Heterocyclic substituted 1,3,4-thiadiazole and pyridazine compounds and methods of use thereof

Abstract

The present disclosure relates to compounds of formula (I), and their prodrugs, pharma- ceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation thereof. The compounds of the present disclosure may function as small molecule splicing modulator compounds that modulate the splicing of mRNAs, such as pre-mRNAs, the encoded genes, and methods of using the compounds to modulate splicing and treat related diseases and conditions. The compounds disclosed herein may have activity on a variety of genetic pathways and are therefore useful in methods of treatment of the human or animal body. JPEG2024540608000191.jpg31164

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 281,988, filed November 22, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] More than 90% of human genes produce multiple mature transcripts through alternative splicing. This process is essential for generating distinct transcripts in different cell and tissue types during developmental processes and in response to internal and external signals. Alternative splicing is common not only for protein-coding genes but also for most other types of genes, including microRNA genes and long non-coding genes. Splicing is performed by the spliceosome. Small nuclear RNAs (snRNAs) are key components of the spliceosome. The main spliceosome contains U1, U2, U4, U5, and U6 snRNAs and catalyzes the removal of approximately 95% of human introns, while the remaining introns (called U12-type introns) are removed by smaller spliceosomes containing U11, U12, U4atac, U5, and U6atac snRNAs. These snRNAs form complexes with their respective protein partners to form the functional units of small nuclear ribonucleoproteins (snRNPs).

[0003] Splicing is a highly regulated process, regulated by both cis-elements and trans-factors. Cis-elements recognized by snRNAs include 5' splice sites, 3' splice sites, and branch points, each of which is associated with sequence motifs recognized by components of the spliceosome. In addition, there are intronic splicing enhancers (ISEs), intronic splicing silencers (ISSs), exonic splicing enhancers (ESEs), and exonic splicing enhancers (ESSs), which are recognized by a myriad of trans-factors, commonly known as RNA-binding proteins (RBPs). Some of these RBPs directly bind to cis-elements in a sequence-specific manner, while others recognize RNA structures (e.g., RNA duplexes or unpaired loop regions), and still others function through protein-protein interactions. Approximately 1600 RBPs have been annotated in the human genome, which are expressed in a cell-type specific manner and form an extensive regulatory network for splicing regulation.

[0004] Dysregulation of splicing is involved in about half of human diseases. Some diseases are caused by mutations in spliceosome components or RBPs, while others are caused by mutations in cis elements such as splice sites, branch points, or various splicing enhancers and silencers. Current approaches to treat these diseases, such as CRISPR-based genome editing, virus-assisted gene therapy, or various oligonucleotide-based technologies, continue to improve, but they still suffer from significant technical and clinical challenges. In particular, oligonucleotide-based therapeutics exhibit unfavorable pharmacokinetics, cannot be administered orally, and cannot be effectively delivered to many tissues, especially the brain. Small molecule drugs, with excellent pharmacokinetics, effective delivery, and bioavailability, have only recently become available to modulate RNA splicing. However, the currently available molecules are brought about by a few limited chemical series. Thus, there is a great need to develop additional small molecule splicing modulators (SMSMs). Summary of the Invention [Means for solving the problem]

[0005] Here, we describe a series of novel small molecule splicing modulators (SMSMs) that can be used to treat a wide variety of diseases, including neurological diseases. These SMSMs target regions of the primary RNA transcript that are cis elements, such as splice sites, branch points, splicing enhancers, or splicing silencers. These regions may contain unpaired nucleotides in the RNA duplex, called bulges. The bulges may be naturally occurring or caused by disease. When SMSMs contact the RNA transcript, they may be bound by the spliceosome or other trans factors, most notably RNA-binding proteins (RBPs). The SMSMs reported herein may cause changes in the sequence or amount of the mature transcript, which may cause differences in the sequence or amount of a functional protein if the transcript is protein-coding, or may cause differences in the sequence or amount of a functional RNA if the transcript is non-coding.

[0006] In some aspects, the present disclosure relates to, inter alia, a compound of formula (I), (II), or (III): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0007] In some aspects, the disclosure provides compounds that may be obtained by or are obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described herein).

[0008] In some aspects, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, and a pharma- ceutically acceptable diluent or carrier.

[0009] In some aspects, the disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described herein).

[0010] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0011] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0012] In some aspects, the disclosure provides a compound of the disclosure or a pharma- ceutically acceptable salt, solvate, or prodrug thereof for use in the treatment or prevention of a disease or disorder disclosed herein.

[0013] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment of a disease or disorder disclosed herein.

[0014] In some aspects, the disclosure provides the use of a compound of the disclosure or a pharma- ceutically acceptable salt, solvate, or prodrug thereof for treating or preventing a disease or disorder disclosed herein.

[0015] In some aspects, the disclosure provides the use of a compound of the disclosure or a pharma- ceutically acceptable salt, solvate, or prodrug thereof for treating a disease or disorder disclosed herein.

[0016] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0017] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0018] In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0019] In some aspects, the disclosure provides a method of preparing a compound, comprising one or more of the steps described herein.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will prevail. In addition, the materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0021] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The compounds described herein are generally designed to treat the diseases and disorders disclosed herein.

[0023] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0024] As used herein, "alkyl", "C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Alkyl" or "C 1 -C 6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Linear (straight-chain) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C 5 , or C 6 It is intended to include branched saturated aliphatic hydrocarbon groups. For example, C 1 -C 6 Alkyl is C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 It is intended to include alkyl groups. Examples of alkyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight or branched chain alkyl has 6 or fewer carbon atoms (e.g., C for straight chain). 1 -C 6 , C for branched chain 3 -C 6 ), and in another embodiment the straight or branched chain alkyl has 4 or fewer carbon atoms.

[0025] As used herein, "alkenyl" is intended to mean a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, containing one or more carbon-carbon double bonds, and no triple bonds ("C 2 -C 6 The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). 2 -C 6 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc.

[0026] As used herein, "alkynyl" is intended to include straight or branched chain hydrocarbon groups having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2 -C 6 The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). 2 -C 4 Examples of alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), but are not limited to these.

[0027] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing 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, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0028] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties with one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0029] As used herein, the term "alkoxy" or "alkoxyl" refers to the group -OR, where R is alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms.

[0030] As used herein, "heteroalkyl", "C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Heteroalkyl" or "C 1 -C 6 Heteroalkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Linear (straight-chain) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C 5 , or C 6 It is intended to include branched saturated aliphatic hydrocarbon groups in which at least one of the carbons is replaced with N, O, or S. The heteroatom is bonded to any necessary hydrogens to complete the valence of the heteroatom (e.g., CH 2 may be replaced by "O" or "NH", CH may be replaced by N, etc.). Such substituents include, for example, -O-CH(CH 3 ) 2 , -CH 2 -N(CH 3 )-CH 2 CH 2 OCH 3 , -S-CH 2 CH 2 -O-CH 2 CH 3 etc.

[0031] As used herein, the term "cycloalkyl" refers to an alkyl group having 3 to 30 carbon atoms (e.g., C 3 -C 12 , C 3 -C 10 , or C 3 -C 8 (e.g., fused, bridged, or spirocyclic) systems having a cyclic or cyclic ring system. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of a polycyclic cycloalkyl, only one of the rings in the cycloalkyl must be non-aromatic.

[0032] The term "heterocycloalkyl" or "heterocyclyl," as used herein, unless otherwise specified, refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic) or 11-14 membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms (such as O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-Oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl , 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-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 Examples of heterocycloalkyls include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl must be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0033] As used herein, the term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like. For convenience, aryl is phenyl.

[0034] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heteroaromatic ring consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)). p , where p=1 or 2). Note that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0035] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphtholidine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0036] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can have one or more ring positions (e.g., at a ring-forming carbon or heteroatom such as N) bearing a substituent as described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, aryl ... The aryl and heteroaryl groups may be substituted with aryl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkylaryl, or aromatic or heteroaromatic moieties. The aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0037] As used herein, the term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced with a selection from the specified group, provided that the replacement does not exceed the normal valence of the specified atom, and that the replacement results in a stable compound. If the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. Keto substituents are not present in aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.

[0038] When a bond to a substituent is shown to cross the bond joining two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is recited without indicating the atom through which it is bonded to the remainder of the compound of a given formula, such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0039] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, that group may be optionally substituted with up to 2 R moieties, with R at each occurrence being independently selected from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0040] As used herein, the term "hydroxy" or "hydroxyl" refers to -OH or -O - The formula includes groups having the formula:

[0041] As used herein, the term "cyano" refers to the group --CN.

[0042] As used herein, the term "nitro" refers to the radical -NO 2 Refers to...

[0043] As used herein, "oxo" refers to =O.

[0044] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0045] As used herein, the term "haloalkyl" refers to a branched or unbranched alkyl substituted with one or more halogens. For example, C 1-6 Haloalkyl is an alkyl group of 1 to 7 carbons in which at least one H is replaced by a halogen. Examples of haloalkyl include CFH 2 , C.F. 2 H, C.F. 3 , C.H. 2 CF 3 , C.F. 2 CF 3 , C(F)(CH 3 ) 2 , C.H. 2 CH 2 Br, CH(I)CH 2 F, and CH 2 Examples of suitable amines include, but are not limited to, Cl.

[0046] As used herein, the term "haloalkoxy" refers to an alkoxy structure substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine.

[0047] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0048] As used herein, phrases such as "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," and the like are used interchangeably and all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

[0049] It should be understood that the present disclosure provides methods for the synthesis of any of the compounds of the formulae described herein. The present disclosure also provides detailed methods for the synthesis of the various disclosed compounds of the present disclosure according to the following schemes, as well as those shown in the Examples.

[0050] It should be understood that throughout this specification, when a composition is described as having, including, or comprising certain components, it is contemplated that the composition also consists essentially of or consists of the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process also consists essentially of or consists of the recited process steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0051] It will be appreciated that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups, and thus variously substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although in some cases it may be desirable to further convert the compound to a pharma-ceutically acceptable salt thereof.

[0052] It is understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily preparable intermediates by employing standard synthetic methods and procedures that are known to those of skill in the art or that will be apparent to those of skill in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Examples include, but are not limited to, any one or more sources, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, 1999, pp. 111-115, 2002; th edition, John Wiley & Sons: New York, 2001, Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are incorporated herein by reference and are useful and recognized reference texts in organic synthesis known to those of skill in the art.

[0053] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0054] Unless otherwise stated, any description of a method of treatment is understood to include the use of a compound to provide treatment or prophylaxis as described herein, as well as the use of a compound to prepare a medicament for treating or preventing such conditions. Unless otherwise stated, any description of a method of treatment is understood to include the use of a compound to provide treatment or prophylaxis as described herein, as well as the use of a compound to prepare a medicament for treating such conditions. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0055] As used herein, the term "subject" is interchangeable with the term "subject in need thereof," both of which refer to a subject having a disease or at high risk of developing a disease. "Subject" includes mammals. 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 one embodiment, the mammal is a human. The subject in need thereof may be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. The subject in need thereof may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, the subject in need thereof may be a subject at high risk of developing such a disease or disorder compared to the general population (i.e., a subject prone to developing such a disorder compared to the general population). The subject in need thereof may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at the beginning of treatment or may become resistant during treatment.In some embodiments, the subject in need thereof has undergone and failed all known effective treatments for the disease or disorder disclosed herein.In some embodiments, the subject in need thereof has undergone at least one prior treatment.

[0056] As used herein, the term "treating" or "treat" describes the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include the treatment of a cell in vitro or in an animal model.

[0057] It should be understood that references to "treating" or "treatment" include the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a health condition, disorder, or condition includes (1) delaying the appearance of clinical symptoms of the health condition, disorder, or condition that develop in a human who may be afflicted with or predisposed to the health condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the health condition, disorder, or condition, (2) inhibiting the health condition, disorder, or condition, i.e., preventing, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) palliating or attenuating the disease, i.e., causing regression of the health condition, disorder, or condition, or at least one of its clinical or subclinical symptoms.

[0058] It is to be understood that the compounds of the present disclosure, or pharma- ceutically acceptable salts or solvates thereof, can also be or may be used to prevent associated diseases, conditions, or disorders, or to identify suitable candidates for such purposes.

[0059] As used herein, the terms "preventing," "prevent," or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0060] It should be understood that those skilled in the art may refer to general reference texts for detailed descriptions of known techniques described herein or equivalent techniques. 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 (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000), Colligan et al., Current Protocols in Immunology, John Wiley & Sons, NY, Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY, Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing. Co.,Easton,PA,18 th Edition (1990), which texts may, of course, be referenced when making or using aspects of the present disclosure.

[0061] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharma- ceutically acceptable excipient or carrier.

[0062] As used herein, the term "pharmaceutical composition" refers to a formulation containing the disclosed compound in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, 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 salt, hydrate, solvate, or isomer) in a unit dosage composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that routine modifications to dosage may be required depending on the age and condition of the subject. Dosage also varies according to the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of the present 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 pharma- ceutically acceptable carrier, and any required preservatives, buffers, or propellants.

[0063] As used herein, the term "pharmacologically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and are within the scope of safe medical judgment and commensurate with a reasonable benefit / risk ratio.

[0064] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and useful in preparing pharmaceutical compositions, and includes excipients acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0065] It is understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents, antimicrobial agents such as benzyl alcohol and methylparabens, antioxidants such as ascorbic acid and sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates, and phosphates, and agents for adjusting osmolality such as sodium chloride or dextrose. The pH can be adjusted using acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple dose vials.

[0066] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject in many of the well-known methods currently used in chemotherapy treatment.For example, the compound of the present disclosure can be injected into the bloodstream or body cavity, taken orally, or applied through the skin with a patch.The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects.The disease state (e.g., disease or disorder disclosed herein) and the subject's health should be closely monitored during and for a reasonable period after treatment.

[0067] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents a specified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The exact effective amount for a subject will vary depending on the subject's weight, size, and health, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0068] "Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated.

[0069] It is understood that for any compound, the therapeutically effective amount can be initially predicted in either cell culture assays, e.g., tumor cells, or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, the sensitivity of the subject, and the route of administration.

[0070] Dosage and administration are adjusted to provide sufficient levels of active agent(s) or to maintain the desired effect. Factors that may be taken into account include the severity of the disease state, the general health of the subject, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), reaction sensitivity, and tolerance / response to therapy.

[0071] The pharmaceutical composition containing the active compound of the present disclosure can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee making, suspending, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be formulated in a conventional manner using one or more pharma-ceutically acceptable carriers, including excipients and / or auxiliary agents that facilitate the processing of the active compound into a preparation that can be used pharma-ceutically.Of course, the appropriate formulation depends on the selected route of administration.

[0072] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. The composition should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols (such as mannitol and sorbitol), and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

[0073] Sterile injection solution can be prepared by incorporating the required amount of active compound into a suitable solvent with one or a combination of the above-listed components as required, followed by filtration sterilization.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other components required from the above-listed components.In the case of sterile powder for preparing sterile injection solution, the preparation method is vacuum drying and freeze-drying, which produces a powder of active ingredient plus any additional desired components from its previously sterile filtered solution.

[0074] Oral compositions generally contain an inert diluent or an edible pharma- ceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is orally applied and allowed to flow in the mouth, and then expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as silicon dioxide colloid; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring, or compounds of a similar nature.

[0075] For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0076] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is generally formulated into ointments, salves, gels, or creams, as is generally known in the art.

[0077] The active compounds can be prepared in pharma- ceutically acceptable carriers that prevent the compound from being rapidly removed from the body, including, for example, 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 apparent to those skilled in the art. Materials can also be commercially obtained from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells using monoclonal antibodies against viral antigens) can also be used as pharma-ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0078] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in dosage unit form.As used herein, unitary dosage form refers to a physically separate unit suitable as a unitary dosage for treating a subject; each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of unitary dosage form of the present disclosure is determined and directly depends on the unique characteristics of active compound and the specific therapeutic effect to be achieved.

[0079] In therapeutic applications, the dosage of pharmaceutical compositions used according to the present disclosure will vary depending on, among other factors, the agent, the age, weight, and clinical condition of the recipient subject, as well as the experience and judgment of the clinician or medical practitioner administering the treatment, which will affect the dosage selected. In general, the dosage should be sufficient to slow, and preferably cause regression, and preferably cause complete regression of the disease or disorder disclosed herein. An effective amount of a pharmaceutical agent is one that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improved survival and growth indicate regression. As used herein, the term "dosage effective manner" refers to the amount of active compound to obtain a desired biological effect in a subject or cell.

[0080] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0081] For compounds of the present disclosure that are capable of further forming salts, it is understood that all of these forms are also contemplated within the scope of the claimed disclosure.

[0082] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, which is modified by making 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, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include the 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 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthalene acid, and the like. The preferred acids include, but are not limited to, those derived from inorganic and organic acids selected from acetic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0083] In some embodiments, the pharma- ceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0084] Other examples of pharma- ceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, 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-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that in the salt form, 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.

[0085] It should be understood that all references to pharma- ceutically acceptable salts include the solvent addition forms (solvates) of the same salt as defined herein.

[0086] The compound, or a pharma- ceutically acceptable salt thereof, may be administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingual, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0087] Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0088] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt.Similarly, salts can be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate).Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion.The substituted compounds disclosed herein also include those salts containing a quaternary nitrogen atom.

[0089] It should be understood that the compounds of the present disclosure, for example, salts of the compounds, can exist in either 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.

[0090] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a certain molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is a compound formed by combining one or more water molecules with water, where the water is H 2 It is formed by combination with one molecule of a substance that retains its molecular state as O.

[0091] As used herein, the term "analog" refers to a compound that is structurally similar to another but differs slightly in composition (such as the replacement of one atom with an atom of a different element or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance, but not in structure or origin, to the reference compound.

[0092] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0093] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of bioisostere replacement is to create a new compound with similar biological properties as the parent compound. Bioisostere replacement can be physicochemical or topological based. Examples of bioisosteres of carboxylic acids include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0094] It is also to be understood that a particular compound of any one of the formulas disclosed herein can exist in solvated or unsolvated forms, such as, for example, hydrated forms. Suitable pharma- ceutically acceptable solvates are hydrates, such as, for example, hemihydrates, monohydrates, dihydrates, or trihydrates.

[0095] Compounds of any one of the formulae disclosed herein may exist in several different tautomeric forms, and references to compounds of formulae (I), (II), and (III) include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other compounds are nevertheless encompassed by formulae (I), (II), and (III). Examples of tautomeric forms include, for example, keto-, enol-, and enolate-forms of the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enithiol, and nitro / acinito. [ka]

[0096] Compounds of any one of the formulas disclosed herein that contain an amine functional group can also form N-oxides. Reference herein to compounds of formulas (I), (II), and (III) that contain an amine functional group also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Particular examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be made by the procedure of LW Deady (see, for example, Syn. Comm. 1977, 7, 509-514), which involves reacting an amine compound with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0097] The compound of any one of the formulas disclosed herein may be administered in the form of a prodrug that breaks down in the human or animal body to release the compound of the present disclosure. Prodrugs may be used to modify the physical properties and / or pharmacokinetic properties of the compound of the present disclosure. Prodrugs can be formed when the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives that contain an alkyl or acyl substituent that can be cleaved in vivo in the ester or amide group in any one of the formulas disclosed herein.

[0098] As used herein, the term "isomerism" means compounds that have the same molecular formula but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual optical isomeric forms of opposite chirality is called a "racemic mixture."

[0099] As used herein, the term "chiral center" refers to a carbon atom bonded to four non-identical substituents.

[0100] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule 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).

[0101] As used herein, the term "geometric isomers" refers to diastereomers that owe their existence to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate whether the groups are on the same or opposite sides of a double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0102] It is to be understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers. Also, when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and it is to be understood that the naming of the compound does not mean that all isomers may have the same level of activity.

[0103] It is understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof, and it is also understood that not all atropisomers may have the same level of activity.

[0104] As used herein, the term "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers exist because of the restricted rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, but as a result of recent advances in chromatography techniques, it has become possible to isolate mixtures of two atropisomers in selected cases.

[0105] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in a formal shift of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerism is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar molecule reacting with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (annular) form as exhibited by glucose.

[0106] It is understood that the compounds of the present disclosure may be represented as different tautomers. It is also understood that, when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It is understood that certain tautomers may have a higher level of activity than other tautomers.

[0107] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R- and S-sequencing rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0108] The compounds of the present disclosure may have one or more asymmetric centers, and therefore such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in this specification and claims is intended to include both individual optical isomers and their racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemic forms (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomeric centers (E and Z isomers).

[0109] Thus, the present disclosure includes any one of the compounds of the formulas disclosed herein as defined herein when made available by organic synthesis and made available in the human or animal body by cleavage of its prodrug.Thus, the present disclosure also includes any one of the compounds of the formulas disclosed herein that are produced by organic synthesis means, as well as such compounds that are produced in the human or animal body by metabolism of precursor compounds, and any one of the compounds of the formulas disclosed herein can be synthetically produced compounds or metabolically produced compounds.

[0110] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein are those that, based on reasonable medical judgment, are suitable for administration to a subject, lacking undesirable pharmacological activity and lacking undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14, and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0111] Suitable pharma- ceutically acceptable prodrugs of the compounds of any one of the formulae disclosed herein that have a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of the compounds of any one of the formulae disclosed herein that contain a hydroxy group are, for example, pharma-ceutically acceptable esters or ethers that are cleaved in a subject to generate the parent hydroxy compound. Suitable pharma-ceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharma-ceutically acceptable ester-forming groups for hydroxy groups include C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1 -C 10 Alkanoyl group, ethoxycarbonyl, etc. 1 -C 10 Alkoxycarbonyl group, N,N-(C 1 -C 6 Alkyl) 2 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 -C 4 Suitable pharma- ceutical-acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl.

[0112] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, an amine such as ammonia, a C-amino group such as methylamine, etc. 1-4 Alkylamines, (C 1 -C 4 Alkyl) 2Amines, such as dimethylamine, N-ethyl-N-methylamine or diethylamine, 2-methoxyethylamine, etc. 1 -C 4 Alkoxy-C 2 -C 4 Phenyl-C such as alkylamines and benzylamines 1 -C 4 amides formed with alkylamines and amino acids such as glycine or their esters.

[0113] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharma- ceutically acceptable amides from an amino group include, for example, C-type amides such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1 -C 10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 -C 4 and alkyl)piperazin-1-ylmethyl.

[0114] The dosage regimen utilizing the compound is selected according to various factors, including the type, species, age, weight, sex, and medical condition of the subject, the severity of the condition being treated, the route of administration, the renal and hepatic function of the subject, and the specific compound or salt thereof used.A physician or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progression of the condition.A physician or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to counter or stop the progression of the condition.

[0115] Techniques for formulation and administration of the disclosed compounds of this disclosure can be found in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharma- ceutically acceptable salts are used in pharmaceutical preparations in combination with pharma- ceutically acceptable carriers or diluents. Suitable pharma- ceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0116] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The examples provided show different components and methodologies useful for implementing the present disclosure. These examples do not limit the claimed disclosure. Based on the present disclosure, a person skilled in the art can identify and employ other components and methodologies useful for implementing the present disclosure.

[0117] In the synthesis schemes described herein, compounds may be drawn in one specific configuration for simplicity.Such specific configurations should not be interpreted as limiting the present disclosure to one or more isomers, tautomers, positional isomers, or stereoisomers, and do not 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.

[0118] All publications and patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is relevant prior art, nor is any admission as to their contents or date. Although the invention has now been described by way of written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the following foregoing description and examples are for illustrative purposes only and are not intended to limit the scope of the following claims.

[0119] As used herein, the phrase "compounds of the present disclosure" refers generically and specifically to those compounds disclosed herein.

[0120] Compounds of the Disclosure In some aspects, the present disclosure relates to, inter alia, a compound of formula (I): Compounds of formula (I) [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, W is -S- or -HC=CH-; R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, -(CH 2 ) 0-2 -C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1-C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or -(CH 2 ) 0-2 -heterocyclyl, where the heterocyclyl is a 4-7 membered ring and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S; and the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is aryl, a 5-7 membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S; and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 and the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH 2 optionally replaced by Each R 4are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, -CH 2 C 3 -C 8 Cycloalkyl, heterocyclyl, -CH 2 Heterocyclyl, -CH 2 CH 2 Heterocyclyl, -CH 2-(5-6 membered heteroaryl), where heterocyclyl is a 4-7 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 5 But one or more halogens, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, Spiro C 3 -C 8 optionally substituted with cycloalkyl, spiro 4-7 membered heterocyclyl, 5-6 membered heteroaryl, oxo, cyano, or hydroxyl; R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, The present invention provides a compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5.

[0121] In some embodiments, the present disclosure relates to, inter alia, a compound of formula (Ic): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6Haloalkoxyl, -(CH 2 ) 0-2 -C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or -(CH 2 ) 0-2 -heterocyclyl, where the heterocyclyl is a 4-7 membered ring and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S; and the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is aryl, a 5-7 membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S; and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2and the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, -CH 2 C 3 -C 8 Cycloalkyl, heterocyclyl, -CH2 Heterocyclyl, -CH 2 CH 2 Heterocyclyl, -CH 2 -(5-6 membered heteroaryl), where heterocyclyl is a 4-7 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 5 But one or more halogens, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, Spiro C 3 -C 8 optionally substituted with cycloalkyl, spiro 4-7 membered heterocyclyl, 5-6 membered heteroaryl, oxo, cyano, or hydroxyl; R 6 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, The present invention provides a compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5.

