Heterocyclic amides and methods of use thereof

Abstract

The present disclosure relates to a compound of formula (I) The present invention relates to compounds of TIFF2024540532000504.tif31165 and its subformulas, and to their 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 regulate the splicing of genes encoded by mRNAs, such as pre-mRNAs, and methods of using the compounds to regulate 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 treating diseases or disorders of the human or animal body.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 280,939, filed November 18, 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 development 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 carried out by the spliceosome. Small nuclear RNAs (snRNAs) are essential components of the spliceosome. The main spliceosome, containing U1, U2, U4, U5, and U6 snRNAs, catalyzes the removal of approximately 95% of human introns. 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- 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. Additionally, there are intronic splicing enhancers (ISEs), intronic splicing silencers (ISSs), exonic splicing enhancers (ESEs), and exonic splicing enhancers (ESSs), which are recognized by numerous 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 1,600 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 approximately 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, viral-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, particularly the brain. Small molecule drugs, with excellent pharmacokinetics, effective delivery, and bioavailability, have only recently become available to modulate RNA splicing. However, current molecules are limited to a few chemical series. Therefore, there is a great need to develop additional small molecule splicing modulators (SMSMs).

[0005] Nearly 50 genetic disorders in humans result from an increase in the number of copies of a single repeat in genomic DNA. These DNA repeats appear prone to such expansions because they have abnormal structural properties that disrupt cellular replication, repair, and recombination mechanisms. The presence of expanded DNA repeats alters gene expression in human cells, leading to disease.

[0006] One of these genetic disorders is Huntington's disease (HD). HD is a fatal neurodegenerative disorder with no cure, accompanied by cognitive impairment, dementia, and loss of motor coordination. It is characterized by a progressive and heritable increase in the length of CAG trinucleotide repeats, which encode polyglutamine expansions, in the Huntington gene (HTT) coding region. These repeats can increase from one generation to the next. Normal alleles of the HTT gene contain fewer than 36 CAG repeats, while mutant alleles contain more than 36 repeats. Most HD patients have one normal allele and one mutant allele that cause the disease. Functionally, the abnormal accumulation of CAG repeats is thought to result in a deleterious gain of function in the mutant HD protein, leading to aggregation, the formation of protein deposits (i.e., inclusion bodies), and the induction of cell death. The severity of the disease generally reflects the extent of the repeat expansion in the mutant HTT protein.

[0007] Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are associated with long poly-CUG and poly-CCUG repeats in the 3'-UTR and intron 1 regions of the transcripts of myotonic dystrophy protein kinase (DMPK) and zinc finger protein 9 (ZNF9), respectively. Normal individuals have up to 30 CTG repeats, while DMI patients have higher repeat numbers, ranging from 50 to several thousand. Disease severity and age of onset correlate with the number of repeats. Adult-onset patients exhibit mild symptoms and have fewer than 100 repeats, while juvenile-onset DM1 patients have up to 500 repeats, and congenital cases typically have approximately 1,000 CTG repeats. Expanded transcripts containing CUG repeats form secondary structures, accumulate as nucleoli, and sequester RNA-binding proteins (RNA-BPs).

[0008] In addition to the extra copy of the repeat inherited at birth, in many repeat expansion disorders, the repeats are highly unstable, and the repeat number continues to expand throughout the patient's lifetime. Experimental studies have shown that this repeat instability is mediated by proteins in the DNA mismatch repair (MMR) process, including PMS1, MLH1, and MSH3. Human genetic data from genome-wide association studies have shown that variants in MMR proteins are associated with clinically relevant HD symptoms, including age at progression, rate of progression, and somatic instability. Knockdown and knockout of MMR genes has been shown to halt or slow somatic repeat expansion in various preclinical models of repeat expansion disorders. Therefore, there is a need for splicing modulators of MMR genes as potential therapeutic agents for treating various repeat expansion disorders. Summary of the Invention [Means for solving the problem]

[0009] Here, we describe a series of novel small molecule splicing modulators (SMSMs) that can be used to treat a wide variety of diseases, including neurodegenerative and repeat expansion disorders. These SMSMs target regions of primary RNA transcripts 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. Bulges can occur naturally or be caused by disease. When SMSMs contact an RNA transcript, they can be bound by spliceosomes or other trans-factors, most notably RNA-binding proteins (RBPs). The SMSMs reported herein can cause changes in the sequence or abundance of the mature transcript, which can result in differences in the sequence or abundance of a functional protein if the transcript is protein-coding, or in the sequence or abundance of a functional RNA if the transcript is non-coding.

[0010] In some embodiments, the present disclosure provides, inter alia, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N or CR 1 and Y is N or CR 2 and Z is N or CR 3 and R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, hydroxy, cyano, —COOH, —C(O)—Ci-C6 alkyl, —C(O)O—Ci-C6 alkyl, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, Ci-C6 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(Ci-C6 alkyl), N(Ci-C6 alkyl), —NHC(O)—Ci-C6 alkyl, —N(Ci-C6 alkyl)—C(O)—Ci-C6 alkyl, —C(O)—NH, —C(O)—NH(Ci-C6 alkyl), and —C(O)—N(Ci-C6 alkyl) wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; R 5 is H, C1-C6 alkyl, or C1-C6 haloalkyl; A, [ka] is selected from the group consisting of A is 1 to 4 R 9 optionally replaced by R 6 is C1-C3 alkyl or C1-C3 haloalkyl; R 7is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, or heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl; R 8 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 cycloalkyl; Each R 9 are independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; B is not attached to formula (I) by a nitrogen atom and has 1 to 6 R 12 or a heterocycloalkyl optionally substituted with B is NR 10 R 11 and R 10 But -(CH2) 0-3 Aryl, -(CH2) 0-3 Heteroaryl, -(CH2) 0-3 heterocycloalkyl (containing at least one nitrogen ring atom), or C1-C8 heteroalkyl (containing at least one nitrogen atom), and each R 10 However, 1 to 6 R 12 optionally replaced by R 11 But hydrogen, C 1-7 Alkyl, C 1-7 Haloalkyl, or C3-8 cycloalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, and the heterocycloalkyl is selected from 1 to 6 R 12 optionally replaced by Each R 12 are independently selected from halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(CH2) 0-2 -C3-C8 cycloalkyl, -(CH2) 0-2 -SO2-C1-C6 alkyl, C1-C6 heteroalkylene-C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, C1-C6 heteroalkylene-(4-7 membered monocyclic heterocycloalkyl), -O-(4-7 membered monocyclic heterocycloalkyl), -(CH2) 0-2 -(4-7 membered monocyclic heterocycloalkyl), -NH, NH(C-C alkyl), N(C-C alkyl), -NHC(O)-C-C alkyl, -N(C-C alkyl)-C(O)-C-C alkyl, -C(O)-NH, -C(O)-NH(C-C alkyl), and -C(O)-N(C-C alkyl), wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, or NH; and cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C-C alkyl, C-C heteroalkyl, C-C alkoxy, or NH; or Two R on the same carbon 12 can be combined as keto (=O), or a pharmaceutically acceptable salt thereof.

[0011] In some aspects, the disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described herein).

[0012] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable diluent or carrier.

[0013] In some aspects, the present 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).

[0014] 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 pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0015] In some aspects, the present disclosure provides a method of treating 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 pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0016] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

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

[0018] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating or preventing a disease or disorder disclosed herein.

[0019] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating a disease or disorder disclosed herein.

[0020] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0021] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

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

[0023] In some aspects, the disclosure provides methods for preparing compounds comprising one or more of the steps described herein.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure 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 control. Additionally, the materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0025] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0026] The compounds described herein are generally designed to treat the diseases and disorders disclosed herein. definition

[0027] Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0028] As used herein, "alkyl," "C1, C2, C3, C4, C5, C6, or C7 alkyl," or "C1-C7 alkyl" is intended to include C1, C2, C3, C4, C5, C6, or C7 straight-chain (straight-chain) saturated aliphatic hydrocarbon groups and C3, C4, C5, C6, or C7 branched saturated aliphatic hydrocarbon groups. For example, C1-C7 alkyl is intended to include C1, C2, C3, C4, C5, C6, and C7 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 chain or branched chain alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in other embodiments, a straight chain or branched chain alkyl has 4 or fewer carbon atoms.

[0029] As used herein, "alkenyl" is intended to mean a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2- C6 alkenyl). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2- Examples of C6 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.

[0030] 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- C6 alkynyl). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-Examples of C4 alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.

[0031] 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.

[0032] 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.

[0033] As used herein, "heteroalkyl," "C, C, C, C, C, C, C, or C heteroalkyl," or "C-C heteroalkyl" is intended to include C, C, C, C, C, C, C, C, or C straight-chain (straight-chain) saturated aliphatic hydrocarbon groups and C, C, C, C, C, C, or C branched saturated aliphatic hydrocarbon groups, wherein 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 may be replaced with "O" or "NH," CH may be replaced with N, etc.). Such substituents may include, for example, -O-CH(CH), -CH-N(CH)-CHCHOCH, -S-CHCH-O-CHCH, and the like.

[0034] As used herein, a "heteroalkylene" is a divalent heteroalkyl group having two open valencies. Such substituents can include, for example, -CH2-O-CH2-, -O-CH2CH(CH3)-NH-CH2-, -CH2-O-CH2CH2-S-CH2-, and the like.

[0035] As used herein, the term "alkoxy" 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.

[0036] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10, or C3-C8), a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) 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 polycyclic cycloalkyl, only one of the rings in the cycloalkyl need be non-aromatic.

[0037] As used herein, the term "heterocycloalkyl" or "heterocyclyl," 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 (fused, bridged, or spirocyclic) ring system 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. For polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl must be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0038] As used herein, the term "cycloalkyloxy" refers to an -O-cycloalkyl group, where cycloalkyl is as defined herein. Preferably, cycloalkyloxy is a C-C cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.

[0039] As used herein, the term "aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π 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.

[0040] 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 defined substituent). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p, where p=1 or 2). Note that the total number of S and O atoms in 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).

[0041] 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.

[0042] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can have one or more ring positions (e.g., 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, The aryl and heteroaryl groups may be substituted with carboxyl, 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. Aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0043] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a selection from the designated group, provided that the replacement does not exceed the normal valence of the designated atom, and that the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =0), 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.

[0044] When a bond to a substituent is shown to cross the bond joining two atoms in a ring, then 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, then such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0045] 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 to 2 R moieties, that group may be optionally substituted with up to 2 R moieties, and R at each occurrence is selected independently of the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0046] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH or -O - The group includes a group having the formula:

[0047] As used herein, the term "cyano" refers to the group --CN.

[0048] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0049] As used herein, the term "haloalkyl" refers to a branched or unbranched alkyl substituted with one or more halogens. For example, C 1-7 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, but are not limited to, CFH, CF, CH, CF, CF, C(F)(CH), CHCHBr, CH(I)CHF, and CHCl.

[0050] 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.

[0051] 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," "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.

[0052] It is to be understood that the present disclosure provides methods for the synthesis of any compound of the formula 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.

[0053] It should be understood that throughout this specification, when a composition is described as having, including, or comprising particular 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 particular 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 conducted simultaneously.

[0054] It will be understood 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 pharmaceutically acceptable salt thereof.

[0055] It will be 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 skilled in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. See, for example, but not limited to, any one or more sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001, Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are classic texts incorporated herein by reference and are useful and recognized reference texts in organic synthesis known to those skilled in the art.

[0056] 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 the reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish between similar functional groups in a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0057] Unless otherwise specified, any description of a method of treatment will be understood to include the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds to prepare a medicament for treating or preventing such conditions. Unless otherwise specified, any description of a method of treatment will be understood to include the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds to prepare a medicament for treating such conditions. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0058] As used herein, the term "subject" is interchangeable with the term "subject in need thereof," and both refer to a subject having a disease or at high risk of developing a disease. "Subject" includes mammals. A mammal can 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. A subject can also be a bird or poultry. In one embodiment, the mammal is a human. A subject in need thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be a subject at high risk of developing such a disease or disorder compared to the general population (i.e., a subject who is prone to developing such a disorder compared to the general population). A subject in need thereof can 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 to treatment at the beginning or may become resistant during treatment. In some embodiments, the subject in need thereof has undergone and failed all known effective treatments for the diseases or disorders disclosed herein. In some embodiments, the subject in need thereof has undergone at least one prior treatment.

[0059] 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 pharmaceutically acceptable salt 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.

[0060] 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 onset of clinical symptoms of the health condition, disorder, or condition that develop in a person who may be suffering from 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, alleviating, or delaying the onset or recurrence of the disease (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.

[0061] It is to be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can also be or can be used to prevent the associated disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0062] As used herein, the terms "preventing," "prevent," or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0063] 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 rdedition), 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.

[0064] 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 pharmaceutically acceptable excipient or carrier.

[0065] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure 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 may be in 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 dose composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that routine variations in dosage may be necessary depending on the age and condition of the subject. Dosage also varies depending on 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 this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any required preservatives, buffers, or propellants.

[0066] As used herein, the term "pharmaceutically 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 that are within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0067] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are 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.

[0068] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antimicrobial agent such as benzyl alcohol and methylparaben; an antioxidant such as ascorbic acid and sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, and phosphate; and an agent for adjusting osmolality such as sodium chloride or dextrose. pH can be adjusted with 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.

[0069] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject by 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, can be taken orally, or can be applied through the skin with a patch.The selected dose should be sufficient to constitute effective treatment, but not so high as to cause unacceptable side effects.The disease state (e.g., the disease or disorder disclosed herein) and the subject's health condition should be closely monitored during and for a reasonable period after treatment.

[0070] 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 precise 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.

[0071] A "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.

[0072] It is understood that for any compound, the therapeutically effective amount can be initially estimated either in cell culture assays, e.g., tumor cells, or in 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 using 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 ratio between toxic and therapeutic effects is the therapeutic index, which can be determined by the LD ratio (the dose lethal to 50% of the population). 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.

[0073] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be taken into consideration include the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), reaction sensitivity, and tolerance / response to therapy.

[0074] The pharmaceutical composition containing the active compound of the present disclosure can be prepared by a generally known method, for example, by conventional mixing, dissolving, granulating, dragee making, suspending, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be formulated by a conventional method using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliary agents that facilitate the processing of active compound into pharmaceutically usable preparations.Of course, the appropriate formulation depends on the selected route of administration.

[0075] 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 dispersion. 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 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 (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. 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 dispersions, 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, for example, sugars, polyalcohols (such as mannitol and sorbitol), and sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0076] Sterile injectable 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 ingredients as needed, and then sterilize by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other ingredients required from the above-listed ingredients.For the preparation of sterile powder for sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which produces a powder containing active compound and any additional desired ingredients from its previously sterile-filtered solution.

[0077] Oral compositions generally contain an inert diluent or an edible pharmaceutically 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, allowed to flow in the mouth, and then expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. Tablets, pills, capsules, troches, etc. 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 colloidal silicon dioxide; 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.

[0078] 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, eg, a gas such as carbon dioxide, or a nebulizer.

[0079] Systemic administration can also be via transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams, as generally known in the art.

[0080] The active compounds can be prepared in pharmaceutically acceptable carriers that prevent the compound from being rapidly removed from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available 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 pharmaceutically 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.

[0081] For ease of administration and dosage uniformity, it is particularly advantageous to formulate oral or parenteral compositions in dosage unit form.The unit dosage form used herein refers to a physically separate unit that is 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 the unit dosage form of the present disclosure is determined and directly depends on the unique characteristics of active compound and the specific therapeutic effect that is to be achieved.

[0082] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on, among other factors, the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or medical professional administering the treatment, which will affect the selected dosage. Generally, the dose should be sufficient to alleviate, preferably cause regression, and preferably cause complete regression of the symptoms of the diseases or disorders 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 achieve a desired biological effect in a subject or cell.

[0083] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0084] For compounds of the present disclosure that are capable of further forming salts, it should be understood that all of these forms are also contemplated within the scope of the claimed disclosure.

[0085] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, where the parent compound is modified by making acid or base salts thereof. 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 conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, 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, hydroxynaphthoic acid, and the like. The preferred carboxylic 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, and the like.

[0086] In some embodiments, the pharmaceutically 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.

[0087] Other examples of pharmaceutically 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, alkaline earth ion, or 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, for example, 3:1, 2:1, 1:2, or 1:3.

[0088] The compound, or a pharmaceutically acceptable salt thereof, may be administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingually, 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.

[0089] Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on a substituted compound 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).

[0090] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on a substituted compound disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts thereof containing a quaternary nitrogen atom.

[0091] 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.

[0092] 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 the 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 formed by the combination of one or more water molecules with one molecule of a substance, where water retains its molecular state as HO.

[0093] 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.

[0094] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0095] 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 goal of bioisostere replacement is to create a new compound with similar biological properties as the parent compound. Bioisostere replacement can be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0096] It is also to be understood that a particular compound of any one of the formulas disclosed herein can exist in solvated, e.g., hydrated, and unsolvated forms. Suitable pharmaceutically acceptable solvates are hydrates, e.g., hemihydrate, monohydrate, dihydrate, or trihydrate.

[0097] Reference to formula (I) may include subformulas of formula (I), such as formulas (Ix), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), and (Iq).

[0098] Compounds of any one of the formulas disclosed herein can exist in several different tautomeric forms, and a reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all other compounds are nevertheless encompassed by formula (I). Examples of tautomeric forms include 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 / acintro. [ka]

[0099] Any compound of any one of the formulas disclosed herein that contains an amine functional group can also form an N-oxide. Reference herein to a compound of formula (I) that contains an amine functional group also includes an N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. A specific example of an N-oxide is the N-oxide of a nitrogen atom of a tertiary amine or a nitrogen-containing heterocycle. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977. More specifically, N-oxides can be prepared by the procedure of L.W. 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.

[0100] 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 termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual optical isomeric forms of opposite chirality is termed a "racemic mixture."

[0101] As used herein, the term "chiral center" refers to a carbon atom bonded to four non-identical substituents.

[0102] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having 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. 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).

[0103] As used herein, the term "geometric isomer" 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.

[0104] It is understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers, and 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 understood that the naming of the compound does not mean that all isomers may have the same level of activity.

[0105] 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.

[0106] 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 restricted rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, although recent advances in chromatography have made it possible to isolate mixtures of two atropisomers in selected cases.

[0107] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching 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 possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (annular) form, such as that exhibited by glucose.

[0108] It is understood that the compounds of the present disclosure may be represented as different tautomeric forms. It is also understood that, where a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It is understood that certain tautomers may have a higher level of activity than other tautomers.

[0109] 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 each other are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of optical isomers is possible. An optical isomer can be characterized by the absolute configuration of its asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way 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."

[0110] 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 the present 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 isomers and Z isomers).

[0111] Thus, the present disclosure includes compounds of any one 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 the prodrug. Thus, the present disclosure also includes compounds of any one of the formulas disclosed herein produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, and compounds of any one of the formulas disclosed herein can be synthetically produced compounds or metabolically produced compounds.

[0112] 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 subject's renal and hepatic function, and the particular compound or salt thereof used. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or stop the progression of the condition.

[0113] Techniques for formulation and administration of the disclosed compounds of this disclosure are described 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 pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0114] 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 illustrate different components and methodologies useful for implementing the present disclosure. These examples do not limit the claimed disclosure. Based on the present disclosure, one skilled in the art can identify and employ other components and methodologies useful for implementing the present disclosure.

[0115] In the synthetic schemes described herein, compounds may be depicted 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, nor do they 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.

[0116] All publications and patent documents cited herein are incorporated 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 pertinent prior art, nor does it constitute any admission as to the contents or date thereof. While 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 foregoing description and examples which follow are for purposes of illustration and not limiting the scope of the claims which follow.

