 - 1.22 (m, 1 H) 1.24 - 1.31 (m, 2 H) 1.38 (s, 3 H) 1.47 (s, 9 H) 1.59 (s, 3 H) 2.24 - 2.31 (m, 1 H) 2.33 - 2.48 (m, 3 H) 4.22 -4.30 (m, 1 H) 4.35 - 4.41 (m, 1 H) 5.56 (dd, J=16.0, 6.0 Hz, 1 H) 6.64 (dd, J=16.4, 1.2 Hz, 1 H) 7.16 (t, J=8.8 Hz, 2 H) 7.37 (dd, J=8.4, 5.6 Hz, 2 H) 7.45 (d, J=5.6 Hz, 1 H) 7.62 (d, J=5.6 Hz, 1 H).

[1154] In some embodiments, compound 10 is a sodium salt of compound 10.

[1155]

[1156] Step 10. Add TFA (0.5 mL) to a solution of compound 10 (107 mg, 204.33 μmol, 1 eq) in DCM (1.5 mL). Stir the mixture at 25 °C under nitrogen for 0.5 hr. LCMS showed complete consumption of the starting material and detection of the product. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenexluna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN]; gradient: 36%-66% B for 10 min) to obtain a crude product, which was dissolved in THF / H2O (1:1, 1 mL) and adjusted to pH=9, and then further purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(NH3.H2O)-ACN]; gradient: 8% - 28% B for 10 min) to obtain (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thieno[3,2-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoic acid (20.10 mg, 17.83% yield), which was a white solid. 1H NMR: (400 MHz, DMSO-d6) δ 0.98 (dd, J = 8.0, 3.6 Hz, 2 H), 1.06 - 1.12 (m, 2 H), 1.16 (ddd, J = 13.6, 6.4, 4.4 Hz, 1H), 1.38 - 1.46 (m, 1 H), 1.93 (dd, J = 15.2, 8.4 Hz, 1 H), 2.05 - 2.13 (m, 1 H), 2.40 - 2.47 (m, 1 H), 3.61 - 3.64 (m, 1 H), 4.11 - 4.17 (m, 1 H), 5.57 (dd, J = 16.0, 6.0Hz, 1 H), 6.54 (dd, J = 16.0, 1.0 Hz, 1 H), 7.30 - 7.37 (m, 2 H), 7.42 - 7.48 (m, 3 H), 7.98 (d, J = 5.6 Hz, 1 H). LCMS (ESI+): m / z = 428.2 (M-17), RT: 1.573 min. LC / MS: HALO C18 90A 2.7µm 3.0x30mm. Detection method: Diode array detector (DAD). MS mode: Positive ion electrospray ionization. MS range: 50-1050. Mobile phase: At 3.0 min, the flow rate was set at 1.0 mL / min; then, maintaining 95% ACN for 0.60 min, the solution was increased from 5% ACN (0.018% TFA) in water (0.037% TFA) to 95% ACN at a flow rate of 1.0 mL / min to 1.5 mL / min; the solution was then returned to the 5% ACN aqueous solution and maintained at 1.5 mL / min for 0.40 min.

[1157] Example 3. Synthesis of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thiazo[5,4-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoic acid

[1158]

[1159] 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 h. Compound 1 (22 g, 171.13 mmol, 1 eq) was added at 25 °C. The mixture was stirred at 70 °C under N₂ for 3 h. LCMS showed that 96% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was milled with PE / EtOAc = 3:1 (20 mL) at 25 °C for 30 min and filtered. The filter cake was dried under reduced pressure to give compound 2 (21.5 g, 80.24% yield), which was a yellow solid. 1 H NMR: (400 MHz, CDCl3) δ 7.29 (dd, J = 8.4, 4.8 Hz, 1 H), 7.78 (s, 1 H), 8.16 (dd, J = 4.8, 1.2 Hz, 1 H), 8.56 (s, 1 H), 8.77 (dd, J = 8.0, 0.8 Hz, 1 H).

[1160]

[1161] Step 2. Add 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiphosphazenecyclobutane (25.83 g, 63.87 mmol, 1 eq) to a solution of compound 2 (10.0 g, 63.87 mmol, 1 eq) in THF (400 mL). Stir the mixture at 70 °C under N2 for 16 h. LCMS showed 32% of the desired compound was detected. Add the reaction mixture to an aqueous solution of NaHCO3 (100 mL), and extract the mixture with EtOAc (200 mL × 3). Wash the combined organic layers with brine (100 mL), dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The crude product was combined with five batches (using 10 g × 4 and 5 g of compound 2) and purified by rapid column chromatography on silica gel (0–9% EtOAc in PE) to give compound 3 (34.4 g, 79.10% yield), as a yellow solid. LCMS (ESI+): m / z = 137.1 (M+1), RT: 0.204 min. LC / MS: Kinetex® EVO C18 2.1 x 30 mm 5 μm. Detection method was photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range: 50–1050. Mobile phase: The solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) was pumped to an aqueous solution of 95% ACN over 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; finally, the solution was returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1162]

[1163] Step 3. Add m-CPBA (29.82 g, 146.87 mmol, 85% purity, 2 eq) to a solution of compound 3 (10.0 g, 73.44 mmol, 1 eq) in DCM (190 mL). Stir the mixture at 25 °C under N2 for 16 h. LCMS showed that 52% of the desired compound was detected. Add the reactants to an aqueous solution of Na2SO3 (200 mL). Use wet starch-potassium iodide test paper to test the quenching liquid. The test paper remains white in the acidic system. Adjust the reaction mixture to pH = 8 with aq. NaHCO3 and extract with DCM (300 mL × 4). Wash the combined organic layers with brine (300 mL), dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. Combine the residue with parallel batches (using 10 g of compound 3) and grind with PE / EtOAc = 3:1 (10 mL) at 25 °C for 30 min and filter. The filter cake was concentrated under reduced pressure to give compound 4 (2.80 g, 12.52% yield), which was a brown solid. 1 H NMR: (400 MHz, CDCl3) δ 7.48 (dd, J = 8.0, 6.4 Hz, 1 H) 8.06 (d, J = 8.4 Hz, 1 H) 8.40 (d, J = 6.4 Hz, 1 H) 9.12 (s, 1 H).

[1164]

[1165] Step 4. A solution of compound 4 (2.80 g, 18.40 mmol, 1 eq) in POCl3 (10 mL) was stirred at 100 °C for 1 h. LCMS showed that 31% of the desired compound was detected. The reaction mixture was added to a saturated sodium bicarbonate solution (500 mL) at 25 °C and then extracted with EtOAc (500 mL × 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 reversed-phase HPLC (column: Daisogel C18 250*70 mm*10 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 16%-46% B over 23 min) to give compound 5 (1.20 g, 38.22% yield) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ7.54 (d, J =5.2 Hz, 1 H), 8.56 (d, J = 5.2 Hz, 1 H), 9.19 (s, 1 H).