[0122] In some embodiments, the present disclosure relates to, inter alia, a compound of formula (Id): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein W is -S- or -HC=CH-; R 1H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is aryl, a 5-7 membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S; and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3-C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 and the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1-C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, -CH 2 C 3 -C 8 Cycloalkyl, heterocyclyl, -CH 2 Heterocyclyl, -CH 2 CH 2 Heterocyclyl, -CH 2 -(5-6 membered heteroaryl), where heterocyclyl is a 4-7 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 5 But one or more halogens, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, Spiro C 3 -C 8 optionally substituted with cycloalkyl, spiro 4-7 membered heterocyclyl, 5-6 membered heteroaryl, oxo, cyano, or hydroxyl; The present invention provides a compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5.

[0123] In some aspects, the present disclosure relates to, inter alia, a compound of formula (II): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein W is -S- or -HC=CH-; R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is aryl, a 5-7 membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S; and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C6 Alkyl) 2 and the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, -CH 2 C 3 -C8 Cycloalkyl, heterocyclyl, -CH 2 Heterocyclyl, -CH 2 CH 2 Heterocyclyl, -CH 2 -(5-6 membered heteroaryl), where heterocyclyl is a 4-7 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 5 But one or more halogens, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, Spiro C 3 -C 8 optionally substituted with cycloalkyl, spiro 4-7 membered heterocyclyl, 5-6 membered heteroaryl, oxo, cyano, or hydroxyl; R 6 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, m is 0, 1, 2, 3, 4, 5, 6, or 7, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0124] In some aspects, the present disclosure relates to, inter alia, a compound of formula (III): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein W is -S- or -HC=CH-; R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 6- or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S; and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 and the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from one or more of hydroxyl, 4-7 membered heterocyclyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6Alkoxyl, C 3 -C 8 Cycloalkyl, -CH 2 C 3 -C 8 Cycloalkyl, heterocyclyl, -CH 2 Heterocyclyl, -CH 2 CH 2 Heterocyclyl, -CH 2 -(5-6 membered heteroaryl), where heterocyclyl is a 4-7 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 5 But one or more halogens, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, Spiro C 3 -C 8 optionally substituted with cycloalkyl, spiro 4-7 membered heterocyclyl, 5-6 membered heteroaryl, oxo, cyano, or hydroxyl; R 6 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, The present invention provides a compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0125] For compounds of formula (I), (II), or (III), W, R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , m, n, and p may each be selected from groups described herein, where applicable; W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Any group described herein for any of W, R, m, n, and p, if applicable, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 It is understood that one or more of the remainder of m, n, and p may be combined with any group described herein.

[0126] In some embodiments, the compound of formula I is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0127] In some embodiments, the compound of formula I is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0128] In some embodiments, the compound of formula I is a compound of formula (Ic): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0129] In some embodiments, the compound of formula I is a compound of formula (Id): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0130] In some embodiments, the compound of formula II is a compound of formula (IIa): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0131] In some embodiments, the compound of formula II is a compound of formula (IIb): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0132] In some embodiments, the compound of formula III is a compound of formula (IIIa): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0133] In some embodiments, the compound of formula III is a compound of formula (IIIb): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0134] For compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), where applicable:

[0135] In some embodiments, W is -S-.

[0136] In some embodiments, W is -HC=CH-.

[0137] In some embodiments, R 1 is H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0138] In some embodiments, R 1 is H.

[0139] In some embodiments, R 1 is halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; heterocyclyl, where alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 Optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0140] In some embodiments, R 1 is halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4- to 7-membered heterocyclyl heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0141] In some embodiments, R 1 is halogen, hydroxyl, or cyano.

[0142] In some embodiments, R 1 is halogen. In some embodiments, R 1 is F, Cl, Br, or I. In some embodiments, R 1is F, Cl, or Br. In some embodiments, R 1 is F or Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.

[0143] In some embodiments, R 1 is hydroxyl.

[0144] In some embodiments, R 1 is cyano.

[0145] In some embodiments, R 1 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; and alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 Optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0146] In some embodiments, R 1 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0147] In some embodiments, R 1 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 It is alkynyl.

[0148] In some embodiments, R 1 is C 1 -C 6 It is an alkyl.

[0149] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is iso-propyl. In some embodiments, R 1 is iso-butyl. In some embodiments, R1 is sec-butyl. In some embodiments, R 1 is tert-butyl.

[0150] In some embodiments, R 1 is one or more C 3 -C 8 C optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 1 -C 6 In some embodiments, R 1 is one or more C 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 1 -C 6 In some embodiments, R 1 is one C 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 1 -C 6 In some embodiments, R 1 There are two C's 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 1 -C 6 In some embodiments, R 1 The three C's 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 1 -C 6 It is an alkyl.

[0151] In some embodiments, R 1 is C 2 -C 6 In some embodiments, R is alkenyl. 1 is C 2 In some embodiments, R is alkenyl. 1 is C 3 In some embodiments, R is alkenyl. 1 is C 4 In some embodiments, R is alkenyl. 1 is C 5 In some embodiments, R is alkenyl. 1 is C 6 It is alkenyl.

[0152] In some embodiments, R 1 is one or more C 3 -C 8 C optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 In some embodiments, R is alkenyl. 1 is one or more C 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 In some embodiments, R is alkenyl. 1 is one C 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 In some embodiments, R is alkenyl. 1 There are two C's 3 -C 8C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 In some embodiments, R is alkenyl. 1 The three C's 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 It is alkenyl.

[0153] In some embodiments, R 1 is C 2 -C 6 In some embodiments, R is alkynyl. 1 is C 2 In some embodiments, R is alkynyl. 1 is C 3 In some embodiments, R is alkynyl. 1 is C 4 In some embodiments, R is alkynyl. 1 is C 5 In some embodiments, R is alkynyl. 1 is C 6 It is alkynyl.

[0154] In some embodiments, R 1 is one or more C 3 -C 8 C optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 In some embodiments, R is alkynyl. 1 is one or more C 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C6 In some embodiments, R is alkynyl. 1 is one C 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 In some embodiments, R is alkynyl. 1 There are two C's 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 In some embodiments, R is alkynyl. 1 The three C's 3 -C 8 C substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 2 -C 6 It is alkynyl.

[0155] In some embodiments, R 1 is C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8Optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0156] In some embodiments, R 1 is C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0157] In some embodiments, R 1 is C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, or C 1 -C 6 haloalkoxyl, the alkoxyl being one or more C 3 -C 8 Optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0158] In some embodiments, R 1 is C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, or C 1 -C 6 It is a haloalkoxyl.

[0159] In some embodiments, R 1is C 1 -C 6 In some embodiments, R 1 is halomethyl. In some embodiments, R 1 is haloethyl. In some embodiments, R 1 is halopropyl. In some embodiments, R 1 is halobutyl. In some embodiments, R 1 is halopentyl. In some embodiments, R 1 is halohexyl.

[0160] In some embodiments, R 1 is C 1 -C 6 In some embodiments, R 1 is methoxyl. In some embodiments, R 1 is ethoxyl. In some embodiments, R 1 is propoxyl. In some embodiments, R 1 is butyoxyl. In some embodiments, R 1 is pentoxyl. In some embodiments, R 1 is hexoxyl.

[0161] In some embodiments, R 1 is C 1 -C 6 In some embodiments, R 1 is halomethoxyl. In some embodiments, R 1 is haloethoxyl. In some embodiments, R 1 is halopropoxyl. In some embodiments, R 1 is halobutoxyl. In some embodiments, R 1 is halopentoxyl. In some embodiments, R 1 is halohexoxyl.

[0162] In some embodiments, R1 is C 3 -C 8 cycloalkyl or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the cycloalkyl and heterocyclyl are each independently selected from one or more C 3 -C 8 Optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0163] In some embodiments, R 1 is C 3 -C 8 cycloalkyl or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0164] In some embodiments, R 1 is C 3 -C 8 In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is cyclohexyl.

[0165] In some embodiments, R 1 is crosslinked C 3 -C 8 In some embodiments, R 1 is condensed C 3 -C 8 In some embodiments, R 1 Spiro C 3 -C 8 It is cycloalkyl.

[0166] In some embodiments, R 1 is one or more C 3 -C8 C optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 3 -C 8 In some embodiments, R 1 is one or more C 3 -C 8 C optionally substituted with cycloalkyl or aryl 3 -C 8 In some embodiments, R 1 is one or more C 3 -C 8 Cycloalkyl or aryl substituted C 3 -C 8 In some embodiments, R 1 is one or more C 3 -C 8 Cycloalkyl-substituted C 3 -C 8 In some embodiments, R 1 is C substituted with one or more aryl 3 -C 8 It is cycloalkyl.

[0167] In some embodiments, R 1 is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0168] In some embodiments, R 1 is a 4-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0169] In some embodiments, R 1 is a 5-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0170] In some embodiments, R 1is a 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0171] In some embodiments, R 1 is a 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0172] In some embodiments, R 1 is one or more C 3 -C 8 R is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, optionally substituted with cycloalkyl, aryl, or a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 1 is one or more C 3 -C 8 R is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, optionally substituted with cycloalkyl or aryl. 1 is one or more C 3 -C 8 R is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, substituted with cycloalkyl or aryl. 1 is one or more C 3 -C 8 In some embodiments, R is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, substituted with cycloalkyl. 1 is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, substituted with one or more aryl.

[0173] In some embodiments, R 1 NH 2 , NH(C 1 -C6 alkyl), or N(C 1 -C 6 Alkyl) 2 It is.

[0174] In some embodiments, R 1 NH 2 It is.

[0175] In some embodiments, R 1 is NH(C 1 -C 6 alkyl) or N(C 1 -C 6 Alkyl) 2 It is.

[0176] In some embodiments, R 1 is NH(C 1 -C 6 In some embodiments, R 1 is NH(methyl). In some embodiments, R 1 is NH(ethyl). In some embodiments, R 1 is NH(propyl). In some embodiments, R 1 is NH(butyl). In some embodiments, R 1 is NH(pentyl). In some embodiments, R 1 is NH (hexyl).

[0177] In some embodiments, R 1 is N(C 1 -C 6 Alkyl) 2 In some embodiments, R 1 is N(methyl) 2 In some embodiments, R 1 is N(ethyl) 2 In some embodiments, R 1 is N(propyl) 2 In some embodiments, R 1 is N(butyl) 2In some embodiments, R 1 is N(pentyl) 2 In some embodiments, R 1 is N(hexyl) 2 It is.

[0178] In some embodiments, R 1 is H or F.

[0179] In some embodiments, R 2 is aryl.

[0180] In some embodiments, R 2 is one or more R 4 In some embodiments, R 2 is one or more R 4 In some embodiments, R 2 is one R 4 In some embodiments, R 2 is two R 4 In some embodiments, R 2 is 3 R 4 is an aryl substituted with

[0181] In some embodiments, R 2 is a 5- to 7-membered cycloalkyl.

[0182] In some embodiments, R 2 is a 5-7 membered saturated cycloalkyl. In some embodiments, R 2 is a 5- to 7-membered partially saturated cycloalkyl.

[0183] In some embodiments, R 2 is one or more R 4 In some embodiments, R 2 is one or more R 4In some embodiments, R 2 is one R 4 In some embodiments, R 2 is two R 4 In some embodiments, R 2 is 3 R 4 is a 5-7 membered cycloalkyl substituted with

[0184] In some embodiments, R 2 is a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0185] In some embodiments, R 2 is a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N and O.

[0186] In some embodiments, R 2 is a 5-, 6-, or 9-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S.

[0187] In some embodiments, R 2 is a 5-, 6-, or 9-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O.

[0188] In some embodiments, R 2 is a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is one or more R 4 is optionally replaced by

[0189] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S.

[0190] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O.

[0191] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the heteroaryl is selected from one or more R 4 is optionally replaced by

[0192] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0193] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the heteroaryl is selected from one or more R 4 has been replaced with.

[0194] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 has been replaced with.

[0195] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the heteroaryl is selected from one R 4 has been replaced with.

[0196] In some embodiments, R 2is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one R 4 has been replaced with.

[0197] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the heteroaryl is selected from two R 4 has been replaced with.

[0198] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from two R 4 has been replaced with.

[0199] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the heteroaryl is selected from three R 4 has been replaced with.

[0200] In some embodiments, R 2 is a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from three R 4 has been replaced with.

[0201] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 has been replaced with.

[0202] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R4 is optionally replaced by

[0203] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 has been replaced with.

[0204] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 has been replaced with.

[0205] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one R 4 has been replaced with.

[0206] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one R 4 has been replaced with.

[0207] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from two R 4 has been replaced with.

[0208] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from two R 4 has been replaced with.

[0209] In some embodiments, R 2is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from three R 4 has been replaced with.

[0210] In some embodiments, R 2 is a 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N and O, the heteroaryl being selected from three R 4 has been replaced with.

[0211] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0212] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0213] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0214] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 has been replaced with.

[0215] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one R 4 has been replaced with.

[0216] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N and O, the heteroaryl being selected from one R 4 has been replaced with.

[0217] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, the heteroaryl being selected from two R 4 has been replaced with.

[0218] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N and O, the heteroaryl being selected from two R 4 has been replaced with.

[0219] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N, O, and S, the heteroaryl being selected from three R 4 has been replaced with.

[0220] In some embodiments, R 2 is a 9-membered heteroaryl containing two heteroatoms independently selected from N and O, the heteroaryl being selected from three R 4 has been replaced with.

[0221] In some embodiments, R 2 is a 9-membered heteroaryl containing three heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0222] In some embodiments, R 2 is a 9-membered heteroaryl containing 3 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0223] In some embodiments, R 2 is a 9-membered heteroaryl containing three heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 has been replaced with.

[0224] In some embodiments, R 2 is a 9-membered heteroaryl containing 3 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 has been replaced with.

[0225] In some embodiments, R 2 is a 9-membered heteroaryl containing three heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one R 4 has been replaced with.

[0226] In some embodiments, R 2 is a 9-membered heteroaryl containing 3 heteroatoms independently selected from N and O, the heteroaryl being selected from one R 4 has been replaced with.

[0227] In some embodiments, R 2 is a 9-membered heteroaryl containing three heteroatoms independently selected from N, O, and S, the heteroaryl being selected from two R 4 has been replaced with.

[0228] In some embodiments, R 2 is a 9-membered heteroaryl containing three heteroatoms independently selected from N and O, the heteroaryl being selected from two R 4 has been replaced with.

[0229] In some embodiments, R 2 is a 9-membered heteroaryl containing three heteroatoms independently selected from N, O, and S, the heteroaryl being selected from three R 4 has been replaced with.

[0230] In some embodiments, R 2 is a 9-membered heteroaryl containing three heteroatoms independently selected from N and O, the heteroaryl being selected from three R 4 has been replaced with.

[0231] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0232] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 is optionally replaced by

[0233] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one or more R 4 has been replaced with.

[0234] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one or more R 4 has been replaced with.

[0235] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from one R 4 has been replaced with.

[0236] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N and O, the heteroaryl being selected from one R 4 has been replaced with.

[0237] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from two R 4 has been replaced with.

[0238] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N and O, the heteroaryl being selected from two R 4 has been replaced with.

[0239] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N, O, and S, the heteroaryl being selected from three R 4 has been replaced with.

[0240] In some embodiments, R 2 is a 9-membered heteroaryl containing 4 heteroatoms independently selected from N and O, the heteroaryl being selected from three R 4 has been replaced with.

[0241] In some embodiments, R 2 is a bicyclic 9-membered heteroaryl.

[0242] In some embodiments, R 2 teeth, [ka] and In the formula, each R 8 are independently 4 It is.

[0243] In some embodiments, R 2 teeth, [ka] It is.

[0244] In some embodiments, each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 It is.

[0245] In some embodiments, at least one R 3 is halogen. In some embodiments, at least one R 3 is F, Cl, Br, or I. In some embodiments, at least one R 3 is F, Cl, or Br. In some embodiments, at least one R 3 is F or Cl. In some embodiments, at least one R 3 is F. In some embodiments, at least one R 3 is Cl. In some embodiments, at least one R 3 is Br. In some embodiments, at least one R 3 is I.

[0246] In some embodiments, each R 3 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, or C 3 -C 8It is cycloalkyl.

[0247] In some embodiments, each R 3 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, or C 3 -C 8 Cycloalkyl, where alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH 2 is optionally replaced by

[0248] In some embodiments, each R 3 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 It is alkynyl.

[0249] In some embodiments, each R 3 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Alkynyl, where the alkyl, alkenyl, or alkynyl is substituted with one or more hydroxyl or NH 2 is optionally replaced by

[0250] In some embodiments, at least one R 3 is C 1 -C 6 In some embodiments, at least one R 3 is methyl. In some embodiments, at least one R 3 is ethyl. In some embodiments, at least one R 3is propyl. In some embodiments, at least one R 3 is butyl. In some embodiments, R 3 is iso-propyl. In some embodiments, at least one R 3 is iso-butyl. In some embodiments, at least one R 3 is sec-butyl. In some embodiments, at least one R 3 is tert-butyl.

[0251] In some embodiments, each R 3 is one or more hydroxyl or NH 2 C optionally substituted with 1 -C 6 It is an alkyl.

[0252] In some embodiments, R 3 is C 2 -C 6 In some embodiments, R is alkenyl. 3 is C 2 In some embodiments, R is alkenyl. 3 is C 3 In some embodiments, R is alkenyl. 3 is C 4 In some embodiments, R is alkenyl. 3 is C 5 In some embodiments, R is alkenyl. 3 is C 6 It is alkenyl.

[0253] In some embodiments, R 3 is one or more hydroxyl or NH 2 C optionally substituted with 2 -C 6 It is alkenyl.

[0254] In some embodiments, R 3 is C 2 -C 6 In some embodiments, R is alkynyl.3 is C 2 In some embodiments, R is alkynyl. 3 is C 3 In some embodiments, R is alkynyl. 3 is C 4 In some embodiments, R is alkynyl. 3 is C 5 In some embodiments, R is alkynyl. 3 is C 6 It is alkynyl.

[0255] In some embodiments, R 3 is one or more hydroxyl or NH 2 C optionally substituted with 2 -C 6 It is alkynyl.

[0256] In some embodiments, each R 3 is independently 1 -C 6 Alkoxy or C 3 -C 8 It is cycloalkyl.

[0257] In some embodiments, each R 3 is independently 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl, alkoxyl and cycloalkyl are each independently one or more hydroxyl or NH 2 is optionally replaced by

[0258] In some embodiments, each R 3 independently, one or more hydroxyl or NH 2 C optionally substituted with 1 -C 6 It is alkoxyl.

[0259] In some embodiments, at least one R 3 is C 1 -C 6In some embodiments, at least one R 3 is methoxyl. In some embodiments, at least one R 3 is ethoxyl. In some embodiments, at least one R 3 is propoxyl. In some embodiments, at least one R 3 is butoxyl. In some embodiments, at least one R 3 is pentoxyl. In some embodiments, at least one R 3 is hexoxyl.

[0260] In some embodiments, each R 3 independently, one or more hydroxyl or NH 2 C optionally substituted with 3 -C 8 It is cycloalkyl.

[0261] In some embodiments, at least one R 3 is independently 3 -C 8 In some embodiments, at least one R 3 is independently cyclopropyl. In some embodiments, at least one R 3 is independently cyclobutyl. In some embodiments, at least one R 3 is independently cyclopentyl. In some embodiments, at least one R 3 is independently cyclohexyl. In some embodiments, at least one R 3 is independently cycloheptyl. In some embodiments, at least one R 3 is independently cyclooctyl.

[0262] In some embodiments, each R 3 Independently, NH 2 , NH(C 1 -C 6 alkyl), or N(C1 -C 6 Alkyl) 2 It is.

[0263] In some embodiments, at least one R 3 NH 2 It is.

[0264] In some embodiments, each R 3 is NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 It is.

[0265] In some embodiments, at least one R 3 is NH(C 1 -C 6 alkyl). In some embodiments, at least one R 3 is NH(methyl). In some embodiments, at least one R 3 is NH(ethyl). In some embodiments, at least one R 3 is NH(propyl). In some embodiments, at least one R 3 is NH(butyl). In some embodiments, at least one R 3 is NH(pentyl). In some embodiments, at least one R 3 is NH (hexyl).

[0266] In some embodiments, at least one R 3 is N(C 1 -C 6 Alkyl) 2 It is. In some embodiments, at least one R 3 is N(methyl) 2 In some embodiments, at least one R 3 is N(ethyl) 2 In some embodiments, at least one R3 is N(propyl) 2 In some embodiments, at least one R 3 is N(butyl) 2 In some embodiments, at least one R 3 is N(pentyl) 2 In some embodiments, at least one R 3 is N(hexyl) 2 It is.

[0267] In some embodiments, R 3 is F or methyl.

[0268] In some embodiments, each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 It is.

[0269] In some embodiments, each R 4 is independently halogen, hydroxyl, cyano, or nitro.

[0270] In some embodiments, at least one R 4 is halogen. In some embodiments, at least one R 4is F, Cl, Br, or I. In some embodiments, at least one R 4 is F, Cl, or Br. In some embodiments, at least one R 4 is F or Cl. In some embodiments, at least one R 4 is F. In some embodiments, at least one R 4 is Cl. In some embodiments, at least one R 4 is Br. In some embodiments, at least one R 4 is I.

[0271] In some embodiments, each R 4 is independently hydroxyl, cyano, or nitro.

[0272] In some embodiments, at least one R 4 is independently hydroxyl.

[0273] In some embodiments, at least one R 4 are independently cyano.

[0274] In some embodiments, at least one R 4 is independently nitro.

[0275] In some embodiments, each R 4 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 is optionally replaced by

[0276] In some embodiments, each R 4 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 It is.

[0277] In some embodiments, each R 4 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6Alkynyl, where alkyl, alkenyl, or alkynyl is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 is optionally replaced by

[0278] In some embodiments, each R 4 is independently 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 It is alkynyl.

[0279] In some embodiments, R 4 is C 1 -C 6 In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is iso-propyl. In some embodiments, R 4 is iso-butyl. In some embodiments, R 4 is sec-butyl. In some embodiments, R 4 is tert-butyl.

[0280] In some embodiments, R 4 is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S; NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C6 Alkyl) 2 C optionally substituted with 1 -C 6 It is an alkyl.

[0281] In some embodiments, R 4 is C 2 -C 6 In some embodiments, R is alkenyl. 4 is C 2 In some embodiments, R is alkenyl. 4 is C 3 In some embodiments, R is alkenyl. 4 is C 4 In some embodiments, R is alkenyl. 4 is C 5 In some embodiments, R is alkenyl. 4 is C 6 It is alkenyl.

[0282] In some embodiments, R 4 is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S; NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 C optionally substituted with 2 -C 6 It is alkenyl.

[0283] In some embodiments, R 4 is C 2 -C 6 In some embodiments, R is alkynyl. 4 is C 2 In some embodiments, R is alkynyl. 4 is C 3 In some embodiments, R is alkynyl. 4 is C 4 In some embodiments, R is alkynyl. 4is C 5 In some embodiments, R is alkynyl. 4 is C 6 It is alkynyl.

[0284] In some embodiments, R 4 is a 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S; NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 C optionally substituted with 2 -C 6 It is alkynyl.

[0285] In some embodiments, each R 4 is independently 1 -C 6 Alkoxy or C 3 -C 8 It is cycloalkyl.

[0286] In some embodiments, each R 4 is independently 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl, where alkoxyl and cycloalkyl are each independently one or more of hydroxyl, 4-7 membered heterocyclyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 is optionally replaced by

[0287] In some embodiments, each R 4 is independently 1 -C 6 In some embodiments, each R 4 is independently methoxyl. In some embodiments, each R 4is independently ethoxyl. In some embodiments, each R 4 is independently propoxyl. In some embodiments, each R 4 is independently butyoxyl. In some embodiments, each R 4 is independently pentoxyl. In some embodiments, each R 4 is independently hexoxyl.

[0288] In some embodiments, each R 4 independently represents one or more of hydroxyl, 4- to 7-membered heterocyclyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 C optionally substituted with 1 -C 6 It is alkoxyl.

[0289] In some embodiments, each R 4 is independently 3 -C 8 In some embodiments, each R 4 is independently cyclopropyl. In some embodiments, each R 4 is independently cyclobutyl. In some embodiments, each R 4 is independently cyclopentyl. In some embodiments, each R 4 is independently cyclohexyl. In some embodiments, each R 4 is independently cycloheptyl. In some embodiments, each R 4 is independently cyclooctyl.

[0290] In some embodiments, each R 4 independently represents one or more of hydroxyl, 4- to 7-membered heterocyclyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C6 Alkyl) 2 Optionally substituted C 3 -C 8 It is cycloalkyl.

[0291] In some embodiments, each R 4 is independently 1 -C 6 Haloalkyl or C 1 -C 6 It is a haloalkoxyl.

[0292] In some embodiments, each R 4 is independently 1 -C 6 In some embodiments, each R 4 is independently halomethyl. In some embodiments, each R 4 is independently haloethyl. In some embodiments, each R 4 is independently halopropyl. In some embodiments, each R 4 is independently halobutyl. In some embodiments, each R 4 is independently halopentyl. In some embodiments, each R 4 is independently halohexyl.

[0293] In some embodiments, each R 4 is independently 3 , CHF 2 , or C.H. 2 It's F.

[0294] In some embodiments, each R 4 is independently 1 -C 6 In some embodiments, each R 4 is independently halomethoxyl. In some embodiments, each R 4 is independently haloethoxyl. In some embodiments, each R 4 is independently halopropoxyl. In some embodiments, each R4 is independently halobutoxyl. In some embodiments, each R 4 is independently halopentoxyl. In some embodiments, each R 4 is independently halohexoxyl.