[0117] As used herein, the phrase "compounds of the present disclosure" refers generically and specifically to those compounds disclosed herein. Compounds of the Disclosure

[0118] In some embodiments, the present disclosure provides, inter alia, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N or CR 1 and Y is N or CR 2 and Z is N or CR 3 and R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; R 5 is H, C1-C6 alkyl, or C1-C6 haloalkyl; A, [ka] is selected from the group consisting of A is 1 to 4 R 9 optionally replaced by R 6 is C1-C3 alkyl or C1-C3 haloalkyl; R 7is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, or heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl; R 8 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 cycloalkyl; Each R 9 are independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; B is not attached to formula (I) by a nitrogen atom and has 1 to 6 R 12 or a heterocycloalkyl optionally substituted with B is NR 10 R 11 and R 10 But -(CH2) 0-3 Aryl, -(CH2) 0-3 Heteroaryl, -(CH2) 0-3 heterocycloalkyl (containing at least one nitrogen ring atom), or C1-C8 heteroalkyl (containing at least one nitrogen atom), and each R 10 However, 1 to 6 R 12 optionally replaced by R 11 But hydrogen, C 1-7 Alkyl, C 1-7 Haloalkyl, or C3-8 cycloalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1 to 6 R 12 optionally replaced by Each R 12 are independently selected from halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(CH2) 0-2 -C3-C8 cycloalkyl, -(CH2) 0-2 -SO2-C1-C6 alkyl, C1-C6 heteroalkylene-C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, -4- to 7-membered monocyclic heterocycloalkyl, C1-C6 heteroalkylene-(4- to 7-membered monocyclic heterocycloalkyl), -O-(4- to 7-membered monocyclic heterocycloalkyl), -(CH2) 0-2 -(4-7 membered monocyclic heterocycloalkyl), -NH, NH(C-C alkyl), N(C-C alkyl), -NHC(O)-C-C alkyl, -N(C-C alkyl)-C(O)-C-C alkyl, -C(O)-NH, -C(O)-NH(C-C alkyl), and -C(O)-N(C-C alkyl), wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, or NH; and cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C-C alkyl, C-C heteroalkyl, C-C alkoxy, or NH; or Two R on the same carbon 12 can be combined as keto (=O), or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the present disclosure provides, inter alia, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N or CR 1 and Y is N or CR 2 and Z is N or CR 3 and R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; R 5 is H, C1-C6 alkyl, or C1-C6 haloalkyl; A, [ka] is selected from the group consisting of A is 1 to 4 R 9 optionally replaced by R 6 is C1-C3 alkyl or C1-C3 haloalkyl; R 7is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, or heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl; R 8 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 cycloalkyl; Each R 9 are independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; B is NR 10 R 11 and R 10 However, 1 to 6 R 12 containing one nitrogen ring atom optionally substituted with -(CH2) 0-1 is heterocycloalkyl, R 11 But hydrogen, C 1-7 Alkyl, C 1-7 Haloalkyl, or C 3-8 cycloalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, and the heterocycloalkyl is selected from 1 to 6 R 12optionally replaced by Each R 12 are independently selected from halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(CH2) 0-2 -C3-C8 cycloalkyl, C1-C6 heteroalkylene-C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, C1-C6 heteroalkylene-(4-7 membered monocyclic heterocycloalkyl), -O-(4-7 membered monocyclic heterocycloalkyl), -(CH2) 0-2 -(4-7 membered monocyclic heterocycloalkyl), -NH, NH(C-C alkyl), N(C-C alkyl), -NHC(O)-C-C alkyl, -N(C-C alkyl)-C(O)-C-C alkyl, -C(O)-NH, -C(O)-NH(C-C alkyl), and -C(O)-N(C-C alkyl), wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, or NH; and cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C-C alkyl, C-C heteroalkyl, C-C alkoxy, or NH; or Two R on the same carbon 12 can be combined as keto (=O), or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the present disclosure provides, inter alia, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N or CR 1 and Y is N or CR 2 and Z is N or CR 3 and R1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; R 5 is H, C1-C6 alkyl, or C1-C6 haloalkyl; A, [ka] is selected from the group consisting of A is 1 to 4 R 9 optionally replaced by R 6 is C1-C3 alkyl or C1-C3 haloalkyl; R 7 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, or heterocycloalkyl; R 8 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 cycloalkyl; Each R 9are independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; B is NR 10 R 11 and R 10 However, 1 to 6 R 12 containing one nitrogen ring atom optionally substituted with -(CH2) 0-1 is heterocycloalkyl, R 11 But hydrogen, C 1-7 Alkyl, C 1-7 Haloalkyl, or C 3-8 cycloalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, and the heterocycloalkyl is selected from 1 to 6 R 12 optionally replaced by Each R 12 are independently selected from halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(CH2) 0-2or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the present disclosure provides, inter alia, a compound of formula (Ix): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 4 are each independently selected from the group consisting of H, halogen, hydroxy, cyano, —COOH, —C(O)—Ci-C6 alkyl, —C(O)O—Ci-C6 alkyl, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, Ci-C6 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(Ci-C6 alkyl), N(Ci-C6 alkyl), —NHC(O)—Ci-C6 alkyl, —N(Ci-C6 alkyl)—C(O)—Ci-C6 alkyl, —C(O)—NH, —C(O)—NH(Ci-C6 alkyl), and —C(O)—N(Ci-C6 alkyl) wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; R 5 is H, C1-C6 alkyl, or C1-C6 haloalkyl; A, [ka] is selected from the group consisting of A is 1 to 4 R 9 optionally replaced by R 6 is C1-C3 alkyl or C1-C3 haloalkyl; R 7 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, or heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl; R 8 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 cycloalkyl; Each R 9 are independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; B is NR 10 R 11 and R 10 However, 1 to 6 R 12 containing one nitrogen ring atom optionally substituted with -(CH2) 0-1 is heterocycloalkyl, R 11 But hydrogen, C 1-7 Alkyl, C 1-7 Haloalkyl, or C 3-8cycloalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, wherein the heterocycloalkyl is selected from 1 to 6 R 12 optionally replaced by Each R 12 are independently selected from halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(CH2) 0-2 -C3-C8 cycloalkyl, C1-C6 heteroalkylene-C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, C1-C6 heteroalkylene-(4-7 membered monocyclic heterocycloalkyl), -O-(4-7 membered monocyclic heterocycloalkyl), -(CH2) 0-2 -(4-7 membered monocyclic heterocycloalkyl), -NH, NH(C-C alkyl), N(C-C alkyl), -NHC(O)-C-C alkyl, -N(C-C alkyl)-C(O)-C-C alkyl, -C(O)-NH, -C(O)-NH(C-C alkyl), and -C(O)-N(C-C alkyl), wherein alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, or NH; and cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C-C alkyl, C-C heteroalkyl, C-C alkoxy, or NH; or Two R on the same carbon 12 can be combined as keto (=O), or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, 0, 1, or 2 of X, Y, and Z are N.

[0123] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the compound is a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the compound is a compound of formula (Ic): [ka] or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the compound is a compound of formula (Id): [ka] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound is a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compound is a compound of formula (If): [ka] or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, R 1 , R 2 , R3 , and R 4 are each independently selected from the group consisting of H, halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and C-C cycloalkyloxy. 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, C1-C6 alkoxy, and C1-C6 alkyl. 1 , R 2 , R 3 , and R 4 are H, respectively.

[0130] In some embodiments, R 5 is H.

[0131] In some embodiments, A is [ka] is selected from the group consisting of A is 1 to 3 R 9 is optionally replaced by

[0132] In some embodiments, A is [ka] is selected from the group consisting of A is 1 to 3 R 9 is optionally replaced by

[0133] In some embodiments, A is [ka] is selected from the group consisting of A is 1 to 3 R 9 is optionally replaced by

[0134] In some embodiments, A is one R selected from the group consisting of halogen and C1-C6 alkyl. 9 In some embodiments, A is substituted by R 9 is not replaced by

[0135] In some embodiments, R 6 is Me.

[0136] In some embodiments, R 7 is C-C alkyl, C-C cycloalkyl, or heterocycloalkyl. In some embodiments, R 7 is Me, Et, isopropyl, or cyclobutyl.

[0137] In some embodiments, A is [ka] , are selected from the group consisting of.

[0138] In some embodiments, A is [ka] , are selected from the group consisting of.

[0139] In some embodiments, A is [ka] is.

[0140] In some embodiments, A is [ka] is.

[0141] In some embodiments, A is [ka] is.

[0142] In some embodiments, A is [ka] is.

[0143] In some embodiments, A is [ka] is.

[0144] In some embodiments, A is [ka] is.

[0145] In some embodiments, B is NR 10 R 11 and R 10 and R 11 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, and the heterocycloalkyl may contain 1, 2, 3, or 4 R 12 is optionally replaced by

[0146] In some embodiments, R 10 and R 11 together with the nitrogen atom to which they are attached form a monocyclic heterocycloalkyl of 4 to 7 ring atoms containing a total of 1 or 2 nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S, wherein the heterocycloalkyl is selected from 1, 2, 3, or 4 R 12 is optionally replaced by In some embodiments, B is [ka] and W is NR13 or CR 14 R 14 and R 13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and -(CH2) 0-2 -C3-C8 cycloalkyl, wherein alkyl, alkenyl, alkynyl is optionally substituted with one or more halogen, hydroxyl, methoxy, or NH2, and cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or NH2; Each R 14 are independently H or R 12 and n is 0, 1, 2, 3, or 4.

[0147] In some embodiments, each R 12 is independently selected from the group consisting of halogen, hydroxy, 4-7 membered monocyclic heterocycloalkyl, C1-C6 heteroalkyl, and C1-C6 alkyl, wherein alkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH2, and heterocycloalkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, or C1-C6 alkyl; R 13 is H or unsubstituted C1-C6 alkyl.

[0148] In some embodiments, each R 12 is independently selected from the group consisting of halogen, hydroxy, and C1-C6 alkyl, wherein alkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH2; R 13 is H or unsubstituted C1-C6 alkyl.

[0149] In some embodiments, each R 12 is independently C1-C6 alkyl.

[0150] In some embodiments, B is [ka] is.

[0151] In some embodiments, R 13 is H or unsubstituted C1-C6 alkyl.

[0152] In some embodiments, each R 12 is independently C1-C6 alkyl.

[0153] In some embodiments, B is a bicyclic 6-14 membered heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, wherein the heterocycloalkyl is selected from 1, 2, 3, or 4 R 12 is optionally replaced by

[0154] In some embodiments, each R 12 is independently C1-C6 alkyl.

[0155] In some embodiments, B is NR 10 R 11 and R 11 is hydrogen, C 1-7 Alkyl, C 1-7 Haloalkyl, or C 3-8 It is cycloalkyl.

[0156] In some embodiments, R 11 is H or C 1-7 alkyl, and R 10 is a C1-C8 heteroalkyl containing at least one nitrogen atom.

[0157] In some embodiments, R 10 contains at least one nitrogen ring atom -(CH2) 0-3 heterocycloalkyl, and each R 10 is 1 to 6 R 12is optionally replaced by

[0158] In some embodiments, the compound is a compound of formula (Ig): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0159] In some embodiments, the compound is a compound of formula (Ih): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0160] In some embodiments, the compound is a compound of formula (Ii): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0161] In some embodiments, the compound is a compound of formula (Ij): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0162] In some embodiments, the compound is a compound of formula (Ik): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0163] In some embodiments, the compound is a compound of formula (Im): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0164] In some embodiments, the compound is a compound of formula (In): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0165] In some embodiments, the compound is a compound of formula (Io): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0166] In some embodiments, the compound is a compound of formula (Ip): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0167] In some embodiments, the compound is a compound of formula (Iq): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0168] In some embodiments, the compound is a compound of formula (Ir): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0169] In some embodiments, the compound is a compound of formula (Is): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0170] In some embodiments, the compound is a compound of formula (It): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0171] In some embodiments, the compound is a compound of formula (Iu): [ka] , or a pharmaceutically acceptable salt thereof; In the formula, each R 15 are independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0172] In some embodiments, the compound is selected from the compounds in Table 1.

[0173] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0174] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0175] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0176] In some aspects, the disclosure provides methods of preparing compounds comprising one or more of the steps described herein.

[0177] In some embodiments, the compound is selected from the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0178] In some embodiments, the compound is selected from the compounds set forth in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

[0179] For the avoidance of doubt, it is to be understood that, as used herein, when a group is modified by "as described herein," that group encompasses the broadest definition on the first occurrence, as well as each and every specific definition for that group.

[0180] The various functional groups and substituents comprising the compound of formula (I) 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.

[0181] It will be understood that the compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers and mixtures of stereoisomers of the compounds.

[0182] It should be understood that compounds of any formula described herein include the compound itself, as well as salts thereof, and solvates thereof, if applicable.

[0183] The in vivo effects 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 effects of any one of the compounds of the formulas disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug).

[0184] Preferably, the present disclosure excludes any individual compound that does not have biological activity as defined herein. Synthesis method

[0185] By way of example only, schemes for preparing the small molecule splicing modulators (SMSMs) described herein are provided.

[0186] In some embodiments, a scheme for preparing SMSM is set forth herein in Scheme 1 below. [ka]

[0187] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0188] In some aspects, the disclosure provides methods of preparing compounds comprising one or more of the steps described herein.

[0189] In some aspects, the disclosure provides compounds that are obtainable by, obtained by, or obtained directly by the methods for preparing the compounds described herein.

[0190] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein.

[0191] 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.

[0192] 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 experiment, and work-up procedures, can be selected by one of ordinary skill in the art.

[0193] 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.

[0194] 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 this 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, and such methods will be selected to remove the protecting group while minimizing interference with groups elsewhere in the molecule. Thus, when reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0195] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on 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, such as an alkali metal hydroxide, for example, lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups may be removed by treatment with a suitable acid, for example hydrochloric, sulfuric or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups (such as benzyloxycarbonyl groups) 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, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

[0196] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), aroyl groups (e.g., benzoyl), or arylmethyl groups (e.g., benzyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on 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, such as an alkali metal hydroxide, for example, lithium, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation over a catalyst, such as palladium on carbon.

[0197] 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.

[0198] Once a compound of formula (I) has been synthesized 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) to another compound of formula (I), and / or (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0199] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0200] The reaction of the compounds is advantageously 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 ethers, 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 dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate; or mixtures of such solvents, or mixtures with water.

[0201] The reaction temperature is preferably between about -100°C and 300°C, depending on the reaction step and conditions used.

[0202] The reaction time generally ranges from 1 minute to several days, depending on the reactivity of each compound and the reaction conditions. Suitable reaction times can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature described above, suitable reaction times are generally within the range of 10 minutes to 48 hours.

[0203] 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 readily accessible by a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what types of reagents and reaction conditions to use and how to apply and adapt them, whenever necessary or useful, to obtain compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can be readily 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, to convert one specific functional group present in a compound of the present disclosure or a suitable precursor molecule to another functional group, which methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or protecting) 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 P.G.M.Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis," 4th edition (2006) (John Wiley & Sons).

[0204] General routes for preparing the compounds of the present application are described herein. Biological assays

[0205] 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 predicted activity, binding activity, and / or binding specificity. Pharmaceutical Compositions

[0206] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0207] 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 time-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.

[0208] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0209] 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, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin, sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0210] Any suitable chelating agent can be used, examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof. Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as 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 sorbic acid, and mixtures thereof.

[0211] 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.

[0212] 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 crosslinked with polyalkenyl ethers or divinyl glycol (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0213] To adjust the formulation to an acceptable pH (typically in the 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. Therefore, depending on the formulation, it may not be necessary to use both an acid and a base; adding one of the acids or bases may be sufficient to bring the mixture to the desired pH range.

[0214] 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 salts thereof including disodium tetraborate), citrate buffers (such as citric acid or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0215] 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.

[0216] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0217] Compositions of the present 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 creams, ointments, gels, or aqueous or oily solutions or suspensions), 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).

[0218] 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.

[0219] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the disease or disorder referred to herein.

[0220] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with the disease or disorder referred to herein.

[0221] The size of a dose of a compound of formula (I) 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. How to use

[0222] 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 dentatorubral-pallidoluysian atrophy, Huntington's disease, spinal-bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia type 1), SCA2 (Spinocerebellar ataxia type 2), SCA3 (Spinocerebellar ataxia type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia type 6), SCA7 (Spinocerebellar ataxia type 7), SCA12 (Spinocerebellar ataxia type 12), SCA17 (Spinocerebellar ataxia type 18), SCA19 (Spinocerebellar ataxia type 21), SCA20 (Spinocerebellar ataxia type 22), SCA21 (Spinocerebellar ataxia type 23), SCA22 (Spinocerebellar ataxia type 24), SCA23 (Spinocerebellar ataxia type 25), SCA24 (Spinocerebellar ataxia type 26), SCA25 (Spinocerebellar ataxia type 27), SCA26 (Spinocerebellar ataxia type 28), SCA27 (Spinocerebellar ataxia type 29), SCA28 (Spinocerebellar ataxia type 29), SCA29 (Spinocerebellar ataxia type 30), SCA29 (Spinocerebellar ataxia type 31), SCA29 (Spinocerebellar ataxia type 32), SCA29 (Spinocerebellar ataxia type 33), SCA30 (Spinocerebellar ataxia type 34), SCA31 (Spinocerebellar ataxia type Provided herein are methods for treating spinocerebellar ataxia type 17, FRAXA (Fragile X syndrome), FXTAS (Fragile X-associated tremor / ataxia syndrome), FRAXE (Fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich ataxia), DM1 (myotonic dystrophy type 1), DM2 (myotonic dystrophy type 2), SCA8 (Spinocerebellar ataxia type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, frontotemporal dementia.

[0223] In some embodiments, the disease is Huntington's disease.

[0224] 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 described herein, wherein the disease is Huntington's disease.

[0225] In some embodiments, the disease is myotonic dystrophy 1.

[0226] 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 described herein, wherein the disease is myotonic dystrophy 1.

[0227] In some embodiments, the disease is selected from the group consisting of FRAXA (Fragile X Syndrome), FXTAS (Fragile X Associated Tremor / Ataxia Syndrome), FRAXE (Fragile XE Mental Retardation).

[0228] 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 described herein, wherein the disease is selected from the group consisting of FRAXA (Fragile X Syndrome), FXTAS (Fragile X-associated Tremor / Ataxia Syndrome), and FRAXE (Fragile XE Mental Retardation). Route of administration

[0229] 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).