[1166]

[1167] Step 5. Cs₂CO₃ (4.58 g, 14.07 mmol, 1 eq) and Pd(dppf)Cl₂.CH₂Cl₂ (574.36 mg, 703.32 μmol, 0.1 eq) were added 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). The mixture was stirred at 100 °C under N₂ for 2 h. LCMS showed that 48% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–10% EtOAc in PE) to give compound 6 (1.50 g, 77.80% yield) as a yellow solid. LCMS (ESI+): m / z = 231.0 (M+1), RT: 0.397 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. Detection method was a photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1168]

[1169] Step 6. Add m-CPBA (2.47 g, 12.16 mmol, 85% purity, 2 eq) to a solution of compound 6 (1.4 g, 6.08 mmol, 1 eq) in DCM (14 mL). Stir the mixture at 25 °C under N2 for 8 hours. LCMS showed that 91% of the desired compound was detected. Add the reactants to an aqueous solution of Na2SO3 (150 mL). Use wet starch-potassium iodide test paper to test the quenching liquid. The test paper remains white in the acidic system. Adjust the reaction mixture to pH = 8 with aq. NaHCO3 and extract with DCM (200 mL × 3). Wash the combined organic layers with brine (200 mL), dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–6% MeOH in DCM) to give compound 7 (1.31 g, 43.75% yield) as a pale yellow solid. LCMS (ESI+): m / z = 246.9 (M+1), RT: 0.445 min. LC / MS: Gemini@5umNX-C18 110A 2*30mm, 5um. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50–1050. Mobile phase: from 5% ACN aqueous solution (0.025% NH3•H2O) to 95% ACN aqueous solution over 0.70 min at a flow rate of 1.7 mL / min, then held at 95% ACN for 0.20 min at a flow rate of 1.7 mL / min; returned to 5% ACN aqueous solution and held for 0.10 min. The flow rate was set to 1.7 mL / min.

[1170]

[1171] Step 7. A solution of compound 7 (1.31 g, 5.32 mmol, 1 eq) in POCl3 (6 mL) was stirred at 100 °C for 2 h. LCMS showed that 94% of the desired compound was detected. The reaction mixture was added to a saturated sodium bicarbonate solution (500 mL) at 25 °C and then extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 8 (1.28 g, 90.90% yield) as a white solid. LCMS (ESI+): m / z = 265.0 (M+1), RT: 0.464 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. Detection method was a photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1172]

[1173] Step 8. Cs₂CO₃ (3.15 g, 9.67 mmol, 1 eq) and Pd(dppf)Cl₂ (353.82 mg, 483.56 μmol, 0.1 eq) were added 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). The mixture was stirred at 100 °C under N₂ for 2 h. LCMS showed that 82% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–5% EtOAc in PE) to give 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_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. Detection method was a photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1174]

[1175] 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 under nitrogen for 1 hour. LCMS showed that 83% of the desired compound was detected. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–5% EtOAc in PE) to give compound 10 (600 mg, 61.93% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ 1.12 - 1.17 (m, 2 H), 1.22 - 1.27 (m, 2 H), 2.75 -2.85 (m, 1 H), 7.20 - 7.26 (m, 2 H), 7.46 (dd, J = 8.8, 5.6 Hz, 2 H), 8.93 (s, 1 H).

[1176] In some embodiments, compound 10 is a sodium salt of compound 10.

[1177]

[1178] Step 10. To a solution of 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), 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) were added. The mixture was stirred at 90 °C under N2 for 16 h. LCMS showed that 58% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0-10% EtOAc in PE) to give the crude product. The crude product was purified by prep-TLC (PE / DCM = 1:3) to give compound 11 (100 mg, 11.09% yield), which was a white solid. 1 HNMR: (400 MHz, CDCl3) δ 1.03 - 1.10 (m, 3 H), 1.19 - 1.24 (m, 1 H), 1.39 (s, 3 H), 1.46 - 1.49 (m, 12 H), 2.24 - 2.33 (m, 1 H), 2.36 - 2.50 (m, 2 H), 4.22 - 4.32 (m, 1H), 4.35 - 4.48 (m, 1 H), 5.61 (dd, J = 16.0, 5.6 Hz, 1 H), 6.61 (dd, J = 16.0, 1.2Hz, 1 H), 7.16 (t, J = 8.8 Hz, 2 H), 7.38 (dd, J = 8.8, 5.6 Hz, 2 H), 8.91 (s,1 H).

[1179] In some embodiments, compound 11 is a sodium salt of compound 11.

[1180]

[1181] Step 11. Add HCl (1 M, 1.5 eq) to a solution of compound 11 (100 mg, 190.60 μmol, 1 eq) in MeCN (1 mL). Stir the mixture at 45 °C for 16 h. LCMS showed that 88% of the desired compound was detected. Adjust the reaction mixture to pH = 9 with 1N NaOH aqueous solution and concentrate under reduced pressure. The residue was purified by reversed-phase HPLC (column: CD02-Waters Xbridge BEH C18 150*25*10um; mobile phase: [water (NH3.H2O)-ACN]; gradient: 0%-29% B for 12 min) to give (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)thiazo[5,4-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoic acid (12.34 mg, 14.34% yield), which was a white solid. 1 H NMR: (400MHz, DMSO-d6) δ 1.03 (dd, J = 7.6, 3.6 Hz, 2 H), 1.10 (d, J = 4.4 Hz, 2 H), 1.17 -1.27 (m, 1 H), 1.41 - 1.50 (m, 1 H), 1.95 - 2.04 (m, 1 H), 2.10 - 2.18 (m, 1 H), 2.45- 2.49 (m, 1 H), 3.68 (td, J = 8.0, 4.0 Hz, 1 H), 4.17 (q, J = 6.0 Hz, 1 H), 5.62 (dd, J = 16.0, 5.6 Hz, 1 H), 6.53 (d, J = 16.0 Hz, 1 H), 7.27 (t, J = 8.8 Hz, 2 H), 7.43 (dd, J = 8.8, 5.6 Hz, 2 H), 9.28 (s, 1 H). LCMS (ESI+): m / z = 429.2 (M+1), RT: 1.635 min. LC / MS: Kinetex® EVO C18 3.0x50mm 2.6um. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from 5% ACN (0.01875% TFA) in water (0.0375% TFA) solution to 95% ACN, over 3.40 min at a flow rate of 0.9 mL / min; then held at 95% ACN for 0.30 min at a flow rate of 0.9 mL / min; returned to 5% ACN aqueous solution and held for 0.30 min. The flow rate was set to 1.2 mL / min.

[1182] Example 4. Synthesis of (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthiazo[5,4-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoic acid

[1183]

[1184] Step 1. Add Et3N (49.16 g, 485.85 mmol, 67.62 mL, 2 eq) to a solution of compound 1 (31.23 g, 242.92 mmol, 1 eq) in Ac2O (125 mL). Stir the mixture at 100 °C for 2 hours. LCMS showed that 93% of the desired compound was detected. Add water (300 mL) to the reaction mixture and extract with EtOAc (300 mL × 3). Wash the combined organic layers with brine (300 mL), dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure to give compound 2 (55.3 g, crude substance) as a yellow oil. LCMS (ESI+): m / z = 213.1 (M+1), RT: 0.241 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5um. The detection method was a photodiode array (PDA). The MS mode was positive ion electrospray ionization. The MS range was 50-1050. Mobile phase A was an aqueous solution of 0.04% TFA, and mobile phase B was a solution of 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held in 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1185]

[1186] Step 2. Add NaOH (1 M, 0.25 eq) to a solution of compound 2 (55 g, 258.66 mmol, 1 eq) in MeOH (500 mL). Stir the mixture at 25 °C for 0.5 h. LCMS showed 100% detection of the desired compound. The reaction was concentrated under reduced pressure. The residue was diluted with water (400 mL), adjusted to pH = 8 with 1 N HCl, and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 3 (46.46 g, crude substance) as a brown solid. LCMS (ESI+): m / z = 171.1 (M+1), RT: 0.169 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C182.1x30mm 5µm. Detection method was photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase A was an aqueous solution of 0.04% TFA, and mobile phase B was a solution of 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1187]