[0295] In some embodiments, each R 4 Independently, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 It is.

[0296] In some embodiments, each R 4 Independently, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 It is.

[0297] In some embodiments, each R 4 Independently, NH 2 It is.

[0298] In some embodiments, each R 4 are independently C(O)NH 2 It is.

[0299] In some embodiments, each R 4 are independently 1 -C 6 alkyl) or N(C 1 -C 6 Alkyl) 2 It is.

[0300] In some embodiments, each R 4 are independently 1 -C 6 In some embodiments, each R4 is independently H (methyl). In some embodiments, each R 4 is independently NH(ethyl). In some embodiments, each R 4 is independently NH(propyl). In some embodiments, each R 4 is independently NH(butyl). In some embodiments, each R 4 is independently NH(pentyl). In some embodiments, each R 4 are independently NH (hexyl).

[0301] In some embodiments, each R 4 are independently N(C 1 -C 6 Alkyl) 2 In some embodiments, each R 4 are independently N(methyl) 2 In some embodiments, each R 4 are independently N(ethyl) 2 In some embodiments, each R 4 are independently N(propyl) 2 In some embodiments, each R 4 are independently N(butyl) 2 In some embodiments, each R 4 are independently N(pentyl) 2 In some embodiments, each R 4 are independently N(hexyl) 2 It is.

[0302] In some embodiments, each R 4 are independently methyl, ethyl, F, or CF 3 It is.

[0303] In some embodiments, each R 4 is independently methyl or ethyl.

[0304] In some embodiments, each R 4 are independently F or CF3 It is.

[0305] In some embodiments, R 5 is H.

[0306] In some embodiments, R 5 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 cycloalkyl, or heterocyclyl, where the heterocyclyl is a 4- to 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; the cycloalkyl and heterocyclyl may further contain one or more halogens, C 1 -C 6 It is optionally substituted with alkyl, or hydroxyl.

[0307] In some embodiments, R 5 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 It is alkynyl.

[0308] In some embodiments, R 5 is C 1 -C 6 In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is propyl. In some embodiments, R 5 is butyl. In some embodiments, R 5 is iso-propyl. In some embodiments, R5 is iso-butyl. In some embodiments, R 5 is sec-butyl. In some embodiments, R 5 is tert-butyl.

[0309] In some embodiments, R 5 is C 2 -C 6 In some embodiments, R is alkenyl. 5 is C 2 -C 6 In some embodiments, R is alkenyl. 5 is C 2 In some embodiments, R is alkenyl. 5 is C 3 In some embodiments, R is alkenyl. 5 is C 4 In some embodiments, R is alkenyl. 5 is C 5 In some embodiments, R is alkenyl. 5 is C 6 It is alkenyl.

[0310] In some embodiments, R 5 is C 2 -C 6 In some embodiments, R is alkynyl. 5 is C 2 -C 6 In some embodiments, R is alkynyl. 5 is C 2 In some embodiments, R is alkynyl. 5 is C 3 In some embodiments, R is alkynyl. 5 is C 4 In some embodiments, R is alkynyl. 5 is C 5 In some embodiments, R is alkynyl. 5 is C 6 It is alkynyl.

[0311] In some embodiments, R 5 is C 1 -C 6 Alkoxy or C 3 -C 8 It is cycloalkyl.

[0312] In some embodiments, R 5 is independently 1 -C 6 In some embodiments, R 5 is independently methoxyl. In some embodiments, R 5 is independently ethoxyl. In some embodiments, R 5 is independently propoxyl. In some embodiments, R 5 is independently butoxyl. In some embodiments, R 5 is independently pentoxyl. In some embodiments, R 5 is independently hexoxyl.

[0313] In some embodiments, R 5 is C 3 -C 8 In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is cyclobutyl. In some embodiments, R 5 is cyclopentyl. In some embodiments, R 5 is cyclohexyl. In some embodiments, R 5 is heptyl. In some embodiments, R 5 is cyclooctyl.

[0314] In some embodiments, R 5 is heterocyclyl, the heterocyclyl being a 4-7 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; cycloalkyl and heterocyclyl are each independently selected from one or more halogens, C 1 -C 6In some embodiments, R 5 is heterocyclyl, the heterocyclyl being a 4-6 membered ring containing 1 or 2 heteroatoms independently selected from N and O, and the cycloalkyl and heterocyclyl are each independently selected from one or more halogens, C 1 -C 6 In some embodiments, R 5 is tetrahydropyranyl or tetrahydrofuranyl.

[0315] In some embodiments, R 5 , H, C 1-6 alkyl, or heterocyclyl, where heterocyclyl is a 4-7 membered ring containing 1 or 2 heteroatoms independently selected from N and O.

[0316] In some embodiments, R 5 is H. In some embodiments, R 6 is H. In some embodiments, R 5 and R 6 Both are H.

[0317] In some embodiments of the compound of formula I, n is 0, 1, 2, 3, 4, or 5. In some embodiments of the compound of formula I, n is 0, 1, 2, 3, or 4. In some embodiments of the compound of formula I, n is 0, 1, 2, or 3. In some embodiments of the compound of formula I, n is 0, 1, or 2. In some embodiments of the compound of formula I, n is 0 or 1. In some embodiments of the compound of formula I, n is 0. In some embodiments of the compound of formula I, n is 1. In some embodiments of the compound of formula I, n is 2. In some embodiments of the compound of formula I, n is 3. In some embodiments of the compound of formula I, n is 4. In some embodiments of the compound of formula I, n is 5.

[0318] In some embodiments of the compound of formula II, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments of the compound of formula II, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of the compound of formula II, m is 0, 1, 2, 3, 4, or 5. In some embodiments of the compound of formula II, m is 0, 1, 2, 3, or 4. In some embodiments of the compound of formula II, m is 0, 1, 2, or 3. In some embodiments of the compound of formula II, m is 0, 1, or 2. In some embodiments of the compound of formula II, m is 0 or 1. In some embodiments of the compound of formula II, m is 0. In some embodiments of the compound of formula II, m is 1. In some embodiments of the compound of formula II, m is 2. In some embodiments of the compound of formula II, m is 3. In some embodiments of the compound of formula II, m is 4. In some embodiments of the compound of formula II, m is 5. In some embodiments of the compound of formula II, m is 6. In some embodiments of the compound of formula II, m is 7.

[0319] In some embodiments of the compound of formula III, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments of the compound of formula III, p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of the compound of formula III, p is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments of the compound of formula III, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of the compound of formula III, p is 0, 1, 2, 3, 4, or 5. In some embodiments of the compound of formula III, p is 0, 1, 2, 3, or 4. In some embodiments of the compound of formula III, p is 0, 1, 2, or 3. In some embodiments of the compound of formula III, p is 0, 1, or 2. In some embodiments of the compound of formula III, p is 0 or 1. In some embodiments of the compound of formula III, p is 0. In some embodiments of the compound of formula III, p is 1. In some embodiments of the compound of formula III, p is 2. In some embodiments of the compound of formula III, p is 3. In some embodiments of the compound of formula III, p is 4. In some embodiments of the compound of formula III, p is 5. In some embodiments of the compound of formula III, p is 6. In some embodiments of the compound of formula III, p is 7. In some embodiments of the compound of formula III, p is 8. In some embodiments of the compound of formula III, p is 9.

[0320] In some embodiments, the compound is selected from the compounds set forth in Table 1 and their pharma- ceutically acceptable salts, solvates, or prodrugs.

[0321] In some embodiments, the compound is selected from the compounds set forth in Table 1 and their pharma- ceutically acceptable salts.

[0322] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 1 and pharma- ceutically acceptable salts thereof.

[0323] For the avoidance of doubt, when a group is modified herein by "as described herein," it is to be understood that such group encompasses the broadest definition appearing first, as well as each and every specific definition for that group.

[0324] The various functional groups and substituents which make up the compounds of formula (I), (II), or (III) are typically selected so that the molecular weight of the compound does not exceed 1000 Daltons. More typically, the molecular weight of the compound is less than 900, e.g., 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, e.g., 550 Daltons or less.

[0325] It will be understood that a compound of any one of the formulas disclosed herein, and any pharma- ceutically acceptable salt thereof, includes all isomeric forms of stereoisomers or mixtures of stereoisomers of the compound.

[0326] It should be understood that a compound of any formula described herein includes the compound itself, as well as its salts, and solvates thereof, if applicable.

[0327] The in vivo effect of any one of the compounds of the formulas disclosed herein may be exerted in part by one or more metabolic products formed in the human or animal body after administration of any one of the compounds of the formulas disclosed herein.As described herein, the in vivo effect of any one of the compounds of the formulas disclosed herein may also be exerted by the metabolism of precursor compounds (prodrugs).

[0328] Suitably, the present disclosure excludes any individual compound that does not have biological activity as defined herein. Method of synthesis

[0329] By way of example only, schemes for preparing the small molecule splicing modulators (SMSMs) described herein are provided.

[0330] In some embodiments, a scheme for preparing SMSM is set forth herein in Scheme 1 below. [ka]

[0331] In some embodiments, a scheme for preparing SMSM is set forth herein below in Scheme 2. [ka]

[0332] In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0333] In some aspects, the disclosure provides a method of preparing a compound, comprising one or more of the steps described herein.

[0334] In some aspects, the disclosure provides compounds that can be obtained by, are obtained by, or are obtained directly by the methods for preparing the compounds described herein.

[0335] In some aspects, the disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein.

[0336] The compounds of the present disclosure may be prepared by any suitable technique known in the art. Specific processes for preparing these compounds are further described in the accompanying Examples.

[0337] In the descriptions of synthetic methods described herein, and in any reference synthetic methods used to prepare starting materials, it is understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected by one of ordinary skill in the art.

[0338] One skilled in the art of organic synthesis understands that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0339] It will be understood that during the synthesis of the compounds of the present disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. Those skilled in the art will understand when such protection is necessary and how such protecting groups can be introduced and subsequently removed. For examples of protecting groups, see one of the many general textbooks on the subject, for example "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to chemists of ordinary skill as suitable for removing the protecting group in question, such a method being selected to remove the protecting group while minimizing disturbance of groups elsewhere in the molecule. Thus, when reactants contain groups such as, for example, amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0340] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, for example acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl, or aroyl groups, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary according to the choice of protecting group. Thus, for example, acyl groups or aroyl groups, such as alkanoyl or alkoxycarbonyl groups, can be removed by hydrolysis using a suitable base, for example an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as the tert-butoxycarbonyl group may be removed by treatment with a suitable acid, for example hydrochloric acid, sulfuric acid or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups (such as the benzyloxycarbonyl group) may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example boron tris(trifluoroacetate).A suitable alternative protecting group for a primary amino group is, for example, the phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

[0341] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, aroyl groups, for example benzoyl, or arylmethyl groups, for example benzyl. The deprotection conditions for the above protecting groups necessarily vary according to the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed by hydrolysis using a suitable base, for example an alkali metal hydroxide, for example lithium, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation, for example, over a catalyst such as palladium on carbon.

[0342] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group, which may be removed by hydrolysis with a base, such as sodium hydroxide, or, for example, a tert-butyl group, which may be removed by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or, for example, a benzyl group, which may be removed by hydrogenation over a catalyst, such as palladium on carbon.

[0343] Once a compound of formula (I), (II) or (III) has been synthesised by any one of the processes defined herein, the process may then further comprise the additional steps of (i) removing any protecting groups present, (ii) converting the compound of formula (I), (II) or (III) to another compound of formula (I), (II) or (III), (iii) forming a pharma- ceutically acceptable salt, hydrate or solvate thereof, and / or (iv) forming a prodrug thereof.

[0344] The resulting compounds of formula (I), (II), or (III) can be isolated and purified using techniques well known in the art.

[0345] Advantageously, the reaction of the compounds is carried out in the presence of a suitable solvent, preferably inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; ethylene glycol, propylene ... Examples of suitable solvents include, but are not limited to, glycol ethers such as ethanol monomethyl or monoethyl ether, or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetylamide, dimethylacetylamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate; or mixtures of such solvents, or with water.

[0346] The reaction temperature is preferably from about -100°C to 300°C, depending on the reaction step and conditions used.

[0347] The reaction time generally ranges from 1 minute to several days, depending on the reactivity of each compound and the respective reaction conditions. Suitable reaction times can be easily determined by methods known in the art, such as reaction monitoring. Based on the above reaction temperatures, suitable reaction times are generally within the range of 10 minutes to 48 hours.

[0348] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure are easily accessible by various synthetic routes, some of which are illustrated in the accompanying examples. The skilled artisan will easily recognize what kind of reagents and reaction conditions to use and how to apply and adapt them, whenever necessary or useful, to obtain the compounds of the present disclosure. In addition, some of the compounds of the present disclosure can be easily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, by converting one specific functional group present in the compounds of the present disclosure or in a suitable precursor molecule thereof to another functional group, which methods are well known to those skilled in the art. Similarly, the skilled artisan will apply synthetic protection (or protective) groups, whenever necessary or useful. Suitable protecting groups, as well as 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, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0349] General routes for preparing the compounds of the present application are described herein. Biological assays

[0350] Once produced, compounds designed, selected, and / or optimized by the above methods can be characterized using a variety of assays known to those of skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to the assays described below, to determine whether they have the expected activity, binding activity, and / or binding specificity. Pharmaceutical Compositions

[0351] In some aspects, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure as an active ingredient.In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described herein, or a pharma-ceutically acceptable salt or solvate thereof, and one or more pharma-ceutically acceptable carriers or excipients.In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0352] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts. The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, etc. The compounds of the present disclosure can also be formulated for intravenous (bolus or intrafusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0353] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.The aqueous vehicle component may comprise water and at least one pharma- ceutically acceptable excipient.Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspension agents, buffers, and pH adjusters, and mixtures thereof.

[0354] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin, sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0355] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. Any suitable preservative can be used.Examples of preservatives include those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and quaternary ammonium salts such as sorbic acid, and mixtures thereof.

[0356] The aqueous vehicle may also contain a tonicity agent to adjust tonicity (osmotic pressure), which may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0357] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers), such as acrylic acid polymers polyalkenyl ethers or acrylic acid polymers crosslinked with divinyl glycol (Carbopol-e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0358] 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 modifier. The pH modifier is typically a mineral acid or 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 modifiers are added to adjust the formulation to a target acceptable pH range. Thus, depending on the formulation, it may not be necessary to use both an acid and a base, and adding one of the acids or bases may be sufficient to bring the mixture to the desired pH range.

[0359] The aqueous vehicle may also contain a buffering agent to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts including disodium tetraborate), citrate buffers (such as citric acid or its salts including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0360] The formulation may further comprise a wetting agent.Suitable types of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0361] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as hereinbefore defined, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, in association with a pharma- ceutically acceptable diluent or carrier.

[0362] The compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as a cream, ointment, gel, or aqueous or oily solution or suspension), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration).

[0363] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives.

[0364] An effective amount of a compound of the disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with a disease or disorder referred to herein.

[0365] An effective amount of a compound of the disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with a disease or disorder referred to herein.

[0366] The size of a dose of a compound of formula (I), (II), or (III) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles.

[0367] How to use A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein, wherein the disease is selected from the group consisting of ALS, Alzheimer's disease, argyrophilic grain disease, corticobasal degeneration, cystic fibrosis, dilated cardiomyopathy, Duchenne muscular dystrophy, Ehlers-Danlos syndrome, Fabry disease, familial dysautonomia, familial hypercholesterolemia, familial persistent hyperinsulinemic hypoglycemia, frontotemporal dementia, FTDP-17, gonorrhea, and the like. Provided herein are methods for treating a disease selected from the group consisting of: Chronic Hepatitis B syndrome, glial globular inclusion tauopathy, HIV-1, Huntington's disease, Hutchinson-Gilford progeria, hypercholesterolemia, Leber's congenital amaurosis, migraine, multiple sclerosis, myelodysplastic syndromes, NASH, Niemann-Pick disease, pain, Parkinson's disease, phenylketonuria, Pick's disease, progressive supranuclear palsy, spinal muscular atrophy, spinocerebellar ataxia type 2, Wilson's disease, sickle cell anemia, Crohn's disease, ulcerative colitis, psoriasis, and rheumatoid arthritis.

[0368] In some embodiments, the disease is Huntington's disease.

[0369] Provided herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein, wherein the disease is a pulmonary disease selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), pulmonary fibrosis, and pulmonary arterial hypertension (PAH).

[0370] Route of Administration The compounds of the present disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0371] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, transdermal (e.g., by patch, plaster, etc.), transmucosal (e.g., by patch, plaster, etc.), intranasal (e.g., by nose spray), intraocular (e.g., by eye drops), pulmonary (e.g., using an aerosol, e.g., via an aerosol, e.g., via the mouth or nose, by inhalation or insufflation therapy), rectal (e.g., by suppository or enema), vaginal (e.g., by pessary), parenteral, e.g., by injection including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, intraarterial, subarachnoid, and intrathoracic, by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular injection.

[0372] The present disclosure includes the following embodiments, numbered 1 through 27. 1. A compound of formula (I), [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein W is -S- or -HC=CH-; R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, -(CH 2 ) 0-2 -C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2, or -(CH 2 ) 0-2 -heterocyclyl, wherein the heterocyclyl is a 4-7 membered ring and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 cycloalkyl, or heterocyclyl, where the heterocyclyl is a 4- to 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the cycloalkyl and heterocyclyl are each independently selected from one or more halogens, C 1 -C 6 optionally substituted with alkyl, or hydroxyl; R 6 H, halogen, C 1 -C 6 Alkyl, or C1 -C 6 is haloalkyl, R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, The compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5. 2. The compound according to embodiment 1 of formula (Ic), [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, -(CH 2 ) 0-2 -C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or -(CH 2 ) 0-2 -heterocyclyl, wherein the heterocyclyl is a 4-7 membered ring and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 cycloalkyl, or heterocyclyl, where the heterocyclyl is a 4- to 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the cycloalkyl and heterocyclyl are each independently selected from one or more halogens, C 1 -C 6 optionally substituted with alkyl, or hydroxyl; R 6 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, The compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5. 3. The compound according to embodiment 1 of formula (Id), [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein W is -S- or -HC=CH-; R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl)2 , or C(O)NH 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 cycloalkyl, or heterocyclyl, where the heterocyclyl is a 4- to 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the cycloalkyl and heterocyclyl are each independently selected from one or more halogens, C 1 -C 6 optionally substituted with alkyl, or hydroxyl; The compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5. 4. A compound of formula (II), [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein W is -S- or -HC=CH-; R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 or a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6alkyl), or N(C 1 -C 6 Alkyl) 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C3 -C 8 cycloalkyl, or heterocyclyl, where the heterocyclyl is a 4- to 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the cycloalkyl and heterocyclyl are each independently selected from one or more halogens, C 1 -C 6 optionally substituted with alkyl, or hydroxyl; R 6 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, The compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein m is 0, 1, 2, 3, 4, 5, 6, or 7. 5. A compound of formula (III), [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein W is -S- or -HC=CH-; R 1 H, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6alkyl), N(C 1 -C 6 Alkyl) 2 or a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C 3 -C 8 optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2 is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 6- or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R 4 optionally replaced by Each R 3 are independently halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from one or more hydroxyl or NH 2 optionally replaced by Each R 4 are independently halogen, hydroxyl, cyano, nitro, C 1 -C 6 Alkyl, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxyl, C 1 -C 6 Haloalkoxyl, C 3 -C 8 Cycloalkyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 Alkyl) 2 , or C(O)NH 2 wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from one or more of hydroxyl, 4- to 7-membered heterocyclyl, NH 2 , NH(C 1 -C 6 alkyl), or N(C 1 -C 6 Alkyl) 2 optionally replaced by R 5 But, H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxyl, or C 3 -C 8 cycloalkyl, or heterocyclyl, where the heterocyclyl is a 4- to 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the cycloalkyl and heterocyclyl are each independently selected from one or more halogens, C 1 -C 6 optionally substituted with alkyl, or hydroxyl; R 6 H, halogen, C 1 -C 6 Alkyl, or C 1 -C6 is haloalkyl, R 7 H, halogen, C 1 -C 6 Alkyl, or C 1 -C 6 is haloalkyl, The compound, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. 6. The compound is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. 7. The compound is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. 8. The compound is a compound of formula (Ie): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. 9. The compound is a compound of formula (If): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. 10. The compound is a compound of formula (IIa): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. 11. The compound is a compound of formula (IIb): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. 12. The compound is a compound of formula (IIIa): [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof. 13. The compound is a compound of formula (IIIb): [ka] or a pharma- ceutically acceptable salt thereof. 14.R 1 is H or F. 15.R 2 but, [ka] and In the formula, each R 8 But independently, R 4 The compound of any one of embodiments 1-14, wherein 16.Each R 8 But independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 Alkoxy, preferably each R 8 However, independently, F, Me, Et, CF 3 , MeO, or EtO. 17.R 2 but, [ka] The compound of any one of embodiments 1-16, wherein 18.R 4is methyl, ethyl, F, or CF 3 The compound of any one of embodiments 1-16, wherein 19.R 5 But, H, C 1-6 The compound according to any one of embodiments 1 to 18, wherein the heterocyclyl is a 4-7 membered ring and contains 1 or 2 heteroatoms independently selected from N and O. 20.R 5 The compound of any one of embodiments 1-18, wherein 21. The compound according to any one of embodiments 1-20, selected from the compounds in Table 1. 22. A compound according to any one of embodiments 1-21, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, for use as a therapeutically active substance. 23. A compound according to any one of embodiments 1-22, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, for use as a small molecule splicing modulator. 24. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 23, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, and one or more pharma- ceutically acceptable excipients. 25. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-23 or a pharmaceutical composition according to embodiment 24, wherein the disease is selected from the group consisting of ALS, Alzheimer's disease, argyrophilic grain disease, corticobasal degeneration, cystic fibrosis, dilated cardiomyopathy, Duchenne muscular dystrophy, Ehlers-Danlos syndrome, Fabry disease, familial dysautonomia, familial hypercholesterolemia, familial persistent hyperinsulinemic hypoglycemia, frontal ganglioside neuropathy, and cerebrovascular disease. the method, wherein the therapeutic target is selected from the group consisting of temporal dementia, FTDP-17, Gaucher disease, glial spheroidal inclusion body tauopathy, HIV-1, Huntington's disease, Hutchinson-Gilford progeria, hypercholesterolemia, Leber's congenital amaurosis, migraine, multiple sclerosis, myelodysplastic syndrome, NASH, Niemann-Pick disease, pain, Parkinson's disease, phenylketonuria, Pick's disease, progressive supranuclear palsy, spinal muscular atrophy, spinocerebellar ataxia type 2, Wilson's disease, sickle cell anemia, Crohn's disease, ulcerative colitis, psoriasis, and rheumatoid arthritis. 26. The method of embodiment 25, wherein the disease is Huntington's disease. 27. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-23 or a pharmaceutical composition according to embodiment 24, wherein the disease is a pulmonary disease selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), pulmonary fibrosis, and pulmonary arterial hypertension (PAH). EXAMPLES

[0373] For illustrative purposes, neutral compounds of formula (I), (II), or (III) are synthesized and tested in the Examples. It is understood that neutral compounds of formula (I), (II), or (III) can be converted to the corresponding pharma- ceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponifying an ester to a carboxylate salt, or by hydrolyzing an amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate salt).

[0374] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as indicated; chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using Bruker or Varian instruments with 8, 16, or 32 scans.

[0375] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as C18 2.1 x 30 mm unless otherwise stated. Injection volumes were 0.7-8.0 μl and flow rates were typically 0.8 or 1.2 ml / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100-1000 Da. Solvents were gradients of water and acetonitrile containing polymerization modifiers such as trifluoroacetic acid or ammonium carbonate (typically 0.01-0.04%).

[0376] Short description: [Table 1]

[0377] Example A. tert-Butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate [ka] Step 1: Preparation of tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate A 100 mL 3-neck round bottom flask equipped with a magnetic stirrer and flushed with Ar was charged with zinc (13.86 g, 211.94 mmol) and DMA (150 mL, anhydrous). 1,2-Dibromoethane (1.99 g, 10.6 mmol) was added slowly, followed by chlorotrimethylsilane (1.15 g, 10.6 mmol). The mixture was stirred at room temperature for 15 min, then a solution of tert-butyl 3-iodoazetidine-1-carboxylate (20.0 g, 70.65 mmol) in DMA (20 mL, anhydrous) was added dropwise. The suspension was stirred at room temperature for 1 h. A 100 mL 3-neck round bottom flask equipped with a mechanical stirrer was charged with copper(I) iodide (1.35 g, 7.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (2.88 g, 3.53 mmol), 3,6-dichloropyridazine (21.05 g, 141.29 mmol), and DMA (100 mL, anhydrous). The dark solution was degassed for 15 min. The clear zinc reagent solution above the residual solid zinc was transferred to the 100 mL flask by cannulation. The dark solution was degassed and heated to 80 °C for 16 h. The resulting mixture was diluted with brine (500 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were washed with water (2 x 200 mL) and brine (200 mL) and subsequently dried over sodium sulfate. The solution was concentrated and the residue was purified by flash column chromatography to give tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (8.0 g, Y: 39.9%) as a pale yellow solid. ESI-MS (M+Na)+: 292. 1 H NMR (500 MHz, DMSO-d 6 )δ 7.87(d,J=8.9 Hz,1H),7.77(d,J=8.9 Hz,1H),4.31-4.17(m,2H),4.15-3.98(m,3H),1.38(s,9H).