[0230] 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 nasal spray), intraocular (e.g., by eye drops), pulmonary (e.g., using an aerosol, e.g., via an aerosol, e.g., through 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 intrapleural, by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular injection. Enumerated Embodiments

[0231] The present disclosure includes the following enumerated embodiments. 1. A compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N or CR 1 and Y is N or CR 2 and Z is N or CR 3 and R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, hydroxy, cyano, —COOH, —C(O)—Ci-C6 alkyl, —C(O)O—Ci-C6 alkyl, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, Ci-C6 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(Ci-C6 alkyl), N(Ci-C6 alkyl), —NHC(O)—Ci-C6 alkyl, —N(Ci-C6 alkyl)-C(O)—Ci-C6 alkyl, —C(O)—NH, —C(O)—NH(Ci-C6 alkyl), and —C(O)—N(Ci-C6 alkyl)2, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; R 5 is H, C1-C6 alkyl, or C1-C6 haloalkyl; A, [ka] is selected from the group consisting of A is 1 to 4 R 9 optionally replaced by R 6 is C1-C3 alkyl or C1-C3 haloalkyl; R 7 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cycloalkyl, or heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl; R 8 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 cycloalkyl; Each R 9 are independently selected from the group consisting of halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkyl, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl), -NHC(O)-C1-C6 alkyl, -N(C1-C6 alkyl)-C(O)-C1-C6 alkyl, -C(O)-NH, -C(O)-NH(C1-C6 alkyl), and -C(O)-N(C1-C6 alkyl)2, wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, methoxy, C3-C8 cycloalkyl, or NH; B is NR 10 R 11 and R 10 However, 1 to 6 R 12 containing one nitrogen ring atom optionally substituted with -(CH2) 0-1 is heterocycloalkyl, R 11 But hydrogen, C 1-7 Alkyl, C 1-7 Haloalkyl, or C 3-8 cycloalkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1 to 6 R 12 optionally replaced by Each R 12 are independently selected from halogen, hydroxy, cyano, -COOH, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(CH2) 0-2-C3-C8 cycloalkyl, C1-C6 heteroalkylene-C3-C8 cycloalkyl, -O-C3-C8 cycloalkyl, -4- to 7-membered monocyclic heterocycloalkyl, C1-C6 heteroalkylene-(4- to 7-membered monocyclic heterocycloalkyl), -O-(4- to 7-membered monocyclic heterocycloalkyl), -(CH2) 0-2 -(4-7 membered monocyclic heterocycloalkyl), -NH, NH(C-C alkyl), N(C-C alkyl), -NHC(O)-C-C alkyl, -N(C-C alkyl)-C(O)-C-C alkyl, -C(O)-NH, -C(O)-NH(C-C alkyl), and -C(O)-N(C-C alkyl), wherein said alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted with one or more halogen, hydroxyl, or NH; and said cycloalkyl and heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, C-C alkyl, C-C heteroalkyl, C-C alkoxy, or NH; or Two R on the same carbon 12 can be combined as keto (=O), or a pharmaceutically acceptable salt thereof. 2. The compound of embodiment 1, wherein 0, 1, or 2 of X, Y, and Z are N. 3. The compound is a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof. 4. The compound is a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof. 5. The compound is a compound of formula (Ic): [ka] or a pharmaceutically acceptable salt thereof. 6. The compound is a compound of formula (Id): [ka] or a pharmaceutically acceptable salt thereof. 7. The compound is a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof. 8. The compound is a compound of formula (If): [ka] or a pharmaceutically acceptable salt thereof. 9.R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 cycloalkyloxy. 10.R 1 , R 2 , R 3 , and R 4 is each independently selected from the group consisting of H, halogen, C1-C6 alkoxy, and C1-C6 alkyl. 11.R 1 , R 2 , R 3 , and R 4 and R are each H. 12.R 5 The compound of any one of embodiments 1-11, wherein is H. 13.A is [ka] is selected from the group consisting of A is 1 to 3 R 9 13. The compound of any one of embodiments 1-12, optionally substituted with: 14. A is one R selected from the group consisting of halogen and C1-C6 alkyl. 9 The compound of any one of embodiments 1-13, substituted by: 15.A is R 9 14. The compound of any one of embodiments 1-13, which is not substituted by: 16.R 6 The compound of any one of embodiments 1-15, wherein is Me. 17.R 7 The compound of any one of embodiments 1-16, wherein is C1-C6 alkyl, C1-C6 cycloalkyl, or heterocycloalkyl. 18.R 7 The compound of any one of embodiments 1-17, wherein is Me, Et, isopropyl, or cyclobutyl. 19.A is, [ka] 19. The compound of any one of embodiments 1-18, selected from the group consisting of: 20.A is, [ka] 20. The compound of any one of embodiments 1-19, wherein: 21.A is, [ka] 21. The compound of any one of embodiments 1-20, wherein 22.B is NR 10 R 11 and R 10 and R 11together with the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1, 2, 3, or 4 R 12 22. The compound of any one of embodiments 1-21, optionally substituted with: 23.R 10 and R 11 together with the nitrogen atom to which they are attached form a monocyclic heterocycloalkyl of 4 to 7 ring atoms containing a total of 1 or 2 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1, 2, 3, or 4 R 12 23. The compound of embodiment 22, optionally substituted with 24.B is, [ka] and W is NR 13 or CR 14 R 14 and R 13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and -(CH2) 0-2 -C3-C8 cycloalkyl, wherein alkyl, alkenyl, alkynyl is optionally substituted with one or more halogen, hydroxyl, methoxy, or NH2, and said cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or NH2; Each R 14 may be independently H or R 12 and The compound of any one of embodiments 1-23, wherein n is 0, 1, 2, 3, or 4. twenty five. Each R 12is independently selected from the group consisting of halogen, hydroxy, 4-7 membered monocyclic heterocycloalkyl, C-C heteroalkyl, and C-C alkyl, wherein alkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, C-C cycloalkyl, or NH, and heterocycloalkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, or C-C alkyl; R 13 is H or unsubstituted C1-C6 alkyl. 26. Each R 12 is independently C1-C6 alkyl. 27.B is, [ka] 25. The compound of embodiment 23 or 24, wherein 28.R 13 is H or unsubstituted C1-C6 alkyl. 29.Each R 12 is independently C1-C6 alkyl. 30. The compound is a compound of formula (Ig), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 31. The compound is a compound of formula (Ih), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 32. The compound is a compound of formula (Ii), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 33. The compound is a compound of formula (Ij), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 34. The compound is a compound of formula (Ik), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 35. The compound is a compound of formula (Im), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 36. The compound is a compound of formula (In), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 37. The compound is a compound of formula (Io), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 38. The compound is a compound of formula (Ip), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 39. The compound is a compound of formula (Iq), [ka] , In the formula, each R 15 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 40. A compound according to any one of the preceding embodiments, selected from the compounds of Table 1. 41. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 42. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, for use as a small molecule splicing modulator. 43. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable excipients. 44. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-42 or a pharmaceutical composition of embodiment 43, wherein the disease is selected from the group consisting of dentatorubral-pallidoluysian atrophy, Huntington's disease, spinal-bulbar muscular atrophy, SCA1 (Spinocerebellar ataxia type 1), SCA2 (Spinocerebellar ataxia type 2), SCA3 (Spinocerebellar ataxia type 3 or Machado-Joseph disease), SCA6 (Spinocerebellar ataxia type 6), SCA7 (Spinocerebellar ataxia type 7), SCA12 (Spinocerebellar ataxia type 8), SCA9 (Spinocerebellar ataxia type 9), SCA10 (Spinocerebellar ataxia type 10), SCA11 (Spinocerebellar ataxia type 11), SCA12 (Spinocerebellar ataxia type 12), SCA13 (Spinocerebellar ataxia type 13 or Machado-Joseph disease), SCA14 (Spinocerebellar ataxia type 14), SCA15 (Spinocerebellar ataxia type 15), SCA16 (Spinocerebellar ataxia type 16), SCA17 (Spinocerebellar ataxia type 17), SCA18 (Spinocerebellar ataxia type 18), SCA19 (Spinocerebellar ataxia type 19), SCA20 (Spinocerebellar ataxia type 20), SCA21 (Spinocerebellar ataxia type 21 or Machado-Joseph disease), SCA22 (Spinocerebellar ataxia type 22 or Machado-Joseph disease), SCA23 (Spinocerebellar a the method, wherein the cause is selected from the group consisting of spinocerebellar ataxia type 12, SCA17 (spinocerebellar ataxia type 17), FRAXA (fragile X syndrome), FXTAS (fragile X-associated tremor / ataxia syndrome), FRAXE (fragile XE mental retardation), Baratela-Scott syndrome, FRDA (Friedreich ataxia), DM1 (myotonic dystrophy type 1), DM2 (myotonic dystrophy type 2), SCA8 (spinocerebellar ataxia type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, and frontotemporal dementia. 45. A method for treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-42 or a pharmaceutical composition of embodiment 43, wherein the disease is Huntington's disease. 46. ​​A method for treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-42 or a pharmaceutical composition of embodiment 43, wherein the disease is myotonic dystrophy 1. 47. A method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-42 or a pharmaceutical composition of embodiment 43, wherein the disease is selected from the group consisting of FRAXA (Fragile X Syndrome), FXTAS (Fragile X-associated Tremor / Ataxia Syndrome), and FRAXE (Fragile XE Mental Retardation). [Example]

[0232] For illustrative purposes, neutral compounds of formula (I) are synthesized and tested in the Examples. It is understood that neutral compounds of formula (I) can be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponifying an ester to a carboxylate, or by hydrolyzing an amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate salt).

[0233] 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.

[0234] Unless otherwise noted, LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument with a C-18 column, such as a C18 2.1 x 30 mm column. The injection volume was 0.7-8.0 μl, and the flow rate was typically 0.8 or 1.2 ml / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) with positive ion electrospray ionization. The MS range was 100-1000 Da. The solvent was a gradient of water and acetonitrile containing a polymerization modifier, such as trifluoroacetic acid or ammonium carbonate (typically 0.01-0.04%).

[0235] Shorthand: [Table 2-1] [Table 2-2] Example 1. 2-Methylimidazo[1,2-a]pyrazine-6-carboxylic acid. [ka]

[0236] Step 1: Preparation of ethyl 2-methylimidazo[1,2-a]pyrazine-6-carboxylate.

[0237] To a mixture of methyl 5-aminopyrazine-2-carboxylate (5 g, 32.7 mmol) in EtOH (50 mL) was added 1-bromopropan-2-one (9 g, 63.4 mmol). The mixture was stirred at 80° C. for 2 days. After cooling to room temperature, the reaction mixture was concentrated. The crude was purified by silica gel column (DCM / MeOH=10:1) to give the title product (3.5 g, Y: 52%) as a gray solid. ESI-MS (M+H) + :206.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 0.9 Hz, 1H), 9.26 (s, 1H), 8.28 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 1.37 (t, J = 7.1 Hz, 4H).

[0238] Step 2: Preparation of 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid.

[0239] To a mixture of 2-methylimidazo[1,2-a]pyrazine-6-carboxylate (400 mg, 1.94 mmol) in THF / water (12 mL, 5:1) was added LiOH.HO (388 mg, 9.71 mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the residue was adjusted to pH=5 with 1 M HCl. The hardened material was purified by reverse-phase column chromatography to give the title product (200 mg, Y: 58%) as a gray solid. ESI-MS (M+H) + :178.1. Example 2. 8-Fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid. [ka]

[0240] Step 1: Preparation of methyl 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylate.

[0241] To a mixture of 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (1 g, 4.37 mmol) in MeOH (20 mL) was added TEA (1.3 g, 13.11 mmol) and Pd(dppf)Cl (322 mg, 0.44 mmol). The resulting mixture was stirred overnight at 60 °C under CO (balloon). The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title product (800 mg, 88%) as a yellow solid. ESI-MS (M+H) + :209.0 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 1.0 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.38 (dd, J = 11.5, 1.0 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H).

[0242] Step 2: Preparation of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0243] To a mixture of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylate (800 mg, 3.85 mmol) in THF (20 mL) was added HO (4 mL) and LiOH·HO (809 mg, 19.23 mmol). The reaction mixture was stirred at room temperature for 2 h. After concentration, the residue was diluted with water, and the mixture was adjusted to pH 5 with HCl (2 M). A solid formed and was collected by filtration, and the cake was washed with water. The solid was dried under vacuum at 55 °C to give the title product (670 mg, 90%) as a white solid. ESI-MS (M+H) + :195.0 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 1.1 Hz, 1H), 8.18 (d, J = 1.4 Hz, 1H), 7.84 (d, J = 10.8 Hz, 1H), 2.48 (d, J = 0.6 Hz, 3H). Example 3. 2,8-Dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid [ka]

[0244] Step 1: Preparation of methyl 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylate.

[0245] To a mixture of 6-bromo-2,8-dimethylimidazo[1,2-a]pyrazine (500 mg, 2.21 mmol) in MeOH (20 mL) was added TEA (670 mg, 6.64 mmol) and Pd(dppf)Cl (162 mg, 0.22 mmol). The resulting mixture was stirred overnight at 80 °C under CO. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give methyl 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylate (420 mg, 92.6%) as a yellow solid. ESI-MS (M+H) + :206.

[0246] Step 2: Preparation of 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid.

[0247] To a mixture of methyl 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylate (420 mg, 2.04 mmol) in MeOH (10 mL) and HO (1 mL) was added LiOH.HO (150 mg, 6.12 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 5 with HCl (2 M). The reaction was concentrated to give 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid (450 mg, crude, containing some inorganic salts) as a yellow solid, which was used in the next step without further purification. ESI-MS (M+H) + :192.1. Example 4. 7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid. [ka]

[0248] Step 1: Preparation of 5-bromo-4-methoxypyridin-2-amine.

[0249] To a solution of 4-methoxypyridin-2-amine (1.00 g, 8.07 mmol) in MeCN (10 mL) was added NBS (1.45 g, 8.07 mmol) in small portions at 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with water (80 mL) and brine (80 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-bromo-4-methoxypyridin-2-amine (1.5 g, crude) as an off-white solid, which was used in the next step without further purification. ESI-MS (M+H) + :203.0.

[0250] Step 2: Preparation of 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine.

[0251] To a solution of 5-bromo-4-methoxypyridin-2-amine (1.50 g, 7.40 mmol) in EtOH (30 mL) was added 1-bromopropan-2-one (2.00 g, 14.90 mmol). The mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in EA, and the organic phase was stirred with saturated aqueous sodium carbamate for 30 minutes. The two phases were separated. The organic phase was concentrated. The crude product was purified by silica gel column (DCM / MeOH=10:1) to give the title product (0.8 g, Y: 47%) as a gray solid. ESI-MS (M+H) + :241.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.45 (s, 1H), 6.95 (s, 1H), 3.89 (s, 3H), 2.26 (s, 3H).

[0252] Step 3: Preparation of methyl 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate.

[0253] To a mixture of 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (0.80 g, 3.32 mmol) in MeOH (20 mL) was added TEA (1.00 g, 9.96 mmol) and Pd(dppf)Cl (243 mg, 0.33 mmol). The mixture was charged with CO three times and stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (0.5 g, crude) as a gray solid. ESI-MS (M+H) + :221.2.

[0254] Step 4: Preparation of 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0255] To a mixture of methyl 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (250 mg, 1.14 mmol) in THF / water (6 mL, 5:1) was added LiOH.HO (100 mg, 3.41 mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the residue was adjusted to pH = 5 with 1 M HCl. The hardened material was purified by reverse-phase column chromatography to give 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (200 mg, Y: 85%) as a gray solid. ESI-MS (M+H) + :207.1. Example 5. 7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid. [ka]

[0256] Step 1: Preparation of 2-amino-5-bromo-4-methoxy-1-(prop-2-yn-1-yl)pyridin-1-ium bromide.

[0257] 5-Bromo-4-methoxypyridin-2-amine (30.2 g, 148.74 mmol), 3-bromoprop-1-yne (21.23 g, 178.49 mmol), and 2-propanol (350 mL) were added to a small Schlenk flask and vigorously stirred at 80 °C overnight. The mixture was then cooled to room temperature, and excess solvent and propargyl bromide were removed under high vacuum. The resulting crude residue, 2-amino-5-bromo-4-methoxy-1-(prop-2-yn-1-yl)pyridin-1-ium bromide (47.0 g, 90.0% purity, 131.37 mmol, 88.3% yield), was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ:8.6 (br s, 2H), 8.57 (s, 1H), 6.75 (s, 1H), 5.06 (s, 2H), 3.97 (s, 3H).

[0258] Step 2: Preparation of 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine.

[0259] To a stirred solution of sodium hydroxide (5.89 g, 147.36 mmol, 5.89 mL, 1.01 equiv.) in deionized HO (300 mL), 2-amino-5-bromo-4-methoxy-1-(prop-2-yn-1-yl)pyridin-1-ium bromide (46.98 g, 145.9 mmol) was added via powder addition funnel over 30 min. Immediately after addition, the solution phase turned yellow, and a yellow oil dispersed as a distinct, separate phase. The oil product was extracted with EtOAc (2 × 150 mL), dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to give 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (22.5 g, 90.0% purity, 84.0 mmol, 57.6% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ:8.76 (s, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 3.87 (s, 3H), 2.55 (s, 3H).

[0260] Step 3: Preparation of methyl 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate.

[0261] 6-Bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (30.68 g, 127.26 mmol) was dissolved in MeOH (250 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (2.08 g, 2.55 mmol) was added, followed by triethylamine (28.33 g, 279.98 mmol). The resulting mixture was transferred to an autoclave and stirred at 130 °C under 40 bar CO pressure overnight. The MeOH was then evaporated, and the residue was partitioned between water (150 mL) and EtOAc (300 mL). The organic layer was separated, dried over NaSO, and evaporated under reduced pressure to give crude methyl 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (19.15 g, 86.96 mmol, 68.3% yield), which was used in the next step without purification. ESI-MS (M+H) + :221.2.

[0262] Step 4: Preparation of 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0263] A mixture of methyl 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (19.15 g, 86.96 mmol) and potassium hydroxide (7.32 g, 130.43 mmol) was stirred overnight in methanol (150 mL) and HO (50 mL). The reaction mixture was concentrated under reduced pressure to remove methanol, and the resulting aqueous solution was neutralized to pH 5 with 1 N HCl to precipitate the carboxylic acid. The solid 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (14.0 g, 95.0% purity, 64.5 mmol, 74.2% yield) was isolated by filtration, washed with HO (20 mL) and MeCN (20 mL), dried, and used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ:9.23 (s, 1H), 7.88 (s, 1H), 7.21 (s, 1H), 3.97 (s, 3H), 2.39 (s, 3H). Example 6. 7-Methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid. [ka]

[0264] Step 1: Preparation of tert-butyl (4-methoxy-3-methylpyridin-2-yl)carbamate.

[0265] To a stirred mixture of tert-butyl (4-methoxypyridin-2-yl)carbamate (4.47 g, 19.93 mmol) in dry THF (100 mL) under N2 atmosphere, n-BuLi (2.5 M, 19.9 mL) was added in an ice-water bath. The reaction was stirred at 0 °C for 1 h. CHCl was then added dropwise within 30 min, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with HO (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with saturated NaCl (20 mL), dried over Na2SO4, and the mixture was concentrated under vacuum to give the crude product, which was purified by silica gel column (PE / EA = 1:1) to give the title product (4.3 g, Y: 86.1%) as a pale yellow solid. ESI-MS (M+H) + :239.1.

[0266] Step 2: Preparation of 4-methoxy-3-methylpyridin-2-amine.

[0267] To a stirred mixture of tert-butyl (4-methoxy-3-methylpyridin-2-yl)carbamate (4.0 g, 16.78 mmol) in DCM (50 mL) was added TFA (10 mL) dropwise at room temperature under a N atmosphere. The reaction was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give the TFA salt of the title product (4.1 g Y: 99%) as a pale yellow solid; the crude mixture was used directly in the next step without further purification. ESI-MS (M+H) + :139.1.

[0268] Step 3: Preparation of 5-bromo-4-methoxy-3-methylpyridin-2-amine.

[0269] To a stirred mixture of 4-methoxy-3-methylpyridin-2-amine (2.70 g, 19.55 mmol) in AcOH (20 mL) was added Br (15.62 g, 97.75 mmol) dropwise within 30 min at 40 °C. The mixture was stirred at 40 °C for 1 h. The mixture was quenched with HO (10 mL), neutralized with NHHCO, and extracted with i-PrOH / CHCl (1:3, v / v, 50 mL × 3). The organic phase was washed with saturated NaCl (20 mL) and dried over NaSO. The mixture was concentrated under vacuum to give the crude product, which was purified by silica gel column (DCM / MeOH = 10:1) to give the title product (2.9 g, Y: 68.3%) as a white solid. ESI-MS (M+H) + :217.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 5.97 (s, 2H), 3.71 (s, 3H), 1.99 (s, 3H).

[0270] Step 4: Preparation of 6-bromo-7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine.