[1188] Step 3. Add 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiaphosphonobutane (96.92 g, 239.63 mmol, 0.8 eq) to a solution of compound 3 (51.1 g, 299.54 mmol, 1 eq) in THF (500 mL). Stir the mixture at 25 °C under N2 for 16 h. LCMS showed that 45% of the desired compound was detected. Add the reactants to an aqueous solution of NaHCO3 (500 mL), and extract the mixture with EtOAc (500 mL × 3). Wash the combined organic layers with brine (500 mL), dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–16% EtOAc in PE) to give compound 4 (42.47 g, 57.58% yield) as a yellow oil. LCMS (ESI+): m / z = 151.1 (M+1), RT: 0.249 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. The detection method was a photodiode array (PDA). The MS mode was positive ion electrospray ionization. The MS range was 50-1050. Mobile phase A was an aqueous solution of 0.04% TFA, and mobile phase B was a solution of 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; then returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1189]

[1190] Step 4. Add m-CPBA (35.95 g, 177.10 mmol, 85% purity, 2 eq) to a solution of compound 4 (13.3 g, 88.55 mmol, 1 eq) in DCM (140 mL). Stir the mixture at 25 °C under N2 for 16 hours. LCMS showed that 86% of the desired compound was detected. Add the reactants to an aqueous solution of Na2SO3. (100 mL). Wet starch-potassium iodide test paper was used to test the quenching liquid. The test paper remained white in the acidic system. The reaction mixture was adjusted to pH 8 with aq. NaHCO3 and extracted with DCM (200 mL × 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 rapid column chromatography on silica gel (0-6% MeOH in DCM) to give compound 5 (5.99 mg, 40.70% yield) as a yellow oil. 1 H NMR: (400 MHz, CDCl3) δ 2.89 (s, 3H), 7.39 (t, J = 7.2 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 8.30 (d, J = 6.4 Hz, 1 H).

[1191]

[1192] Step 5. A solution of compound 5 (6.48 g, 38.99 mmol, 1 eq) in POCl3 (19 mL) was stirred at 100 °C for 2 h. LCMS showed that 65% of the product was detected. The reaction mixture was added to a saturated sodium bicarbonate solution (500 mL) at 25 °C and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (column: Daisogel C18 250*70 mm*10 μm; mobile phase: [water (NH3·H2O)-ACN]; gradient: 10%-40% B for 25 min) to give compound 6 (7.28 g, 50.56% yield) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 2.91 (s, 3 H), 7.44 (d, J = 5.2 Hz, 1 H), 8.43 (d, J = 5.2 Hz, 1 H). LCMS (ESI+): m / z = 184.9 (M+1), RT: 0.292 minutes. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. Detection method was photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase A was an aqueous solution of 0.04% TFA, and mobile phase B was a solution of 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1193]

[1194] Step 6. 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 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). The mixture was stirred at 100 °C under N₂ for 2 h. LCMS showed that 66% of the desired compound was detected. The reaction was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–5% EtOAc in PE) to give 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_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. Detection method was photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase A was 0.04% TFA aqueous solution, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to 5% ACN aqueous solution and held for 0.02 min at a flow rate of 2.0 mL / min.

[1195]

[1196] Step 7. Add m-CPBA (15.12 g, 87.60 mmol, 2 eq) to a solution of compound 7 (10.7 g, 43.80 mmol, 1 eq) in DCM (100 mL). Stir the mixture at 25 °C under N2 for 10 h. LCMS showed that 95% of the desired compound was detected. Add the reactants to an aqueous solution of Na2SO3 (150 mL). Use wet starch-potassium iodide test paper to test the quenching liquid. The test paper remains white in the acidic system. Adjust the reaction mixture to pH = 8 with aq. NaHCO3 and extract with DCM (200 mL × 3). Wash the combined organic layers with brine (200 mL), dry with anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–6% MeOH in DCM) to give compound 8 (9.54 g, 83.68% yield) as a pale yellow solid. LC-MS (ESI+): m / z = 260.9 (M+1), RT: 0.635 min. LC / MS: Gemini@5µmNX-C18 110A 2*30mm, 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50–1050. Mobile phase: from 0% ACN aqueous solution (0.025% NH3•H2O) to 60% ACN aqueous solution over 0.70 min at a flow rate of 1.7 mL / min, then held at 60% ACN for 0.20 min at a flow rate of 1.7 mL / min; returned to 0% ACN aqueous solution and held for 0.10 min. The flow rate was set to 1.7 mL / min.

[1197]

[1198] Step 8. A solution of compound 8 (4.77 g, 18.33 mmol, 1 eq) in POCl3 (19 mL) was stirred at 100 °C for 2 h. LCMS showed that 96% of the desired compound was detected. The reaction mixture was added to a saturated sodium bicarbonate solution (1500 mL) at 25 °C and extracted with EtOAc (1500 mL × 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 9 (9.67 g, 94.65% yield) as a white solid. LCMS (ESI+): m / z = 279.0 (M+1), RT: 0.488 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. The detection method was a photodiode array (PDA). The MS mode was positive ion electrospray ionization. The MS range was 50-1050. Mobile phase A was an aqueous solution of 0.04% TFA, and mobile phase B was a solution of 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; then returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1199]

[1200] Step 9. Cs₂CO₃ (22.61 g, 69.39 mmol, 1 eq) and Pd(dppf)Cl₂ (2.54 g, 3.47 mmol, 0.1 eq) were added 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). The mixture was stirred at 100 °C under N₂ for 2 h. LCMS showed that 80% of the desired compound was detected. The reaction was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0–5% EtOAc in PE) to give compound 10 (8.8 g, 89.20% yield) as a white solid. LCMS (ESI+): m / z = 285.1 (M+1), RT: 0.503 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. Detection method was photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase A was 0.04% aqueous TFA, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to 5% ACN aqueous solution and held for 0.02 min at a flow rate of 2.0 mL / min.

[1201]

[1202] Step 10. Add NBS (2.10 g, 11.82 mmol, 1.2 eq) and TsOH·H2O (187.31 mg, 984.70 μmol, 0.1 eq) to a solution of compound 10 (2.80 g, 9.85 mmol, 1 eq) in DMA (30 mL) and H2O (20 mL). Stir the mixture at 120 °C under N2 for 0.5 h. LCMS showed that 44% of compound 10 and ~15% of the desired compound were detected. The reaction mixture was concentrated under reduced pressure. The residue was combined with two batches (using 3 g × 2 of compound 10) and purified by reversed-phase HPLC (column: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (FA)-ACN]; gradient: 60%–90% B for 5 min) to give compound 11 (1.52 g, 13.57% yield), as a black oil. LCMS (ESI+): m / z = 363.0 (M+1), RT: 0.549 min. 5-95AB_0.8MIN: LC / MS (the column used for chromatography was a Kinetex® EVO C18 2.1x30mm 5µm. Detection method was photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase A was an aqueous solution of 0.04% TFA, and mobile phase B was a solution of 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B for 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1203]

[1204] Step 11. To a solution of 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), 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) were added. The mixture was stirred at 90 °C under N2 for 16 h. LCMS showed that 54% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was combined with parallel batches (using 200 mg of compound 11) and purified by rapid silica gel chromatography (100% EtOAc) to give the crude product. The crude product was purified by reversed-phase HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 80%-100% B for 10 min) and prep-TLC (PE / EtOAc = 5:1) to give compound 12 (100 mg, 16.86% yield), which was a white solid. 1 H NMR: (400 MHz, CDCl3) δ 1.02 (br dd, J= 8.4, 3.2 Hz, 2 H), 1.15 - 1.31 (m, 3 H), 1.38 (s, 3 H), 1.43 (s, 1 H), 1.47 (s, 9H), 1.56 (s, 3 H), 2.25 - 2.32 (m, 1 H), 2.33 - 2.40 (m, 1 H), 2.40 - 2.47 (m, 1 H), 2.74 (s, 3 H), 4.22 - 4.30 (m, 1 H), 4.39 (d, J = 10.4, 7.6 Hz, 1 H), 5.57 (dd, J =16.0, 6.0 Hz, 1 H), 6.56 (d, J = 16.4 Hz, 1 H), 7.07 - 7.19 (m, 2 H), 7.36 (dd, J =8.0, 6.0 Hz, 2 H).