[0378] Example B. 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine [ka] Step 1: Preparation of 5-bromo-3-(trifluoromethyl)pyridin-2-amine A suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (1.84 g, 7.64 mmol) in isopropanol (30 mL) was diluted with pyridine (60.46 mg, 764.36 μmol, 60.0 μl, 0.1 equiv.), 4-methylbenzene-1-sulfonic acid hydrate (145.39 mg, 764.36 μmol, 1-bromo-2,2-dimethoxypropane (1.68 g, 9. The mixture was treated with 6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (1.6 g, Y: 71.3%). ESI-MS (M+H)+: 280.0.

[0379] Step 2: Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine A solution of 6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (1.8 g, 6.45 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.8 g, 7.1 mmol), potassium acetate (1.9 g, 19.35 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (263.43 mg, 322.58 μmol) in dioxane (25 mL) was degassed and purged with Ar. The resulting mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, concentrated in vacuo and the crude 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine (2.75 g) was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.01(s,1H),7.89(s,1H),7.56(s,1H),2.37(s,3H),1.31(s,12H).

[0380] Example C. 7-Methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole [ka] Step 1: Preparation of 5-bromo-7-methoxy-2-methyl-2H-indazole To a solution of 5-bromo-7-methoxy-1H-indazole (500.11 mg, 2.2 mmol) in 10 ml of EtOAc, trimethyloxidanium tetrafluoroborane (977.32 mg, 6.61 mmol) was added at room temperature under stirring. The solution was stirred at room temperature for 2 days. The mixture was poured into saturated NaHCO3 (15 ml), the organic layer was separated, dried under Na2SO4 and evaporated to dryness to give crude 5-bromo-7-methoxy-2-methyl-2H-indazole (460.0 mg, Y: 85%). ESI-MS (M+H)+: 242.0. 1 H NMR (500 MHz, DMSO-d 6 )δ 8.24(s,1H),7.45(s,1H),6.66(s,1H),4.11(s,3H),3.89(s,3H).

[0381] Step 2: Preparation of 7-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole A solution of 5-bromo-7-methoxy-2-methyl-2H-indazole (460.0 mg, 1.91 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (484.7 mg, 1.91 mmol), potassium acetate (561.98 mg, 5.73 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (77.94 mg, 95.44 μmol) in dioxane (15 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was evaporated to give crude 7-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (600.0 mg, Y: 87.3%). ESI-MS (M+H)+: 289.2. 1 H NMR (400 MHz, DMSO-d 6)δ 8.32(s,1H),7.70(s,1H),4.14(s,3H),3.89 s,3H),1.30(s,12H).

[0382] Example 1. 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)phenol, HCl. (Compound 1) [ka] Step 1: Synthesis of 2-bromo-5-iodophenol [ka] To a solution of 5-amino-2-bromophenol (50.0 g, 265.9 mmol) in 400 mL of 2.5 M hydrochloric acid, a solution of sodium nitrite (18.78 g, 272.2 mmol) in water (120 mL) was added dropwise at 0° C. After 15 min, a solution of potassium iodide (49.3 g, 2967 mmol) in water (100 mL) was added dropwise and the whole mixture was heated at 60° C. for 1 h. The resulting mixture was extracted with MTBE (2×300 mL). The organic phase was diluted with Na 2 SO 4 Drying at rt and concentration under reduced pressure gave a brown liquid which was purified by flash chromatography to give 2-bromo-5-iodophenol (60.0 g, 172.6 mmol, 75% yield).

[0383] Step 2: Synthesis of 1-bromo-4-iodo-2-(methoxymethoxy)benzene [ka]

[0384] A mixture of 2-bromo-5-iodophenol (30 g, 100 mmol), potassium carbonate (41.4 g, 300 mmol) and MOM-Cl (24.15, 300 mmol) in DMF (400 mL) was stirred at room temperature for 48 h. The reaction mixture was then diluted with water (1000 mL) and extracted with MTBE (2×600 mL). The organic phase was washed with water and brine and diluted with Na 2 SO 4 Drying at rt and concentration under reduced pressure gave a brown liquid which was purified by flash chromatography to give 1-bromo-4-iodo-2-(methoxymethoxy)benzene (21 g, 61 mmol, 61% yield).

[0385] Step 3: Synthesis of 6-(4-bromo-3-(methoxymethoxy)phenyl)-8-fluoro-2-methylimidazo[1,2-a]pyridine [ka]

[0386] Pd(dppf)Cl 2 A portion of (950 mg, 1.2 mmol) was added to a suspension of 1-bromo-4-iodo-2-(methoxymethoxy)benzene (4 g, 11.7 mmol), 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (3.87 g, 14 mmol), and potassium carbonate (3.31 g, 24 mmol) in 100 mL of dioxane and 2 mL of water. The mixture was stirred at 80° C. for 12 h. After cooling, the solid was collected by filtration and washed with EtOAc. The filtrate was concentrated and partitioned between EtOAc and water. The organic layer was washed with brine and sodium hydroxide. 2 SO 4 Drying at 40° C. and concentration gave the crude product which was purified by column chromatography to give 6-(4-bromo-3-(methoxymethoxy)phenyl)-8-fluoro-2-methylimidazo[1,2-a]pyridine (2 g, 5.5 mmol, 47% yield).

[0387] Step 4: Synthesis of 8-fluoro-6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-a]pyridine [ka]

[0388] 6-(4-bromo-3-(methoxymethoxy)phenyl)-8-fluoro-2-methylimidazo[1,2-a]pyridine (2 g, 5.5 mmol), bis(pinacolato)diboron (1.39 g, 5.5 mmol), potassium acetate (1.61 g, 16 mmol), and Pd(dppf)Cl in dioxane (20 mL). 2 (450 mg, 0.55 mmol) was stirred at 80° C. (under Ar atmosphere) for 12 h. It was then concentrated and treated with EtOAc / water. The extract was dried and evaporated to give the crude material, which was purified by column chromatography to give 8-fluoro-6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-a]pyridine (1.1 g, 2.6 mmol, 46% yield).

[0389] Step 5: Synthesis of tert-butyl 3-(6-(4-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate [ka]

[0390] Pd(dppf)Cl 2A portion of (70 mg, 85.77 μmol) was added to a suspension of 8-fluoro-6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-a]pyridine (350 mg, 0.82 mmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (170 mg, 0.63 mmol), and potassium carbonate (355.6 mg, 2.57 mmol) in dioxane (10 mL) and water (1 mL). The mixture was stirred at 80° C. for 12 h. After cooling, the solid was collected by filtration and washed with EtOAc. The filtrate was concentrated and partitioned between EtOAc and water. The organic layer was washed with brine and diluted with Na 2 SO 4 Drying at 40° C. and concentration gave the crude product, which was purified by column chromatography to give tert-butyl 3-(6-(4-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (50.0 mg, 0.096 mmol, 15% yield).

[0391] Step 6: 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)phenol, HCl

[0392] tert-Butyl 3-(6-(4-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (45 mg, 86.5 μmol) was suspended in 0.5 mL of dioxane / HCl (10%) and stirred for 12 h. It was then evaporated to dryness to give 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)phenol (26 mg, 65.5 μmol, 76%). 1 H NMR (400 MHz, DMSO-d 6)δ 2.44(s,3H),4.35(m,4H),4.44(m,1H),7.44(m,2H),7.96(d,1H),8.06(s,1H),8.1 1(d,1H),8.20(d,1H),8.60(d,1H),9.04(s,1H),9.14(s,1H),9.30(s,1H).LC-HRMS C 21 H 18 FN 5 Calculated for O: m / z = 375.15, found 374.1.0 (M-1).

[0393] Example 2. 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methylimidazo[1,2-a]pyridin-6-yl)phenol, HCl. (Compound 2) [ka] Step 1: Synthesis of 6-(4-bromo-3-(methoxymethoxy)phenyl)-2-methylimidazo[1,2-a]pyridine [ka]

[0394] Pd(dppf)Cl 2 A portion of (0.95 g, 1.2 mmol) was added to a suspension of 1-bromo-4-iodo-2-(methoxymethoxy)benzene (4 g, 11.7 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (3.6 g, 14 mmol) and potassium carbonate (3.3 g, 24 mmol) in dioxane (100 mL) and water (2 mL). The mixture was stirred at 80° C. for 12 h. After cooling, the solid was collected by filtration and washed with EtOAc. The filtrate was concentrated and partitioned between EtOAc and water. The organic layer was washed with brine and sodium hydroxide. 2 SO 4Drying at 40° C. and concentration gave the crude product which was purified by column chromatography to give 6-(4-bromo-3-(methoxymethoxy)phenyl)-2-methylimidazo[1,2-a]pyridine (1.6 g, 4.6 mmol, 42% yield).

[0395] Step 2: Synthesis of 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-a]pyridine [ka]

[0396] 6-(4-bromo-3-(methoxymethoxy)phenyl)-2-methylimidazo[1,2-a]pyridine (1.6 g, 4.6 mmol), bis(pinacolato)diboron (1.17 g, 4.6 mmol), potassium acetate (1.37 g, 14 mmol), and Pd(dppf)Cl in dioxane (20 mL). 2 (375 mg, 0.46 mmol) was stirred at 80° C. (under Ar atmosphere) for 12 h. The reaction mixture was then concentrated and treated with EtOAc / water. The extract was dried and evaporated to give the crude material, which was purified by column chromatography to give 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-a]pyridine (0.9 g, 2.3 mmol, 50% yield).

[0397] Step 3: Synthesis of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methylimidazo[1,2-a]pyridin-6-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate [ka]

[0398] Pd(dppf)Cl 2A portion of (70 mg, 85.8 μmol) was added to a suspension of 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-a]pyridine (350 mg, 1 mmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (216 mg, 0.8 mmol), and potassium carbonate (355.6 mg, 2.57 mmol) in dioxane (10 mL) and water (1 mL). The mixture was stirred at 80° C. for 12 h. After cooling, the solid was collected by filtration and washed with EtOAc. The filtrate was concentrated and partitioned between EtOAc and water. The organic layer was washed with brine and diluted with Na 2 SO 4 Drying at 40° C. and concentration gave the crude product which was purified by column chromatography to give tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methylimidazo[1,2-a]pyridin-6-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (98 mg, 0.195 mmol, 24% yield).

[0399] Step 4: 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methylimidazo[1,2-a]pyridin-6-yl)phenol, HCl

[0400] tert-Butyl 3-(6-(2-(methoxymethoxy)-4-(2-methylimidazo[1,2-a]pyridin-6-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (61 mg, 121 μmol) was suspended in 0.5 ml of dioxane / HCl (10%) and stirred for 12 h. It was then evaporated to dryness to give 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methylimidazo[1,2-a]pyridin-6-yl)phenol, HCl (59 mg, 149.7 μmol). 1 H NMR (400 MHz, DMSO-d 6)δ 2.52(s,3H),4.35(m,4H),4.45(m,1H),7.43(d,1H),7.47(s,1H),7.99(d,2H),8.10(s,1H) ),8.22(d,1H),8.29(d,1H),8.59(d,1H),9.26(s,1H),9.38(s,1H),9.61(s,1H).LC-HRMS C 21 H 19 N 5 Calculated for O: m / z = 357.18, found 358.0 (M+1).

[0401] Example 3. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-{2,8-dimethylimidazo[1,2-b]pyridazin-6-yl}phenol (compound 3) [ka] Step 1: Preparation of 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine hydrobromide To a suspension of 6-chloro-4-methylpyridazin-3-amine (1.35 g, 9.44 mmol) in EtOH (30 mL) was added 1-bromopropan-2-one (2.59 g, 18.88 mmol). The reaction mixture was stirred at 85° C. overnight. The mixture was cooled to room temperature. After concentration, the mixture was diluted with EtOH (5 mL) and EtOAc (30 mL), the mixture was filtered, and the solid was dried under vacuum to give the title product (750 mg, Y: 30%) as a light grey solid. ESI-MS (M+H)+: 182.0. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.03(s,1H),7.19(s,1H),2.53(s,3H),2.38(s,3H).

[0402] Step 2: Preparation of (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid 6-Chloro-2,8-dimethylimidazo[1,2-b]pyridazine hydrobromide (590 mg, 3.26 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (869 mg, 3.42 mmol), KOAc (639 mg, 6.52 mmol), and Pd(dppf)Cl in dioxane (18 mL). 2 A mixture of (238 mg, 0.326 mmol) was added to N 2 The mixture was purged at room temperature for three times with 500 ml of ethyl acetate. The reaction mixture was then stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was used in the next step without further purification. ESI-MS (M+H)+: 192.0.

[0403] Step 3: Preparation of 6-(4-bromo-3-(methoxymethoxy)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine (2,8-Dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (422 mg, 2.22 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (777 mg, 2.26 mmol), K 2 CO 3 (919 mg, 6.66 mmol), and Pd(dppf)Cl 2 A mixture of (161 mg, 0.22 mmol) was added to N 2 The mixture was stirred at 80° C. for 1 h under reduced pressure. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:5) to give the title product (1.0 g, Y: 84%) as a pale yellow solid. ESI-MS (M+H)+: 362.0, 364.0.

[0404] Step 4: Preparation of 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine 6-(4-bromo-3-(methoxymethoxy)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine (500 mg, 1.385 mmol), bis(pinacolato)diboron (422 mg, 1.662 mmol), potassium acetate (272 mg, 2.770 mmol) and Pd(dppf)Cl in dioxane (10 mL). 2 A mixture of (102 mg, 0.139 mmol) was stirred at 100° C. (under Ar atmosphere) for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was used in the next step without further purification. ESI-MS (M+H)+: 410.2

[0405] Step 5: Preparation of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate To the above solution, HO (1.5 mL), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (403 mg, 1.5 mmol), K 2 CO 3 (345 mg, 2.5 mmol), and Pd(dppf)Cl 2 (92 mg, 0.125 mmol) was added. The resulting mixture was diluted with N 2 The mixture was stirred at 100° C. for 2 h under reduced pressure. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:10, v / v) to give the title product (255 mg, Y: 36%) as a yellow solid. ESI-MS (M+H)+: 517.2.

[0406] Step 6: Preparation of 6-(4-(6-(azetidin-3-yl)pyridazin-3-yl)-3-(methoxymethoxy)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine To a solution of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (220 mg, 0.426 mmol) in DCM (10 mL) was added HCl in dioxane (1.1 mL) at 0° C. The mixture was stirred at room temperature overnight. After concentration, the residue was treated with DCM (10 mL) and the solvent was removed again. The crude was purified by preparative HPLC (0.05% HCl in ACN) to give the title product (3.0 mg, Y: 15%) as a pale yellow solid. ESI-MS (M+H)+: 373.4. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.64(br s,1H),9.30(br s,1H),8.59(d,J=9.0 Hz,1H),8.55(s,1H),8.39(s,1H),8.24(d,J=8.3 Hz,1H),8.01(d,J=9.0 Hz,1H),7.83(d,J=1.5 Hz,1H),7.76(d,J=8.3 Hz,1H),4.47(d,J=8.9 Hz,2H),4.36(d,J=6.7 Hz,3H),2.77(s,3H),2.59(s,3H).

[0407] Example 4. Synthesis of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)phenol hydrochloride (compound 4) [ka] Step 1: Preparation of 6-bromo-2,8-dimethylimidazo[1,2-a]pyridine HBr salt To a suspension of 5-bromo-3-methylpyridin-2-amine (2.0 g, 10.70 mmol) in IPA (20 mL) was added 1-bromopropan-2-one (2.9 g, 21.39 mmol). The reaction mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature. After concentration, the mixture was added EtOH (5 mL) and EtOAc (30 mL) and filtered to give the title product (2.8 g, Y: 86%) as a grey solid. ESI-MS (M+H)+: 226.8.1 H NMR (400 MHz, DMSO-d 6 )δ 9.13(s,1H),8.05(d,J=0.8 Hz,1H),7.96(s,1H),2.57(s,3H),2.51(d,J=0.4 Hz,3H).

[0408] Step 2: Preparation of (2,8-dimethylimidazo[1,2-a]pyridin-6-yl)boronic acid 6-Bromo-2,8-dimethylimidazo[1,2-a]pyridine (680 mg, 2.22 mmol, HBr salt) in dioxane (20 mL), B 2 Pin 2 (593 mg, 2.33 mmol), KOAc (653 mg, 6.66 mmol) and Pd(dppf)Cl 2 A mixture of (161 mg, 0.22 mmol) was added to N 2 The mixture was purged at room temperature for three times with 500 ml of ethyl acetate. The reaction mixture was then heated to 80° C. for 1 h. LCMS showed that no starting material remained and the desired product had formed. The reaction was stopped and cooled to room temperature. The mixture was filtered and the filtrate was used in the next step without further purification. ESI-MS (M+H)+: 191.2

[0409] Step 3: Preparation of 6-(4-bromo-3-(methoxymethoxy)phenyl)-2,8-dimethylimidazo[1,2-a]pyridine (2,8-Dimethylimidazo[1,2-a]pyridin-6-yl)boronic acid (crude from above step, 2.22 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (777 mg, 2.26 mmol), K 2 CO 3 (919 mg, 6.66 mmol) and Pd(dppf)Cl 2 A mixture of (161 mg, 0.22 mmol) was added to N 2 The mixture was stirred at 80° C. for 1 h under reduced pressure. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:5) to give the title product (350 mg, Y: 59%) as a red solid. ESI-MS (M+H)+: 363.11 H NMR (400 MHz, CDCl 3 )δ 8.08(s,1H),7.60(d,J=8.2 Hz,1H),7.37(s,1H),7.31(d,J=2.0 Hz,1H),7.12(s,1H),7.12-7.05(m,1H),5.33(s,2H),3.56(s,3H),2.65(s,3H),2.49(s,3H).

[0410] Step 4: Preparation of (4-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(methoxymethoxy)phenyl)boronic acid 6-(4-bromo-3-(methoxymethoxy)phenyl)-2,8-dimethylimidazo[1,2-a]pyridine (300 mg, 0.83 mmol), bis(pinacolato)diboron (232 mg, 0.91 mmol), potassium acetate (244 mg, 2.49 mmol), and Pd(dppf)Cl in dioxane (20 mL). 2 (61 mg, 0.083 mmol) was stirred at 80° C. (under Ar atmosphere) for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was used in the next step without further purification. ESI-MS (M+H)+: 327.0

[0411] Step 5: Preparation of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate To the above solution, 2 O (5 mL), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (245 mg, 0.91 mM), K 2 CO 3 (344 mg, 2.49 mmol), and Pd(dppf)Cl 2 (61 mg, 0.083 mmol) was added. The resulting mixture was diluted with N 2The mixture was stirred at 80° C. for 1 h under reduced pressure. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title product (90 mg, Y: 21%, in two steps) as a yellow solid. ESI-MS (M+H)+: 516.2 1 H NMR (400 MHz, CDCl 3 )δ 8.18(s,1H),8.08(t,J=8.1 Hz,2H),7.52(d,J=8.9 Hz,1H),7.44(d,J=1.5 Hz,1H),7.41-7.36(m,2H),7.23(s,1H),5.30(d,J=3.2 Hz,2H),4.44(t,J=8.6 Hz,2H),4.29(s,1H),4.12(dd,J=14.3,7.1 Hz,2H),3.49(s,3H),2.68(s,3H),2.51(s,3H),1.48(s,9H).

[0412] Step 6: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)phenol hydrochloride To a solution of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (80 mg, 0.155 mmol) in DCM (5 mL) was added HCl in dioxane (1 mL) at 0° C. The mixture was stirred at 0° C. to room temperature overnight. The reaction mixture was concentrated to dryness. The residue was treated with DCM (5 mL) and co-evaporated again. The crude was purified by preparative HPLC (0.05% HCl in ACN) to give the title product (3.0 mg, Y: 5%) as a yellow solid. ESI-MS (M+H)+: 372.1. 1 H NMR (400 MHz, DMSO-d 6)δ 8.81(s,1H),8.57(d,J=9.1 Hz,1H),8.37(s,1H),8.14(d,J=8.2 Hz,1H),7.97(d,J=9.0 Hz,1H),7.70(s,1H),7.43(s,1H),7.35(d,J=8.0 Hz,2H),4.35(d,J=7.6 Hz,1H),4.17(d,J=7.6 Hz,4H),2.53(s,3H),2.36(s,3H).

[0413] Example 5. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenol (Compound 5) [ka] Step 1: Synthesis of 5-bromo-3-(trifluoromethyl)pyridin-2-amine To a mixture of 3-(trifluoromethyl)pyridin-2-amine (3 g, 18.52 mmol) in ACN (30 mL) was added NBS (4.0 g, 22.22 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated Na 2 CO 3 The mixture was adjusted to pH=8 with aqueous solution and extracted with EtOAc (50 mL×3). The organic layer was concentrated. The residue was purified by silica gel column chromatography (PE:EA=10:1) to give the title product (2.8 g, Y: 63%) as a yellow solid. ESI-MS (M+H)+: 241.0. 1 H NMR(400 MHz,DMSO)δ 8.28(d,J=1.7 Hz,1H),7.91(d,J=2.0 Hz,1H),6.73(s,2H).

[0414] Step 2: Synthesis of 6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine To a suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (2.8 g, 11.62 mmol) in EtOH (25 mL) was added 1-bromopropan-2-one (3.2 g, 23.23 mmol). The reaction mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature and a precipitate formed. The mixture was filtered to give the title product (2.4 g, Y: 74%) as a grey solid. ESI-MS (M+H)+: 278.9. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.51(s,1H),8.39(s,1H),8.16(d,J=0.8 Hz,1H),2.51(d,J=0.7 Hz,3H).

[0415] Step 3: Synthesis of (2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)boronic acid 6-Bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (500 mg, 1.79 mmol) in dioxane (15 mL), B 2 Pin 2 (477 mg, 1.88 mmol), KOAc (526 mg, 5.37 mmol) and Pd(dppf)Cl 2 A mixture of (132 mg, 0.18 mmol) was added to N 2 The mixture was purged at room temperature for three times with 500° C. The reaction mixture was then stirred at 80° C. for 1 h. The mixture was filtered and the filtrate was used in the next step without further purification. ESI-MS (M+H)+: 245.0

[0416] Step 4: Synthesis of 6-(4-bromo-3-(methoxymethoxy)phenyl)-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine H 2 (2-Methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)boronic acid (solution from above step), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (737 mg, 2.15 mmol), K 2 CO 3(741 mg, 5.37 mmol), and Pd(dppf)Cl 2 A mixture of (132 mg, 0.18 mmol) was added to N 2 The mixture was stirred at 80° C. for 1 h under reduced pressure. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:5) to give the title product (420 mg, Y: 57%) as a yellow oil. ESI-MS (M+H)+: 414.9 1 H NMR (400 MHz, DMSO-d 6 )δ 9.13(s,1H),7.91-7.89(m,2H),7.72(d,J=8.3 Hz,1H),7.56(d,J=2.0 Hz,1H),7.34(dd,J=8.3,2.0 Hz,1H),5.45(s,2H),3.46(s,3H),2.41(s,3H).

[0417] Step 5: Synthesis of 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine 6-(4-bromo-3-(methoxymethoxy)phenyl)-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (400 mg, 0.96 mmol), bis(pinacolato)diboron (257 mg, 1.01 mmol), potassium acetate (282 mg, 2.88 mmol) and Pd(dppf)Cl in dioxane (20 mL). 2 A mixture of (70 mg, 0.1 mmol) was stirred at 80° C. (under Ar atmosphere) for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was used in the next step without further purification. ESI-MS (M+H)+: 463.0.

[0418] Step 6: Synthesis of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate To the above solution, 2O (2 mL), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (259 mg, 0.96 mmol), K 2 CO 3 (397 mg, 2.88 mmol), and Pd(dppf)Cl 2 (70 mg, 0.096 mmol) was added. The resulting mixture was diluted with N 2 The mixture was stirred at 80° C. for 1 h under reduced pressure. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title product (130 mg, Y: 24%, in two steps) as a yellow solid. ESI-MS (M+H)+: 570.2.

[0419] Step 7: Synthesis of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)phenol hydrochloride To a solution of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (120 mg, 0.21 mmol) in DCM (10 mL) was added HCl in dioxane (2 mL) at 0° C. The mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by preparative HPLC to give the title product (6.4 mg, Y: 10%) as a white solid. ESI-MS (M+H)+: 426.4 1 H NMR(400 MHz,MeOD)δ 9.46(s,1H),8.72-8.62(m,2H),8.24(d,J=0.8 Hz,1H),8.14-8.12(m,2H),7.56-7.50(m,2H),4.63-4.52(m,5H),2.65(s,3H).

[0420] Example 6. Synthesis of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,7-dimethyl-2H-indazol-5-yl)phenol hydrochloride (compound 6) [ka] Step 1: Preparation of 5-(4-bromo-3-(methoxymethoxy)phenyl)-2,7-dimethyl-2H-indazole Dioxane:H 2 To a mixture of 2,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (5.30 g, 19.48 mmol) and 1-bromo-4-iodo-2-(methoxymethoxy)benzene (6.60 g, 19.48 mmol) in 2H2O (90 mL:15 mL) was added Pd(dppf)Cl 2 (712 mg, 0.97 mmol) and K 2 CO 3 (8.00 g, 58.34 mmol) was added. The mixture was stirred at 50° C. for 1 h. LCMS showed that the starting material was completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=1:1) to give the title product (4.0 g, Y: 58%) as a brown solid. ESI-MS (M+H+): 363.0. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.36(s,1H),7.85-7.69(d,J=13.9 Hz,1H),7.70-7.59(s,1H),7.51-7.45(s,1H),7.33(s,1H),7.28-7.19(m,1H),5.38(s,2H),4.18(s,3H),3.43(s,3H),2.55(s,3H).