[0271] To a stirred mixture of 5-bromo-4-methoxy-3-methylpyridin-2-amine (2.0 g, 9.21 mmol) in EtOH (10 mL) was added 1-bromopropan-2-one (2.52 g, 18.42 mmol) in portions at room temperature, and the mixture was stirred in a sealed tube at 80 °C for 8 h. The mixture was quenched with HO (10 mL), neutralized with NaCO, and extracted with EtOAc (50 mL × 3). The organic phase was washed with saturated NaCl (20 mL) and dried over NaSO. After concentration, the crude product was purified by silica gel column (DCM / MeOH = 10:1) to give the title product (1.3 g, Y: 55.3%) as a white solid. ESI-MS (M+H) + :255.0.

[0272] Step 5: Preparation of methyl 7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylate.

[0273] To a solution of 6-bromo-7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine (500 mg, 1.96 mmol) in MeOH (10 mL), TEA (595 mg, 5.88 mmol) and Pd(dppf)Cl (143.28 mg, 0.196 mmol) were added at room temperature under a CO atmosphere (balloon). The mixture was stirred at 90 °C for 4 h. After concentration, the residue was purified by silica gel column (DCM / MeOH = 10:1) to give the title product (245 mg, Y: 53.3%) as a pale yellow solid. ESI-MS (M+H) + :235.1.

[0274] Step 6: Preparation of 7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0275] To a solution of the compound methyl 7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylate (200 mg, 0.85 mmol) in THF (4.0 mL) was added HO (1 mL) and LiOH.HO (59 mg, 2.46 mmol). The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was concentrated under reduced pressure and extracted with CHCl (50 mL × 3). The aqueous solution was then acidified to pH = 2 with 1 M HCl. The aqueous solution was then extracted with EA (50 mL × 3). The combined organic layer was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title product (100 mg, yield: 53.4%) as a yellow solid. ESI-MS (M+H) + :221.0. Example 7. 6-Methoxy-2-methyl-2H-indazole-5-carboxylic acid [ka]

[0276] Step 1: Preparation of 5-bromo-6-methoxy-2-methyl-2H-indazole.

[0277] To a solution of 5-bromo-6-methoxy-1H-indazole (3.2 g, 14.1 mmol) in anhydrous THF (30 mL) was added sodium hydride (1.13 g, 28.2 mmol), and the mixture was stirred under nitrogen for 0.5 h. Iodomethane (4 g, 28.2 mmol) was then added, and the resulting mixture was stirred at 55 °C for 3 h. The mixture was carefully diluted with water and extracted with EA. The organic phase was washed with brine (50 mL), dried over NaSO, and concentrated to dryness. The crude was purified by column chromatography (EA:PE = 2:1, v / v) to give the title product (780 mg, Y: 23%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.77 (s, 1H), 7.02 (s, 1H),4.17 (s, 3H), 3.95 (s, 3H).ESI-MS (M+H) + :240.8, MS (M+2+H) + :242.8.

[0278] Step 2: Preparation of methyl 6-methoxy-2-methyl-2H-indazole-5-carboxylate.

[0279] A mixture of 5-bromo-6-methoxy-2-methyl-2H-indazole (1.10 g, 4.60 mmol), TEA (1.39 g, 13.8 mmol), and Pd(dppf)Cl (341 mg, 0.46 mmol) in MeOH (30 mL) was purged with carbon monoxide three times at room temperature. The mixture was stirred overnight at 85 °C under carbon monoxide. The catalyst was filtered, and the filtrate was concentrated to give the crude product, which was purified by column chromatography (EA:PE = 4:1, v / v) to give methyl 6-methoxy-2-methyl-2H-indazole-5-carboxylate (770 mg, Y: 76%) as an orange solid. ESI-MS (M+H) + :221.

[0280] Step 3: Preparation of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid.

[0281] To a mixture of methyl 6-methoxy-2-methyl-2H-indazole-5-carboxylate (770 mg, 3.21 mmol) in MeOH (10 mL) and HO (5 mL) was added LiOH.HO (1.28 g, 32.10 mmol). The reaction mixture was stirred at room temperature for 2 h. After concentration, the residue was diluted with water and adjusted to pH = 6 with 1 M HCl. The precipitate was collected by filtration and dried under vacuum to give 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (450 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS (M+H) + :207.1. Example 8. tert-Butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate. [ka]

[0282] Step 1: Preparation of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate

[0283] To a suspension of 3,6-dichloropyridazine (1.0 g, 6.75 mmol) and tert-butyl piperazine-1-carboxylate (1.3 g, 6.75 mmol) in NMP (20 mL) was added TEA (2.0 g, 20.2 mmol), and the reaction mixture was stirred at 120 °C for 2 h. After cooling to room temperature, the mixture was diluted with 150 mL of water and 150 mL of EA. The EA layer was separated, washed with brine and water, dried over NaSO, and concentrated to dryness. The crude material was purified by silica gel column chromatography (10–50% EA in PE). The product was obtained as an off-white solid (1.2 g, Y: 60%). 1 H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 9.6 Hz, 1H), 6.77 (d, J = 9.6 Hz, 1H), 3.55 (dd, J = 6.3, 4.0 Hz, 4H), 3.42 (d, J = 5.2 Hz, 4H), 1.48 (s, 9H).

[0284] Step 2: Preparation of tert-butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate

[0285] A mixture of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate (1.5 g, 5.01 mmol), diphenylmethanimine (1.4 g, 7.55 mmol), Pd(dba) (289 mg, 0.25 mmol), BINAP (144 mg, 0.25 mmol), and CsCO (489 mg, 15.0 mmol) in toluene (15 mL) was purged with N three times at room temperature. The reaction mixture was then stirred at 100 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (150 mL) and EA (150 mL). The EA layer was separated, washed with brine and water, dried over NaSO, and concentrated to dryness. The crude material was purified by silica gel column chromatography (10–50% EA in PE). The product was obtained as an off-white solid (1.25 g, yield: 56%). ESI-MS: [M+H] + 480.1

[0286] Step 3: Preparation of tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate

[0287] A mixture of tert-butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate (1.2 g, 2.71 mmol), NHOH.HCl (378 mg, 5.42 mmol), and NaOAc (1.1 g, 13.5 mmol) in MeOH (15 mL) was stirred at room temperature for 1 h. After dilution with water, the mixture was extracted with EA (30 mL × 2). The combined organics were washed with brine and dried over NaSO. After concentration, the crude was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 9.5 Hz, 1H), 6.90 (d, J = 9.5 Hz, 1H), 3.62 (br s, 4H), 3.59 - 3.55 (m, 4H), 1.49 (s, 9H). Example 9. 8-Fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid. [ka]

[0288] Step 1: Preparation of 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine HBr.

[0289] A mixture of 5-bromo-3-fluoropyridin-2-amine (50 g, 262 mmol), 1-bromo-2,2-dimethoxypropane (57.5 g, 315 mmol), and PPTS (6.6 g, 26.2 mmol) in i-PrOH (300 mL) was stirred at 70 °C for 16 h. The reaction mixture was then filtered, and the resulting solid was rinsed with cold i-PrOH (2 × 100 mL) and dried in vacuo to give 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (35 g, 113 mmol, 43% yield) as the HBr salt. ESI-MS: 230.1 (M+H). + .

[0290] Step 2: Preparation of methyl 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylate.

[0291] A mixture of 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine HBr (35 g, 113 mmol), Pd(dppf)Cl (9.2 g, 11.3 mmol), and TEA (63 mL, 452 mmol) in MeOH (300 mL) was stirred at 50 °C in an autoclave (under CO atmosphere, 10 atm) for 14 h. The reaction mixture was then concentrated in vacuo and purified by column chromatography to give the title compound (9 g, 43 mmol, 38% yield). ESI-MS: 209.2 (M+H). + .

[0292] Step 3: Preparation of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0293] Lithium hydroxide monohydrate (2.4 g, 100 mmol) was added to a stirred solution of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylate (9 g, 43 mmol) in THF / water (100 mL / 50 mL), and the resulting solution was stirred at room temperature for 14 h. The reaction mixture was then concentrated in vacuo, acidified to pH = 6, and extracted with EtOAc. The organics were washed with water, dried over Na2SO4, and evaporated to give 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (7.2 g, 37 mmol, 86% yield). ESI-MS: 195.2 (M+H). + . Example 10. N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide HCl salt (Compound 101). [ka]

[0294] Step 1: Preparation of tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate.

[0295] A mixture of 2,4-difluoro-1-nitrobenzene (100 mg, 0.63 mmol), K2CO3 (217 mg, 1.57 mmol), and tert-butyl piperazine-1-carboxylate (98 mg, 0.52 mmol) in HMPA (1 mL) was heated to 100 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The crude was purified by preparative TLC (EA:PE = 1:5, v / v) to give the title product (140 mg, Y: 82.8%) as a yellow solid. ESI-MS (M+H) + :326.1. 1 H NMR (400 MHz, CDCl3) δ 8.07 - 8.02 (m, 1H), 6.61 - 6.50 (m, 2H), 3.62 - 3.48 (m, 4H), 3.47 - 3.36 (m, 4H), 1.49 (s, 9H).

[0296] Step 2: Preparation of tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate.

[0297] A mixture of tert-butyl 4-(3-fluoro-4-nitrophenyl)piperazine-1-carboxylate (140 mg, 0.43 mmol) and Pd / C (14 mg, 10% wt / wt) in MeOH (10 mL) was purged with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 30 minutes. The catalyst was filtered and the filtrate was concentrated to give the title product, which was used in the next step without further purification. ESI-MS (M+H) + :296.1.

[0298] Step 3: Preparation of tert-butyl 4-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)piperazine-1-carboxylate.

[0299] To a stirred solution of 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (100 mg, 0.56 mmol), tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylic acid (110 mg, 0.373 mmol), and DIPEA (240 mg, 1.865 mmol) in DMF (6 mL) was added HATU (284 mg, 0.746 mmol) at room temperature. After the addition was complete, the mixture was stirred for 2 h. The reaction mixture was treated with EA / water (100 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude was slurried in EA / PE (1:10, v / v, 5 mL) at room temperature for 30 min. The solid was then collected by filtration and washed with EA / PE (1:10, v / v, 3 mL x 3). The product was obtained as a light brown solid (64 mg, Y: 37.9%), which was used in the next step without further purification. ESI-MS (M+H) + :455.1.

[0300] Step 4: Preparation of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide HCl salt.

[0301] To a solution of tert-butyl 4-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)piperazine-1-carboxylate (64 mg, 0.141 mmol) in DCM (5 mL) was added HCl-dioxane (4 M, 0.36 mL, 1.41 mmol) at 0° C., and the mixture was warmed to room temperature and stirred for 1 h. After concentration, the residue was treated with DCM (10 mL) and EA (10 mL). The solid was collected by filtration and washed with EA three times (3 mL×3). The solid was dried under vacuum at 55° C. to give the title product (35.3 mg, yield: 60%) as a pale gray solid. ESI-MS (M+H) + :355.1. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.47 (s, 3H), 9.19 (s, 1H), 8.24 (s, 1H), 7.80 - 7.74 (m, 1H), 7.01 (dd, J = 13.9, 2.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 3.48 - 3.42 (m, 4H), 3.20 (s, 4H), 2.53 (s, 3H). Example 11. 2-Methyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (Compound 102). [ka]

[0302] Step 1: Preparation of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate.

[0303] A mixture of 1-fluoro-4-nitrobenzene (500 mg, 3.55 mmol), tert-butyl piperazine-1-carboxylate (989 mg, 5.32 mmol), and triethylamine (1.1 g, 10.65 mmol) in MeCN (10 mL) was stirred at 80° C. for 4 hours. After cooling to room temperature, the mixture was concentrated. The crude was purified by silica gel column (PE:EA=10:1) to give the title product (490 mg, Y: 45%) as a yellow solid. ESI-MS (M+H) + :308.2.

[0304] Step 2: Preparation of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate.

[0305] A mixture of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (490 mg, 1.6 mmol) and Pd / C (50 mg, 10% wt / wt) in MeOH (10 mL) / THF (2 mL) was purged with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 1 hour. The catalyst was filtered, and the filtrate was concentrated to give the title product (400 mg, Y: 90%), which was used in the next step without further purification. ESI-MS (M+H) + :278.1. 1 H NMR (400 MHz, DMSO-d6) δ 6.70 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 4.60 (s, 2H), 3.46 - 3.38 (m, 4H), 2.87 - 2.78 (m, 4H), 1.41 (s, 9H).

[0306] Step 3: Preparation of tert-butyl 4-(4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)piperazine-1-carboxylate.

[0307] To a stirred solution of 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (150 mg, 0.85 mmol), tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (196 mg, 0.71 mmol), and DIPEA (275 mg, 2.13 mmol) in DMF (3 mL) was added HATU (405 mg, 1.07 mmol) at room temperature. After the addition was complete, the mixture was stirred for 1 h. After dilution with water, the precipitate was collected by filtration. The solid was washed with MeCN and dried to give the title product (160 mg, Y: 52%) as a yellow solid. ESI-MS (M+H) + :437.2. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 7.7 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H), 3.46 (br s, 4H), 3.07 (br s, 4H), 2.46 (s, 3H), 1.42 (s, 9H).

[0308] Step 4: Preparation of 2-methyl-N-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide hydrochloride.

[0309] To a solution of tert-butyl 4-(4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)piperazine-1-carboxylate (80 mg, 0.18 mmol) in DCM (2 mL) was added HCl-dioxane (4 M, 0.5 mL, 2 mmol) at 0° C., and the mixture was warmed to room temperature and stirred for 2 h. After concentration, the residue was treated with EA (5 mL). The solid was collected by filtration and washed with EA three times (5 mL). The solid was dried under vacuum to give the title product (60 mg, yield: 90%) as a yellow solid. ESI-MS (M+H) + :337.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.47 (s, 1H), 9.37 (br s, 2H), 9.19 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 9.1 Hz, 2H), 7.05 (d, J = 9.1 Hz, 2H), 3.45 - 3.33 (m, 4H), 3.24 - 3.21 (m, 4H), 2.54 (s, 3H). Example 12. 2-Methyl-N-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide (Compound 103). [ka]

[0310] Step 1: Preparation of tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate.

[0311] A mixture of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), EtN (1.92 g, 18.9 mmol), and tert-butyl piperazine-1-carboxylate (2.35 g, 12.6 mmol) in CHCN (10 mL) was stirred at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed once with water (30 mL) and brine (30 mL). The organic layer was dried over NaSO and concentrated to dryness. The crude was purified by silica gel column (EA:PE = 1:5, v / v) to give the title product (1.8 g, Y: 92%) as a yellow solid. ESI-MS (M+H) + :309.4.

[0312] Step 2: Preparation of tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate.

[0313] A mixture of tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (1.0 g, 3.2 mmol) and Pd / C (100 mg, 10% wt / wt) in MeOH (10 mL) was purged with nitrogen three times and then with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 30 minutes. The catalyst was filtered, and the filtrate was concentrated to give the crude title product, which was used in the next step without further purification. ESI-MS (M+H) + :279.0.

[0314] Step 3: Preparation of tert-butyl 4-(5-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)pyridin-2-yl)piperazine-1-carboxylate.

[0315] To a stirred solution of 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (76 mg, 0.43 mmol), tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylic acid (100 mg, 0.36 mmol), and DIPEA (138 mg, 1.07 mmol) in DMF (5 mL) was added HATU (204 mg, 0.54 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with EA / water (50 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was subjected to thermal treatment on a silica gel column (DCM / MeOH = 10:1) to give the title product (46 mg, Y: 24%) as a black solid. ESI-MS (M+H) + :438.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.30 (s, 1H), 8.99 (s, 1H), 8.60 (s, 1H), 8.04-8.09 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 3.44 (s, 8H), 2.46 (s, 3H), 1.43 (s, 9H).

[0316] Step 4: Preparation of 2-methyl-N-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide hydrochloride.

[0317] To a solution of tert-butyl 4-(5-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)pyridin-2-yl)piperazine-1-carboxylate (26 mg, 0.059 mmol) in DCM (5 mL) was added HCl-dioxane (4 M, 0.50 mL, 2 mmol) at 0° C. and warmed to room temperature for 1 h. After concentration, the residue was treated with DCM (5 mL×1) and EA (5 mL×1). The solid was collected by filtration and washed three times with EA (3 mL×3). The solid was dried under vacuum at 55° C. to give the title product (8.6 mg, yield: 39%) as a pale gray solid. ESI-MS (M+H) + :338.1. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.38 - 9.36 (m, 3H), 9.03 (s, 1H), 8.69 (s, 1H), 8.22-8.13 (m, 2H), 7.08-7.10 (d, J = 8.0 Hz, 1H), 3.69 - 3.64 (m, 4H), 3.19 (s, 4H), 2.47 (s, 3H). Example 13. (R)—N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride (Compound 104). [ka]

[0318] Step 1: Preparation of tert-butyl (R)-2-methyl-4-(5-nitropyridin-2-yl)piperazine-1-carboxylate.

[0319] A mixture of 2-chloro-5-nitropyridine (0.30 g, 1.90 mmol), EtN (0.60 g, 5.93 mmol), and tert-butyl (R)-2-methylpiperazine-1-carboxylate (0.46 g, 2.30 mmol) in CHCN (10 mL) was stirred at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over NaSO and concentrated to dryness. The crude was purified by silica gel column (EA:PE = 1:5, v / v) to give the title compound (500 mg, Y: 81%) as a yellow solid. ESI-MS (M-56+H) + :267.0.

[0320] Step 2: Preparation of tert-butyl (R)-4-(5-aminopyridin-2-yl)-2-methylpiperazine-1-carboxylate.

[0321] A mixture of tert-butyl (R)-2-methyl-4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (0.2 g, 0.62 mmol) and Pd / C (20 mg, 10% wt / wt) in MeOH (10 mL) was purged with nitrogen three times and then with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 30 minutes. The solid was filtered. The mother liquor was concentrated in vacuo to give the title product (180 mg, Y: 99%) as a purple solid, which was used in the next step without further purification. ESI-MS (M+H) + :293.4.

[0322] Step 3: Preparation of tert-butyl (R)-2-methyl-4-(5-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)pyridin-2-yl)piperazine-1-carboxylate.

[0323] To a stirred solution of 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (73 mg, 0.41 mmol), tert-butyl (R)-4-(5-aminopyridin-2-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.34 mmol), and DIPEA (133 mg, 1.03 mmol) in DMF (6 mL) was added HATU (195 mg, 0.51 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with EA / water (80 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were dried over sodium sulfate. After concentration under reduced pressure, the crude was slurried in EA / PE (1:10, v / v, 5 mL) at room temperature for 30 minutes. The solid was then collected by filtration and washed with EA / PE (1:10, v / v, 3 mL x 3). The product (30 mg, Y: 19.5%) was obtained as a light brown solid, which was used in the next step without further purification. ESI-MS (M+H) + :452.4.

[0324] Step 4: Preparation of (R)—N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride.

[0325] To a solution of tert-butyl (R)-2-methyl-4-(5-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)pyridin-2-yl)piperazine-1-carboxylate (30 mg, 0.067 mmol) in DCM (5 mL) was added HCl-dioxane (4 M, 0.50 mL, 2 mmol) at 0° C., and the mixture was warmed to room temperature and stirred for 1 h. After concentration, the residue was treated with DCM (5 mL×1) and EA (5 mL×1). The solid was collected by filtration and washed three times with EA (3 mL×3). The solid was dried under vacuum at 55° C. to give the title product (8.2 mg, yield: 32%) as a light gray solid. ESI-MS (M+H) + :352.2. 1 H NMR (400 MHz, CD3OD) δ 9.49 (s, 1H), 9.32 (s, 1H), 8.85 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 4.35-4.32 (m, 2H), 3.49-3.63 (m, 4H), 3.33-3.39 (m, 1H), 2.66 (s, 3H), 1.45 (d, J = 8.0 Hz, 3H). Example 14. (R)—N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride (Compound 105). [ka]

[0326] Step 1: Preparation of tert-butyl (R)-4-(3-fluoro-4-nitrophenyl)-2-methylpiperazine-1-carboxylate.