[1205] In some embodiments, compound 12 is a sodium salt of compound 12.

[1206]

[1207] Step 12. HCl (1.5 M, 1.5 eq) 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 h. LCMS 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 reversed-phase HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH3.H2O)-ACN]; gradient: 4%-34% B for 10 min) to give sodium (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthiazo[5,4-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoate (35.3 mg, 47.75% yield), which was a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 0.94 - 1.03 (m, 2 H), 1.05 - 1.13 (m, 2 H), 1.26 - 1.55 (m, 2H), 1.96 - 2.08 (m, 1 H), 2.11 - 2.19 (m, 1 H), 2.41 - 2.48 (m, 1 H), 2.69 (s, 3 H), 3.77 - 3.90 (m, 1 H), 4.17 - 4.24 (m, 1 H), 5.65 (ddd, J = 16.0, 5.6, 2.0 Hz, 1 H), 6.50 (dd, J = 16.0, 1.2 Hz, 1 H), 7.19 - 7.28 (m, 2 H), 7.31 - 7.46 (m, 2 H). LCMS (ESI+): m / z = 443.2 (M+1), RT: 1.610 min. LC / MS: Kinetex® XBridge C18 3.0*50mm, 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from 0% ACN aqueous solution (0.025% NH3•H2O) to 60% ACN in 3.00 min at a flow rate of 0.9 mL / min; then maintained at 60% ACN for 0.70 min at a flow rate of 0.9 mL / min; returned to 0% ACN aqueous solution and held for 0.30 min at a flow rate of 1.2 mL / min.

[1208] Example 5. Synthesis of (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-2-methylthiopheno[2,3-b]pyridin-5-yl)-3,5-dihydroxyhept-6-enoic acid

[1209]

[1210] Step 1: Compound 1A (7.12 g, 122.59 mmol, 1 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 (10 g, 61.29 mmol, 1 eq) in EtOH (100 mL). The mixture was degassed and purged three times with N2 and stirred at 70 °C under N2 atmosphere for 2 h. LCMS showed complete consumption of the reactants and a peak with 58% of the desired mass was detected. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), and washed with brine (30 mL × 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 / EtOAc = 1 / 0 to 10 / 1) to give compound 2 (5.3 g, 26.75% yield) as a yellow solid.

[1211] LCMS (ESI+): m / z = 236.0 (M+1), RT: 0.423 min. LC / MS: Kinetex® EVO C182.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1212]

[1213] Step 2: 3-Cyclopropyl-3-oxopropionitrile (2.90 g, 26.61 mmol, 2 eq) and H₂SO₄ (2.61 g, 26.61 mmol, 1.42 mL, 2 eq) were added to a solution of compound 2 (4.3 g, 13.30 mmol, 1 eq) in AcOH (20 mL). The mixture was stirred at 100 °C for 1 hour. LCMS showed complete consumption of the reactants and a peak with 56% of the desired mass was detected. The reaction was quenched by adding 50 mL of water at 25 °C. The mixture was extracted with ethyl acetate (50 mL × 3) and washed with brine (50 mL × 3). The organic layer was then evaporated, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (FA)-ACN]; gradient: 60%-90% B for 22 min) and concentrated under vacuum to give compound 3 (4 g, 75.09% yield) as a yellow solid. 1 ¹H NMR: (400 MHz, CDCl₃) δ ppm 1.05 - 1.14 (m, 2H), 1.19 - 1.26 (m, 2H), 2.47 (s, 3H), 2.53 - 2.58 (m, 1H), 6.65 (s, 1H), 7.15 - 7.20 (m, 2H), 7.46 (dd, J = 8.0, 5.6 Hz, 2H). LCMS (ESI+): m / z = 309.0 (M+1), RT: 0.466 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: The solution was pumped from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN over 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; finally, the solution was returned to the aqueous solution of 5% ACN and held at a flow rate of 2.0 mL / min for 0.02 min.

[1214]

[1215] 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. DIBAL-H (1 M, 12.49 mL, 2 eq) was then slowly added to the solution at 0 °C. The mixture was stirred at 25 °C under N2 atmosphere for 1 hr. LCMS showed complete consumption of the reactants and a peak with 36% of the desired mass was detected. The reaction was quenched at 0 °C by the slow addition of 10 mL MeOH and 5 mL of 15% NaOH solution. The mixture was stirred at 25 °C under N2 atmosphere for 15 min, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 0 to 10 / 1) to give compound 4 (0.8 g, 19.21% yield) as a yellow solid. LCMS (ESI+): m / z = 311.9 (M+1), RT: 0.618 min. LC / MS: HALO C18 90A 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1216]

[1217] Step 4: NaBH4 (136.12 mg, 3.60 mmol, 1.5 eq) was added to a solution of compound 4 (0.8 g, 2.40 mmol, 1 eq) in MeOH (8 mL) under a N2 atmosphere at 0 °C. The mixture was degassed and purged three times with N2 and stirred at 25 °C for 1 h under a N2 atmosphere. LCMS showed complete consumption of the reactants and a peak with 89% of the desired mass was detected. The reaction was quenched by the slow addition of 20 mL of H2O at 0 °C. The mixture was extracted with ethyl acetate (10 mL × 3) and washed with brine (10 mL × 3). 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 / EtOAc = 1 / 0 to 10 / 1) to give compound 5 (0.6 g, 78.55% yield) as a white solid. 1¹H NMR: (400 MHz, CDCl₃) δ ppm 1.00 - 1.11 (m, 2H), 1.24 - 1.31 (m, 2H), 1.66 (br s, 1H), 2.50 (s, 3H), 4.74 (s, 2H), 6.47 (s, 1H), 7.20 (t, J = 8.4 Hz, 2H), 7.38 (dd, J = 8.4, 5.6 Hz, 2H). LCMS (ESI+): m / z = 314.0 (M+1), RT: 0.465 min. LC / MS: Kinetex® EVO C18 2.1x30 mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: The solution was pumped from 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN over 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; finally, the solution was returned to the aqueous solution of 5% ACN and held at a flow rate of 2.0 mL / min for 0.02 min.