[0421] Step 2: Preparation of 5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,7-dimethyl-2H-indazole 5-(4-bromo-3-(methoxymethoxy)phenyl)-2,7-dimethyl-2H-indazole (4.00 g, 11.11 mmol) in dioxane (200 mL) and B 2 pin 2 To a mixture of (28.00 g, 111.11 mmol) Pd(dppf)Cl 2(406 mg, 0.55 mmol) and KOAc (8.70 g, 88.88 mmol) were added. The mixture was stirred at 110° C. for 16 h. LCMS showed that the starting material was completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (PE:EA=1:1) to give the title product (1.6 g, Y: 35.5%) as a brown solid. ESI-MS (M+H+): 409.0. 1 H NMR (400 MHz, CDCl 3 )δ 7.91(s,1H),7.76(d,J=7.5 Hz,1H),7.68(s,1H),7.31(d,J=1.5 Hz,1H),7.29(d,1H),7.26(s,1H),5.28(s,2H),4.25(s,3H),3.56(s,3H),2.68(s,3H),1.37(s,12H).

[0422] Step 3: Preparation of tert-butyl 3-(6-(4-(2,7-dimethyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate Dioxane:H 2 To a mixture of 5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,7-dimethyl-2H-indazole (1.60 g, 3.92 mmol) and tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (1.06 g, 3.92 mmol) in 2H2O (63 mL:9 mL) was added Pd(dppf)Cl 2 (196 mg, 0.20 mmol) and K 2 CO 3 (1.62 g, 11.76 mmol) was added. The mixture was stirred at 80° C. for 2 h. LCMS showed that the starting material was completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=40:1) to give the title product (1.40 g, Y: 70%) as a yellow solid. ESI-MS (M+H+): 516.2. 1H NMR (400 MHz, CDCl 3 )δ 8.10-8.05(m,2H),7.95(d,J=4.1 Hz,1H),7.75-7.72(m,1H),7.51(d,J=8.8 Hz,2H),7.39-7.34(m,2H),5.31(s,2H),4.48-4.37(m,3H),4.27(s,3H),4.21-4.09(m,2H),3.49(s,3H),2.70(s,3H),1.48(s,9H).

[0423] Step 4: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)phenol hydrochloride A mixture of tert-butyl 3-(6-(4-(2,7-dimethyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (1.30 g, 2.52 mmol) in TFA (15 mL) was stirred at room temperature for 16 h. LCMS showed that the starting material was completely consumed. The mixture was concentrated in vacuo and the crude was purified by preparative HPLC to give the title product (500 mg, Y: 54%) as a yellow solid. ESI-MS (M+H+): 372.1. 1 H NMR (400 MHz, MeOD-d 4 )δ 9.02-8.88(m,2H),8.51(d,J=8.9 Hz,1H),8.17(s,1H),8.00(d,J=8.2 Hz,1H),7.91(s,1H),7.53(d,J=8.1 Hz,1H),7.47(s,1H),4.75-4.67(m,1H),4.63-4.54(m,4H),4.47(s,3H),2.72(s,3H).

[0424] Example 7. 5-{4-[6-(azetidin-3-yl)pyridazin-3-yl]-3-hydroxyphenyl}-1,3-dimethyl-1,2-dihydropyridin-2-one (compound 7) [ka] Step 1: Preparation of 4-bromo-2-methoxy-6-methylaniline hydrobromide A solution of 2-methoxy-6-methylaniline (25 g, 182 mmol) in MeOH (250 mL) was diluted with Br in AcOH (50 mL). 2 (29.25 g, 182 mmol) was added dropwise at room temperature and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (1000 mL) and stirred for 5 min. The solid was collected by filtration and washed with EtOAc (100 mL x 2) to give the title compound (44.4 g, 83% yield) as a pink solid. ESI-MS (M+H)+: 216.0.

[0425] Step 2: Preparation of 5-bromo-7-methoxy-1H-indazole CHCl 3 To a solution of 4-bromo-2-methoxy-6-methylaniline hydrobromide (10 g, 46.512 mmol) in 10 mL of KOAc (5.47 g, 55.814 mmol), Ac 2 O (18.977 g, 186.048 mmol) was added and the mixture was stirred at room temperature for 1 h and then at 70° C. for 2 h. ter-Butyl-nitrile (9.6 g, 93.024 mmol) and 18-crown-6 (982 mg, 3.721 mmol) were added and the solution was stirred at 70° C. for 16 h. The mixture was then cooled to 5° C. with 100% CO. 2 CO 3 Aqueous solution (38.512 g, 279.072 mmol) was added and stirred at room temperature for 5 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (200 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 Drying at rt and evaporation afforded the title compound as a grey solid (8.7 g, Y: 83%). ESI-MS (M+H)+: 226.9.

[0426] Step 3: Preparation of 5-bromo-7-methoxy-2-methyl-2H-indazole To a solution of 5-bromo-7-methoxy-1H-indazole (45 g, crude) in DMF (250 mL) was added Cs 2 CO 3(108 g, 331.85 mmol) was added and after 15 min, MeI (24 g, 165.93 mmol) was added and the mixture was stirred at 45° C. for 5 h. The reaction mixture was diluted with water (1300 mL) and extracted with EtOAc (1300 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 The crude was purified by silica gel column chromatography eluted with (EtOAc / PE=50%-100%) to give the title compound (6.03 g, 11% yield) as a brown solid. ESI-MS (M+H)+: 241.9. 1 H NMR (400 MHz, CDCl 3 )δ 7.79(s,1H),7.37(d,J=1.2 Hz,1H),6.63(d,J=1.0 Hz,1H),4.19(s,3H),4.00(s,3H).

[0427] Step 4: Preparation of 7-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 5-Bromo-7-methoxy-2-methyl-2H-indazole (6.03 g, 25 mmol) in 1,4-dioxane (250 mL), B 2 pin 2 (16 g, 62.5 mmol), KOAc (8.6 g, 87.5 mmol), and Pd(dppf)Cl 2 (1.83 g, 2.5 mmol) was added and the mixture was treated with N 2 Fill three times with N 2 The mixture was stirred under reduced pressure at 100° C. for 2 h. The reaction mixture was used in the next step without further purification. ESI-MS (M+H)+: 288.7.

[0428] Step 5: Preparation of 5-(4-bromo-3-(methoxymethoxy)phenyl)-7-methoxy-2-methyl-2H-indazole A mixture of 7-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (6.5 g, 22.56 mmol) in 1,4-dioxane (230 mL) was diluted with 1-bromo-4-iodo-2-(methoxymethoxy)benzene (10 g, 29.34 mmol), Pd(dppf)Cl 2 (1.642g, 2.25mmol), K 2 CO 3 (9.344 g, 67.70 mmol) and water (38 mL) were added and the mixture was rinsed with N 2 The mixture was charged with 3 portions of ethyl acetate and stirred at 100° C. for 16 h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (200 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 Drying at 40° C. and evaporation gave the crude title compound. The crude was purified by silica gel column chromatography (PE:EA=5:1 to 1:1) to give the title product (5 g, Y: 8.8%, in two steps) as a brown solid. ESI-MS (M+H)+: 378.9. 1 H NMR (400 MHz, CDCl 3 )δ 7.89(s,1H),7.59(d,J=8.2 Hz,1H),7.40(d,J=2.1 Hz,1H),7.36(d,J=1.3 Hz,1H),7.17-7.14(m,1H),6.73(d,J=1.2 Hz,1H),5.33(s,2H),4.23(s,3H),4.07(s,3H),3.57(s,3H).

[0429] Step 6: Preparation of 7-methoxy-5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-2H-indazole 5-(4-bromo-3-(methoxymethoxy)phenyl)-7-methoxy-2-methyl-2H-indazole (2.27 g, 6.04 mmol) in 1,4-dioxane (80 mL), B 2 pin 2 To a mixture of (3.06 g, 12.07 mmol) Pd(dppf)Cl 2(438 mg, 0.604 mmol) and KOAc (1.78 g, 18.12 mmol) were added and the mixture was cooled to 5° C. 2 Fill three times with N 2 The mixture was stirred under reduced pressure at 85° C. for 8 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 Drying at 40° C. and evaporation gave the crude title compound. The crude was purified by silica gel column chromatography (PE:EA=4:1 to 1:1) to give the title product (2.88 g, crude) as a brown oil. ESI-MS (M+H)+: 425.2

[0430] Step 7: Preparation of tert-butyl 3-(6-(4-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate 1,4-Dioxane: 7-Methoxy-5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-2H-indazole (2.68 g, 6.32 mmol) and tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (1.87 g, 6.95 mmol) in HO (67 mL:13 mL) and K 2 CO 3 To a mixture of (2.62 g, 18.96 mmol) Pd(dppf)Cl 2 (461 mg, 0.632 mmol) was added. The mixture was diluted with N 2 The mixture was stirred at 80° C. for 2 h under reduced pressure. The mixture was cooled to room temperature, concentrated under reduced pressure, water (100 mL) was added, extracted with EA (100 mL×3), and the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=2:1 to 1:3) to give the title product (2.43 g, Y: 68%) as a white solid. ESI-MS (M+H)+: 532.2. 1 H NMR (400 MHz, CDCl 3)δ 8.09(d,J=1.2 Hz,1H),8.07(s,1H),7.92(s,1H),7.51(d,J=8.7 Hz,2H),7.47-7.45(m,2H),6.84(d,J=0.9 Hz,1H),5.31(s,2H),4.43(t,J=8.6 Hz,2H),4.32-4.28(m,2H),4.25(s,3H),4.17-4.13(m,1H),4.10(s,3H),3.48(s,3H),1.48(s,9H).

[0431] Step 8: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(7-methoxy-2-methyl-2H-indazol-5-yl)phenol To a solution of tert-butyl 3-(6-(4-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (2.2 g, 4.143 mmol) in DCM (15 mL) was added TFA (15 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (60 mL), concentrated in vacuo, and lyophilized to give the title product (3.0 g, crude) as an orange solid. 200 mg of the crude was purified by preparative HPLC (0.05% FA / CH in water). 3 CN) to give the title product (30 mg, 25%) as a yellow solid. ESI-MS (M+H)+: 388.2. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.55(d,J=8.0 Hz,1H),8.38-8.36(m,2H),8.10(d,J=8.0 Hz,1H),7.95(d,J=8.0 Hz,1H),7.60(s,1H),7.37-7.36(m,2H),6.93(s,1H),4.45-4.32(m,1H),4.16(s,3H),4.15-4.13(m,4H),4.02(s,3H).

[0432] Example 8. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-4-fluoro-5-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}phenol (compound 8) [ka] Step 1: Preparation of 2-bromo-5-chloro-4-fluorophenol A 0.5 L reaction flask was charged with 3-chloro-4-fluorophenol (10.0 g, 68.24 mmol) and chloroform (200 mL) and cooled to -10 °C. Bromine (12 g, 75 mmol, 3.9 mL) was added, maintaining the temperature of the solution in the reaction flask below 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 3 h. Then, saturated NaHSO 3 Aqueous solution (100 mL) was added to the reaction solution, the organic layer was separated, and anhydrous Na 2 SO 4 The extract was washed with saturated aqueous NaCl (100 mL), dried over 1000 cc and concentrated to dryness under reduced pressure to give crude 2-bromo-5-chloro-4-fluorophenol (12.46 g, Y: 99.7%), which was used in the next step without purification. 1 H NMR (500 MHz, DMSO-d 6 )δ 10.57(s,1H),7.57(d,J=8.8 Hz,1H),7.00(d,J=6.8 Hz,1H).

[0433] Step 2: Preparation of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene 2-Bromo-5-chloro-4-fluorophenol (5.9 g, 26.17 mmol) was dissolved in anhydrous CH 2 Cl 2 (150 mL). Ethyl bis(propan-2-yl)amine (4.06 g, 31.41 mmol) was then added at room temperature. The mixture was cooled to 0° C. and chloro(methoxy)methane (2.53 g, 31.41 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 11 h. The resulting mixture was then diluted with saturated NaHCO 3 Quench with aqueous solution (250 mL), separate the organic layer, wash with brine (200 mL) and add anhydrous Na 2 SO 4The solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (eluent Hex / EtOAc 30 / 1, Rf approx. 0.4) to give 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene (1.58 g, Y: 23.1% yield) as a white solid. 1 H NMR (500 MHz, chloroform-d) δ 7.36 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 6.7 Hz, 1H), 5.19 (s, 2H), 3.52 (s, 3H).

[0434] Step 3: Preparation of 2-[4-chloro-5-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene (1.58 g, 5.86 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.49 g, 5.86 mmol), potassium acetate (1.73 g, 17.59 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (239.4 mg, 293.15 μmol) in DMSO (20 mL) was degassed and purged with Ar. The reaction mixture was heated at 90° C. overnight. The resulting mixture was poured into ice water (40 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (15 mL) and concentrated with Na 2 SO 4 Drying at 40° C. and evaporation under reduced pressure gave the crude, which was purified by column chromatography using Hex / EtOAc (8 / 1) as the eluent to give 2-[4-chloro-5-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900.0 mg, Y: 43.6%) as a yellow oil. 1 H NMR (500 MHz, DMSO-d 6 )δ 7.37(d,J=8.2,1H),7.28(d,J=6.7,1H),5.15(s,2H),3.39(s,3H),1.26(s,12H).

[0435] Step 4: Preparation of tert-butyl 3-6-[4-chloro-5-fluoro-2-(methoxymethoxy)phenyl]pyridazin-3-yl-azetidine-1-carboxylate A solution of 2-[4-chloro-5-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (450.35 mg, 1.42 mmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (383.72 mg, 1.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (58.09 mg, 71.13 μmol), and potassium carbonate (393.23 mg, 2.85 mmol) in dioxane (15 mL) and water (2 mL) was degassed and purged with Ar. The reaction mixture was heated at 90° C. overnight. The resulting mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography using Hex / EtOAc 1 / 1 as eluent to give tert-butyl 3-6-[4-chloro-5-fluoro-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (440.0 mg, Y: 65.7%). ESI-MS (M+H)+: 424.2. 1 H NMR(400MHz,chloroform-d)δ 8.01(d,J=8.8 Hz,1H),7.84(d,J=9.6 Hz,1H),7.50(d,J=8.8 Hz,1H),7.33(d,J=6.0 Hz,1H),5.15(s,2H),4.40(t,J=8.6 Hz,2H),4.27-4.18(m,2H),4.15-4.07(m,1H),3.43(s,3H),1.45(s,9H).

[0436] Step 5: Preparation of tert-butyl 3-[6-(5-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate A solution of tert-butyl 3-6-[4-chloro-5-fluoro-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (439.98 mg, 1.04 mmol), 8-fluoro-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (343.94 mg, 1.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (42.38 mg, 51.9 μmol), and cesium carbonate (1.01 g, 3.11 mmol) in dioxane (15 mL) and water (2 mL) was degassed and purged with Ar. The reaction mixture was heated at 90° C. overnight. The resulting mixture was cooled to room temperature, diluted with MTBE (15 mL), and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by preparative HPLC to give tert-butyl 3-[6-(5-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate (92.0 mg, Y: 14.8%). ESI-MS (M+H)+: 538.0.

[0437] Step 6: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-4-fluoro-5-8-fluoro-2-methylimidazo[1,2-a]-pyridin-6-ylphenol as the trifluoroacetate salt tert-Butyl 3-[6-(5-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate (91.96 mg, 171.06 μmol) was dissolved in CH 2 Cl 2(3 mL) and 2,2,2-trifluoroacetic acid (195.05 mg, 1.71 mmol) was added. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to give the crude material. The residue was triturated with MeCN / MTBE (1 / 4, 2 mL) and the resulting precipitate was filtered and dried in vacuum to give pure 2-[6-(azetidin-3-yl)pyridazin-3-yl]-4-fluoro-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol (35.0 mg, Y: 40.3%) as the trifluoroacetate salt. ESI-MS (M+H)+: 394.2. 1 H NMR (500 MHz, DMSO-d 6 )δ 12.68(s,1H),9.1-8.5(m,3H),8.2-7.8(m,3H),7.5-.7.3(m,1H),7.3-7.2(m,1H),4.55-4.25(m,5H),2.39(s,3H).

[0438] Example 9. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-{2,8-dimethylimidazo[1,2-a]pyrazin-6-yl}phenol (Compound 9) [ka] Step 1: Preparation of tert-butyl 3-(6-(4-bromo-2-methoxyphenyl)pyridazin-3-yl)azetidine-1-carboxylate To a mixture of tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (2.0 g, 7.43 mmol) in 1,4-dioxane (50 mL), (4-bromo-2-methoxyphenyl)boronic acid (1.88 g, 8.18 mmol), Pd(dppf)Cl 2 (540mg, 0.74mmol), K 2 CO 3 (3.08 g, 22.3 mmol), and water (5 mL) were added and the mixture was rinsed with N 2 The mixture was charged with 3 portions of ethyl acetate and stirred at 100° C. for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine and diluted with Na 2 SO4 The crude was purified by column chromatography eluted with (PE / EA=1:1) to give the title compound (1.2 g, 38.7% yield) as a yellow solid. ESI-MS (M+H)+: 422.1. 1 H NMR (400 MHz, CDCl 3 )δ 8.00(d,J=8.8 Hz,1H),7.89(d,J=8.3 Hz,1H),7.47(d,J=8.8 Hz,1H),7.28(dd,J=8.3,1.8 Hz,1H),7.17(d,J=1.7 Hz,1H),4.41(t,J=8.6 Hz,2H),4.33-4.20(m,2H),4.15-4.10(m,1H),3.88(s,3H),1.47(s,9H).

[0439] Step 2: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-bromophenol BBr 3 A mixture of tert-butyl 3-(6-(4-bromo-2-methoxyphenyl)pyridazin-3-yl)azetidine-1-carboxylate (1.2 g, 2.88 mmol) in (28.8 mL, 1.0 M in DCM) was stirred at room temperature for 48 h. The mixture was concentrated in vacuo to give the title compound (900 mg, crude) as a yellow solid. ESI-MS (M+H)+: 305.8.

[0440] Step 3: Preparation of tert-butyl 3-(6-(4-bromo-2-hydroxyphenyl)pyridazin-3-yl)azetidine-1-carboxylate To a mixture of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-bromophenol (900 mg, 2.95 mmol) in DCM (20 mL) was added TEA (5.96 g, 59.0 mmol) and the Boc 2 O (3.22 g, 14.75 mmol) was added dropwise to the mixture and stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4The crude was purified by column chromatography eluted with (PE / EA=2:1) ​​to give the title compound (500 mg, 41.7% yield) as a yellow solid. ESI-MS (M+H)+: 407.8. 1 H NMR (400 MHz, CDCl 3 )δ 13.74(s,1H),8.05(d,J=9.2 Hz,1H),7.66(d,J=9.1 Hz,1H),7.57(d,J=8.6 Hz,1H),7.30(d,J=2.0 Hz,1H),7.10(dd,J=8.5,2.0 Hz,1H),4.44(t,J=8.7 Hz,2H),4.27-4.18(m,2H),4.14-4.08(m,1H),1.48(s,9H).

[0441] Step 4: Preparation of tert-butyl 3-(6-(4-bromo-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate To a mixture of tert-butyl 3-(6-(4-bromo-2-hydroxyphenyl)pyridazin-3-yl)azetidine-1-carboxylate (500 mg, 1.23 mmol) in DMF (20 mL), 2 CO 3 (509 mg, 3.69 mmol) was added, and MOMBr (306 mg, 2.46 mmol) was added dropwise to the mixture and stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The organic layer was washed with brine and Na 2 SO 4 The crude was purified by column chromatography eluted with (PE / EA=2:1) ​​to give the title compound (100 mg, 18.1% yield) as a yellow solid. ESI-MS (M+H)+: 452.1. 1 H NMR (400 MHz, CDCl 3)δ 7.99(s,1H),7.86(d,J=8.3 Hz,1H),7.48(s,1H),7.44(d,J=1.8 Hz,1H),7.33(dd,J=8.3,1.8 Hz,1H),5.21(s,2H),4.41(d,J=8.6 Hz,2H),4.30-4.25(m,2H),4.12(d,J=5.1 Hz,1H),3.45(s,3H),1.47(s,9H).

[0442] Step 5: Preparation of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate tert-Butyl 3-(6-(4-bromo-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (100 mg, 0.22 mmol) in 1,4-dioxane (5 mL), B 2 pin 2 (145 mg, 0.572 mmol), KOAc (84.1 mg, 0.858 mmol), Pd(dppf)Cl 2 (21 mg, 0.029 mmol) was added and the mixture was treated with N 2 Fill three times with N 2 The mixture was stirred at 90° C. for 2 h under reduced pressure. The reaction mixture was used in the next step without further purification. ESI-MS (M+H)+: 498.3.

[0443] Step 6: Preparation of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate To a mixture of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (0.286 mmol) in 1,4-dioxane (5 mL), 6-bromo-2,8-dimethylimidazo[1,2-a]pyrazine (64 mg, 0.286 mmol), Pd(dppf)Cl2 (20.4 mg, 0.029 mmol), K 2 CO 3 (118 mg, 0.858 mmol), and water (0.5 mL) were added and the mixture was flushed with N 2 The mixture was charged with 3 portions of ethyl acetate and stirred at 90° C. for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and evaporated to give the crude title compound. The crude was purified by C18 column chromatography eluted with (MeCN:H2O=30%-60%) to give the title compound (40 mg, 27% yield for two steps) as a yellow solid. ESI-MS (M+H)+: 517.3.

[0444] Step 7: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)phenol To a solution of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (40 mg, 0.077 mmol) in EtOAc (1 mL) was added 3M HCl / EtOAc (2 mL) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (0.05% NH in water). 3 .H 2 O / CH 3 CN) to afford the title compound (10 mg, 35.7%) as a yellow solid. 1 H NMR (400 MHz, MeOD-d 4 )δ 8.78(s,1H),8.40(d,J=9.2 Hz,1H),8.00(d,J=8.4 Hz,1H),7.83(d,J=9.1 Hz,1H),7.77(s,1H),7.63(d,J=1.7 Hz,1H),7.59(dd,J=8.3,1.8 Hz,1H),4.36(t,J=8.1 Hz,1H),4.16-4.07(m,4H),2.85(s,3H),2.47(s,3H).ESI-MS(M+H)+:373.0

[0445] Example 10. 6-[6-(azetidin-3-yl)pyridazin-3-yl]-2-fluoro-3-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}phenol (Compound 10) [ka] Step 1: Preparation of 4-chloro-3-fluoro-2-methoxyaniline To a solution of 3-fluoro-2-methoxybenzenamine (15.0 g, 106.28 mmol) in DMF (50 mL) was added 1-chloropyrrolidine-2,5-dione (NCS) (14.19 g, 106.28 mmol) in portions over 10 min. The reaction mixture was stirred for 1 day. The resulting mixture was then diluted with water (100 mL) and the residue was extracted with EtOAc (100 mL). The organic layer was separated and purified by H 2 0 (50 mL), brine (50 mL), dried and evaporated under reduced pressure. The resulting mixture of isomers was purified by column chromatography using Hex / EtOAc (4 / 1) as eluent to give pure 4-chloro-3-fluoro-2-methoxyaniline (5.75 g, Y: 29.3%). 1 H NMR (400 MHz, chloroform-d) δ 6.84 (t, J = 8.5 Hz, 1H), 6.40 (d, J = 9.8, 1.9 Hz, 1H), 3.90 (s, 3H).

[0446] Step 2: Preparation of 1-bromo-4-chloro-3-fluoro-2-methoxybenzene 4-Chloro-3-fluoro-2-methoxyaniline (5.54 g, 31.56 mmol) was dissolved in HBr (48% in water, 50 mL) and the solution was cooled to 0 °C. A solution of CuBr (5.43 g, 37.87 mmol) in water (30 mL) was added slowly (about 0.5 h) to the stirred slurry while maintaining the temperature of the reaction mixture below 5 °C. A purple solution of sodium nitrite (2.4 g, 34.71 mmol) in HBr (48% in water, 20 mL) was added dropwise to the reaction mixture while maintaining the temperature below 5 °C. The resulting reaction mixture was heated at 60 °C until gas evolution ceased (about 1.5 h). The resulting mixture was cooled to room temperature and the product was extracted with DCM (2 × 50 mL). The combined organic extracts were washed with brine (50 mL) and MgSO 4 Drying at 40° C. and evaporation under reduced pressure gave 1-bromo-4-chloro-3-fluoro-2-methoxybenzene (6.8 g, Y: 81%). 1 H NMR (500 MHz, DMSO-d 6 )δ 7.26(t,J=8.5,1H),7.01(d,J=9.5,7.0,1H),3.98(s,3H).

[0447] Step 3: Preparation of 6-bromo-3-chloro-2-fluorophenol 1-Bromo-4-chloro-3-fluoro-2-methoxybenzene (6.8 g, 28.4 mmol) was dissolved in dichloromethane (200 mL) and cooled to -78 °C. Tribromoborane (14.23 g, 56.79 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The resulting mixture was quenched with ice water (200 mL), the organic layer was separated and diluted with 5% NaHCO 3 Wash with aqueous solution (100 mL) and add Na 2 SO 4 It was dried at 40° C. and evaporated under reduced pressure to give 6-bromo-3-chloro-2-fluorophenol (4.15 g, Y: 61.6%). 1 H NMR (400 MHz, chloroform-d) δ 7.24 (t, J = 8.5, 1H), 6.88 (d, J = 9.5, 7.0, 1H), 5.75-5.55 (br s, 1H).