[0327] A mixture of 2,4-difluoro-1-nitrobenzene (318 mg, 2.0 mmol), tert-butyl (R)-2-methylpiperazine-1-carboxylate (400 mg, 2.0 mmol), and potassium carbonate (276 mg, 2.0 mmol) in HMPA (5 mL) was stirred at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude was purified by preparative TLC (EA:PE = 1:10, v / v) to give the title product (200 mg, Y: 29%) as a brown oil. ESI-MS (M-56+H) + :284.0. 1 H NMR (400 MHz, CDCl3) δ 8.04 (t, J = 9.1 Hz, 1H), 6.60 - 6.42 (m, 2H), 4.34 (br s, 1H), 3.98 - 3.89 (m, 1H), 3.75 - 3.67 (m, 1H), 3.61 - 3.54 (m, 1H), 3.44 - 3.32 (m, 2H), 3.22 - 3.12 (m, 1H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H).

[0328] Step 2: Preparation of tert-butyl (R)-4-(4-amino-3-fluorophenyl)-2-methylpiperazine-1-carboxylate.

[0329] A mixture of tert-butyl (R)-4-(3-fluoro-4-nitrophenyl)-2-methylpiperazine-1-carboxylate (220 mg, 0.65 mmol) and Pd / C (25 mg) in MeOH (3 mL) was purged with nitrogen three times and then with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 30 minutes. LCMS showed that the starting material was completely consumed and all of the starting material was converted to the desired product. The reaction was stopped and the solid was filtered. The mother liquor was removed under vacuum. The residual title compound was used in the next step without further purification. ESI-MS (M+H) + :310.4.

[0330] Step 3: Preparation of tert-butyl (R)-4-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)-2-methylpiperazine-1-carboxylate.

[0331] To a stirred solution of tert-butyl (R)-4-(4-amino-3-fluorophenyl)-2-methylpiperazine-1-carboxylate (100 mg, 0.32 mmol) in DMF (3 mL) was added 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (63 mg, 0.36 mmol), DIEA (120 mg, 0.97 mmol), and HATU (185 mg, 0.49 mmol). The mixture was stirred at room temperature for 3 hours. Water was added, and the precipitate was collected by filtration. The filter cake was washed with water (5 mL × 3) and dried under vacuum to give the title compound (96 mg, Y: 62%) as a yellow solid, which was used in the next step without further purification. ESI-MS (M+H) + :469.2. 1 H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 9.01 - 8.89 (m, 2H), 8.30 (t, J = 8.9 Hz, 1H), 7.62 (s, 1H), 6.76 - 6.62 (m, 2H), 4.35 (br s, 1H), 3.95 (d, J = 13.2 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.41 - 3.21 (m, 2H), 3.01 - 2.94 (m, 1H), 2.82 - 2.73 (m, 1H), 2.57 (s, 3H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H).

[0332] Step 4: Preparation of (R)—N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride.

[0333] To a solution of tert-butyl (R)-4-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)-2-methylpiperazine-1-carboxylate (100 mg, 0.213 mmol) in DCM (3 mL) was added a solution of HCl in 1,4-dioxane (0.55 mL, 4 mmol, 4 M) at 0° C. The mixture was stirred at room temperature for 1.5 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with EA (5 mL) and PE (5 mL) to give the title product (68 mg, Y: 87%) as a yellow solid. ESI-MS (M+H) + :369.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.42 (br s, 1H), 9.37 (d, J = 1.2 Hz, 1H), 9.16 (br s, 1H), 9.08 (s, 1H), 8.15 (s, 1H), 7.81 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 14.0, 2.5 Hz, 1H), 6.88 (dd, J = 8.9, 2.3 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.40 - 3.29 (m, 2H), 3.11 - 3.00 (m, 2H), 2.84 - 2.80 (m, 1H), 2.49 (s, 3H), 1.31 (d, J = 6.5 Hz, 3H). Example 15. N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-fluorophenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide (Compound 106). [ka]

[0334] Step 1: Preparation of tert-butyl (1R,5S)-3-(3-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0335] A mixture of 2,4-difluoro-1-nitrobenzene (100 mg, 0.63 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (133 mg, 0.63 mmol), and potassium carbonate (260 mg, 1.89 mmol) in HMPA (1 mL) was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na SO and concentrated to dryness. The crude was purified by preparative TLC (EA:PE = 1:10, v / v) to give the title product (70 mg, Y: 32%) as a yellow solid. ESI-MS (M+H) + :352.1. 1 H NMR (400 MHz, CDCl3) δ 8.04 (t, J = 9.2 Hz, 1H), 6.58 - 6.45 (m, 2H), 4.42 (s, 2H), 3.57 - 3.38 (m, 2H), 3.20 (d, J = 9.0 Hz, 2H), 2.08 - 1.98 (m, 2H), 1.81 - 1.75 (m, 2H), 1.48 (s, 9H).

[0336] Step 2: Preparation of tert-butyl (1R,5S)-3-(4-amino-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0337] A mixture of tert-butyl (1R,5S)-3-(3-fluoro-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.19 mmol) and Pd / C (10 mg) in MeOH (10 mL) was purged with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 1 hour. The catalyst was filtered, and the filtrate was concentrated to give the title product (60 mg, Y: 94%) as a pink solid, which was used in the next step without further purification. ESI-MS (M+H) + :322.0.

[0338] Step 3: Preparation of tert-butyl (1R,5S)-3-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0339] To a stirred solution of 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (41 mg, 0.23 mmol), tert-butyl (1R,5S)-3-(4-amino-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.16 mmol), and DIPEA (60 mg, 0.46 mmol) in DMF (2 mL) was added HATU (89 mg, 0.23 mmol) at room temperature. After the addition was complete, the mixture was stirred for 1 h. After dilution with water, the precipitate was collected by filtration. The solid was washed with PE / EA (10:1) and dried to give the title product (66 mg, Y: 74%) as a yellow solid. ESI-MS (M+H) + :481.2.

[0340] Step 4: Preparation of N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-fluorophenyl)-2-methylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride.

[0341] To a solution of tert-butyl (1R,5S)-3-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-carboxamido)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66 mg, 0.14 mmol) in DCM (10 mL) was added HCl-dioxane (4 M, 0.5 mL, 2 mmol) at 0° C., and the mixture was warmed to room temperature and stirred for 2 h. After concentration, the residue was treated with EA. The solid was collected by filtration and washed with EA. The solid was dried under vacuum to give the title product (16 mg, yield: 27%) as a yellow solid. ESI-MS (M+H) + :381.0. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.42 - 9.27 (m, 3H), 9.06 (s, 1H), 8.13 (s, 1H), 7.84 - 7.72 (m, 1H), 6.99 - 6.86 (m, 1H), 6.82 - 6.73 (m, 1H), 4.14 (s, 2H), 3.71 - 3.59 (m, 2H), 3.17 - 3.08 (m, 2H), 2.48 (s, 3H), 2.03 - 1.90 (m, 4H). Example 16 (S)-8-Fluoro-2-methyl-N-(5-(3-methylpiperazine-1- (yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide TFA salt (compound 107). [ka]

[0342] Step 1: Preparation of tert-butyl (S)-2-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate.

[0343] To a suspension of 5-bromo-2-nitropyridine (1 g, 4.93 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (1.1 g, 5.42 mmol) in NMP (15 mL) was added TEA (1.5 g, 14.8 mmol), and the reaction mixture was stirred at 120 °C for 6 h. After cooling to room temperature and diluting with water, the mixture was extracted with EA. The combined organics were washed with brine and water, dried over NaSO, and concentrated to dryness. The crude was purified by silica gel column (PE / EA = 3:1). The product (1 g, Y: 63%) was obtained as a yellow solid. ESI-MS (M+H) + :323.0.

[0344] Step 2: Preparation of tert-butyl (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1-carboxylate.

[0345] To a mixture of tert-butyl (S)-2-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (1 g, 3.11 mmol) in MeOH (10 mL) was added Pd / C (100 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 1 hour. The solvent was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give the desired product (750 mg, yield: 83%) as a purple semi-solid, which was used in the next step without further purification. ESI-MS (M+H) + :293.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 2.8 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.41 (d, J = 8.8 Hz, 1H), 5.45 (s, 2H), 4.18 (br s, 1H), 3.81 - 3.72 (m, 1H), 3.27 - 3.20 (m, 1H), 3.15 - 3.07 (m, 2H), 2.66 - 2.60 (m, 1H), 2.49 - 2.40 (m, 1H), 1.42 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H).

[0346] Step 3: Preparation of tert-butyl (S)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxamide)pyridin-3-yl)-2-methylpiperazine-1-carboxylate.

[0347] To a mixture of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (300 mg, 1.95 mmol) in DMF (8 mL) was added tert-butyl (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1-carboxylate (299 mg, 1.54 mmol), DIEA (399 mg, 3.09 mmol), and HATU (585 mg, 1.54 mmol). The mixture was stirred at room temperature for 5 hours. After dilution with water, the mixture was filtered, and the cake was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title product (280 mg, 33%) as a yellow solid. ESI-MS (M+H) + :469.0.

[0348] Step 4: Preparation of (S)-8-fluoro-2-methyl-N-(5-(3-methylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide TFA salt.

[0349] To a solution of butyl (S)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.21 mmol) in DCM (10 ml) was added TFA (1 mL) at 0° C. The mixture was stirred at room temperature for 1 hour. After concentration, the residue was diluted with DCM (5 ml) and concentrated again. The residue was purified by preparative HPLC to give the title product (31.72 mg, yield: 41%) as a red solid. ESI-MS (M+H) + :369.1. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.25 - 9.24 (m, 2H), 8.85 (d, J = 9.4 Hz, 1H), 8.19 (d, J = 2.9 Hz, 1H), 8.07 - 8.02 (m, 2H), 7.89 - 7.83 (m, 1H), 7.57 (dd, J = 9.2, 3.0 Hz, 1H), 3.87 - 3.78 (m, 2H), 3.45 - 3.42 m, 2H), 3.19 - 3.17 (m, 1H), 3.01 - 2.98 (m, 1H), 2.80 - 2.76 (m, 1H), 2.43 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H). Example 17. 8-Fluoro-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 108). [ka]

[0350] Step 1: Preparation of tert-butyl 4-(3-fluoro-4-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxamido)phenyl)piperazine-1-carboxylate.

[0351] To a stirred solution of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.52 mmol), tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (168 mg, 0.57 mmol), and DIEA (335 mg, 2.60 mmol) in DMF (10 mL) was added HATU (396 mg, 1.04 mmol) at room temperature. After the addition was complete, the mixture was stirred for 2 hours. After concentration, the crude product was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title product (123 mg, 51.2% yield) as a brown solid. ESI-MS (M+H) + :472.4.

[0352] Step 2: Preparation of 8-fluoro-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide hydrochloride.

[0353] To a solution of tert-butyl 4-(3-fluoro-4-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxamido)phenyl)piperazine-1-carboxylate (50 mg, 0.11 mmol) in EtOAc (1 mL) was added HCl-EA (3 M, 1 mL), and the mixture was stirred at room temperature for 1 h. The precipitate was filtered and lyophilized to give the title product (35 mg, yield: 70%). ESI-MS (M+H) + :372.2. 1 H NMR (400 MHz, CD3OD) δ 9.26 (s, 1H), 8.30 - 8.17 (m, 2H), 7.61 (t, J = 8.6 Hz, 1H), 6.93 (dd, J = 17.9, 11.5 Hz, 2H), 3.48 (d, J = 4.8 Hz, 4H), 3.39 (d, J = 4.6 Hz, 4H), 2.62 (s, 3H). Example 18. N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride (Compound 109). [ka]

[0354] Step 1: Preparation of tert-butyl 4-(4-(2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamido)-3-fluorophenyl)piperazine-1-carboxylate.

[0355] To a mixture of 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid (50 mg, 0.26 mmol) in DMF (8 mL) was added tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (115 mg, 0.39 mmol), DIEA (101 mg, 0.78 mmol), and HATU (149 mg, 0.39 mmol). The mixture was stirred at room temperature for 5 hours and quenched with water (10 mL). The mixture was filtered, and the cake was purified by silica gel column chromatography (DCM:MeOH=20:1) to give tert-butyl 4-(4-(2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamido)-3-fluorophenyl)piperazine-1-carboxylate (50 mg, 41%) as a yellow solid. ESI-MS (M+H) + :469.3.

[0356] Step 2: Preparation of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride.

[0357] To a solution of tert-butyl 4-(4-(2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamide)-3-fluorophenyl)piperazine-1-carboxylate (50 mg, 0.11 mmol), HCl in dioxane (5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The precipitate was filtered and lyophilized to give N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamide hydrochloride (3 mg, yield: 7.6%) as a yellow solid. ESI-MS (M+H) + :369.3. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.20 (s, 1H), 8.94 (s, 2H), 8.07 (s, 1H), 7.88 - 7.83 (m, 1H), 7.02 (d, J = 14.2 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 3.40 (d, J = 4.8 Hz, 4H), 3.23 (s, 4H), 2.82 (s, 3H), 2.46 (s, 3H). Example 19. 7-Methoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide HCl salt (Compound 110). [ka]

[0358] Step 1: Preparation of tert-butyl 4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate.

[0359] To a stirred solution of 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.48 mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (140 mg, 0.49 mmol), and DIEA (190 mg, 1.46 mmol) in DMF (4 mL) was added HATU (289 mg, 0.76 mmol) at room temperature. After the addition was complete, the mixture was stirred for 1 h. After dilution with water, the solid was collected by filtration and washed with MeCN to give the product (100 mg, Y: 44.8%) as a light brown solid, which was used in the next step without further purification. ESI-MS (M+H) +:467.3. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.00 (s, 1H), 8.10 - 8.08 (m, 2H), 7.67 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 4.00 (s, 3H), 3.47 (br.s, 4H), 2.34 (s, 3H), 1.43 (s, 9H).

[0360] Step 2: Preparation of 7-methoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide HCl salt.

[0361] To a solution of tert-butyl 4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide)pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.214 mmol) in 1,4-dioxane (1 mL), HCl-dioxane (4 M, 0.5 mL) was added at room temperature and stirred for 1 hour. The precipitate was filtered and lyophilized to give 7-methoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide HCl salt (17 mg, 21.8% yield) as a yellow solid. ESI-MS (M+H) + :367.2. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.82 (s, 2H), 9.23 (s, 1H), 8.17 - 8.05 (m, 2H), 8.00 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.36 (s, 1H), 4.07 (s, 3H), 3.48 (s, 4H), 3.20 (s, 4H), 2.45 (s, 3H). Example 20. N-(2-Fluoro-4-(piperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 111). [ka]

[0362] Step 1: Preparation of tert-butyl 4-(3-fluoro-4-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)phenyl)piperazine-1-carboxylate.

[0363] To a stirred solution of 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.48 mmol), tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (130 mg, 0.49 mmol), and DIEA (190 mg, 1.46 mmol) in DMF (4 mL) was added HATU (289 mg, 0.76 mmol) at room temperature. After the addition was complete, the mixture was stirred for 1 h. After dilution with water, the solid was collected by filtration and washed with MeCN to give the title product (30 mg, Y: 12.8%) as a light brown solid, which was used in the next step without further purification. ESI-MS (M+H) + :484.3.

[0364] Step 2: Preparation of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide hydrochloride.

[0365] To a solution of tert-butyl 4-(3-fluoro-4-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide)phenyl)piperazine-1-carboxylate (30 mg, 0.06 mmol) in 1,4-dioxane (1 mL), HCl-dioxane (4 M, 0.5 mL) was added at room temperature and stirred for 1 hour. The precipitate was filtered and lyophilized to give N-(2-fluoro-4-(piperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide (12 mg, yield: 52.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.68 (s, 2H), 9.24 (s, 1H), 7.98 (s, 1H), 7.68 (t, J = 8.9 Hz, 1H), 7.34 (s, 1H), 6.99 (d, J = ESI-MS (M+H) + :384.2. Example 21. 7-Methoxy-2,8-dimethyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide (Compound 112). [ka]

[0366] Step 1: Preparation of tert-butyl 4-(6-(7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate.

[0367] To a stirred solution of 7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.45 mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (152 mg, 0.55 mmol), and DIEA (176 mg, 1.36 mmol) in DMF (5 mL) was added HATU (259 mg, 0.681 mmol) at room temperature. After the addition was complete, the mixture was stirred for 2 hours. The reaction mixture was treated with EA / water (100 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was purified by preparative HPLC (0.05% FA / MeCN in water) to give tert-butyl 4-(6-(7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate (60 mg, yield: 27.6%) as a white solid. ESI-MS (M+H) + :481.1.

[0368] Step 2: Preparation of 7-methoxy-2,8-dimethyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide HCl salt.

[0369] To a solution of tert-butyl tert-butyl 4-(6-(7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate (60 mg, 0.124 mmol) in EA (3 mL) was added HCl-EA (3 M, 2 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 1 h. After concentration, the residue was purified by preparative HPLC (0.05% HCl / MeCN in water) to give the title compound (5.0 mg, yield: 10.6%) as a yellow solid. 1H NMR (400 MHz, MeOD-d4) δ 9.16 (s, 1H), 8.30 (dd, J = 9.5, 2.6 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 4.07 (s, 3H), 3.69 - 3.61 (m, 4H), 3.48 - 3.40 (m, 4H), 2.59 (s, 3H), 2.57 (s, 3H).ESI-MS (M+H) + :381.1. Example 22. 6-Methoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)-2H-indazole-5-carboxamide HCl salt (Compound 113). [ka]

[0370] Step 1: Preparation of tert-butyl 4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridin-3-yl)piperazine-1-carboxylate.

[0371] To a stirred solution of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (80 mg, 0.38 mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (128 mg, 0.46 mmol), and DIEA (152 mg, 1.16 mmol) in DMF (6 mL) was added HATU (220 mg, 0.58 mmol) at room temperature. After the addition was complete, the mixture was stirred for 2 hours. The reaction mixture was treated with EA / water (40 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (25 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude was purified by C18 flash (0.1% FA / CH3CN in water) to give tert-butyl 4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridin-3-yl)piperazine-1-carboxylate (60 mg, Y: 33.2%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.70 (s, 1H), 8.35 (d, J = 9.1 Hz, 1H), 8.03 - 7.97 (m, 2H), 7.33 (dd, J = 9.0, 2.9 Hz, 1H), 7.10 (s, 1H), 4.20 (s, 3H), 4.11 (s, 3H), 3.64 - 3.57 (m, 4H), 3.15 - 3.09 (m, 4H), 1.62 (s, 9H).ESI-MS (M+H) + :467.3.

[0372] Step 2: Preparation of 6-methoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)-2H-indazole-5-carboxamide HCl salt.

[0373] To a solution of 4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridin-3-yl)piperazine-1-carboxylate (60 mg, 0.129 mmol) in EA (2 mL) was added HCl-EA (3 M, 2 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 1 h. After concentration, the solid was collected by filtration and washed with EA three times (3 mL×3). The solid was dried under vacuum at 55° C. to give the title product (10 mg, yield: 21.2%) as a pale yellow solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.66 (s, 1H), 8.52 (s, 1H), 8.33 (dd, J = 9.5, 2.3 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 9.5 Hz, 1H), 7.24 (s, 1H), 4.29 (s, 3H), 4.11 (s, 3H), 3.68 - 3.60 (m, 4H), 3.49 - 3.41 (m, 4H).ESI-MS (M+H) + :367.2. Example 23 (S)—N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-6-methoxy- 2-Methyl-2H-indazole-5-carboxamide HCl salt (compound 114). [ka]

[0374] Step 1: Preparation of tert-butyl (S)-4-(3-fluoro-4-nitrophenyl)-2-methylpiperazine-1-carboxylate.