[1218]

[1219] Step 5: PPh3 (494.18 mg, 1.88 mmol, 2 eq) and CBr4 (468.62 mg, 1.41 mmol, 1.5 eq) were added to a solution of compound 5 (0.3 g, 942.06 μmol, 1 eq) in DCM (3 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed complete consumption of the reactants and a peak with 24% of the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 0 to 10 / 1) to give compound 6 (0.65 g, 90.23% yield) as a white solid. LCMS (ESI+): m / z = 375.9 (M+1), RT: 0.588 min. LC / MS: Kinetex® EVO C18 2.1 x 30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive ion electrospray ionization. The MS range was 50-1050. The mobile phase was prepared by increasing the flow rate from a 5% ACN (0.01875% TFA) solution in water (0.0375% TFA) to a 95% ACN aqueous solution over 0.60 min at a flow rate of 2.0 mL / min; then maintaining the flow rate at 95% ACN for 0.18 min at 2.0 mL / min; finally, returning to the 5% ACN aqueous solution and maintaining it for 0.02 min at a flow rate of 2.0 mL / min.

[1220]

[1221] 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. The mixture was then stirred at 110 °C under N2 atmosphere for 1 h. LCMS showed complete consumption of the reactants and a peak with 11% of the desired mass was detected. The mixture was concentrated under reduced pressure to give compound 7 (1.09 g, 100.00% yield) as a white solid.

[1222] LCMS (ESI+): m / z = 558.1 (M-79), RT: 0.458 min. LC / MS: Kinetex® EVO C182.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1223]

[1224] Step 7: LCMS showed complete consumption of the reactants and a peak with 18% of the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 0 to 10 / 1) to give the crude product. The crude product was purified by prep-TLC (PE / EtOAc = 10 / 1) to give compound 8 (0.2 g, 21.53% yield), which was a colorless oil. 1H NMR: (400 MHz, CDCl3) δ ppm 0.97 - 1.01 (m, 2 H), 1.14 - 1.24 (m, 2 H), 1.37 (s, 3 H), 1.43 - 1.49 (m, 12 H), 1.60 - 1.61 (m, 2 H), 2.22 - 2.30 (m, 1 H), 2.31 - 2.38 (m, 1 H), 2.39 - 2.46 (m, 1 H), 2.49 (s, 3 H), 4.19 - 4.31 (m, 1 H), 4.32- 4.41 (m, 1 H), 5.53 (dd, J = 16.0, 6.0 Hz, 1 H), 6.48 (s, 1 H), 6.54 (d, J = 16.0 Hz (1 H), 7.08 - 7.17 (m, 2 H), 7.18 - 7.27 (m, 2 H). LCMS (ESI+): m / z = 538.2 (M+1), RT: 2.402 min. LC / MS: Kinetex® EVO C18 3.0 x 50 mm 2.6 μm. Detection method: PDA. MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from 5% ACN (0.01875% TFA) in water (0.0375% TFA) solution to 95% ACN in 2.40 min at a flow rate of 1.2 mL / min; then held at 95% ACN for 0.30 min at a flow rate of 1.2 mL / min; returned to 5% ACN aqueous solution and held for 0.30 min. The flow rate was set to 1.2 mL / min.

[1225]

[1226] Step 8: Add HCl (1 M, 734.86 μL, 2 eq) to a solution of compound 8 (200 mg, 367.43 μmol, 1 eq) in MeCN (2 mL). Stir the mixture at 45 °C for 12 h. Then add NaOH (1.5 M, 1.22 mL, 5 eq) to the solution. Stir the mixture at 45 °C for 1 h. LCMS showed complete consumption of the reactants and a 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 prep-HPLC (column: CD02-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water (NH3H2O)-ACN]; gradient: 15%-35% B for 10 min) and directly lyophilized to give (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-2-methylthieno[2,3-b]pyridin-5-yl)-3,5-dihydroxyhept-6-enoic acid (68.22 mg, 37.44% yield) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ ppm 0.70 - 0.87 (m, 2 H), 0.98 - 1.14 (m, 2 H), 1.21 - 1.45 (m, 2 H), 2.14 - 2.26 (m, 2 H), 2.27 - 2.36 (m, 1 H), 2.37 - 2.47 (m, 3 H), 3.98 - 4.37 (m, 2 H), 5.38 (dd, J = 16.0, 5.2 Hz, 1 H), 6.34 - 6.49 (m, 2 H), 6.89 - 7.01 (m, 2H), 7.01 - 7.12 (m, 2 H). LCMS (ESI+): m / z = 442.0 (M+1), RT: 1.403 min. LC / MS: Kinetex® XBridge C18 3.0*50 mm, 5 μm. Detection method: PDA. MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from 5% ACN aqueous solution (0.025% NH3•H2O) to 95% ACN in 3.00 min at a flow rate of 0.9 mL / min; then maintained at 95% ACN for 0.70 min at a flow rate of 0.9 mL / min; returned to 5% ACN aqueous solution and maintained for 0.30 min at a flow rate of 1.2 mL / min.

[1227] Example 6. Synthesis of sodium (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-3-methylthiopheno[2,3-b]pyridin-5-yl)-3,5-dihydroxyhept-6-enoate

[1228]

[1229] Step 1: A mixture of 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) was degassed and purged three times with N2. The mixture was then stirred at 50 °C under N2 atmosphere for 15 h. LCMS showed that 63% of the desired compound was detected. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was milled with PE / EtOAc = 10:1 (50 mL) and filtered. The filter cake was dried under reduced pressure to give compound 2 (6.8 g, 44.80% yield) as a yellow solid. LCMS (ESI+): m / z = 235.9.0 (M+23), RT: 0.446 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50–1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1230]

[1231] Step 2: Concentrated H₂SO₄ (1.33 g, 13.60 mmol, 1 eq) was added to a solution of compound 2 (1.6 g, 6.80 mmol, 1 eq) and compound 2A (1.48 g, 13.60 mmol, 2 eq) in AcOH (15 mL), and the mixture was stirred at 100 °C for 2 h. LCMS showed complete consumption of the reactants and 58% of the desired product was observed. The mixture was poured into a saturated aqueous solution of Na₂CO₃ (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (0–5% EtOAc in PE) to give compound 3 (1.25 g, 59.61% yield) as a yellow solid. LCMS (ESI+): m / z = 309.1 (M+1), RT: 0.529 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1232] In some embodiments, compound 2 is a sodium salt of compound 2.

[1233] In some embodiments, compound 3 is a sodium salt of compound 3.

[1234]

[1235] Step 3: DIBAL-H (1 M, 8.11 mL, 2 eq) was added to a solution of compound 3 (1.25 g, 4.05 mmol, 1 eq) in toluene (10 mL) at -78 °C, and the mixture was stirred at -78 °C under N2 for 0.5 h. The mixture was then warmed to 25 °C and stirred under N2 for 2 h. LCMS showed complete consumption of the reactants and 58% of the desired product was observed. The reaction was quenched with MeOH (10 mL) at 0 °C, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (0-5% EtOAc in PE) to give compound 4 (400 mg, 31.69% yield) as a yellow solid. LCMS (ESI+): m / z = 312.1 (M+1), RT: 0.531 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1236] In some embodiments, compound 4 is a sodium salt of compound 4.

[1237]

[1238] Step 4: NaBH4 (72.90 mg, 1.93 mmol, 1.5 eq) was added to a solution of compound 4 (400 mg, 1.28 mmol, 1 eq) in MeOH (4 mL), and the mixture was stirred at 25 °C under N2 for 2 h. LCMS showed complete consumption of the reactants and 92% of the desired product was observed. The reaction was quenched with a saturated aqueous solution of NH4Cl (20 mL), and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (0–10% EtOAc in PE) to give compound 5 (355 mg, 88.18% yield) as a yellow oil. LCMS (ESI+): m / z = 314.1 (M+1), RT: 0.453 min. LC / MS: Kinetex® EVO C18 2.1 x 30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive ion electrospray ionization. The MS range was 50-1050. Mobile phase: The flow rate was increased from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then maintained at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; then returned to the aqueous solution of 5% ACN and maintained for 0.02 min at a flow rate of 2.0 mL / min.