[0448] Step 4: Preparation of 1-bromo-4-chloro-3-fluoro-2-(methoxymethoxy)benzene 6-Bromo-3-chloro-2-fluorophenol (4.15 g, 18.41 mmol) was dissolved in anhydrous CH 2 Cl 2 (100 mL). Ethyl bis(propan-2-yl)amine (3.57 g, 27.61 mmol) was then added at room temperature. The mixture was cooled to 0° C. and chloro(methoxy)methane (2.22 g, 27.61 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, then allowed to warm to room temperature and stirred for 11 h. The resulting mixture was then diluted with saturated NaHCO 3 Quench with aqueous solution (100 mL), separate the organic layer, wash with brine (200 mL) and add anhydrous Na 2 SO 4 The solvent was removed under reduced pressure to give 1-bromo-4-chloro-3-fluoro-2-(methoxy-methoxy)benzene (4.05 g, Y: 77.6%). 1 H NMR (400 MHz, chloroform-d) δ 7.29-7.22 (m, 1H), 7.08-6.97 (m, 1H), 5.19 (s, 2H), 3.63 (s, 3H).

[0449] Step 5: Preparation of 2-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of 1-bromo-4-chloro-3-fluoro-2-(methoxymethoxy)benzene (4.0 g, 14.84 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.77 g, 14.84 mmol), potassium acetate (4.37 g, 44.53 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (606.1 mg, 742.2 μmol) in dioxane (50 mL) was degassed and purged with Ar. The reaction mixture was heated at 90° C. overnight. The resulting mixture was diluted with EtOAc (40 mL) and filtered. The filtrate was evaporated under reduced pressure to give the crude, which was purified by column chromatography using Hex / EtOAc (8 / 1) as the eluent to give 2-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, Y: 26.3%) as a yellow oil. 1 H NMR (500 MHz, DMSO-d 6 )δ 7.43(d,J=8.2,1H),7.13(dd,J=7.0,1H),5.15(s,2H),3.62(s,3H),1.34(s,12H).

[0450] Step 6: Preparation of tert-butyl 3-6-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]pyridazin-3-yl-azetidine-1-carboxylate A solution of 2-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (305.46 mg, 964.93 μmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (260.27 mg, 964.93 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (39.4 mg, 48.25 μmol), and potassium carbonate (400.08 mg, 2.89 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The reaction mixture was heated at 90° C. overnight. The resulting mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum and the residue was purified by column chromatography using Hex / EtOAc (1 / 1) as eluent to give tert-butyl 3-6-[4-chloro-3-fluoro-2-(methoxy-methoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (269.0 mg, Y: 65.8%). ESI-MS (M+H)+: 424.2.

[0451] Step 7: Preparation of tert-butyl 3-[6-(3-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate tert-Butyl 3-6-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (230.24 mg, 543.2 μmol), 8-fluoro-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (157.48 mg, 570.36 μmol), Pd in ​​dioxane (10 mL) and water (2 mL). 2 (dba) 3A solution of (24.87 mg, 27.16 μmol) and dicyclohexyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (38.84 mg, 81.48 μmol) was degassed and purged with Ar. The reaction mixture was heated at 100° C. overnight. The resulting mixture was cooled to room temperature, diluted with EtOAc (10 mL) and purified by filtration through a pad of Celite. 2 SO 4 The filtrate was concentrated in vacuo to give a crude residue which was triturated with MTBE (5 mL) and the precipitate was filtered to give pure tert-butyl 3-[6-(3-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate (200.0 mg, Y: 65.8%). ESI-MS (M+H)+: 538.2.

[0452] Step 8: Preparation of 6-[6-(azetidin-3-yl)pyridazin-3-yl]-2-fluoro-3-8-fluoro-2-methylimidazo[1,2-a]-pyridin-6-ylphenol as the trifluoroacetate salt tert-Butyl 3-[6-(3-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate (200.23 mg, 372.48 μmol) was dissolved in CH 2 Cl 2 (5 mL) and 2,2,2-trifluoroacetic acid (424.71 mg, 3.72 mmol) was added. The resulting mixture was stirred at room temperature overnight and then evaporated to dryness to give the crude material. The residue was triturated with MeCN / MTBE (1 / 4, 2 mL) and the resulting precipitate was filtered and dried in vacuum to give pure 6-[6-(azetidin-3-yl)pyridazin-3-yl]-2-fluoro-3-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol (183.0 mg, Y: 92%) as the trifluoroacetate salt. ESI-MS (M+H)+: 394.0. 1H NMR (500 MHz, DMSO-d 6 )δ 9.07(br s,1H),8.9-8.8(m,2H),8.6(d,J=8.8 Hz,1H),8.0-7.9(m,3H),7.68(d,J=10.8 Hz,1H),7.26(t,J=7.2 Hz,1H),4.45-4.38(m,5H),2.4(s,3H).HzH

[0453] Example 11. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-3-fluoro-5-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}phenol (Compound 11) [ka] Step 1: Preparation of 4-bromo-3-fluoro-5-methoxyaniline A solution of 3-fluoro-5-methoxyaniline (10.0 g, 70.85 mmol) in DMF (100 mL) was treated with N-bromosuccinimide (12.61 g, 70.85 mmol) and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (150 mL) and ethyl acetate (150 mL). The phases were separated and the aqueous phase was extracted with additional ethyl acetate (100 mL). The combined organic phases were washed with water (150 mL) and brine (150 mL), dried over sodium sulfate and concentrated under reduced pressure to give 4-bromo-3-fluoro-5-methoxyaniline (14.7 g, Y: 89.6%). 1 H NMR (400 MHz, DMSO-d 6 )δ 6.16-6.08(m,1H),6.06(dd,J=11.2,2.3 Hz,1H)3.71(s,3H).

[0454] Step 2: Preparation of 2-bromo-5-chloro-1-fluoro-3-methoxybenzene To a mixture of dichlorocopper dihydrate (12.01 g, 70.44 mmol) and tert-butyl nitrite (7.26 g, 70.44 mmol) in acetonitrile (100 mL) was added a solution of 4-bromo-3-fluoro-5-methoxyaniline (10.0 g, 45.45 mmol) in acetonitrile (20 mL) dropwise at 0° C. After all the aniline was added, the reaction mixture was stirred at room temperature for 1 h, poured into 0.5 N HCl, and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (100 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C. The suspension was filtered and the filtrate was concentrated in vacuum The residue was purified by column chromatography to give 2-bromo-5-chloro-1-fluoro-3-methoxybenzene (10.6 g, Y: 92.5%). 1 H NMR (400 MHz, DMSO-d 6 )δ 7.17(dt,J=8.5,1.8 Hz,1H),7.06(s,1H),3.87(s,3H).

[0455] Step 3: Preparation of 2-bromo-5-chloro-3-fluorophenol 2-Bromo-5-chloro-1-fluoro-3-methoxybenzene (10.6 g, 44.26 mmol) was dissolved in dichloromethane (200 mL) and cooled to -78°C. Tribromoborane (22.18 g, 88.53 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The resulting mixture was quenched with ice water (300 mL) and extracted with DCM (200 mL). The organic layer was washed with brine (150 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-bromo-5-chloro-3-fluorophenol (8.5 g, Y: 80.9%). 1 H NMR (400 MHz, chloroform-d) δ 6.85 (s, 1H), 6.75 (dd, J = 8.1, 2.4 Hz, 1H), 5.71 (s, 1H).

[0456] Step 4: Preparation of 2-bromo-5-chloro-1-fluoro-3-(methoxymethoxy)benzene 2-Bromo-5-chloro-3-fluorophenol (8.5 g, 37.7 mmol) was dissolved in anhydrous CH 2 Cl 2 (100 mL). Ethyl bis(propan-2-yl)amine (5.85 g, 45.24 mmol) was then added at room temperature. The mixture was cooled to 0° C. and chloro(methoxy)methane (3.64 g, 45.24 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 11 h. The resulting mixture was then diluted with saturated NaHCO 3 (250 mL), separate the organic layer, wash with brine (200 mL) and anhydrous Na 2 SO 4 The solvent was removed under reduced pressure to give 2-bromo-5-chloro-1-fluoro-3-(methoxymethoxy)benzene (9.0 g, Y: 84.1%). 1 H NMR (400 MHz, DMSO-d 6 )δ 7.22(dt,J=8.6,2.7 Hz,1H),7.13(s,1H),5.33(s,2H),3.37(s,3H).

[0457] Step 5: Preparation of 2-[4-chloro-2-fluoro-6-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of 2-bromo-5-chloro-1-fluoro-3-(methoxymethoxy)benzene (9.85 g, 36.55 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (9.28 g, 36.55 mmol), potassium acetate (10.76 g, 109.65 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.49 g, 1.83 mmol) in dioxane (150 mL) was degassed and purged with Ar. The reaction mixture was heated at 90° C. overnight. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was evaporated under reduced pressure to give the crude, which was purified by column chromatography using Hex / EtOAc (8 / 1) as the eluent to give 2-[4-chloro-2-fluoro-6-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.0 g, Y: 27.7%) as a yellow oil. 1 H NMR (500 MHz, chloroform-d) δ 6.84(s, 1H), 6.72(dt, J=8.3, 1.8 Hz, 1H), 5.13(s, 2H), 3.47(s, 3H), 1.36(s, 12H).

[0458] Step 6: Preparation of tert-butyl 3-6-[4-chloro-2-fluoro-6-(methoxymethoxy)phenyl]pyridazin-3-yl-azetidine-1-carboxylate A solution of 2-[4-chloro-2-fluoro-6-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (845.57 mg, 2.67 mmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (400.26 mg, 1.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (60.59 mg, 74.2 μmol), and potassium carbonate (410.18 mg, 2.97 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The reaction mixture was heated at 90° C. overnight. The resulting mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography using Hex / EtOAc (1 / 1) as eluent to give tert-butyl 3-6-[4-chloro-2-fluoro-6-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (100.0 mg, Y: 15.1%). ESI-MS (M+H)+: 424.0.

[0459] Step 7: Preparation of tert-butyl 3-[6-(2-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-6-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate tert-Butyl 3-6-[4-chloro-2-fluoro-6-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (100.14 mg, 236.25 μmol), 8-fluoro-2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (65.23 mg, 236.25 μmol), Pd in ​​dioxane (15 mL) and water (3 mL). 2 (dba) 3A solution of (10.82 mg, 11.81 μmol) and dicyclohexyl[[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (16.89 mg, 35.44 μmol) was degassed and purged with Ar. The resulting mixture was heated at 100 °C overnight. The resulting mixture was cooled to room temperature, diluted with EtOAc (20 mL) and purified with NaCl through a pad of Celite. 2 SO 4 The filtrate was concentrated in vacuo to give a crude residue, which was purified by HPLC to give pure tert-butyl 3-[6-(2-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-6-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate (66.0 mg, Y: 52%). ESI-MS (M+H)+: 538.2.

[0460] Step 8: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-3-fluoro-5-8-fluoro-2-methylimidazo[1,2-a]-pyridin-6-ylphenol as the trifluoroacetate salt tert-Butyl 3-[6-(2-fluoro-4-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-6-(methoxymethoxy)phenyl)pyridazin-3-yl]azetidine-1-carboxylate (66.0 mg, 122.78 μmol) was dissolved in CH 2 Cl 2 (3 mL) and 2,2,2-trifluoroacetic acid (140.0 mg, 1.23 mmol) was added. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to give the crude material. The residue was triturated with MeCN / MTBE (1 / 4, 2 mL) and the resulting precipitate was filtered and dried in vacuum to give pure 2-[6-(azetidin-3-yl)pyridazin-3-yl]-3-fluoro-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol (56.0 mg, Y: 87.2%) as the trifluoroacetate salt. ESI-MS (M+H)+: 394.0. 1 H NMR (400 MHz, DMSO-d 6)δ 9.00-8.90(m,2H),8.85-8.75(m,1H),7.99(d,J=8.8 Hz,1H),7.96-7.92(m,J=8.8 Hz,1H),7.81(d,1H),7.77-7.69(m,1H),7.25(dd,J=7.8 Hz,1.1 Hz,1H),7.20-7.15(m,1H),4.45-4.30(m,5H),2.40(s,3H).

[0461] Example 12. 5-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 12) [ka] Step 1: Preparation of 5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-[6-(1-methyl-azetidin-3-yl)-pyridazin-3-yl]phenol hydrochloride To a stirred solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol hydrochloride (100.05 mg, 242.92 μmol) in EtOH (5 mL) was added formaldehyde (191.95 mg, 6.39 mmol) followed by acetic acid (58.35 mg, 971.69 μmol). The mixture was stirred for 1 h, then sodium cyanoborohydride (45.8 mg, 728.76 μmol) was added and the reaction mixture was stirred overnight. The solvent was then evaporated and the crude residue was purified by HCl distillation. 2 2H 2 O (5 mL) and EtOAc (10 mL). The precipitate was filtered and dried in vacuum. The residue was dissolved in MeOH (2 mL) and HCl / dioxane (1 mL) was added at 0° C. The resulting solution was evaporated under high vacuum to give 5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-[6-(1-methyl-azetidin-3-yl)-pyridazin-3-yl]phenol hydrochloride (124.0 mg, Y: 95% yield). ESI-MS (M+H)+: 390.2. 1 H NMR (500 MHz, DMSO-d6 )δ 9.21(s,1H),8.54(t,J=9.9 Hz,1H),8.31(d,J=10.8 Hz,1H),8.16(s,2H),7.92(dd,J=16.6,9.0 Hz,1H),7.48-7.38(m,2H),4.63-4.55(m,2H),4.45-4.30(m,3H),3.16(s,3H),2.51(s,3H).

[0462] Example 13. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-{2-methylpyrazolo[1,5-a]pyridin-5-yl}phenol (Compound 13) [ka] Step 1: Preparation of 5-[4-bromo-3-(methoxymethoxy)phenyl]-2-methylpyrazolo[1,5-a]pyridine 2-Methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2.62 g, 10.15 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (2.78 g, 8.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane adduct (663.03 mg, 811.91 μmol), and potassium carbonate (3.37 g, 24.36 mmol) were mixed in dioxane / water under argon atmosphere. The reaction mixture was heated to 90° C. overnight. After treatment with EtOAc and crystallization from MTBE, 5-[4-bromo-3-(methoxymethoxy)phenyl]-2-methylpyrazolo[1,5-a]pyridine (2.8 g, Y: 79.5%) was obtained and used in the next step without further purification. ESI-MS(M+H)+:348.0.

[0463] Step 2: Preparation of 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpyrazolo[1,5-a]pyridine 5-[4-Bromo-3-(methoxymethoxy)phenyl]-2-methylpyrazolo[1,5-a]pyridine (2.8 g, 8.06 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.54 g, 6.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (658.66 mg, 806.55 μmol), and potassium acetate (2.37 g, 24.2 mmol) were mixed in dioxane under an argon atmosphere. The reaction mixture was heated to 100° C. overnight and concentrated under reduced pressure. Purification of the residue via flash column chromatography afforded 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-2-methylpyrazolo[1,5-a]pyridine (500.0 mg, 1.27 mmol, Y: 15.7%), which was used in the next step without further purification. ESI-MS (M+H)+: 395.2.

[0464] Step 3: Preparation of tert-butyl 3-6-[2-(methoxymethoxy)-4-2-methylpyrazolo[1,5-a]pyridin-5-ylphenyl]pyridazin-3-ylazetidine-1-carboxylate 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpyrazolo[1,5-a]pyridine (179.85 mg, 456.16 μmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (111.85 mg, 414.69 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (33.87 mg, 41.47 μmol), and potassium carbonate (171.94 mg, 1.24 mmol) were mixed in dioxane / water under an argon atmosphere. The reaction mixture was heated to 90° C. overnight. After treatment with EtOAc, tert-butyl 3-6-[2-(methoxymethoxy)-4-2-methylpyrazolo[1,5-a]pyridin-5-ylphenyl]pyridazin-3-ylazetidine-1-carboxylate (200.0 mg, Y.: 67.3% yield) was obtained and used in the next step without further purification. ESI-MS (M+H)+: 502.2.

[0465] Step 4: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-2-methylpyrazolo[1,5-a]pyridin-5-ylphenol tert-Butyl 3-6-[2-(methoxymethoxy)-4-2-methylpyrazolo[1,5-a]pyridin-5-ylphenyl]pyridazin-3-ylazetidine-1-carboxylate (200.0 mg, 398.74 μmol) was dissolved in DCM (1 mL) and TFA (1 mL) and the reaction mixture was stirred at room temperature overnight. After complete evaporation and HPLC, pure 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-2-methylpyrazolo[1,5-a]pyridin-5-ylphenol (25.5 mg, Y: 13.5%) was obtained as TFA. ESI-MS (M+H)+: 358.2. 1 H NMR (500 MHz, DMSO-d 6)δ 12.95(s,1H),8.95(br s,1H),8.82(br s,1H),8.62(d,J=8.2 Hz,1H),8.55(d,J=8.2 Hz,1H),8.14(d,J=8.3 Hz,1H),7.96(s,1H),7.89(d,J=9.0 Hz,1H),7.46-7.37(m,2H),7.17(dd,J=7.3,2.3 Hz,1H),6.45(s,1H),4.45-4.30(m,5H),2.40(s,3H).

[0466] Example 14. 2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]-5-{2-methylimidazo[1,2-a]pyridin-6-yl}phenol (Compound 14) [ka] Step 1: Preparation of 2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]-5-2-methylimidazo[1,2-a]pyridin-6-ylphenol as the trifluoroacetate salt A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-2-methylimidazo[1,2-a]pyridin-6-ylphenol hydrochloride (20.04 mg, 50.88 μmol) and formaldehyde (40.21 mg, 1.34 mmol) in methanol was stirred at ambient temperature for 2 h. Then sodium cyanoborohydride (9.59 mg, 152.65 μmol) was added, followed by acetic acid (17.5 mg, 291.48 μmol) and the reaction mixture was stirred at ambient temperature for 16 h. The resulting mixture was diluted with water and the formed precipitate was filtered and dried in vacuum. The residue was dissolved in MeOH (2 mL) and TFA (0.1 mL) was added at 0° C. The resulting solution was evaporated under high vacuum to give 2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]-5-2-methylimidazo[1,2-a]pyridin-6-ylphenol as the trifluoroacetate salt (20.0 mg, Y: 97.4%). ESI-MS (M+H)+: 372.0. 1 H NMR (400 MHz, DMSO-d 6)δ 10.27-10.07(br s,1H),9.34(s,1H),8.65-8.57(m,1H),8.28(d,J=9.1 Hz,1H),8.22(d,J=8.1 Hz,1H),8.07(s,1H),7.99(d,J=9.1 Hz,1H),7.93(d,J=9.1 Hz,1H),7.44(d,J=11.6 Hz,2H),4.65-4.55(m,2H),4.46-4.29(m,3H),2.95(s,3H),2.49(s,3H).

[0467] Example 15. 5-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}-2-{6-[1-(propan-2-yl)azetidin-3-yl]pyridazin-3-yl}phenol (compound 15) [ka] Step 1: Preparation of 5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-6-[1-(propan-2-yl)azetidin-3-yl]pyridazin-3-ylphenol trifluoroacetate A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol hydrochloride (29.99 mg, 72.82 μmol) and propan-2-one (42.29 mg, 728 μmol) in methanol was stirred at ambient temperature for 2 hours. Sodium cyanoborohydride (13.73 mg, 218 μmol) was then added, followed by acetic acid (17.5 mg, 291.48 μmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The resulting mixture was diluted with water and the precipitate formed was filtered and dried in vacuum. The residue was dissolved in MeOH (2 mL) and TFA (0.1 mL) was added at 0° C. The resulting solution was evaporated under high vacuum to give 5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-6-[1-(propan-2-yl)azetidin-3-yl]pyridazin-3-ylphenol trifluoroacetate (18.0 mg, Y: 56.3%). ESI-MS (M+H)+: 418.2. 1H NMR (400 MHz, DMSO-d 6 )δ 10.34-10.11(br s,1H),8.95(s,1H),8.63-8.59(m,1H),8.20-8.14(m,1H),7.99-7.92(m,1H),7.90(s,1H),7.7 5-7.70(m,1H),7.40(s,2H),4.60-4.30(m,5H),3.55-3.45(m,1H),2.41(s,3H),1.20(d,J=5.6 Hz,6H).

[0468] Example 16. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(2-methyl-2H-indazol-5-yl)phenol (Compound 16) [ka] Step 1: Preparation of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 5-Bromo-2-methyl-2H-indazole (800 mg, 3.79 mmol) in 1,4-dioxane (25 mL), B 2 (Pin) 2 (1.925 g, 7.58 mmol) and KOAc (1.114 g, 11.37 mmol), Pd(dppf)Cl 2 (309 mg, 0.379 mmol) was added. The mixture was diluted with N 2 The mixture was stirred at 85° C. for 6 h under reduced pressure. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=4:1 to 1:1) to give the title product (732 mg, Y: 75%) as a white solid. ESI-MS (M+H)+: 259.2. 1 H NMR (400 MHz, CDCl 3 )δ 8.22(s,1H),7.91(s,1H),7.66-7.65(m,2H),4.21(s,3H),1.36(s,12H).

[0469] Step 2: Preparation of 5-(4-bromo-3-(methoxymethoxy)phenyl)-2-methyl-2H-indazole 1,4-Dioxane:H 2 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (1 g, 3.88 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (1.6 g, 4.656 mmol) and K in O (40 mL:8 mL). 2 CO 3 (1.6 g, 11.64 mmol) was added to a solution of Pd(dppf)Cl 2 (317 mg, 0.388 mmol) was added. The mixture was diluted with N 2 The mixture was stirred at 80° C. for 2 h under reduced pressure. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=4:1 to 1:2) to give the title product (1.2 g, Y: 92%) as a brown solid. ESI-MS (M+H)+: 347.1. 1 H NMR (400 MHz, CDCl 3 )δ 7.94(s,1H),7.81-7.80(m,1H),7.75(d,J=9.0 Hz,1H),7.59(d,J=8.2 Hz,1H),7.52-7.49(m,1H),7.41(d,J=2.1 Hz,1H),7.17-7.14(m,1H),5.33(s,2H),4.24(s,3H),3.56(s,3H).

[0470] Step 3: Preparation of 5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-2H-indazole 5-(4-bromo-3-(methoxymethoxy)phenyl)-2-methyl-2H-indazole (1.6 g, 4.62 mmol) in 1,4-dioxane (100 mL), B 2 (Pin) 2 A mixture of Pd(dppf)Cl (5.9 g, 23.12 mmol) and KOAc (2.3 g, 23.12 mmol) was 2 (377 mg, 0.462 mmol) was added. The mixture was diluted with N 2The mixture was stirred at 100° C. for 16 h under reduced pressure. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=2:1 to 1:3) to give the title product (2 g, crude) as a brown oil. ESI-MS (M+H)+: 395.4.

[0471] Step 4: Preparation of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methyl-2H-indazol-5-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate 1,4-Dioxane:H 2 5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-2H-indazole (1.9 g, 4.8 mmol) and tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (1.29 g, 4.8 mmol) in 20 (50 mL:10 mL) and K 2 CO 3 To a mixture of (2.0 g, 14.5 mmol) Pd(dppf)Cl 2 (392 mg, 0.48 mmol) was added. The mixture was diluted with N 2 The mixture was stirred at 80° C. for 2 h under reduced pressure. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE:EA=2:1 to 1:3) to give the title product (450 mg, Y: 19%) as a white solid. ESI-MS (M+H)+: 502.4.

[0472] Step 5: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(imidazo[1,2-a]pyridin-6-yl)phenol TFA salt A solution of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methyl-2H-indazol-5-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (50 mg, 0.10 mmol) in TFA (5 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and lyophilized to give the title product (38 mg, Y: 81%) as a yellow solid. ESI-MS (M+H)+: 358.0. 1 H NMR (400 MHz, MeOD-d 4 )δ 8.44(d,J=9.1 Hz,1H),8.29(s,1H),8.01(d,J=8.5 Hz,2H),7.77(d,J=9.0 Hz,1H),7.72-7.64(m,2H),7.38-7.31(m,2H),4.61-4.52(m,4H),4.50-4.45(m,1H),4.24(s,3H).

[0473] Example 17. 2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]-5-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}phenol (Compound 17) [ka] Step 1: Preparation of 2-[6-(1-ethylazetidin-3-yl)-pyridazin-3-yl]-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol as the trifluoroacetate salt A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-phenol hydrochloride (30.01 mg, 72.87 μmol) and acetaldehyde (32.1 mg, 728.71 μmol) in methanol (2 mL) was stirred at ambient temperature for 2 hours. Sodium cyanoborohydride (13.74 mg, 218.61 μmol) was then added, followed by acetic acid (17.5 mg, 291.48 μmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The resulting mixture was diluted with water (3 mL) and the formed precipitate was filtered and purified by HPLC. The residue was dissolved in a mixture of MeCN / TFA (1 / 0.1 mL) and evaporated under reduced pressure to give 2-[6-(1-ethylazetidin-3-yl)-pyridazin-3-yl]-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol as the trifluoroacetate salt (17.0 mg, Y: 57.8%). ESI-MS (M+H)+: 404.2. 1 H NMR (500MHz, methanol-d 4 )δ 8.98(s,1H),8.47(t,J=8.7 Hz,1H),8.19-8.04(m,3H),7.82(dd,J=9.2,3.7 Hz,1H),7.46-7.32(m,2H),4.77-4.62(m,2H),4.58-4.35(m,3H),3.42(q,J=7.5 Hz,2H),2.59(s,3H),1.29(t,J=7.3,3H).