[0375] A mixture of 2,4-difluoro-1-nitrobenzene (5 g, 21 mmol), K2CO3 (6.9 g, 50 mmol), and tert-butyl (S)-2-methylpiperazine-1-carboxylate (4.2 g, 21 mmol) in HMPA (50 mL) was heated to 100 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The crude was purified by silica gel column (EA:PE = 1:5, v / v) to give the title product (4 g, Y: 80%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.98 (t, J = 9.1 Hz, 1H), 6.47 (dd, J = 9.5, 2.5 Hz, 1H), 6.40 (dd, J = 14.8, 2.6 Hz, 1H), 4.27 (s, 1H), 3.93 - 3.82 (m, 1H), 3.65 - 3.62 (m, 1H), 3.51 (d, J = 11.2 Hz, 1H), 3.34 - 3.24 (m, 2H), 3.14 - 3.05 (m, 1H), 1.46 (s, 9H), 1.15 (d, J = 6.7 Hz, 3H).

[0376] Step 2: Preparation of tert-butyl (S)-4-(4-amino-3-fluorophenyl)-2-methylpiperazine-1-carboxylate.

[0377] A mixture of tert-butyl (S)-4-(3-fluoro-4-nitrophenyl)-2-methylpiperazine-1-carboxylate (2 g, 5.9 mmol) and Pd / C (320 mg, 10% wt / wt) in MeOH (50 mL) was purged with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 30 minutes. The catalyst was filtered, and the filtrate was concentrated to give the title product, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 6.77 - 6.69 (m, 1H), 6.62 (dd, J = 13.4, 2.5 Hz, 1H), 6.55 (dd, J = 8.5, 2.1 Hz, 1H), 4.32 (s, 1H), 3.95 - 3.92 (m, ESI-MS (M+H) + :310.2.

[0378] Step 3: Preparation of tert-butyl (S)-4-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)-2-methylpiperazine-1-carboxylate.

[0379] To a stirred solution of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (80 mg, 0.38 mmol), tert-butyl (S)-4-(4-amino-3-fluorophenyl)-2-methylpiperazine-1-carboxylate (181 mg, 0.58 mmol), and DIEA (253 mg, 0.76 mmol) in DMF (10 mL) was added HATU (297 mg, 0.78 mmol) at room temperature. After the addition was complete, the mixture was stirred for 2 hours. The reaction mixture was treated with EA / water (100 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude was slurried in EA / PE (1:10, v / v, 5 mL) at room temperature for 30 minutes. The solid was then collected by filtration and washed with EA / PE (1:10, v / v, 3 mL x 3). The product was obtained as a light brown solid (90 mg, Y: 49%). ESI-MS (M+H) + :498.3. 1 H NMR (400 MHz, CDCl3) δ 10.21 (d, J = 2.3 Hz, 1H), 8.73 (d, J = 3.8 Hz, 1H), 8.41 (dd, J = 11.7, 6.7 Hz, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 6.7 Hz, 1H), 6.72 - 6.56 (m, 2H), 4.35 (s, 1H), 4.20 (s, 3H), 4.09 (s, 3H), 3.95 - 3.91 (m, 1H), 3.46 - 3.42 (m, 1H), 3.33 - 3.30 (m, 1H), 3.29 - 3.21 (m, 1H), 2.94 - 2.90 (m, 1H), 2.79 - 2.71 (m, 1H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H).

[0380] Step 4: Preparation of (S)—N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide HCl salt.

[0381] To a solution of tert-butyl (S)-4-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)-2-methylpiperazine-1-carboxylate (64 mg, 0.141 mmol) in EtOAc (1 mL) was added HCl-EA (3 M, 1 mL), and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered and lyophilized to give (S)-N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide hydrochloride (35.3 mg, yield: 60%). ESI-MS(M+H)+:398. 1H NMR (400 MHz, MeOD-d4) δ 8.71 (s, 1H), 8.55 (s, 1H), 8.05 (t, J = 8.9 Hz, 1H), 7.24 (s, 1H), 7.00 - 6.85 (m, 2H), 4.30 (s, 3H), 4.14 (s, 3H), 3.85 - 3.81 (m, 2H), 3.55 - 3.45 (m, 2H), 3.36 - 3.32 (m, 1H), 3.09 - 2.95 (m, 1H), 2.85 - 2.82 (m, 1H), 1.41 (d, J = 6.6 Hz, 3H). Example 24. N-(2-Fluoro-4-(piperazin-1-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide HCl salt (Compound 115). [ka]

[0382] Step 1: Preparation of tert-butyl 4-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)piperazine-1-carboxylate.

[0383] To a stirred solution of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (60 mg, 0.29 mmol), tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (96 mg, 0.32 mmol), and DIEA (114 mg, 0.87 mmol) in DMF (3 mL) was added HATU (150 mg, 0.39 mmol) at room temperature. After the addition was complete, the mixture was stirred for 2 hours. The crude was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title product (80 mg, 57.1% yield) as a yellow solid. ESI-MS (M+H) + :484.1 1 H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.73 (s, 1H), 8.42 (dd, J = 11.6, 6.8 Hz, 1H), 7.99 (s, 1H), 7.10 (s, 1H), 6.75 - 6.68 (m, 2H), 4.20 (s, 3H), 4.09 (s, 3H), 3.60 - 3.57 (m, 4H), 3.14 - 3.09 (m, 4H), 1.49 (s, 9H).

[0384] Step 2: Preparation of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide HCl salt.

[0385] To a solution of tert-butyl 4-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)piperazine-1-carboxylate (80 mg, 0.16 mmol) in EA (0.5 mL) was added HCl-EA (3 M, 0.5 mL) and the mixture was stirred for 1 h. The precipitate was filtered and lyophilized to give the title product (35 mg, yield: 55.5%) as a yellow solid. ESI-MS (M+H) + :383.9. 1H NMR (400 MHz, MeOD-d4) δ 8.70 (s, 1H), 8.55 (s, 1H), 8.05 (t, J = 8.8 Hz, 1H), 7.24 (s, 1H), 6.96 (dd, J = 13.6, 2.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 4.31 (s, 3H), 4.13 (s, 3H), 3.46 - 3.43 (m, 4H), 3.39 - 3.36 (m, 4H). Example 25. N-(2-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide TFA salt (Compound 116). [ka]

[0386] Step 1: Preparation of tert-butyl 6-(3-fluoro-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

[0387] A mixture of 2,4-difluoro-1-nitrobenzene (722 mg, 4.54 mmol), K2CO3 (732 mg, 5.30 mmol), and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 1.51 mmol) in HMPA (10 mL) was heated to 100 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (60 mL) and washed with water (60 mL) and brine (60 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The crude was purified by preparative TLC (EA:PE = 1:5, v / v) to give the title product (260 mg, Y: 50.9%) as a yellow solid. ESI-MS (M+H) + :338.1.

[0388] Step 2: Preparation of tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate.

[0389] A mixture of tert-butyl 6-(3-fluoro-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (460 mg, 1.36 mmol) and Pd / C (92 mg, 20% wt / wt) in MeOH (30 mL) was purged with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature for 30 minutes. The catalyst was filtered, and the filtrate was concentrated to give the title product, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 6.70 (t, J = 9.0 Hz, 1H), 6.19 (dd, J = 12.5, 2.3 Hz, 1H), 6.11 (dd, J = 8.4, 1.7 Hz, 1H), 4.07 (br.s, 4H), 3.87 (br.s, 4H), 1.44 (s, 9H).

[0390] Step 3: Preparation of tert-butyl 6-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

[0391] To a stirred solution of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (60 mg, 0.29 mmol), tert-butyl 6-(4-amino-3-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (80 mg, 0.26 mmol), and DIEA (114 mg, 0.87 mmol) in DMF (3 mL) was added HATU (150 mg, 0.38 mmol) at room temperature. After the addition was complete, the mixture was stirred for 2 hours. The crude was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title product (50 mg, 39.0% yield) as a yellow solid. ESI-MS (M+H) + :496.1. 1H NMR (400 MHz, CDCl3) δ 10.15 (d, J = 2.2 Hz, 1H), 8.72 (s, 1H), 8.34 (t, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.09 (s, 1H), 6.24 (dd, J = 9.5, 4.9 Hz, 2H), 4.20 (s, 3H), 4.10 (s, 4H), 4.08 (s, 3H), 3.96 (s, 4H), 1.45 (s, 9H).

[0392] Step 4: Preparation of N-(2-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide TFA salt.

[0393] To a solution of tert-butyl 6-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (50 mg, 0.10 mmol) in DCM (4 mL), TFA (1 mL) was added and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title product (10 mg, yield: 25%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.78 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.82 (t, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.43 - 6.27 (m, 2H), 4.18 (s, 4H), 4.14 (s, 3H), 3.98 (d, J = 3.5 Hz, 7H).ESI-MS (M+H) + :396.1. Example 26. N-(2-fluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide (Compound 117). [ka]

[0394] Step 1: Preparation of tert-butyl 5-(3-fluoro-4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

[0395] A mixture of 2,4-difluoro-1-nitrobenzene (450 mg, 2.83 mmol), K2CO3 (391 mg, 2.83 mmol), and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (300 mg, 1.41 mmol) in HMPA (8.00 mL) was heated at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (60 mL) and brine (30 mL). The organic layer was dried over Na2SO4. After concentration, the crude was purified by gel silica chromatography (PE:EA = 10:1 to 5:1) to give the title product (270 mg, Y: 64.5%) as a yellow solid. ESI-MS (M+H -56) + :296.1.

[0396] Step 2: Preparation of tert-butyl 5-(4-amino-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

[0397] A mixture of tert-butyl 5-(3-fluoro-4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (270 mg, 0.912 mmol) and Pd / C (50.0 mg) in EA (5.00 mL) was purged with hydrogen three times at room temperature. The mixture was stirred under hydrogen at room temperature overnight. The catalyst was filtered, and the filtrate was concentrated to give the title product, which was used in the next step without further purification. ESI-MS (M+H) + :322.1.

[0398] Step 3: Preparation of tert-butyl 5-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

[0399] To a mixture of tert-butyl 5-(4-amino-3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg, 0.31 mmol) in DMF (8 mL) was added 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (128 mg, 0.62 mmol), DIEA (121 mg, 0.93 mmol), and HATU (178 mg, 0.47 mmol). The mixture was stirred at room temperature for 2 hours. After dilution with water, the mixture was filtered, and the cake was purified by C18 (0.1% FA / CHCN in water) to give the title product (40 mg, 25%) as a white solid. ESI-MS (M+H) + :510.1. 1 H NMR (400 MHz, MeOD-d4) δ 8.51 (s, 1H), 8.31 (s, 1H), 7.75 (dd, J = 8.8, 6.2 Hz, 1H), 7.12 (s, 1H), 6.83 (dd, J = 11.1, 2.8 Hz, 1H), 6.74 - 6.69 (m, 1H), 4.19 (s, 3H), 4.04 (s, 3H), 3.63 (dd, J = 11.3, 7.9 Hz, 2H), 3.34 (s, 2H), 3.24 (dd, J = 11.3, 4.0 Hz, 2H), 3.09 (d, J = 9.0 Hz, 2H), 3.00 (dd, J = 8.6, 5.1 Hz, 2H), 1.43 (s, 9H).

[0400] Step 4: Preparation of N-(2-fluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-6-methoxy-2-methyl-2H-indazole-5-carboxamide hydrochloride.

[0401] To a solution of tert-butyl 5-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (40 mg, 0.078 mmol), HCl-EA (3 M, 5 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered and lyophilized to give the title product (24 mg, yield: 75%) as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.70 (s, 1H), 8.51 (s, 1H), 7.63 (dd, J = 8.8, 6.1 Hz, 1H), 7.27 (s, 1H), 6.93 (dd, J = 10.8, 2.7 Hz, 1H), 6.83 (dd, J = 8.3, 2.7 Hz, 1H), 4.32 (s, 3H), 4.13 (s, 3H), 3.53 - 3.46 (m, 2H), 3.32 (s, 2H), 3.19 - 3.15 (m, 6H).ESI-MS (M+H) + :410.2. Example 27. 7-Methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridazin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide (Compound 118). [ka]

[0402] Step 1: Preparation of 4-(6-7-methoxy-2-methylimidazo[1,2-a]pyridin-6-amidopyridazin-3-yl)piperazine-1-carboxylate.

[0403] 7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.229 g, 1.11 mmol) was suspended in DMF (4 mL) and ethylbis(propan-2-yl)amine (0.215 g, 1.66 mmol, 290.0 μL, 1.5 equiv.) was added, followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]dimethylazanium, hexafluoro-lambda 5-phosphanide (0.506 g, 1.33 mmol). The resulting mixture was stirred at room temperature for 30 minutes. tert-Butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (0.223 g, 798.34 μmol) was then added in one portion, and the reaction mixture was stirred at room temperature overnight. The precipitate that formed was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried in vacuo to give pure tert-butyl 4-(6-7-methoxy-2-methylimidazo[1,2-a]pyridin-6-amidopyridazin-3-yl)piperazine-1-carboxylate (0.120 g, 256.67 μmol, 23.1% yield). ESI-MS (M+H) analysis. + :468.4.

[0404] Step 2: Preparation of 7-methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridazin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide TFA salt.

[0405] To a stirred solution of tert-butyl 4-(6-7-methoxy-2-methylimidazo[1,2-a]pyridin-6-amidopyridazin-3-yl)piperazine-1-carboxylate (0.050 g, 106.97 μmol) in dichloromethane (15 mL), 2,2,2-trifluoroacetic acid (0.122 g, 1.07 mmol) was added in one portion, and the resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with MTBE / MeCN (5 / 2 mL). The precipitate was filtered and dried under vacuum to give 7-methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridazin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide TFA salt (0.042 g, 101.78 μmol, quantitative yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.14 (s, 1H), 9.07 - 8.82 (br s, 2H), 8.19 (d, J = 9.9 Hz, 1H), 7.90 (s, 1H), 7.51 (d, J = 9.8 Hz, 1H), 7.34 (s, 1H), 4.05 (s, 3H), 3.77 (s, 4H), 3.23 (s, 4H).ESI-MS (M+H) + :368.2. Example 28. 7-Methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide (Compound 119). [ka]

[0406] Step 1: Preparation of tert-butyl 4-(5-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-amidopyridin-2-yl)piperazine-1-carboxylate.

[0407] 7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.200 g, 969.94 μmol) was suspended in DMF (4 mL), and ethylbis(propan-2-yl)amine (0.314 g, 2.43 mmol) was added, followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]dimethylazanium, hexafluoro-lambda 5-phosphanide (0.443 g, 1.17 mmol). The resulting mixture was stirred at room temperature for 30 minutes. tert-Butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (0.270 g, 970.99 μmol) was then added in one portion, and the reaction mixture was stirred at room temperature overnight. The formed precipitate was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried in vacuo to give pure tert-butyl 4-(5-7-methoxy-2-methylimidazo[1,2-a]pyridin-6-amidopyridin-2-yl)piperazine-1-carboxylate (0.250 g, 535.87 μmol, 55.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.55 (s, 1H), 6.91 (s, 1H), 6.84 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H), 3.39 (s, 8H), 2.24 (s, 3H), 1.39 (s, 9H).ESI-MS (M+H) + :467.2.

[0408] Step 2: Preparation of 7-methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide TFA salt.

[0409] tert-Butyl 4-(5-7-methoxy-2-methylimidazo[1,2-a]pyridin-6-amidopyridin-2-yl)piperazine-1-carboxylate (0.050 g, 107.25 μmol) was dissolved in dichloromethane (10 mL) and 2,2,2-trifluoroacetic acid (0.122 g, 1.07 mmol) was added. The resulting mixture was stirred overnight at room temperature, evaporated, and triturated with a mixture of MTBE / MeCN (5 / 2 mL). The formed precipitate was filtered and dried in vacuo to give the desired 7-methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide TFA salt (0.109 g, 226.88 μmol, quantitative yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.11 (s, 1H), 8.80 (s, 2H), 8.42 (s, 1H), 7.88 (m, 2H), 7.30 (s, 1H), 6.95 (s, 1H), 4.02 (s, 3H), 3.64 (s, 4H), 3.17 (s, 4H), 2.40 (s, 3H).ESI-MS (M+H) + :367.2. Example 29. 7-Methoxy-2-methyl-N-(2-(piperazin-1-yl)pyrimidin-5-yl)imidazo[1,2-a]pyridine-6-carboxamide (Compound 120). [ka]

[0410] Step 1: Preparation of tert-butyl 4-(5-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyrimidin-2-yl)piperazine-1-carboxylate.

[0411] 7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.200 g, 969.94 μmol) was suspended in DMF (4 mL) and ethylbis(propan-2-yl)amine (0.313 g, 2.42 mmol) was added, followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]dimethylazanium, hexafluoro-lambda 5-phosphanide (0.442 g, 1.16 mmol). The resulting mixture was stirred at room temperature for 30 minutes. tert-Butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (0.270 g, 969 μmol) was then added in one portion, and the reaction mixture was stirred at room temperature overnight. The precipitate that formed was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried in vacuo to give pure tert-butyl 4-(5-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyrimidin-2-yl)piperazine-1-carboxylate (0.234 g, 500 μmol, 51.7% yield). ESI-MS (M+H) + :468.2.

[0412] Step 2: Preparation of 7-methoxy-2-methyl-N-(2-(piperazin-1-yl)pyrimidin-5-yl)imidazo[1,2-a]pyridine-6-carboxamide TFA salt.

[0413] tert-Butyl 4-(5-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide)pyrimidin-2-yl)piperazine-1-carboxylate (0.234 g, 500 μmol) was dissolved in dichloromethane (10 mL) and 2,2,2-trifluoroacetic acid (0.571 g, 5.01 mmol) was added. The resulting mixture was stirred overnight at room temperature, evaporated, and triturated with a mixture of MTBE / MeCN (5 / 2 mL). The formed precipitate was filtered and dried in vacuo to give the desired 7-methoxy-2-methyl-N-(2-(piperazin-1-yl)pyrimidin-5-yl)imidazo[1,2-a]pyridine-6-carboxamide TFA salt (0.215 g, 447 μmol, quantitative) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.14 (s, 1H), 8.94 (s, 2H), 8.68 (d, J = 1.7 Hz, 2H), 7.88 (s, 1H), 7.32 (s, 1H), 4.02 (s, 3H), 3.89 (s, 4H), 3.15 (s, 4H), 2.40 (s, 3H).ESI-MS (M+H) + :368.2. Example 30. 8-Fluoro-2-methyl-N-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (Compound 121). [ka]

[0414] Step 1: Preparation of tert-butyl 4-(5-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-2-yl)piperazine-1-carboxylate.

[0415] A mixture of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.5 g, 2.6 mmol), HATU (1.18 g, 3.12 mmol), tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (0.7 g, 2.5 mmol), and TEA (0.72 mL, 5.2 mmol) in DMF (20 mL) was stirred at room temperature for 14 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organics were washed with water, dried over NaSO, and evaporated to give the crude title compound (0.9 g, 2 mmol, 79% yield), which was used in the next step without further purification. ESI-MS: 455.2 (M+H). + .

[0416] Step 2: Preparation of 8-fluoro-2-methyl-N-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide HCl.