[1239] In some embodiments, compound 5 is a sodium salt of compound 5.

[1240]

[1241] Step 5: PPh3 (594.22 mg, 2.27 mmol, 2 eq) and CBr4 (563.49 mg, 1.70 mmol, 1.5 eq) were added to a solution of compound 5 (355 mg, 1.13 mmol, 1 eq) in DCM (5 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. LCMS showed complete consumption of the reactants and 80% of the desired product was observed. The mixture was concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (0-5% EtOAc in PE) to give compound 6 (256 mg, 60.06% yield) as a white solid. LCMS (ESI+): m / z = 376.0 (M+1), RT: 0.570 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; then returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1242] In some embodiments, compound 6 is a sodium salt of compound 6.

[1243]

[1244] Step 6: PPh3 (267.66 mg, 1.02 mmol, 1.5 eq) was added to a solution of compound 6 (256 mg, 680.34 μmol, 1 eq) in toluene (3 mL), and the mixture was stirred at 100 °C for 1 h. LCMS showed complete consumption of the reactants and 66% of the desired product was observed. The mixture was concentrated under reduced pressure to give compound 7 (434 mg, crude substance), a white solid. LCMS (ESI+): m / z = 558.2 (M-79), RT: 0.455 min. LC / MS: Kinetex® EVOC18 2.1 x 30 mm 5 μm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50–1050. Mobile phase: The solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) was increased to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; then returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1245] In some embodiments, compound 7 is a sodium salt of compound 7.

[1246]

[1247] Step 7: Cs₂CO₃ (664.32 mg, 2.04 mmol, 3 eq) was added 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), and the mixture was stirred at 25 °C for 5 h. LCMS showed complete consumption of the reactants and 55% of the desired product was observed. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (0–5% EtOAc in PE) to give compound 8 (177 mg, 48.44% yield) as a colorless oil. LCMS (ESI+): m / z = 538.3 (M+1), RT: 0.623 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min. 1 H NMR: (400 MHz, CDCl3)

[1248] δ 0.83 - 0.90 (m, 2 H), 0.95 - 1.02 (m, 3 H), 1.22 (dd, J = 4.8, 3.2 Hz, 1H), 1.36 (s, 3 H), 1.45 (s, 3 H), 1.46 (s, 9 H), 1.65 (d, J = 0.8 Hz, 3 H), 2.22 - 2.30 (m, 1 H), 2.32 - 2.46 (m, 2 H), 4.18 - 4.27 (m, 1 H), 4.27 - 4.37 (m, 1 H), 5.57 (dd, J = 16.4, 6.0 Hz, 1 H), 6.33 - 6.40 (m, 1 H), 6.92 (d, J = 0.8 Hz, 1 H), 7.06 - 7.19 (m, 4 H).

[1249] In some embodiments, compound 8 is the sodium salt of compound 8.

[1250]

[1251] Step 8: HCl (1 M, 658.38 μL, 2 eq) was added to a solution of compound 8 (177 mg, 329.19 μmol, 1 eq) in ACN (2 mL), and the mixture was stirred at 45 °C for 16 h. 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 h. LCMS showed complete consumption of the reactants and observation of 99% of the desired product. The mixture was purified by prep-HPLC (column: CD02-Waters Xbidge BEHC18 150*25*10um; mobile phase: [water (NH3.H2O)-ACN]; gradient: 11%-41% B for 10 min) to give sodium (3R,5S,E)-7-(6-cyclopropyl-4-(4-fluorophenyl)-3-methylthiopheno[2,3-b]pyridin-5-yl)-3,5-dihydroxyhept-6-enoate (104.80 mg, 72.11% yield), which was a white solid. 1 H NMR: (400 MHz, CDCl3) δ 0.85 (s, 2H), 1.13 (s, 2H), 1.23 (d, J = 0.8 Hz, 1H), 1.30 - 1.44 (m, 1H), 1.46 - 1.54 (m, 3H), 2.09 - 2.17 (m, 1H), 2.18 - 2.28 (m, 2H), 3.95 - 4.08 (m, 1H), 4.10 - 4.36 (m, 1H), 5.39 - 5.52 (m, 1H), 6.23 - 6.38 (m, 1H), 6.72 - 6.83 (m, 1H), 6.84 -7.01 (m, 4H). LCMS (ESI+): m / z = 442.1 (M+1), RT: 1.365 minutes. LC / MS: Kinetex® EVOC18 3.0x50mm 2.6µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in 3.40 min at a flow rate of 0.9 mL / min; then held at 95% ACN for 0.30 min at a flow rate of 0.9 mL / min; returned to the 5% ACN aqueous solution and held for 0.30 min at a flow rate of 1.2 mL / min.

[1252] Example 7. Synthesis of sodium (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthiopheno[3,2-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoate

[1253]

[1254] 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. The mixture was then stirred at 40 °C under N2 atmosphere for 1 h. LC-MS showed complete consumption of the starting material and the desired MS was observed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0 to 20% EtOAc in PE) to give compound 2 (12 g, 64.74% yield) as a yellow solid.

[1255] LCMS (ESI+): m / z = 236.0 (M+1), RT: 0.417 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1256] In some embodiments, compound 1 is a sodium salt of compound 1.

[1257] In some embodiments, compound 2 is a sodium salt of compound 2.

[1258]

[1259] Step 2: A mixture of 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) was degassed and purged three times with N₂. The mixture was then stirred at 100 °C under N₂ atmosphere for 1 h. LC-MS showed the desired MS. After cooling to room temperature, the reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0 to 10% EtOAc in PE) to give compound 3 (4.4 g, 50.86% yield) as a yellow solid. LCMS (ESI+): m / z = 309.1 (M+1), RT: 0.517 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1260] In some embodiments, compound 3 is a sodium salt of compound 3.

[1261]

[1262] Step 3: DIBAL-H (1 M, 11.67 mL, 2 eq) was added to a solution of compound 3 (1.8 g, 5.84 mmol, 1 eq) in toluene (20 mL) at -78 °C, and the mixture was stirred at -78 °C under N2 for 0.5 h. The mixture was then warmed to 25 °C and stirred under N2 for 2 h. LCMS showed the desired MS. The reaction was quenched at 0 °C by adding CH3OH (20 mL), and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0 to 6% EtOAc in PE) to give compound 4 (760 mg, 41.82% yield) as a yellow solid. LCMS (ESI+): m / z = 312.0 (M+1), RT: 0.487 min. LC / MS: Kinetex® EVO C18 2.1 x 30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive ion electrospray ionization. The MS range was 50-1050. The mobile phase was prepared by increasing the flow rate from a 5% ACN (0.01875% TFA) solution in water (0.0375% TFA) to a 95% ACN aqueous solution over 0.60 min at a flow rate of 2.0 mL / min; then maintaining the 95% ACN solution for 0.18 min at a flow rate of 2.0 mL / min; finally, returning to the 5% ACN aqueous solution and maintaining it for 0.02 min at a flow rate of 2.0 mL / min.

[1263] In some embodiments, compound 4 is a sodium salt of compound 4.