[0474] Example 18. 5-{8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}-2-{6-[1-(oxan-4-yl)azetidin-3-yl]pyridazin-3-yl}phenol (compound 18) [ka] Step 1: Preparation of 5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-6-[1-(oxan-4-yl)azetidin-3-yl]pyridazin-3-ylphenol as the trifluoroacetate salt A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylphenol hydrochloride (30.0 mg, 72.84 μmol) and oxan-4-one (14.6 mg, 145.81 μmol, 10.0 μL) in ethanol was stirred at 45° C. for 2 h. Then sodium cyanoborane (13.74 mg, 218.71 μmol) was added, followed by acetic acid (17.5 mg, 291.48 μmol) and the reaction mixture was stirred at 80° C. for 16 h. The resulting mixture was diluted with water and the formed precipitate was filtered and dried in vacuum. The residue was dissolved in MeOH (2 mL) and TFA (0.1 mL) was added at 0° C. The resulting solution was evaporated under high vacuum to give 5-8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-2-6-[1-(oxan-4-yl)azetidin-3-yl]pyridazin-3-ylphenol (20.0 mg, Y: 59.7%) as the trifluoroacetate salt. ESI-MS (M+H)+: 460.2. 1 H NMR (500MHz, methanol-d 4 )δ 8.98(s,1H),8.47(t,J=8.7 Hz,1H),8.19-8.04(m,3H),7.82(dd,J=9.2,3.7 Hz,1H),7.46-7.32(m,2H),4.79-4.53(m,5H),4.13-4.00(m,2H),3.69-3.61(m,1H),3.46(t,J=11.7 Hz,2H),2.58(s,3H),2.10-2.00(m,2H),1.62-1.52(m,2H).

[0475] Example 19. 5-(2-Methyl-2H-indazol-5-yl)-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 19) [ka] Step 1: Preparation of 5-(2-methyl-2H-indazol-5-yl)-2-(6-(1-methylazetidin-3-yl)pyridazin-3-yl)phenol hydrochloride To a solution of 2,2,2-trifluoroacetaldehyde-2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methyl-2H-indazol-5-yl)phenol (600 mg, 1.68 mmol) in MeOH (80 mL), (HCHO) n (252 mg, 8.4 mmol) and acetic acid (302 mg, 5.04 mmol) were added. The mixture was stirred at room temperature for 1 h, then sodium cyanoborohydride (318 mg, 5.04 mmol) was added and the mixture was stirred at 50° C. for 5 h. Water (10 mL) was added and the solution was concentrated in vacuo. To the crude, MeOH (10 mL) was added and stirred for 3 h, the precipitate was filtered, washed with MeOH (30 mL), then diluted with 8 mL of water (0.1% HCl in H2O) and lyophilized to give the title product (185 mg, yield: 27%) as a yellow solid. ESI-MS (M+H)+: 372.1. 1 H NMR (400 MHz, MeOD-d 4 )δ 8.49(d,J=9.0 Hz,1H),8.35(s,1H),8.05(s,1H),8.03-7.96(m,1H),7.91-7.82(m,1H),7.71(s,2H),7.41-7. 30(m,2H),4.80-4.76(m,1H),4.74-4.68(m,1H),4.55-4.41(m,3H),4.26(s,3H),3.09(d,J=4.8 Hz,3H).

[0476] Example 20. 5-{2,8-dimethylimidazo[1,2-a]pyrazin-6-yl}-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 20) [ka] Step 1: 5-(2,8-Dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(6-(1-methylazetidin-3-yl)pyridazin-3-yl)phenol hydrochloride To a mixture of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)phenol (8 mg, 0.02 mmol) in MeOH (5 mL), (HCHO) n (3.2 mg, 0.108 mmol) and HOAc (0.1 ml) were added at room temperature. The mixture was stirred at this temperature for 0.5 h and NaBH 3 CN (4 mg, 0.064 mmol) was added. The mixture was stirred for 16 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (0.05% HCl in water / CH 3 CN) to give 5-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(6-(1-methylazetidin-3-yl)pyridazin-3-yl)phenol hydrochloride (2.4 mg, Y: 28.8%) as a white solid. 1 H NMR (400 MHz, MeOD-d 4 )δ 9.22(s,1H),8.55-8.46(m,1H),8.17(s,1H),8.13(d,J=7.1 Hz,1H),7.86(d,J=8.9 Hz,1H),7.81(d,J=1.5 Hz,1H),7.76(d,J=8.3 Hz,1H),4.76-4.66(m,2H),4.55-4.41(m,3H),3.09(d,J=7.6 Hz,3H),2.66(s,3H).ESI-MS(M+H)+:387.1

[0477] Example 21. 2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]-5-{2-methylpyrazolo[1,5-a]pyridin-5-yl}phenol (Compound 21) [ka] Step 1: Preparation of 2-(6-(1-methylazetidin-3-yl)pyridazin-3-yl)-5-(2-methylpyrazolo[1,5-a]pyridin-5-yl)phenol 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methylpyrazolo[1,5-a]pyridin-5-yl)phenol (30 mg, 0.08 mmol) and (HCHO) in MeOH (3 mL). n (13 mg, 0.40 mmol) was added with HOAc (0.05 mL) at room temperature. After stirring at room temperature for 1 h, NaBH 3 CN (15 mg, 0.24 mmol) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (0.05% NH in HO). 3 .H 2 O / MeCN) to give the title product (5 mg, Y: 17%) as a yellow solid. ESI-MS (M+H)+: 372.0. 1 H NMR (400 MHz, CDCl 3 +CD 3 OD)δ 8.45(d,J=7.2 Hz,1H),8.37(d,J=9.1 Hz,1H),8.01(d,J=8.1 Hz,1H),7.87-7.76(m,3H),7.36(s,1H),7.13(d,J=7.1 Hz,1H),6.44(s,1H),4.06(d,J=7.6 Hz,1H),3.88(t,J=7.6 Hz,2H),3.59(t,J=7.5 Hz,2H),3.31(s,3H),2.47(s,3H).

[0478] Example 22. 5-(2-Methyl-2H-indazol-5-yl)-2-{6-[1-(oxan-4-yl)azetidin-3-yl]pyridazin-3-yl}phenol (Compound 22) [ka] Step 1: Preparation of 5-(2-methyl-2H-indazol-5-yl)-2-(6-(1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)pyridazin-3-yl)phenol hydrochloride To a solution of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methyl-2H-indazol-5-yl)phenol (1.2 g, 3.36 mmol) in MeOH (100 mL) was added tetrahydro-4H-pyran-4-one (1.68 g, 16.807 mmol) and acetic acid (1 g, 16.807 mmol). The mixture was stirred at room temperature for 1 h, then sodium cyanoborohydride (635 mg, 10.08 mmol) was added under ice bath, the mixture was stirred at room temperature for 2 h, then water (10 mL) was added and the solution was concentrated in vacuo. The crude was purified by preparative HPLC (0.05% HCl in water / CH 3 CN) to give the title compound (657 mg, yield: 44.3%) as a yellow solid. ESI-MS (M+H)+: 442.2. 1 H NMR (400 MHz, DMSO-d 6 )δ 12.13-11.31(m,1H),8.64-8.56(m,1H),8.45(s,1H),8.13-8.07(m,2H),7.99(d,J=9.1 Hz,1H),7.71(d,J=9.0 Hz,1H),7.65-7.60(m,1H),7.39-7.36(m,2H),4.64-4.31(m,5H),4.21(s,3H),4.02-3. 92(m,2H),3.67-3.44(m,1H),3.34-3.23(m,2H),1.98-1.88(m,2H),1.63-1.49(m,2H).

[0479] Example 23. 2-(6-(1-isopropylazetidin-3-yl)pyridazin-3-yl)-5-(2-methyl-2H-indazol-5-yl)phenol (Compound 23) [ka] Step 1: Preparation of 2-(6-(1-isopropylazetidin-3-yl)pyridazin-3-yl)-5-(2-methyl-2H-indazol-5-yl)phenol To a solution of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methyl-2H-indazol-5-yl)phenol (50 mg, 0.14 mmol) and HOAc (0.09 mL) in MeOH (5 mL) was added acetone (40 mg, 0.7 mmol) in MeOH (5 mL) and the reaction mixture was stirred at room temperature for 1 h. NaBH 3 CN (26 mg, 0.42 mmol) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 2 h. The resulting reaction mixture was diluted with water (5 mL) and extracted with DCM (30 mL×3). The combined organic layer was concentrated under reduced pressure and purified by preparative HPLC (0.05% NH 3 .H 2 O / CH 3 CN) to give the title product (7.11 mg, Y: 12%) as a white solid. ESI-MS (M+H)+: 400.1. 1 H NMR (400 MHz, DMSO-d 6 )δ 13.35(s,1H),8.58(d,J=9.2 Hz,1H),8.48(s,1H),8.17-8.13(m,2H),8.02(d,J=9.1 Hz,1H),7.75(d,J=9.0 Hz,1H),7.70-7.67(m,1H),7.42-7.38(m,2H),4.26(s,3H),3.96-3.92(m,1H),3.70(t,J=7.0 Hz,2H),2.56(br.s,2H),2.45(br.s,1H),0.96(d,J=6.2 Hz,6H).

[0480] Example 24. 2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]-5-(2-methyl-2H-indazol-5-yl)phenol (Compound 24) [ka] Step 1: Preparation of 5-(4-bromo-3-(methoxymethoxy)phenyl)-2-methyl-2H-indazole A solution of 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (500.33 mg, 1.94 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (664.76 mg, 1.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (79.15 mg, 96.92 μmol), and potassium carbonate (535.78 mg, 3.88 mmol) in dioxane (10 mL) and water (2 ml) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, EtOAc (15 mL) was added, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by flash column chromatography (Hex / EtOAc 3 / 1) to give 5-[4-bromo-3-(methoxymethoxy)phenyl]-2-methyl-2H-indazole (380.0 mg, Y: 50.8%). ESI-MS (M+H)+: 347.0 1 H NMR (400 MHz, DMSO-d 6 )δ 8.41(s,1H),7.99(s,1H),7.66(dd,J=13.2,8.6 Hz,2H),7.58-7.41(m,2H),7.27(dd,J=8.3,2.1 Hz,1H),5.42(s,2H),4.19(s,3H),3.45(s,3H).

[0481] Step 2: Preparation of 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-2H-indazole A solution of 5-[4-bromo-3-(methoxymethoxy)phenyl]-2-methyl-2H-indazole (380.0 mg, 1.09 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (278.24 mg, 1.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (89.48 mg, 109.57 μmol), and potassium acetate (215.07 mg, 2.19 mmol) in TolH (10 mL) was degassed and purged with Ar. The resulting mixture was heated at 110° C. overnight. The reaction mixture was diluted with EtOAc (10 mL) and filtered. The filtrate was evaporated to give crude 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-2H-indazole (430.0 mg, Y: 51.8%), which was used in the next step without purification. ESI-MS (M+H)+: 395.2.

[0482] Step 3: Preparation of tert-butyl 3-6-[2-(methoxymethoxy)-4-(2-methyl-2H-indazol-5-yl)phenyl]pyridazin-3-ylazetidine-1-carboxylate A solution of 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-2H-indazole (432.0 mg, 1.1 mmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (295.77 mg, 1.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (44.77 mg, 54.83 μmol), and potassium carbonate (303.1 mg, 2.19 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with MTBE (15 mL), and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by preparative HPLC to give tert-butyl 3-6-[2-(methoxymethoxy)-4-(2-methyl-2H-indazol-5-yl)phenyl]pyridazin-3-ylazetidine-1-carboxylate (207.0 mg, Y: 37.6%). ESI-MS (M+H)+: 502.2.

[0483] Step 4: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(2-methyl-2H-indazol-5-yl)phenol trifluoroacetate To a solution of tert-butyl 3-6-[2-(methoxymethoxy)-4-(2-methyl-2H-indazol-5-yl)phenyl]pyridazin-3-ylazetidine-1-carboxylate (207.47 mg, 413.63 μmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (472.64 mg, 4.15 mmol, 320.0 μl) and the mixture was stirred overnight. The mixture was then evaporated to dryness under reduced pressure to give crude 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(2-methyl-2H-indazol-5-yl)phenol trifluoroacetate (135.0 mg, Y: 69.2%), which was used in the next step without purification. ESI-MS (M+H)+: 358.2

[0484] Step 5: Preparation of 2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]-5-(2-methyl-2H-indazol-5-yl)phenol trifluoroacetate 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(2-methyl-2H-indazol-5-yl)phenol trifluoroacetate (134.02 mg, 284.29 μmol) and acetaldehyde (124.8 mg, 2.83 mmol, 160.0 μl) in methanol were stirred at ambient temperature for 2 h. Sodium cyanoborohydride (89.33 mg, 1.42 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and the precipitate formed was filtered and purified by HPLC to give 2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]-5-(2-methyl-2H-indazol-5-yl)phenol trifluoroacetate (2.2 mg, Y: 1.4%). ESI-MS (M+H)+: 386.2.

[0485] Example 25. 2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]-5-{2-methylpyrazolo[1,5-a]pyridin-5-yl}phenol (Compound 25) [ka] Step 1: Preparation of 5-[4-bromo-3-(methoxymethoxy)phenyl]-2-methylpyrazolo[1,5-a]pyridine A solution of 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (399.97 mg, 1.55 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (531.41 mg, 1.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (63.27 mg, 77.48 μmol), and potassium carbonate (428.3 mg, 3.1 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, EtOAc (15 mL) was added, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by CC (Hex / EtOAc 1 / 1) to give 5-[4-bromo-3-(methoxymethoxy)phenyl]-2-methylpyrazolo[1,5-a]pyridine (356.0 mg, Y: 66.2%). ESI-MS (M+H)+: 347.2. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.60(d,J=7.6,1H),7.89(s,1H),7.67(d,J=8.3,1H),7.55(s,1H),7.33(d,J=8. 5,1H),7.11(d,J=7.2,1H),6.43(s,1H),5.43(s,2H),3.43(s,3H),2.39(s,3H).

[0486] Step 2: Preparation of 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpyrazolo[1,5-a]pyridine A solution of 5-[4-bromo-3-(methoxymethoxy)phenyl]-2-methylpyrazolo[1,5-a]pyridine (199.9 mg, 575.74 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (146.2 mg, 575.75 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (23.51 mg, 28.79 μmol), and potassium acetate (169.51 mg, 1.73 mmol) in dioxane (10 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was evaporated to give crude 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpyrazolo[1,5-a]pyridine (400.0 mg), which was used in the next step without purification. ESI-MS (M+H)+: 395.4

[0487] Step 3: Preparation of tert-butyl 3-6-[2-(methoxymethoxy)-4-2-methylpyrazolo[1,5-a]pyridin-5-ylphenyl]pyridazin-3-ylazetidine-1-carboxylate A solution of 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpyrazolo[1,5-a]pyridine (230.32 mg, 584.16 μmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (157.56 mg, 584.16 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (47.7 mg, 58.42 μmol), and potassium carbonate (161.47 mg, 1.17 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with MTBE (15 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by preparative HPLC to give tert-butyl 3-6-[2-(methoxymethoxy)-4-2-methylpyrazolo[1,5-a]pyridin-5-ylphenyl]pyridazin-3-ylazetidine-1-carboxylate (54.0 mg, Y: 18.4%). ESI-MS (M+H)+: 502.4.

[0488] Step 4: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-2-methylpyrazolo[1,5-a]pyridin-5-ylphenol trifluoroacetate To a solution of tert-butyl 3-6-[2-(methoxymethoxy)-4-2-methylpyrazolo[1,5-a]pyridin-5-ylphenyl]pyridazin-3-ylazetidine-1-carboxylate (54.05 mg, 107.76 μmol) in dichloromethane (3 mL), 2,2,2-trifluoroacetic acid (122.87 mg, 1.08 mmol) was added and the mixture was stirred overnight. The mixture was then evaporated to dryness under reduced pressure to give crude 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-2-methylpyrazolo[1,5-a]pyridin-5-ylphenol trifluoroacetate (50.0 mg, Y: 73.8%), which was used in the next step without purification. ESI-MS (M+H)+: 358.2.

[0489] Step 5: Preparation of 2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]-5-2-methylpyrazolo[1,5-a]pyridin-5-ylphenol trifluoroacetate A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-2-methylpyrazolo[1,5-a]pyridin-5-ylphenol trifluoroacetate (50.0 mg, 106.06 μmol) and acetaldehyde (46.74 mg, 1.06 mmol) in methanol was stirred at ambient temperature for 2 h. Sodium cyanoborohydride (33.34 mg, 530.53 μmol) was added and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and the precipitate formed was filtered and purified by HPLC to give 2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]-5-2-methylpyrazolo[1,5-a]pyridin-5-ylphenol trifluoroacetate (25.0 mg, Y: 61.1%). ESI-MS (M+H)+: 386.4. 1 H NMR (400MHz, acetonitrile-d 3 )δ 8.66(d,J=7.4 Hz,1H),8.48(br s,1H),8.34-8.25(m,1H),7.96(dd,J=8.3,1.9 Hz,1H),7.92(s,1H),7.75-7.67(m,1H),7.36-7.33(m,1H),7.32-7.26(m,1H),4.7 1-4.54(m,2H),4.46-4.27(m,3H),3.34(q,J=6.9,2H),2.47(s,3H),1.95(d,J=2.3 Hz,11H),1.21(t,J=7.4 Hz,3H).

[0490] Example 26. 5-[2-Methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 26) [ka] Step 1: Preparation of 6-[4-bromo-3-(methoxymethoxy)phenyl]-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine A solution of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-(trifluoromethyl)imidazo[1,2-a]pyridine (500.0 mg, 1.53 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (526.16 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (62.64 mg, 76.71 μmol), and potassium carbonate (424.07 mg, 3.07 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, EtOAc (20 mL) was added, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by flash column chromatography (Hex / EtOAc 1 / 1) to give 6-[4-bromo-3-(methoxymethoxy)phenyl]-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (283.0 mg, Y: 41.8%). ESI-MS (M+H)+: 415.0.

[0491] Step 2: Preparation of 6-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine A solution of 6-[4-bromo-3-(methoxymethoxy)phenyl]-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (283.0 mg, 681.59 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (190.34 mg, 749.56 μmol), potassium acetate (200.63 mg, 2.04 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.82 mg, 34.07 μmol) in dioxane (8 mL) was degassed and purged with Ar. The resulting mixture was heated at 90 °C overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite, concentrated in vacuo and the residue (315 mg) was used directly in the next step without further purification. ESI-MS (M+H)+: 463.2.

[0492] Step 3: Preparation of tert-butyl 3-6-[2-(methoxymethoxy)-4-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenyl]pyridazin-3-ylazetidine-1-carboxylate A solution of 6-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (315.0 mg, 681.42 μmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (183.74 mg, 681.21 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.82 mg, 34.06 μmol), and potassium carbonate (188.29 mg, 1.36 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The resulting mixture was heated at 95° C. overnight. The reaction mixture was cooled to room temperature. EtOAc (20 mL) was added and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by HPLC to give tert-butyl 3-6-[2-(methoxymethoxy)-4-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenyl]pyridazin-3-ylazetidine-1-carboxylate (125.9 mg, Y: 32.4%). ESI-MS (M+H)+: 570.2.

[0493] Step 4: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenol trifluoroacetate To a solution of tert-butyl 3-6-[2-(methoxymethoxy)-4-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenyl]pyridazin-3-ylazetidine-1-carboxylate (125.65 mg, 220.6 μmol) in dichloromethane (4 mL) was added 2,2,2-trifluoroacetic acid (251.09 mg, 2.2 mmol, 170.0 μl) and the mixture was stirred overnight. The mixture was then evaporated to dryness under reduced pressure to give 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenol trifluoroacetate (135.0 mg, Y: 98%). ESI-MS (M+H)+: 426.2.

[0494] Step 5: Preparation of 5-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol trifluoroacetate A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]phenol trifluoroacetate (135.0 mg, 250.26 μmol), acetic acid (150.32 mg, 2.5 mmol), and formaldehyde (75.16 mg, 2.5 mmol) in methanol was stirred at ambient temperature for 2 hours. Sodium cyanoborohydride (157.31 mg, 2.5 mmol) was added and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water and the precipitate formed was filtered and dried to give 5-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol trifluoroacetate (78.0 mg, Y: 64.5%). ESI-MS (M+H)+: 440.2. 1 H NMR (400MHz, methanol-d 4)δ 8.86(s,1H),8.31(d,J=9.1 Hz,1H),7.95(d,J=8.7 Hz,1H),7.85(s,1H),7.77-7.68(m,2H),7.26-7.22(m,2H),4.56-4.49( m,2H),4.45-4.39(m,2H),4.36-4.29(m,1H),2.99(s,3H),2.40(s,3H).

[0495] Example 27. 5-(2,7-Dimethyl-2H-indazol-5-yl)-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 27) [ka] Step 1: Preparation of 5-[4-bromo-3-(methoxymethoxy)phenyl]-2,7-dimethyl-2H-indazole A solution of 2,7-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (400.0 mg, 1.47 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (504.13 mg, 1.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (60.02 mg, 73.5 μmol), and potassium carbonate (406.31 mg, 2.94 mmol) in dioxane (15 mL) and water (4 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, MTBE (25 mL) was added, and the formed precipitate was filtered through a pad of Celite. The precipitate was washed with MeCN / MTBE (1 / 1, 5 mL) and the filtrate was concentrated in vacuo to give pure 5-[4-bromo-3-(methoxymethoxy)phenyl]-2,7-dimethyl-2H-indazole (400.0 mg, Y: 66.3%). ESI-MS (M+H)+: 361.0.

[0496] Step 2: Preparation of 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,7-dimethyl-2H-indazole A solution of 5-[4-bromo-3-(methoxymethoxy)phenyl]-2,7-dimethyl-2H-indazole (236.22 mg, 653.93 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (166.06 mg, 653.93 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (53.4 mg, 65.39 μmol), and potassium acetate (128.36 mg, 1.31 mmol) in TolH (10 mL) was degassed and purged with Ar. The resulting mixture was heated at 120° C. overnight. The reaction mixture was diluted with EtOAc (10 mL) and filtered. The filtrate was evaporated to give crude 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,7-dimethyl-2H-indazole (300.0 mg), which was used in the next step without purification. ESI-MS (M+H)+: 409.4.

[0497] Step 3: Preparation of tert-butyl 3-6-[4-(2,7-dimethyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate A solution of 5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,7-dimethyl-2H-indazole (299.33 mg, 733.12 μmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (98.87 mg, 366.56 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (29.93 mg, 36.66 μmol), and potassium carbonate (101.32 mg, 733.12 μmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with MTBE (15 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by preparative HPLC to give tert-butyl 3-6-[4-(2,7-dimethyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (80.0 mg, Y: 34.7%). ESI-MS (M+H)+: 516.2.

[0498] Step 4: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(2,7-dimethyl-2H-indazol-5-yl)phenol trifluoroacetate To a solution of tert-butyl 3-6-[4-(2,7-dimethyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl]-pyridazin-3-ylazetidine-1-carboxylate (79.98 mg, 155.11 μmol) in dichloromethane (3 mL), 2,2,2-trifluoroacetic acid (176.86 mg, 1.55 mmol) was added and the mixture was stirred overnight. The mixture was then evaporated to dryness under reduced pressure to give 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(2,7-dimethyl-2H-indazol-5-yl)phenol trifluoroacetate (80.0 mg, Y: 95.6%), which was used in the next step without purification. ESI-MS (M+H)+: 372.0.

[0499] Step 5: Preparation of 5-(2,7-dimethyl-2H-indazol-5-yl)-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol trifluoroacetate A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(2,7-dimethyl-2H-indazol-5-yl)phenol trifluoroacetate (119.55 mg, 246.25 μmol) and formaldehyde (73.94 mg, 2.46 mmol) in methanol was stirred at ambient temperature for 2 h. Sodium cyanoborohydride (46.43 mg, 738.76 μmol) was added and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and the precipitate formed was filtered and purified by HPLC to give 5-(2,7-dimethyl-2H-indazol-5-yl)-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol trifluoroacetate (22.0 mg, Y: 17.9%). ESI-MS (M+H)+: 386.2. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.54(d,J=9.2 Hz,1H),8.36(s,1H),8.07(d,J=8.2 Hz,1H),7.91(d,J=9.1 Hz,1H),7.85(s,1H),7.39(s,1H),7.31-7.22(m,2H),4.18(s,3H),4.11-3.82(m,2H),3.70-3.60(m,3H),2.29(s,3H).

[0500] Example 28. 5-(7-Methoxy-2-methyl-2H-indazol-5-yl)-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 28) [ka] Step 1: Preparation of 5-[4-bromo-3-(methoxymethoxy)phenyl]-7-methoxy-2-methyl-2H-indazole 1-Bromo-4-iodo-2-(methoxymethoxy)benzene (761.86 mg, 2.22 mmol), 7-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (800.0 mg, 2.78 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (90.71 mg, 111.07 μmol), and potassium carbonate (614.03 mg, 4.44 mmol) in dioxane (10 mL) and water (2 mL) were degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, EtOAc (15 mL) was added, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by CC (Hex / EtOAc 1 / 1) to give 5-[4-bromo-3-(methoxymethoxy)phenyl]-7-methoxy-2-methyl-2H-indazole (370.0 mg, 980.83 μmol, 44.2% yield). ESI-MS (M+H)+: 378.2. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.34(s,1H),7.64(d,J=8.3,1H),7.49(d,J=9.1,2H),7.36-7.20(m,1H),6. 85(s,1H),5.42(s,2H),4.15(s,3H),3.99(s,3H),3.41(s,3H),3.32(s,1H).