[0417] tert-Butyl 4-(5-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-2-yl)piperazine-1-carboxylate (0.9 g, 2 mmol) was dissolved in MeOH (20 mL). 10% dioxane / HCl solution was then added, and the resulting solution was stirred at room temperature for 10 hours. The reaction mixture was evaporated in vacuo, and the residue was purified by HPLC to give the title compound (73 mg, 19% yield) as the hydrochloride salt. ESI-MS: 355.2 (M+H). + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.05 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 9.2, 2.8 Hz, 1H), 7.61 (d, J = 12 Hz, 1H), 6.83 (d, J = 9.6 Hz, 1H), 3.33-3.39 (m, 4H), 2.74-2.82 (m, 4H), 2.38 (s, 3H). Example 31. tert-Butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate [ka]

[0418] Step 1: Preparation of tert-butyl (S)-4-(6-chloropyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0419] To a solution of 3,6-dichloropyridazine (3.0 g, 15 mmol) in 1,4-dioxane (20 mL) was added DIEA (3.87 g, 30 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (2.4 g, 12 mmol). The mixture was stirred at 100 °C overnight. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with EtOAc (50 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE / EA = 5:1) to give the title product (1.4 g, Y: 36.8%) as a pale yellow solid. ESI-MS (M+H) + :313.1. 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 9.5 Hz, 1H), 6.86 (d, J = 9.5 Hz, 1H), 4.36 (br s, 1H), 4.15 (d, J = 11.6 Hz, 1H), 4.06 - 3.92 (m, 2H), 3.37 (dd, J = 13.2, 4.0 Hz, 1H), 3.29 - 3.26 (m, 1H), 3.11 - 3.08 (m, 1H), 1.49 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H).

[0420] Step 2: Preparation of tert-butyl (S)-4-(6-((diphenylmethylene)amino)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0421] To a solution of tert-butyl (S)-4-(6-chloropyridazin-3-yl)-2-methylpiperazine-1-carboxylate (1.4 g, 4.5 mmol) in 1,4-dioxane (20 mL) was added Pd(OAc) (412 mg, 0.45 mmol), CsCO (3.0 g, 9.0 mmol), BINAP (518 mg, 0.9 mmol), and diphenylmethanimine (851 mg, 6.6 mmol), and the mixture was stirred overnight at 80 °C under nitrogen. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE / EA = 5:1) to give the title product (590 mg, Y: 29.5%) as a pale yellow solid. ESI-MS (M+H) + :458.2

[0422] Step 3: Preparation of tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0423] To a solution of tert-butyl (S)-4-(6-((diphenylmethylene)amino)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (590 mg, 1.3 mmol) in MeOH (10 mL) was added NaOAc (320 mg, 3.9 mmol), NH2OH.HCl (449 mg, 6.5 mmol), and the mixture was stirred at room temperature overnight. The resulting reaction mixture was neutralized with saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with tert-butyl methyl ether (10 mL) to give the title product (330 mg, crude) as a yellow solid. ESI-MS (M+H) + :294.2. 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 9.6 Hz, 1H), 6.74 (d, J = 9.5 Hz, 1H), 4.47 - 4.30 (m, 3H), 3.96 - 3.94 (m, 2H), 3.81 - 3.78 (m, 1H), 3.25 - 3.22 (m, 1H), 3.13 - 3.07 (m, 1H), 2.92 - 2.87 (m, 1H), 1.48 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H). Example 32. 7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate. [ka]

[0424] Step 1: Preparation of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol A: A solution of 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (5 g, 21 mmol) in BBr3 (210 mL, 1 M in DCM) was stirred overnight at room temperature. The reaction mixture was diluted with saturated sodium bicarbonate and concentrated, and the residue was purified by column chromatography (DCM / MeOH=20:1) to give the title product (2.8 g, Y: 58%) as a pale yellow solid. ESI-MS (M+H) + :226.9. 1 HNMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.28 (s, 1H), 6.47 (s, 1H), 2.33 (s, 3H).

[0425] Step 2: Preparation of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine.

[0426] To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (0.8 g, 3.5 mmol) in DMF (10 mL) was added iodoethane (0.6 mL, 7.1 mmol) and K2CO3 (0.966 mg, 7 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column (EA / PE=1:1) to give the title product (255 mg, Y: 28.2%) as a gray solid. ESI-MS (M+H) + :254.8 / 256.8. 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.06 (s, 1H), 6.73 (s, 1H), 4.18 - 3.92 (m, 2H), 2.32 (d, J = 0.7 Hz, 3H), 1.44 (t, J = 7.0 Hz, 3H).

[0427] Step 3: Preparation of methyl 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate.

[0428] To a solution of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (255 mg, 1.00 mmol) in MeOH (10 mL) was added TEA (303 mg, 3.00 mmol) and Pd(dppf)Cl (73.2 mg, 0.1 mmol). The mixture was charged with CO three times and stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title product (220 mg, crude) as a gray solid. ESI-MS (M+H) + :235.0.

[0429] Step 4: Preparation of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0430] To a mixture of methyl 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (210 mg, 0.9 mmol) in MeOH / water (12 mL, 5:1) was added LiOH.HO (43 mg, 1.8 mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the residue was adjusted to pH=5 with 1 M HCl. The residue was purified by reverse phase column chromatography to give the title product (100 mg) as a gray solid. ESI-MS (M+H) + :221.0. Example 33. 7-Isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid [ka]

[0431] Step 1: Preparation of 6-bromo-7-isopropoxy-2-methylimidazo[1,2-a]pyridine.

[0432] To a mixture of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (800 mg, 3.51 mmol) in DMF (10 mL) was added NaH (280 mg, 7.02 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, 2-bromopropane (1.8 g, 10.53 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried over Na SO , and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA) to give the title compound (900 mg, 95% yield). ESI-MS (M+H) + :269.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.44 (s, 1H), 6.97 (s, 1H), 4.77 - 4.73 (m, 1H), 2.26 (s, 3H), 1.31 (d7.2 Hz, 6H).

[0433] Step 2: Preparation of methyl 7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate.

[0434] To a mixture of 6-bromo-7-isopropoxy-2-methylimidazo[1,2-a]pyridine (400 mg, 1.48 mmol) in MeOH (20 mL) was added TEA (449 mg, 4.44 mmol) and Pd(dppf)Cl (108 mg, 0.15 mmol). The resulting mixture was charged with CO three times and stirred under CO at 80 °C overnight. The mixture was cooled to room temperature and concentrated. The residue was used directly without purification. ESI-MS (M+H) + :249.0.

[0435] Step 3: Preparation of 7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0436] To a mixture of methyl 7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (400 mg, 1.61 mmol) in THF (5 mL) and HO (1 mL) was added LiOH.HO (145 mg, 6.04 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM (15 mL). The pH of the aqueous phase was adjusted to 5 with HCl (1 M). The aqueous phase was concentrated to give a black solid, which was washed with DCM. The organic phase was concentrated to give the title product (420 mg, crude). ESI-MS (M+H) + :235.1 Example 34. 7-Cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid [ka]

[0437] Step 1: Preparation of 6-bromo-7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine.

[0438] A mixture of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (800 mg, 3.51 mmol), bromocyclobutane (2.37 g, 17.54 mmol), KI (291 mg, 1.75 mmol), and CsCO (3.43 g, 10.52 mmol) in DMF (15 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (60 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to give the title compound (630 mg, 64% yield) as a yellow solid. ESI-MS (M+H) + :281.0. 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.12 (s, 1H), 6.68 (s, 1H), 4.71 (p, J = 7.1 Hz, 1H), 2.60 - 2.49 (m, 2H), 2.38 (s, 3H), 2.32 - 2.20 (m, 2H), 1.97 - 1.88 (m, 1H), 1.78 - 1.75 (m, 1H).

[0439] Step 2: Preparation of methyl 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate.

[0440] To a mixture of 6-bromo-7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine (630 mg, 2.24 mmol) in MeOH (20 mL) was added TEA (679 mg, 6.72 mmol) and Pd(dppf)Cl (183 mg, 0.22 mmol). The resulting mixture was stirred under CO at 80 °C overnight. The mixture was cooled to room temperature and concentrated. The residue was used directly without purification. ESI-MS (M+H) + :260.9

[0441] Step 3: Preparation of 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid.

[0442] To a mixture of methyl 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (300 mg, 1.14 mmol) in THF (5 mL) and HO (1 mL) was added LiOH.HO (138 mg, 5.74 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM (15 mL). The pH of the aqueous phase was adjusted to 5 with HCl (1 M). The aqueous phase was concentrated to give a black solid, which was washed with DCM. The organic phase was concentrated to give the title product (450 mg, crude). ESI-MS (M+H) + :247.2. Example 35. tert-Butyl (S)-4-(5-aminopyrazin-2-yl)-2-methylpiperazine-1-carboxylate [ka]

[0443] Step 1: Preparation of tert-butyl (S)-4-(5-bromopyrazin-2-yl)-2-methylpiperazine-1-carboxylate

[0444] To a suspension of 2,5-dibromopyrazine (2.95 g, 12.50 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (3.00 g, 15.00 mmol) in NMP (60 mL), DIEA (3.23 g, 25.00 mmol) was added, and the reaction mixture was stirred at 110 °C for 3 h. After cooling to room temperature, the mixture was diluted with 150 mL of water and 150 mL of EA. The EA layer was separated, washed with brine and water, dried over NaSO, and concentrated to dryness. The crude material was purified by silica gel column (10–50% EA in PE). The product (3.30 g, Y: 62%) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 1.2 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 4.35 - 4.34 (m, 1H), 4.07 - 4.02 (m, 1H), 3.97 - 3.93 (m, 2H), 3.30 - 3.21 (m, 2H), 3.08 - 3.01 (m, 1H), 1.48 (s, 9H), 1.18 (d, J = 6.4 Hz, 3H).

[0445] Step 2: Preparation of tert-butyl (S)-4-(5-((diphenylmethylene)amino)pyrazin-2-yl)-2-methylpiperazine-1-carboxylate.

[0446] A mixture of tert-butyl (S)-4-(5-bromopyrazin-2-yl)-2-methylpiperazine-1-carboxylate (3.30 g, 9.27 mmol), diphenylmethanimine (2.01 g, 11.12 mmol), Pd(OAc) (104 mg, 0.46 mmol), BINAP (577 mg, 0.93 mmol), and CsCO (6.04 g, 18.54 mmol) in 1,4-dioxane (80 mL) was purged with N three times at room temperature. The reaction mixture was then stirred at 120 °C for 48 h. After cooling to room temperature, the mixture was diluted with water (150 mL) and EA (150 mL). The EA layer was separated, washed with brine and water, dried over NaSO, and concentrated to dryness. The crude material was purified by silica gel column chromatography (10–50% EA in PE). The product was obtained as a yellow solid (1.50 g, yield: 36%). ESI-MS: [M+H] + 458.2

[0447] Step 3: Preparation of tert-butyl (S)-4-(5-aminopyrazin-2-yl)-2-methylpiperazine-1-carboxylate.

[0448] A mixture of tert-butyl (S)-4-(5-((diphenylmethylene)amino)pyrazin-2-yl)-2-methylpiperazine-1-carboxylate (1.5 g, 3.28 mmol), NH2OH.HCl (1.13 g, 16.4 mmol), and NaOAc (807 mg, 9.84 mmol) in MeOH (30 mL) was stirred at room temperature for 1 h. After dilution with water, the mixture was extracted with EA (30 mL × 2). The combined organics were washed with brine and dried over Na2SO4. After concentration, the crude was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 4.39 - 4.32 (m, 1H), 4.05 (br s, 2H), 3.97 - 3.93 (m, 1H), 3.89 - 3.84 (m, 1H), 3.75 - 3.71 (m, 1H), 3.27 - 3.20 (m, 1H), 3.00 - 2.97 (m, 1H), 2.82 - 2.76 (m, 1H), 1.48 (s, 9H), 1.25 (d, J = 6.8Hz, 3H). Example 36. 7-Ethoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 130). [ka]

[0449] Step 1: Preparation of tert-butyl 4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate.

[0450] To a mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.45 mmol) in DMF (4 mL) was added HATU (343 mg, 0.9 mmol), DIEA (291 mg, 0.9 mmol), and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (63 mg, 0.23 mmol). The mixture was stirred at room temperature for 2 hours. The crude was purified by reverse-phase column chromatography to give the title product (20 mg, Y: 9.2%) as a gray solid. ESI-MS (M+H) + :481.57.

[0451] Step 2: Preparation of 7-ethoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride.

[0452] A mixture of tert-butyl 4-(6-(7-ethoxy-2-methylimidazo[1,2-a-pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.145 mmol) in 3M HCl / EA (2 mL) was stirred at room temperature for 2 h. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product (8 mg, Y: 47.1%) as a yellow solid. ESI-MS (M+H) + :382. 1 H NMR (400 MHz, MeOD-d4) δ 9.20 (s, 1H), 8.07 - 8.04 (m, 2H), 7.89 - 7.87 (m, 2H), 7.36 (s, 1H), 4.47 (q, J = 6.8 Hz, 2H), 3.55 - 3.53 (m, 4H), 3.44 - 3.42 (m, 4H), 2.51 (s, 3H), 1.60 (t, J = 6.8 Hz, 3H). Example 37. 7-Isopropoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 129) [ka]

[0453] Step 1: Preparation of tert-butyl 4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate.

[0454] To a mixture of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.36 mmol) in DMF (5 mL) was added 7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.43 mmol), DIEA (140 mg, 1.08 mmol), and HATU (202 mg, 0.54 mmol). The mixture was stirred at room temperature for 5 hours and quenched with water (10 mL). The precipitate was filtered and purified by reverse-phase column chromatography (0.1% FA / CHCN in water) to give the title product (30 mg, 34%) as a yellow solid. ESI-MS (M+H) + :495.1

[0455] Step 2: Preparation of 7-isopropoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride

[0456] tert-Butyl 4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate (30 mg, 0.11 mmol) was dissolved in 3M HCl / EA (5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The precipitate was filtered and the solid was dried to give the title product (3.0 mg, yield: 13%) as a yellow solid. ESI-MS (M+H) + :395.0 1H NMR (400 MHz, MeOD-d4) δ 9.18 (s, 1H), 8.20 - 8.07 (m 2H), 7.87 - 7.75 (m, 2H), 7.38 (d, J = 5.5 Hz, 1H), 5.09 - 5.03 (m, 1H), 3.66 - 3.57 (m, 4H), 3.47 - 3.40 (m, 4H), 2.52 (s, 3H), 1.53 (dd, J = 5.9, 3.0 Hz, 6H). Example 38. 7-Cyclobutoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 128) [ka]

[0457] Step 1: Preparation of tert-butyl 4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate.

[0458] To a mixture of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.358 mmol) in DMF (5 mL) was added 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (133 mg, 0.54 mmol), DIEA (140 mg, 1.07 mmol), and HATU (205 mg, 0.54 mmol). The mixture was stirred at room temperature for 5 hours and extracted with water (10 mL). The precipitate was filtered and purified by reverse-phase column (0.1% FA / CHCN in water) to give the title product (20 mg, 11%) as a yellow solid. ESI-MS (M+H) + :507.2. 1H NMR (400 MHz, MeOD-d4) δ 9.06 (s, 1H), 8.25 - 8.14 (m, 2H), 8.06 (d, J = 2.8 Hz, 1H), 7.60 (s, 1H), 7.48 (dd, J = 9.1, 3.0 Hz, 1H), 6.83 (s, 1H), 5.03 (p, J = 6.9 Hz, 1H), 3.60 - 3.58 (m, 4H), 3.18 - 3.15 (m, 4H), 2.66 - 2.64 (m, 2H), 2.41 - 2.39 (m, 5H), 2.01 - 1.83 (m, 2H), 1.48 (s, 9H).

[0459] Step 2: Preparation of 7-cyclobutoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride

[0460] To a solution of tert-butyl 4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridin-3-yl)piperazine-1-carboxylate (20 mg, 0.04 mmol) in EA (1 mL) was added 3 M HCl / EA (5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The precipitate was filtered and the solid was dried under vacuum to give the title product (4 mg, yield: 25%) as a yellow solid. ESI-MS (M+H) + :407.0. 1 H NMR (400 MHz, MeOD) δ 9.20 (s, 1H), 8.29 - 8.17 (m, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.87 (s, 1H), 7.84 - 7.75 (m, 1H), 7.17 (d, J = 3.6 Hz, 1H), 5.11 (p, J = 7.1 Hz, 1H), 3.73 - 3.60 (m, 4H), 3.50 - 3.41 (m, 4H), 2.71 - 2.58 (m, 2H), 2.52 (d, J = 0.9 Hz, 3H), 2.43 - 2.30 (m, 2H), 2.04 - 1.76 (m, 2H). Example 39. (S)-6-Methoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride (Compound 125). [ka]

[0461] Step 1: Preparation of tert-butyl (S)-4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0462] To a mixture of 6-methoxy-2H-indazole-5-carboxylic acid (72 mg, 0.35 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.35 mmol) in DMF (5 mL) was added HATU (267 mg, 0.7 mmol) and DIEA (226 mg, 1.75 mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the crude was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title product (50 mg, Y: 30.5%) as a yellow solid. ESI-MS (M+H) + :482.1.

[0463] Step 2: Preparation of (S)-6-Methoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride.

[0464] A mixture of tert-butyl (S)-4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.145 mmol) in 3M HCl / EA (4 mL) was stirred at room temperature for 2 hours. The precipitate was filtered and the solid was dried in vacuo to give the title product (19 mg, Y: 44.2%) as a yellow solid. ESI-MS (M+H) +:382.0. 1 H NMR (400 MHz, MeOD-d4) δ 8.52 (s, 1H), 8.47 (s, 1H), 8.25 - 8.18 (m, 2H), 7.19 (s, 1H), 4.49 (d, J = 14.0 Hz, 2H), 4.23 (s, 3H), 4.10 (s, 3H), 3.61 - 3.46 (m, 3H), 3.33 - 3.31 (m, 2H), 1.44 (d, J = 7.2 Hz, 3H). Example 40. (S)-2,8-Dimethyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide hydrochloride (Compound 124). [ka]

[0465] Step 1: tert-Butyl (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0466] To a stirred solution of 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid (50 mg, 0.26 mmol), tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (84 mg, 0.28 mmol), and DIEA (100 mg, 0.78 mmol) in DMF (5 mL) was added HATU (128 mg, 0.33 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with EA / water (50 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were dried over sodium sulfate. After concentration, the crude was purified by preparative HPLC (0.05% FA / CH3CN in water) to give the title product (15 mg, Y: 12%) as an off-white solid. ESI-MS (M+H) + :467.2. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.40 (d, J = 9.8 Hz, 1H), 7.51 (s, 1H), 7.07 (d, J = 9.8 Hz, 1H), 4.35 - 4.07 (m, 2H), 3.95 - 3.92 (m, 2H), 3.30 -3.25 (m, 2H), 3.09 - 3.07 (m, 1H), 2.83 (s, 3H), 2.47 (s, 3H), 1.42 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H).

[0467] Step 2: Preparation of (S)-2,8-dimethyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide hydrochloride.

[0468] To a solution of tert-butyl (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (15 mg, 0.03 nmol) in EA (1 mL) was added HCl-EA (3 M, 1.0 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 1 h. The solid was collected by filtration and washed with EA (2 mL×3). The solid was dried under vacuum at 55° C. to give the title product (5 mg, yield: 45%) as a pale gray solid. ESI-MS (M+H) + :367.0. 1 H NMR (400 MHz, MeOD-d4) δ 9.48 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 9.9 Hz, 1H), 8.29 (d, J = 3.9 Hz, 1H), 8.14 - 8.07 (m, 1H), 4.50 (d, J = 13.8 Hz, 2H), 3.57- 3.51 (m, 3H), 3.37- 3.35 (m, 2H), 3.03 (s, 3H), 2.68 (s, 3H), 1.45 (d, J = 6.5 Hz, 3H). Example 41. 6-Methoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride (Compound 123) [ka]

[0469] Step 1: tert-Butyl 4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate.