[1264]

[1265] Step 4: NaBH4 (138.51 mg, 3.66 mmol, 1.5 eq) was added to a solution of compound 4 (760 mg, 2.44 mmol, 1 eq) in MeOH (8 mL), and the mixture was stirred at 25 °C under N2 for 2 h. LC-MS showed complete consumption of the starting material and the desired MS was observed. The reaction was quenched by the addition of saturated NH4Cl (20 mL), and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0 to 20% EtOAc in PE) to give compound 5 (610 mg, 79.75% yield) as a white solid. LC-MS (ESI+): m / z = 314.5 (M+1), RT: 0.322 min. LC / MS: Kinetex® EVO C18 2.1 x 30 mm 5 μm. The detection method was a photodiode array (PDA). The MS mode was positive ion electrospray ionization. The MS range was 50-1050. The mobile phase was prepared by increasing the flow rate from a 5% ACN (0.01875% TFA) solution in water (0.0375% TFA) to a 95% ACN aqueous solution over 0.60 min at a flow rate of 2.0 mL / min; then maintaining the 95% ACN solution for 0.18 min at a flow rate of 2.0 mL / min; finally, returning to the 5% ACN aqueous solution and maintaining it for 0.02 min at a flow rate of 2.0 mL / min.

[1266] In some embodiments, compound 5 is a sodium salt of compound 5.

[1267]

[1268] Step 5: CBr4 (968.25 mg, 2.92 mmol, 1.5 eq) and PPh3 (1.02 g, 3.89 mmol, 2 eq) were added to a solution of compound 5 (0.61 g, 1.95 mmol, 1 eq) in DCM (8 mL) at 0 °C. The resulting mixture was stirred at 25 °C under N2 atmosphere for 1 h. LCMS showed the desired MS. The reaction was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0 to 5% EtOAc in PE) to give compound 6 (770 mg, 50% purity, 52.57% yield) as a white solid. LCMS (ESI+): m / z = 376.0 (M+1), RT: 0.483 min. LC / MS: Kinetex® EVOC18 2.1 x 30 mm 5 μm. Detection was performed using a photodiode array (PDA). MS mode was positive ion electrospray ionization. MS range was 50-1050. Mobile phase: The flow rate was increased from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN over 0.60 min at a flow rate of 2.0 mL / min; then maintained at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; finally, the flow rate was reduced to 5% ACN and maintained for 0.02 min at a flow rate of 2.0 mL / min.

[1269] In some embodiments, compound 6 is a sodium salt of compound 6.

[1270]

[1271] Step 6: PPh3 (268.36 mg, 1.02 mmol, 1 eq) was added to a solution of compound 6 (0.77 g, 1.02 mmol, 1 eq) in toluene (10 mL), and the mixture was stirred at 110 °C under a N2 atmosphere for 1 h. LCMS showed complete consumption of the starting material and observation of the desired product. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give compound 7 (655 mg, crude substance), a colorless liquid. LCMS (ESI+): m / z = 558.2 (M-Br), RT: 0.433 min. LC / MS: Kinetex® EVO C18 2.1x30 mm 5 μm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50–1050. Mobile phase: The solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) was pumped to an aqueous solution of 95% ACN over 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; and finally returned to the aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1272] In some embodiments, compound 7 is a sodium salt of compound 7.

[1273]

[1274] Step 7: Cs₂CO₃ (668.40 mg, 2.05 mmol, 2 eq) was added 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), and the mixture was stirred at 25 °C under a N₂ atmosphere for 16 h. LCMS showed complete consumption of the starting material and the desired MS was observed. The reaction was concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0 to 6% EtOAc in PE) to give compound 8 (210 mg, 37.70% yield) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 0.90 - 1.00 (m, 3 H), 1.07 - 1.28 (m, 3 H), 1.32 (s, 3 H), 1.41 (s, 12 H), 2.17 - 2.43 (m, 3 H), 2.50 (s, 3 H), 4.15 - 4.25 (m, 1 H), 4.32 (td, J = 5.6, 4.4 Hz, 1 H), 5.48 (dd, J = 16.0, 6.0 Hz, 1 H), 6.56 (d, J = 16.0 Hz, 1 H), 7.03 - 7.12 (m, 3 H), 7.22 (s, 1 H), 7.26 - 7.30 (m, 1 H). LCMS (ESI+): m / z = 538.4 (M+1), RT: 0.506 min. LC / MS: Kinetex® EVO C18 2.1x30mm 5µm. Detection method: photodiode array (PDA). MS mode: positive ion electrospray ionization. MS range: 50-1050. Mobile phase: from a solution of 5% ACN (0.01875% TFA) in water (0.0375% TFA) to an aqueous solution of 95% ACN in 0.60 min at a flow rate of 2.0 mL / min; then held at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; returned to an aqueous solution of 5% ACN and held for 0.02 min at a flow rate of 2.0 mL / min.

[1275] In some embodiments, compound 8 is the sodium salt of compound 8.

[1276]

[1277] Step 8: HCl (1.5 M, 1.5 eq) was added to a solution of compound 8 (130 mg, 241.78 μmol, 1 eq) in ACN (2 mL), and the mixture was stirred at 45 °C under N2 atmosphere for 14 h. NaOH (1 M, 2 eq) was added and stirred at 45 °C under N2 atmosphere for 2 h. LCMS showed complete consumption of the starting material and the desired MS was observed. The reaction mixture was purified by prep-HPLC (column: CD02-Waters Xbidge BEH C18 150*25*10um; mobile phase: [water (NH3H2O)-ACN]; gradient: 12%-32% B for 10 min) to give sodium (3R,5S,E)-7-(5-cyclopropyl-7-(4-fluorophenyl)-2-methylthiopheno[3,2-b]pyridin-6-yl)-3,5-dihydroxyhept-6-enoate (50.30 mg, 46.65% yield), which was a white solid. 1H NMR: (400 MHz, DMSO-d6) δ 0.96 (dd, J = 7.6, 3.6 Hz, 2 H), 1.05 (d, J = 4.4 Hz, 2 H), 1.09 - 1.18 (m, 1 H), 1.35 - 1.46 (m, 1 H), 1.87 (dd, J = 14.8, 8.4Hz, 1 H), 2.04 (dd, J = 14.8, 4.0 Hz, 1 H), 2.37 - 2.45 (m, 1 H), 2.52 (s, 3 H), 3.59 (tt, J = 8.4, 4.0 Hz, 1 H), 4.13 (q, J = 6.0 Hz, 1 H), 5.54 (dd, J = 16.0, 5.6 Hz, 1H), 6.51 (d, J = 16.0 Hz, 1H), 7.15 (d, J = 0.8 Hz, 1H), 7.27 - 7.36 (m, 2H), 7.38 - ...

Claims

1. Compounds of formula (I'): (I’), Or a pharmaceutically acceptable salt thereof, wherein: It can be a single or double bond, as long as the valence key allows it; It can be a single bond or a double bond, wherein the double bond is an (E) isomer; 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 to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl. R2 is C3-C 10 cycloalkyl; B1 is H or -OH; B2 is H or -OH; Y represents H, -C(O)OR3, or -C(O)N(R3)2. Each R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; R A1 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl or C3-C 10 cycloalkyl; R A2 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl; and R A3 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, optional substituted 3- to 10-membered heterocyclic groups with one or more C1-C6 alkyl groups, C6-C 10 aryl, or optionally substituted with one or more C1-C6 alkyl groups, 5 to 10-membered heteroaryl groups. The condition is: (a) When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H; and (b) When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

2. The compound of claim 1, wherein... It can be a single or double bond, as long as the valence key allows it; 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 to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl. R2 is C3-C 10 cycloalkyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; R A1 It can be H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; R A2 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; and R A3 It is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl. The condition is: (a) When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And A2 is CR A2 When, then R A1 and R A2 At least one of them is not H; and (b) When R2 is cyclopropyl, X1 is N, and A1 is CR A1 And when A2 is CH, then R A1 It is not ethyl.