[0501] Step 2: Preparation of 7-methoxy-5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-2H-indazole A solution of 5-[4-bromo-3-(methoxymethoxy)phenyl]-7-methoxy-2-methyl-2H-indazole (365.0 mg, 967.57 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (245.98 mg, 968.66 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (79.1 mg, 96.87 μmol), and potassium acetate (190.13 mg, 1.94 mmol) in dioxane (10 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was evaporated to give crude 7-methoxy-5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-2H-indazole (290.0 mg), which was used in the next step without purification. ESI-MS (M+H)+: 425.2.

[0502] Step 3: Preparation of tert-butyl 3-6-[4-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate A solution of 7-methoxy-5-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-2H-indazole (290.53 mg, 684.72 μmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (92.34 mg, 342.36 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.96 mg, 34.24 μmol), and potassium carbonate (94.63 mg, 684.72 μmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with Ar. The resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with MTBE (15 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the crude, which was purified by preparative HPLC to give tert-butyl 3-6-[4-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (29.0 mg, Y: 12.7%). ESI-MS (M+H)+: 532.2.

[0503] Step 4: Preparation of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(7-methoxy-2-methyl-2H-indazol-5-yl)phenol trifluoroacetate To a solution of tert-butyl 3-6-[4-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-(methoxymethoxy)phenyl]pyridazin-3-ylazetidine-1-carboxylate (29 mg, 54.64 μmol) in dichloromethane (3 mL), 2,2,2-trifluoroacetic acid (122.87 mg, 1.08 mmol) was added and the mixture was stirred overnight. The mixture was then evaporated to dryness under reduced pressure to give crude 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(7-methoxy-2-methyl-2H-indazol-5-yl)phenol trifluoroacetate (28.0 mg, 96.0% purity, 53.6 μmol, 98.1% yield), which was used in the next step without purification. ESI-MS (M+H)+: 388.2.

[0504] Step 5: Preparation of 5-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol trifluoroacetate A solution of 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-(7-methoxy-2-methyl-2H-indazol-5-yl)phenol trifluoroacetate (28.0 mg, 53.6 μmol) and formaldehyde (45.68 mg, 1.52 mmol, 40.0 μl, 10.0 equiv.) in methanol was stirred at ambient temperature for 2 hours. Sodium cyanoborohydride (10.9 mg, 173.43 μmol) was added and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water and the precipitate formed was filtered and purified by HPLC to give 5-(7-methoxy-2-methyl-2H-indazol-5-yl)-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol trifluoroacetate (6.7 mg, Y: 21.4%). ESI-MS(M+H)+:402.0.

[0505] Example 29. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-{2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl}phenol (Compound 29) [ka] Step 1: Preparation of 5-(4-bromo-3-(methoxymethoxy)phenyl)-2,7-dimethylpyrazolo[1,5-a]pyridine 1,4-Dioxane / H 2 1-Bromo-4-iodo-2-(methoxymethoxy)benzene (1.23 g, 3.6 mmol), 2,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (956 mg, 3.6 mmol), Na in O (110 mL / 11 mL). 2 CO 3 (1.13 g, 1.08 mmol), and Pd(dppf)Cl 2 (262 mg, 0.36 mmol) was stirred at 80° C. for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (150 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 Drying at 40° C. and evaporation gave the crude title compound. The crude was purified by silica gel column chromatography (PE / EA=5:1) to give the title compound (360 mg, 30% yield) as a yellow solid. ESI-MS (M+H)+: 361.1. 1 H NMR (400 MHz, CDCl 3 )δ 7.60(d,J=8.2 Hz,1H),7.49(s,1H),7.39(d,J=1.8 Hz,1H),7.15(dd,J=8.2,1.9 Hz,1H),6.74(s,1H),6.37(s,1H),5.33(s,2H),3.57(s,3H),2.78(s,3H),2.54(s,3H).

[0506] Step 2: Preparation of 5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,7-dimethylpyrazolo[1,5-a]pyridine 5-(4-bromo-3-(methoxymethoxy)phenyl)-2,7-dimethylpyrazolo[1,5-a]pyridine (360 mg, 9.7 mmol) in 1,4-dioxane (35 mL), B 2 Pin 2 (2 g, 7.76 mmol), KOAc (480 mg, 4.85 mmol), and Pd(dppf)Cl 2 (140 mg, 0.196 mmol) was stirred at 110° C. for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 Drying at 400° C. and evaporation gave the crude title compound. The crude was purified by silica gel column chromatography (PE / EA=2:1) ​​to give the title compound (360 mg, 90% yield) as a yellow solid. ESI-MS (M+H)+: 409.1. 1 H NMR (400 MHz, CDCl 3 )δ 7.78(d,J=8.2 Hz,1H),7.60-7.47(m,1H),7.29(dd,J=11.3,4.4 Hz,2H),6.80(s,1H),6.37(s,1H),5.28(s,2H),3.56(s,3H),2.78(s,3H),2.54(s,3H),1.37(s,12H).

[0507] Step 3: Preparation of tert-butyl 3-(6-(4-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate 1,4-Dioxane / H 2 5-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,7-dimethylpyrazolo[1,5-a]pyridine (360 mg, 0.88 mmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (236.7 mg, 0.88 mmol), K 2 CO 3 (364.32 mg, 2.64 mmol), and Pd(dppf)Cl2 (64 mg, 0.088 mmol) was stirred at 80° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine and diluted with Na 2 SO 4 The crude was purified by HPLC using C18-flash (0.1% FA in water / CH 3 CN) to give the title compound (240 mg, 52.8% yield) as a yellow solid. ESI-MS (M+H)+: 516.4. 1 H NMR (400 MHz, CDCl 3 )δ 8.09(d,J=2.1 Hz,1H),8.07(d,J=2.9 Hz,1H),7.60(s,1H),7.53(d,J=8.8 Hz,2H),7.47(dd,J=8.1,1.6 Hz,1H),6.85(s,1H),6.41(s,1H),5.31(s,2H),4.47-4.39(m,2H),4.35-4.23( m,2H),4.20-4.06(m,1H),3.50(s,3H),2.81(s,3H),2.55(s,3H),1.48(s,9H).

[0508] Step 4: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)phenol To a solution of tert-butyl 3-(6-(4-(2,7-dimethylpyrazolo[1,5-a]pyridin-5-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (240 mg, 0.48 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature. The reaction mixture was stirred for 24 h. The reaction mixture was diluted with DCM (100 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (0.05% TFA in water / CH 3 CN) to give the title compound (180 mg, Y: 79%) as a yellow solid. ESI-MS (M+H)+: 372.2. 1 H NMR (400 MHz, DMSO-d 6)δ 8.94-8.92(m,2H),8.59(d,J=9.1 Hz,1H),8.16(d,J=8.2 Hz,1H),7.92(d,J=9.1 Hz,1H),7.90(s,1H),7.47-7.44(m,2H),7.18(s,1H),6.52(s,1H),4.45-4.31(m,5H),2.73(s,3H),2.45(s,3H).

[0509] Example 30. 5-{2,8-dimethylimidazo[1,2-b]pyridazin-6-yl}-2-[6-(1-methylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 30) [ka] Step 1: Preparation of 6-(4-bromo-3-(methoxymethoxy)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine Dioxane:H 2 A mixture of (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (1.47 g, 4.29 mmol) and 1-bromo-4-iodo-2-(methoxymethoxy)benzene (836 mg, 4.31 mmol) in 200 (20 mL:5 mL) was added to Pd(dppf)Cl 2 (315 mg, 0.43 mmol) and K 2 CO 3 (1.77 g, 12.80 mmol) was added. The mixture was stirred at 50° C. for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=1:1) to give the title product (0.7 g, Y: 45.22%) as a brown solid. ESI-MS (M+H+): 363.9. 1 H NMR (400 MHz, CDCl 3 )δ 7.75(d,J=6.8 Hz,1H),7.73(s,1H),7.66(d,J=8.3 Hz,1H),7.44(d,J=8.2 Hz,1H),7.19(s,1H),5.37(s,2H),3.57(s,3H),2.70(s,3H),2.53(s,3H).

[0510] Step 2: Preparation of 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine 6-(4-bromo-3-(methoxymethoxy)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine (605 mg, 1.68 mmol) in dioxane (20 mL) and B 2 pin 2 A mixture of (5.12 g, 20.17 mmol) Pd(dppf)Cl 2 (409 mg, 0.56 mmol) and KOAc (2.74 g, 27.98 mmol) were added. The mixture was backfilled with Ar three times and stirred at 95° C. for 16 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (PE:EA=1:1) to give the title product (425 mg, Y: 59.52%) as a brown solid. ESI-MS (M+H+): 410.1. 1 H NMR (400 MHz, CDCl 3 )δ 7.80(d,J=7.7 Hz,1H),7.76(s,1H),7.61(s,1H),7.55(d,J=8.5 Hz,1H),7.24(s,1H),5.31(s,2H),3.57(s,3H),2.70(s,3H),2.53(s,3H),1.38(s,12H).

[0511] Step 3: Preparation of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate Dioxane:H 2 To a mixture of 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,8-dimethylimidazo[1,2-b]pyridazine (425 mg, 1.04 mmol) and tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (300 mg, 1.12 mmol) in 200 (20 mL:5 mL), Pd(dppf)Cl 2(80 mg, 0.11 mmol) and K 2 CO 3 (431 mg, 3.12 mmol) was added. The mixture was stirred at 80° C. for 2 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM:MeOH=40:1) to give the title product (200 mg, Y: 38.76%) as a yellow solid. ESI-MS (M+H+): 517.2.

[0512] Step 4: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)phenol A mixture of tert-butyl 3-(6-(4-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(methoxymethoxy)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (200 mg, 0.39 mmol) in TFA (10 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give the title product (125 mg, Y: 86.21%) as a yellow solid. ESI-MS (M+H+): 373.1. 1 H NMR (400 MHz, MeOD-d 4 )δ 8.48(d,J=9.1 Hz,1H),8.25(s,1H),8.17-8.11(m,2H),7.81(d,J=9.0 Hz,1H),7.77(d,J=1.6 Hz,1H),7.76-7.72(m,1H),4.55-4.49(m,5H),2.77(s,3H),2.62(s,3H).

[0513] Step 5: Preparation of 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(6-(1-methylazetidin-3-yl)pyridazin-3-yl)phenol hydrochloride 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.11 mmol) and (HCHO) in MeOH (10 mL) and HOAc (1 drop). n (28 mg, 0.93 mmol) was added to a mixture of NaBH3 CN (35 mg, 0.56 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was diluted with water (0.5 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (0.05% HCl / CH in water). 3 CN) to give the title product (7 mg, Y: 16.49%) as a yellow solid. ESI-MS (M+H+): 387.2. 1 H NMR (400 MHz, MeOD-d 4 )δ 8.73-8.67(m,1H),8.34(s,1H),8.29(s,1H),8.20-8.12(m,2H),7.85(s,1H),7.71( s,1H),4.59-4.48(m,3H),3.10(s,3H),3.06-3.00(m,2H),2.82(s,3H),2.67(s,3H).

[0514] Example 31. 2-[6-(azetidin-3-yl)pyridazin-3-yl]-5-{2-methylimidazo[1,2-b]pyridazin-6-yl}phenol (Compound 31) [ka] Step 1: Preparation of 6-chloro-2-methylimidazo[1,2-b]pyridazine To a solution of 6-chloropyridazin-3-amine (9.3 g, 72 mmol) in EtOH (200 mL) was added 1-bromopropan-2-one (19.8 g, 144 mmol) in EtOH (20 mL). The mixture was stirred at 90° C. for 16 h. The reaction mixture was concentrated and to the residue was added 2M aqueous NaOH (150 mL) and then stirred at room temperature for 2 h. The precipitate was filtered and concentrated in vacuum. The filter cake was dispersed in MTBE (200 mL), stirred at room temperature for 2 h, filtered with PE:MTBE=1:1 (200 mL:200 mL) and dried in vacuum to give the title product (8.2 g, Y: 68.0%) as a grey solid. ESI-MS (M+H)+: 168.1. 1 H NMR (400 MHz, CDCl 3)δ 7.79(d,J=9.4 Hz,1H),7.71(s,1H),7.00(d,J=9.4 Hz,1H),2.50(s,3H).

[0515] Step 2: Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine 6-Chloro-2-methylimidazo[1,2-b]pyridazine (5.2 g, 31 mmol) in 1,4-dioxane (250 mL), B 2 (Pin) 2 (15.8 g, 62 mmol) and KOAc (9.1 g, 93 mmol) were added to a solution of Pd(dppf)Cl 2 (2.5 g, 3.1 mmol) was added. The mixture was then heated under reduced pressure with N 2 The mixture was stirred at 90° C. for 4 h under reduced pressure. The reaction mixture was used directly without purification. ESI-MS (M+H)+: 178.1.

[0516] Step 3: Preparation of 6-(4-bromo-3-(methoxymethoxy)phenyl)-2-methylimidazo[1,2-b]pyridazine 1,4-Dioxane:H 2 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (2.50 g, 14 mmol), 1-bromo-4-iodo-2-(methoxymethoxy)benzene (5.00 g, 14 mmol) and K in O (250 mL:25 mL). 2 CO 3 (5.70 g, 42 mmol) was added to a solution of Pd(dppf)Cl 2 (1.14 g, 1.4 mmol) was added. The mixture was diluted with N 2 The mixture was stirred under reduced pressure at 50° C. for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA=10:1) to give the title product (2.0 g, Y: 40.8%) as a black solid. ESI-MS (M+H)+: 349.7.

[0517] Step 4: Preparation of 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-b]pyridazine 6-(4-bromo-3-(methoxymethoxy)phenyl)-2-methylimidazo[1,2-b]pyridazine (1.90 g, 5.40 mmol) in 1,4-dioxane (150 mL), B 2 (Pin) 2 (27.6 g, 109 mmol) and KOAc (5.29 g, 54 mmol), Pd(dppf)Cl 2 (310 mg, 0.38 mmol) was added. The mixture was stirred at 110° C. under N2 for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (PE:EA=10:1) to give the title product (912 mg, Y: 42.4%) as a yellow solid. ESI-MS (M+H)+: 396.2. 1 H NMR (400 MHz, CDCl 3 )δ 7.91(d,J=9.4 Hz,1H),7.83-7.79(m,2H),7.64(d,J=1.3 Hz,1H),7.57-7.54(m,1H),7.44(s,1H),5.31(s,2H),3.56(s,3H),2.52(s,3H),1.38(s,12H).

[0518] Step 5: Preparation of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methylimidazo[1,2-b]pyridazin-6-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate 1,4-Dioxane:H 2 6-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylimidazo[1,2-b]pyridazine (900 mg, 2.27 mmol), tert-butyl 3-(6-chloropyridazin-3-yl)azetidine-1-carboxylate (610 mg, 2.27 mmol) and K in 100 mL:10 mL of O 2 CO 3(939 mg, 6.81 mmol) of Pd(dppf)Cl 2 (179 mg, 0.22 mmol) was added. The mixture was diluted with N 2 The mixture was stirred at 80° C. for 1 h under reduced pressure. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=5:1) to give the title product (450 mg, Y: 39.4%) as a yellow solid. ESI-MS (M+H)+: 503.1.

[0519] Step 6: Preparation of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2-methylimidazo[1,2-b]pyridazin-6-yl)phenol trifluoroacetate A solution of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(2-methylimidazo[1,2-b]pyridazin-6-yl)phenyl)pyridazin-3-yl)azetidine-1-carboxylate (50 mg, 0.09 mmol) in TFA (2.5 mL) was stirred at room temperature for 5 h. The mixture was concentrated and purified by preparative HPLC (0.05% TFA in water / CH 3 CN) to give the title product (25.28 mg, Y: 70.9%) as a grey solid. ESI-MS (M+H)+: 359.0. 1 H NMR (400 MHz, MeOD-d 4 )δ 8.49(d,J=9.1 Hz,1H),8.32(d,J=9.6 Hz,1H),8.28-8.23(m,2H),8.17(d,J=8.4 Hz,1H),7.81(d,J=9.2 Hz,2H),7.78-7.75(m,1H),4.56-4.51(m,5H),2.62(d,J=0.7 Hz,3H).

[0520] Example 32. 5-{2,8-dimethylimidazo[1,2-a]pyrazin-6-yl}-2-[6-(1-ethylazetidin-3-yl)pyridazin-3-yl]phenol (Compound 32) [ka] Step 1: Preparation of 5-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(6-(1-ethylazetidin-3-yl)pyridazin-3-yl)phenol To a solution of 2-(6-(azetidin-3-yl)pyridazin-3-yl)-5-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)phenol (20 mg, 0.054 mmol) in MeOH (4 mL) was added acetaldehyde (12 mg, 0.27 mmol) and acetic acid (16 mg, 0.27 mmol). The mixture was stirred at room temperature for 1 h, then sodium cyanoborohydride (10 mg, 0.161 mmol) was added under ice bath, the mixture was stirred at room temperature for 3 h, then water (1 mL) was added and the solution was concentrated in vacuo. The...

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: W is —S— or —HC═CH—; R １ H, halogen, hydroxyl, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxyl, C １ -C ６ Haloalkoxyl, (CH ２ ) 0-2 C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , or (CH ２ ) ０－２ heterocyclyl, wherein the heterocyclyl is a 4- to 7-membered ring and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and said alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C ３ -C ８ optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R ２ is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and said aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R ４ optionally replaced by Each R ３ are independently halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), or N(C １ -C ６ alkyl) ２ wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH ２ optionally replaced by Each R ４ are independently selected from halogen, hydroxyl, cyano, nitro, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxyl, C １ -C ６ Haloalkoxyl, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , or C(O)NH ２ wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH ２ , NH(C １ -C ６ alkyl), or N(C １ -C ６ alkyl) ２ optionally replaced by R ５ But H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, CH ２ C ３ -C ８ Cycloalkyl, heterocyclyl, CH ２ Heterocyclyl, CH ２ CH ２ heterocyclyl, CH2 (5-6 membered heteroaryl), where the heterocyclyl is a 4-7 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R ５ is one or more halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, Spiro C ３ -C ８ optionally substituted with cycloalkyl, spiro 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, oxo, cyano, or hydroxyl; R ６ H, halogen, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, R ７ H, halogen, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1 of formula (Ic): 【Chemistry 2】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R １ H, halogen, hydroxyl, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxyl, C １ -C ６ Haloalkoxyl, (CH ２ ) 0-2 C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , or (CH ２ )0-2 heterocyclyl, wherein the heterocyclyl is a 4- to 7-membered ring and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and wherein said alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C ３ -C ８ optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R ２ is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and said aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R ４ optionally replaced by Each R ３ are independently halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), or N(C １ -C ６ alkyl) ２ wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH ２ optionally replaced by Each R ４ are independently selected from halogen, hydroxyl, cyano, nitro, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxyl, C １ -C ６ Haloalkoxyl, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , or C(O)NH ２ wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from one or more hydroxyl, N, O, and S, NH ２ , NH(C １ -C ６ alkyl), or N(C １ -C ６ alkyl) ２ optionally replaced by R ５ But H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, —CH ２ C ３ -C ８ Cycloalkyl, heterocyclyl, CH ２ Heterocyclyl, CH ２ CH ２ heterocyclyl, CH2 (5-6 membered heteroaryl), where the heterocyclyl is a 4-7 membered ring and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S; R ５ is one or more halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, Spiro C ３ -C ８ optionally substituted with cycloalkyl, spiro 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, oxo, cyano, or hydroxyl; R ６ H, halogen, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, R ７ H, halogen, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5.

3. The compound according to claim 1 of formula (Id): 【Transformation 3】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: W is —S— or —HC═CH—; R １ H, halogen, hydroxyl, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxyl, C １ -C ６ Haloalkoxyl, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ or a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein said alkyl, alkenyl, alkynyl, alkoxyl, cycloalkyl, and heterocyclyl are each independently selected from one or more C ３ -C ８ optionally substituted with cycloalkyl, aryl, or 4-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R ２ is an aryl, a 5- to 7-membered cycloalkyl, a 5-, 6-, or 9-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 5-, 6-, or 9-membered heteroaryl containing 2, 3, or 4 heteroatoms independently selected from N, O, and S, and said aryl, cycloalkyl, heterocyclyl, or heteroaryl is selected from one or more R ４ optionally replaced by Each R ３ are independently halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), or N(C １ -C ６ alkyl) ２ wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are each independently selected from the group consisting of one or more hydroxyl or NH ２ optionally replaced by Each R ４ are independently selected from halogen, hydroxyl, cyano, nitro, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxyl, C １ -C ６ Haloalkoxyl, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , or C(O)NH ２ wherein the alkyl, alkenyl, alkynyl, alkoxyl, and cycloalkyl are selected from one or more hydroxyl, 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, NH ２ , NH(C １ -C ６ alkyl), or N(C １ -C ６ alkyl) ２ optionally replaced by R ５ But H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, —CH ２ C ３ -C ８ Cycloalkyl, heterocyclyl, —CH ２ Heterocyclyl, —CH ２ CH ２ Heterocyclyl, —CH ２ -(5- to 6-membered heteroaryl), wherein the heterocyclyl is a 4- to 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; and R ５ is one or more halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Alkoxyl, C ３ -C ８ Cycloalkyl, Spiro C ３ -C ８ optionally substituted with cycloalkyl, spiro 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, oxo, cyano, or hydroxyl; The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, or 5.

4. The compound is a compound of formula (Ia): 【Chemistry 4】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

5. The compound is a compound of formula (Ib): 【Transformation 5】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

6. The compound is a compound of formula (Ie): 【Transformation 6】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

7. The compound is a compound of formula (If), 【Transformation 7】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

8. R １ is H or F, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

9. R ２ but, 【Transformation 8】 and In the formula, each R ８ But independently, R ４ 2. The compound of claim 1, wherein:

10. Each R4 is independently halogen, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ alkoxy, preferably each R4 is independently F, Me, Et, CF ３ 10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,

11. R ２ but, 【Chemistry 9】 2. The compound of claim 1, wherein:

12. R ４ is Me, Et, F, or CF ３ 11. The compound of claim 10, wherein:

13. R ５ But H, C １－ C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is alkyl, R is aryl ...

14. R ５ is H, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

15. 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] [Transformation 10-5] 【Chemistry 10-6】 【Chemistry 10-7】 [Transformation 10-8] 【Chemistry 10-9】 【Chemistry 10-10】 【Chemistry 10-11】 [Chemistry 10-12] [Chemistry 10-13] [Chemistry 10-14] [Chemistry 10-15] [Chemistry 10-16] 【Chemistry 10-17】 [Chemistry 10-18] [Chemistry 10-19] [Chemistry 10-20] 【Chemistry 10-21】 [Chemistry 10-22] [Chemistry 10-23] [Chemistry 10-24] [Chemistry 10-25] [Chemistry 10-26] [Chemistry 10-27] [Chemistry 10-28] [Chemistry 10-29] [Chemistry 10-30] 【Chemistry 10-31】 【Chemistry 10-32】 【Chemistry 10-33】 【Chemistry 10-34】 [Chemistry 10-35] 【Chemistry 10-36】 【Chemistry 10-37】 [Chemistry 10-38] [Chemistry 10-39] [Chemistry 10-40] 【Chemistry 10-41】 【Chemistry 10-42】 【Chemistry 10-43】 [Chemistry 10-44] [Chemistry 10-45] [Chemistry 10-46] [Chemistry 10-47] [Chemistry 10-48] [Chemistry 10-49] [Chemistry 10-50] 【Chemistry 10-51】 【Chemistry 10-52】 【Chemistry 10-53】 [Chemistry 10-54] 【Chemistry 10-55】 [Chemistry 10-56] 【Chemistry 10-57】 [Chemistry 10-58] [Chemistry 10-59] [Chemistry 10-60] 【Chemistry 10-61】 【Chemistry 10-62】 【Chemistry 10-63】 [Chemistry 10-64] 【Chemistry 10-65】 【Chemistry 10-66】 【Chemistry 10-67】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from:

16. A composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as a therapeutically active substance.

17. 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is a small molecule splicing modulator.

18. 16. A pharmaceutical composition for use in treating a disease in a subject in need thereof, comprising the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable excipients, wherein the disease is ALS, Alzheimer's disease, argyrophilic grain disease, corticobasal degeneration, cystic fibrosis, dilated cardiomyopathy, Duchenne muscular dystrophy, Ehler-Danlos syndrome, Fabry disease, familial dysautonomia, familial hypercholesterolemia, or familial persistent hyperinsulinemia. the pharmaceutical composition is selected from the group consisting of chronic hypoglycemia, frontotemporal dementia, FTDP-17, Gaucher disease, glial spheroid inclusion body tauopathy, HIV-1, Huntington's disease, Hutchinson-Gilford progeria syndrome, hypercholesterolemia, Leber's congenital amaurosis, migraine, multiple sclerosis, myelodysplastic syndrome, NASH, Niemann-Pick disease, pain, Parkinson's disease, phenylketonuria, Pick's disease, progressive supranuclear palsy, spinal muscular atrophy, spinocerebellar ataxia type 2, Wilson's disease, sickle cell anemia, Crohn's disease, ulcerative colitis, psoriasis, and rheumatoid arthritis.

19. 19. The pharmaceutical composition of claim 18, wherein the disease is Huntington's disease.

20. A pharmaceutical composition for use in treating a disease in a subject in need thereof, comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable excipients, wherein the disease is a pulmonary disease selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), pulmonary fibrosis, and pulmonary arterial hypertension (PAH).

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