3. The compound of claim 1 or claim 2, wherein X1 is N.

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

5. The compound according to any one of the preceding claims, wherein A2 is CR A2 .

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

7. The compound according to any one of the preceding claims, wherein R1 is a C6 aryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

8. The compound according to any one of the preceding claims, wherein R1 is , , , , , , ,or .

9. The compound according to any one of the preceding claims, wherein R2 is .

10. The compound according to any one of the preceding claims, wherein R3 is H or methyl.

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

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

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

14. The compound according to any one of the preceding claims, wherein the compound of formula (I') is of formula (I'): (I’), Or its pharmaceutically acceptable salt.

15. The compound according to any one of the preceding claims, wherein the compound of formula (I') is of formula (Ia), (Ib), (Ic), or (Id): (I-a), (I-b), (Ic), or (I-d), Or its pharmaceutically acceptable salt.

16. The compound according to any one of the preceding claims, wherein the compound of formula (I') is of formula (I'-a), (I'-b), (I'-c), or (I'-d): (I’-a), (I’-b), (I'-c), or (I’-d), Or its pharmaceutically acceptable salt.

17. The compound according to any one of claims 1-15, wherein the compound of formula (I') is of formula (Id), (Ie), (If), or (Ig): (I-d), (Ie), (If), or (I-g), Or its pharmaceutically acceptable salt.

18. The compound according to any one of the preceding claims, wherein the compound of formula (I') is of formula (I'-d), (I'-e), (I'-f), or (I'-g): (I’-d), (I'-e), (I'-f), or (I’-g), Or its pharmaceutically acceptable salt.

19. The compound according to any one of claims 1-15, wherein the compound of formula (I') is of formula (Ih), (Ii), (Ij), or (Ik): (I-h), (I-i), (Ij), or (I-k), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

20. The compound according to any one of the preceding claims, wherein the compound of formula (I') is of formula (I'-h), (I'-i), (I'-j), or (I'-k): (I’-h), (I’-i), (I'-j), or (I’-k), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

21. The compound according to any one of claims 1-15, wherein the compound of formula (I') is of formula (Il), (Im), (In), or (Io): (I-l), (I-m), (In), or (Io), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

22. The compound according to any one of the preceding claims, wherein the compound of formula (I') is of formula (I'-1), (I'-m), (I'-n), or (I'-o): (I’-l), (I’-m), (I'-n), or (I'-o), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

23. Compounds of formula (II'): (II’), Or a pharmaceutically acceptable salt thereof, wherein: It is a double bond, wherein the double bond is an (E) or (Z) isomer; R1 is C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. 1a ; Each R 1a It is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl; R2 is C3-C 10 cycloalkyl or methyl; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl; R4 is H, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic groups, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C3-C 10 The cycloalkyl group is optionally substituted with one or more C1-C6 alkoxy groups or -O (C3-C6 alkoxy groups). 10 cycloalkyl), or R5 and an R 1a Together with atoms in between, they form 3- to 10-membered heterocyclic groups; and m is 0 or 1. The condition is: (a) When R2 is cyclopropyl and R5 is a C1 alkyl group substituted with a C1 alkoxy group, then R4 is not isopropyl; and (b) When R1 is a monosubstituted C6 aryl group with one fluorine substituted group, R2 is a cyclopropyl group, and R5 is a C1 alkyl group with a C1 substituted alkoxy group, then R4 is not a cyclopropyl group; and (c) When R2 is methyl, then R4 is not a C1-C6 alkyl.

24. The compound of claim 23, wherein R1 is a C6 aryl group, which is substituted with one or more halogens, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

25. The compound of claim 23 or claim 24, wherein R1 is , , , , , , , , , , , ,or .

26. The compound according to any one of claims 23-25, wherein R2 is methyl. or .

27. The compound according to any one of claims 23-26, wherein R3 is H.

28. The compound according to any one of claims 23-27, wherein R4 is H, , ,or .

29. The compound according to any one of claims 23-28, wherein R5 is –(CH2)-OCH3, –(CH2)-O-cyclopropyl, cyclopropyl, or H, or R5 and one R 1a Together with the atoms in between, they form tetrahydropyran.

30. The compound according to any one of claims 23-29, wherein the compound of formula (II') is of formula (II-a) or (II-b): (II-a) or (II-b), Or its pharmaceutically acceptable salt.

31. The compound according to any one of claims 23-30, wherein the compound of formula (II') is of formula (II-c): (II-c), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

32. The compound according to any one of claims 23-31, wherein the compound of formula (II') is of formula (II-d) or (II-e): (II-d) or (II-e), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

33. The compound according to any one of claims 23-32, wherein the compound of formula (II') is of formula (II-f) or (II-g): (II-f) or (II-g), Or its pharmaceutically acceptable salt.

34. The compound according to any one of claims 23-33, wherein in some embodiments, the compound of formula (II') is of formula (II-h): (II-h), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

35. The compound according to any one of claims 23-34, wherein in some embodiments, the compound of formula (II') is of formula (II-i) or (II-j): (II-i) or (II-j), Or a pharmaceutically acceptable salt thereof, wherein R 1a It is a halogen, -CN, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 haloalkyl, and n is 0, 1, 2, 3 or 4.

36. The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in Table 1 or Table 1A, or pharmaceutically acceptable salts thereof.

37. The compound according to any one of the preceding claims, wherein the compound is selected from the compounds described in Table 2 or Table 2A, or pharmaceutically acceptable salts thereof.

38. The compound according to any one of the preceding claims, wherein the compound is selected from the compounds listed in Table 3, or pharmaceutically acceptable salts thereof.

39. A compound which can be obtained by or through the methods described herein; optionally, the methods include one or more steps as described in schemes 1-7.

40. A pharmaceutical composition comprising a compound of 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 1-34, 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 1-39 or a pharmaceutical composition according to claim 40 or 41.

43. The compound according to any one of claims 1-39 or the pharmaceutical composition according to claim 40 or claim 41, for regulating STMN2 activity.

44. Use of the compound according to any one of claims 1-39 in the preparation of a medicament for regulating STMN2 activity.

45. A method of treating or preventing a disease or disorder in a subject in need, comprising administering to the subject a compound of any one of claims 1-39 or a pharmaceutical composition of claim 40 or 41.

46. ​​The compound of any one of claims 1-39 or the pharmaceutical composition of claim 40 or claim 41, for the treatment or prevention of a disease or disorder.

47. Use of the compound according to any one of claims 1-39 in the preparation of a medicament for treating or preventing a disease or disorder.

48. The method, compound, pharmaceutical composition, or use according to any one of claims 45-47, wherein the disease or disorder is related to involved STMN2 activity.

49. The method, compound, pharmaceutical composition, or use according to any one of claims 45-48, 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 45-48, wherein the disease or disorder is an axonal lesion.

51. The method, compound, pharmaceutical composition, or use of 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, age-related border-dominant TDP-43 encephalopathy neuropathology (LATE-NC), Lewy body dementia (LBD), peripheral neuropathy (chemotherapy-induced neuropathy, injury-induced neuropathy), and autism spectrum disorder.

52. The method, compound, pharmaceutical composition, or use according to any one of claims 42-51, wherein the subject is a human being.

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