[0470] To a stirred solution of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (120 mg, 0.58 mmol), tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (180 mg, 0.64 mmol), and DIEA (224 mg, 1.74 mmol) in DMF (5 mL) was added HATU (286 mg, 0.75 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with EA / water (50 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were dried over sodium sulfate. After concentration, the crude was purified by preparative HPLC (0.05% FA / CH3CN in water) to give the title product (60 mg, Y: 22%) as an off-white solid. ESI-MS (M+H) + :468.2.

[0471] Step 2: Preparation of 6-methoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride.

[0472] To a solution of tert-butyl 4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate (50 mg, 0.107 nmol) in EA (1 mL) was added HCl / EA (3 M, 1.0 mL) at 0° C. and warmed to room temperature for 1 h. The solid was collected by filtration and washed with EA (2 mL×3). The solid was concentrated in vacuo to give the title product (15 mg, yield: 37%) as a yellow solid. ESI-MS (M+H) + :368.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.53 (s, 2H), 8.47 (s, 1H), 8.38 (d, J = 9.8 Hz, 1H), 8.30 (s, 1H), 7.76 (d, J = 9.7 Hz, 1H), 7.15 (s, 1H), 4.15 (s, 3H), 3.98 (br s, 3H), 3.88 (br s, 4H), 3.24 (s, 4H). Example 42. (S)-7-Cyclobutoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 122). [ka]

[0473] Step 1: Preparation of tert-butyl (S)-4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0474] To a mixture of 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (95 mg, 0.38 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (85 mg, 0.29 mmol) in DMF (3 mL) was added HATU (165 mg, 0.44 mmol) and DIPEA (112 mg, 0.87 mmol). The mixture was stirred at room temperature overnight. Water (10 mL) was added to the mixture, filtered, and the crude product was purified by preparative HPLC (0.05% NH3H2O / CH3CN in water) to give the title product (15 mg, Y: 9.9%) as a yellow solid. ESI-MS (M+H) + :522.3. 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.98 (s, 1H), 8.42 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.00 (d, J = 9.9 Hz, 1H), 6.83 (s, 1H), 4.97 - 4.87 (m, 1H), 4.38 (s, 1H), 4.17 (d, J = 12.2 Hz, 1H), 4.05 - 3.94 (m, 2H), 3.36 - 3.25 (m, 2H), 3.11 - 3.03 (m, 1H), 2.69 - 2.62 (m, 2H), 2.50 - 2.44 (m, 2H), 2.44 (s, 3H), 2.00 - 1.96 (m, 1H), 1.86 - 1.84 (m, 1H), 1.49 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H).

[0475] Step 2: Preparation of (S)-7-cyclobutoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride.

[0476] A mixture of tert-butyl (S)-4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (15 mg, 0.029 mmol) in 3M EtOAc / HCl (2 mL) was stirred at room temperature for 2 hours. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product (11.2 mg, Y: 85.1%) as a yellow solid. ESI-MS (M+H) + :422.2. 1 H NMR (400 MHz, CD3OD) δ 9.19 (s, 1H), 8.51 (d, J = 10.0 Hz, 1H), 8.01 (d, J = 10.1 Hz, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 5.15 - 5.09 (m, 1H), 4.51 - 4.39 (m, 2H), 3.64 - 3.52 (m, 3H), 3.41 - 3.33 (m, 2H), 2.70 - 2.59 (m, 2H), 2.51 (s, 3H), 2.43 - 2.31 (m, 2H), 2.02 -1.95 (mz, 1H), 1.89 - 1.82 (m, 1H), 1.45 (d, J = 6.6 Hz, 3H). Example 43. (S)-7-Methoxy-2-methyl-N-(5-(3-methylpiperazin-1-yl)pyrazin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 198). [ka]

[0477] Step 1: Preparation of tert-butyl (S)-4-(5-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyrazin-2-yl)-2-methylpiperazine-1-carboxylate.

[0478] A mixture of tert-butyl (S)-4-(5-aminopyrazin-2-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.34 mmol), HATU (181 mg, 0.48 mmol), 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (84 mg, 0.41 mmol), and DIEA (132 mg, 1.02 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL), and the precipitate was filtered and concentrated in vacuo. The residue was purified by reverse-phase column chromatography (0.1% FA / CHCN in water) to give the title compound (40 mg, 24% yield) as a yellow solid. ESI-MS (M+H) + :482.2. 1 H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 9.16 (s, 1H), 8.99 (s, 1H), 7.83 (s, 1H), 7.30 (s, 1H), 6.92 (s, 1H), 4.40 - 4.34 (m, 1H), 4.10 (s, 3H), 4.09 - 4.07 (m, 1H), 3.99 - 3.95 (m, 2H), 3.31 - 3.23 (m, 2H), 3.05 - 2.98 (m, 1H), 2.43 (s, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.8 Hz, 3H).

[0479] Step 2: Preparation of (S)-7-methoxy-2-methyl-N-(5-(3-methylpiperazin-1-yl)pyrazin-2-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride.

[0480] tert-Butyl (S)-4-(5-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyrazin-2-yl)-2-methylpiperazine-1-carboxylate (40 mg, 0.044 mmol) was dissolved in 3M HCl / EA (4 mL), and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed with EA three times (3 mL × 3) to give the title compound (20 mg, 59% yield) as the hydrochloride salt. ESI-MS (M+H) +:382.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.59 (br s, 1H), 9.48 (br s, 1H), 9.19 (s, 1H), 8.93 (s, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.33 (s, 1H), 4.35 - 4.31 (m, 2H), 4.07 (s, 3H), 3.38 - 3.25 (m, 3H), 3.09 - 3.03 (m, 2H), 2.46 (s, 3H), 1.33 (d, J = 6.4 Hz, 3H). Example 44. (S)-7-Isopropoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (Compound 199). [ka]

[0481] Step 1: tert-Butyl (S)-4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0482] To a stirred solution of 7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.427 mmol), tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (125 mg, 0.427 mmol), and NMI (105 mg, 1.281 mmol) in MeCN (5 mL) was added TCFH (180 mg, 0.641 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with EA / water (50 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL). The combined organic layers were dried over sodium sulfate. After concentration, the crude product was purified by preparative HPLC (0.05% NH3.H2O / CH3CN in water) to give the title product (60 mg, Y: 27%) as an off-white solid. ESI-MS (M+H) + :510.3. 1 H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H), 9.01 (s, 1H), 8.41 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.13 (s, 1H), 7.02 - 6.98 (m, 1H), 4.94 - 4.86 (m, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.04 - 3.95 (m, 2H), 3.36 - 3.27 (m, 2H), 3.11 - 3.03 (m, 1H), 2.48 (s, 3H), 2.01 (s, 1H), 1.62 (s, 3H), 1.61 (s, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H).

[0483] Step 2: Preparation of (S)-7-isopropoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide.

[0484] To a solution of tert-butyl (S)-4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (60 mg, 0.177 mmol) in EA (1 mL) was added 3M HCl / EA (1 mL) and the mixture was stirred at room temperature for 2 h. The solid was collected by filtration and washed with EA three times (3 mL × 3) to give the title compound (25 mg, 52% yield) as the hydrochloride salt. ESI-MS (M+H) + :410.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.97 - 9.75 (m, 2H), 9.26 (s, 1H), 8.29 (d, J = 9.3 Hz, 1H), 7.98 (s, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.37 (s, 1H), 5.06 - 4.97 (m, 1H), 4.45 - 4.33 (m, 2H), 3.51 - 3.42 (m, 1H), 3.37 - 3.35 (m, 2H), 3.27 - 3.17 (m, 1H), 3.14 - 3.03 (m, 1H), 2.46 (s, 3H), 1.41 (d, J = 6.0 Hz, 6H), 1. Example 45. Preparation of Compound C highlighted in Table 2. [ka]

[0485] To a mixture of 1 equivalent of N-(4-bromo-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide and 1.5 equivalents of amine (B) in 1 mL of dioxane, 0.1 equivalent of RuPhosPdG4, 0.1 equivalent of RuPhos, and 2 equivalents of Cs2CO3 were added under an inert atmosphere. The reaction mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the solvent was evaporated, 1 mL of TFA was added, and the mixture was stirred at room temperature for 4 h. The mixture was evaporated. The residue was dissolved in DMSO (approximately 1 mL), treated with scavenger SiliaMetS DMT, and filtered. The resulting solution was purified by HPLC using deionized water (phase A) and HPLC-grade acetonitrile (phase B) as eluents to give the final compound (C). In most cases, TFA was used as an additive.

[0486] Instrument: Agilent 1260 Infinity system equipped with DAD and mass detector

[0487] Column: Waters Sunfire C18 OBD Prep column, 100A, 5µm, 19mm x 100mm, with SunFire C18 Prep Guard cartridge, 100A, 10µm, 19mm x 10mm [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] Example 46. Synthesis of (S)-6-methoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride (Compound 200) [ka] Step 1: Preparation of tert-butyl (S)-4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate

[0488] To a mixture of 6-methoxy-2H-indazole-5-carboxylic acid (72 mg, 0.35 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.35 mmol) in DMF (5 mL) was added HATU (267 mg, 0.7 mmol) and DIEA (226 mg, 1.75 mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the crude was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title product (50 mg, Y: 30.5%) as a yellow solid. ESI-MS (M+H): 482.1. Step 2: Preparation of (S)-6-methoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride

[0489] A mixture of tert-butyl (S)-4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.145 mmol) in 3M HCl / EA (4 mL) was stirred at room temperature for 2 hours. The precipitate was filtered and the solid was dried in vacuo to give the title product (19 mg, Y: 44.2%) as a yellow solid. ESI-MS (M+H)+: 382.0. 1 H NMR (400 MHz, MeOD-d4) δ 8.52 (s, 1H), 8.47 (s, 1H), 8.25 - 8.18 (m, 2H), 7.19 (s, 1H), 4.49 (d, J = 14.0 Hz, 2H), 4.23 (s, 3H), 4.10 (s, 3H), 3.61 - 3.46 (m, 3H), 3.33 - 3.31 (m, 2H), 1.44 (d, J = 7.2 Hz, 3H). Example 47. Synthesis of (S)-2,8-dimethyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide hydrochloride (Compound 201) [ka] Step 1: tert-Butyl (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate

[0490] To a stirred solution of 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid (50 mg, 0.26 mmol), tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (84 mg, 0.28 mmol), and DIEA (100 mg, 0.78 mmol) in DMF (5 mL) was added HATU (128 mg, 0.33 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with EA / water (50 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were dried over sodium sulfate. After concentration, the crude was purified by preparative HPLC (0.05% FA / CH3CN in water) to give the title product (15 mg, Y: 12%) as an off-white solid. ESI-MS(M+H)+:467.2. 1 H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.40 (d, J = 9.8 Hz, 1H), 7.51 (s, 1H), 7.07 (d, J = 9.8 Hz, 1H), 4.35 - 4.07 (m, 2H), 3.95 - 3.92 (m, 2H), 3.30 -3.25 (m, 2H), 3.09 - 3.07 (m, 1H), 2.83 (s, 3H), 2.47 (s, 3H), 1.42 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H). Step 2: Preparation of (S)-2,8-dimethyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide hydrochloride

[0491] To a solution of tert-butyl (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (15 mg, 0.03 nmol) in EA (1 mL) was added HCl-EA (3 M, 1.0 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 1 h. The solid was collected by filtration and washed with EA (2 mL × 3). The solid was dried under vacuum at 55° C. to give the title product (5 mg, yield: 45%) as a pale gray solid. ESI-MS (M+H)+: 367.0. 1 H NMR (400 MHz, MeOD-d4) δ 9.48 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 9.9 Hz, 1H), 8.29 (d, J = 3.9 Hz, 1H), 8.14 - 8.07 (m, 1H), 4.50 (d, J = 13.8 Hz, 2H), 3.57- 3.51 (m, 3H), 3.37- 3.35 (m, 2H), 3.03 (s, 3H), 2.68 (s, 3H), 1.45 (d, J = 6.5 Hz, 3H). Example 48. Synthesis of 6-methoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride (Compound 202) [ka] Step 1: tert-butyl 4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate

[0492] To a stirred solution of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (120 mg, 0.58 mmol), tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (180 mg, 0.64 mmol), and DIEA (224 mg, 1.74 mmol) in DMF (5 mL) was added HATU (286 mg, 0.75 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with EA / water (50 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL × 1). The combined organic layers were dried over sodium sulfate. After concentration, the crude was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title product (60 mg, Y: 22%) as an off-white solid. ESI-MS (M+H): 468.2. Step 2: Preparation of 6-methoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide hydrochloride.

[0493] To a solution of tert-butyl 4-(6-(6-methoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate (50 mg, 0.107 nmol) in EA (1 mL) was added HCl / EA (3 M, 1.0 mL) at 0° C. and warmed to room temperature for 1 h. The solid was collected by filtration and washed with EA (2 mL×3). The solid was concentrated in vacuo to give the title product (15 mg, yield: 37%) as a yellow solid. ESI-MS (M+H): 368.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.53 (s, 2H), 8.47 (s, 1H), 8.38 (d, J = 9.8 Hz, 1H), 8.30 (s, 1H), 7.76 (d, J = 9.7 Hz, 1H), 7.15 (s, 1H), 4.15 (s, 3H), 3.98 (br s, 3H), 3.88 (br s, 4H), 3.24 (s, 4H). Example 49. Synthesis of (S)-7-cyclobutoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 203) [ka] Step 1: Preparation of tert-butyl (S)-4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0494] To a mixture of 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (95 mg, 0.38 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (85 mg, 0.29 mmol) in DMF (3 mL) was added HATU (165 mg, 0.44 mmol) and DIPEA (112 mg, 0.87 mmol). The mixture was stirred at room temperature overnight. Water (10 mL) was added to the mixture, filtered, and the crude product was purified by preparative HPLC (0.05% NH3HO / CH3CN in water) to give the title product (15 mg, Y: 9.9%) as a yellow solid. ESI-MS (M+H)+: 522.3. 1H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 8.98 (s, 1H), 8.42 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.00 (d, J = 9.9 Hz, 1H), 6.83 (s, 1H), 4.97 - 4.87 (m, 1H), 4.38 (s, 1H), 4.17 (d, J = 12.2 Hz, 1H), 4.05 - 3.94 (m, 2H), 3.36 - 3.25 (m, 2H), 3.11 - 3.03 (m, 1H), 2.69 - 2.62 (m, 2H), 2.50 - 2.44 (m, 2H), 2.44 (s, 3H), 2.00 - 1.96 (m, 1H), 1.86 - 1.84 (m, 1H), 1.49 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-7-cyclobutoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride.

[0495] A mixture of tert-butyl (S)-4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (15 mg, 0.029 mmol) in 3M EtOAc / HCl (2 mL) was stirred at room temperature for 2 hours. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product (11.2 mg, Y: 85.1%) as a yellow solid. ESI-MS (M+H)+: 422.2. 1H NMR (400 MHz, CD3OD) δ 9.19 (s, 1H), 8.51 (d, J = 10.0 Hz, 1H), 8.01 (d, J = 10.1 Hz, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 5.15 - 5.09 (m, 1H), 4.51 - 4.39 (m, 2H), 3.64 - 3.52 (m, 3H), 3.41 - 3.33 (m, 2H), 2.70 - 2.59 (m, 2H), 2.51 (s, 3H), 2.43 - 2.31 (m, 2H), 2.02 -1.95 (mz, 1H), 1.89 - 1.82 (m, 1H), 1.45 (d, J = 6.6 Hz, 3H). Example 50. Synthesis of (S)-7-isopropoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (Compound 204) [ka] Step 1: tert-Butyl (S)-4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0496] To a stirred solution of 7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.427 mmol), tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (125 mg, 0.427 mmol), and NMI (105 mg, 1.281 mmol) in MeCN (5 mL) was added TCFH (180 mg, 0.641 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with EA / water (50 mL, 1:1). The organic phase was separated, and the aqueous phase was extracted with EA (50 mL). The combined organic layers were dried over sodium sulfate. After concentration, the crude product was purified by preparative HPLC (0.05% NH3.H2O / CH3CN in water) to give the title product (60 mg, Y: 27%) as an off-white solid. ESI-MS (M+H)+: 510.3. 1 H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H), 9.01 (s, 1H), 8.41 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.13 (s, 1H), 7.02 - 6.98 (m, 1H), 4.94 - 4.86 (m, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.04 - 3.95 (m, 2H), 3.36 - 3.27 (m, 2H), 3.11 - 3.03 (m, 1H), 2.48 (s, 3H), 2.01 (s, 1H), 1.62 (s, 3H), 1.61 (s, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-7-isopropoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide

[0497] To a solution of tert-butyl (S)-4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (60 mg, 0.177 mmol) in EA (1 mL) was added 3M HCl / EA (1 mL) and the mixture was stirred at room temperature for 2 h. The solid was collected by filtration and washed with EA three times (3 mL × 3) to give the title compound (25 mg, 52% yield) as the hydrochloride salt. ESI-MS (M+H)+: 410.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.97 - 9.75 (m, 2H), 9.26 (s, 1H), 8.29 (d, J = 9.3 Hz, 1H), 7.98 (s, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.37 (s, 1H), 5.06 - 4.97 (m, 1H), 4.45 - 4.33 (m, 2H), 3.51 - 3.42 (m, 1H), 3.36 (d, J = 12.3 Hz, 2H), 3.27 - 3.17 (m, 1H), 3.14 - 3.03 (m, 1H), 2.46 (s, 3H), 1.41 (d, J = 6.0 Hz, 6H), 1.35 (d, J = 6.4 Hz, 3H). Example 51. Synthesis of 7-cyclobutoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 205) [ka] Step 1: Preparation of tert-butyl 4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate

[0498] To a mixture of tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (100 mg, 0.358 mmol) in DMF (5 mL) was added 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (133 mg, 0.54 mmol), DIEA (140 mg, 1.07 mmol), and HATU (205 mg, 0.54 mmol). The mixture was stirred at room temperature for 5 hours and quenched with water (10 mL). The precipitate was filtered and purified by C18 flash (0.1% FA / CH3CN in water) to give the title product (11 mg, 6%) as a yellow solid. ESI-MS (M+H): 508.2. Step 2: Preparation of 7-cyclobutoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride

[0499] To a solution of tert-butyl 4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate (11 mg, 0.02 mmol), 3M HCl / EA (5 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the solid was washed with EA and dried to give the title product (2 mg, yield: 22.7%) as a yellow solid. ESI-MS (M+H)+: 408.0. 1 H NMR (400 MHz, MeOD-d4) δ 9.20 (s, 1H), 8.50 (d, J = 9.9 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 5.18 - 5.07 (m, 1H), 4.00 (br.s, 4H), 3.48 - 3.41 (m, 4H), 2.71 - 2.60 (m, 2H), 2.50 (s, 3H), 2.44 - 2.31 (m, 2H), 2.01 - 1.96 (m, 1H), 1.92 - 1.81 (m, 1H). Example 52. 2-Methyl-N-(6-((S)-3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 206) [ka] Preparation of 2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid [ka] Step 1A: Preparation of tetrahydrofuran-3-yl methanesulfonate

[0500] To a solution of tetrahydrofuran-3-ol (4.0 g, 45.4 mmol) in DCM (50 mL), TEA (13.6 g, 136 mmol) and MsCl (6.2 g, 54.5 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 2 h. TLC (MeOH:DCM = 1:4, R f =0.3) indicated that the reaction was complete. The mixture was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography eluting with PE:EtOAc = 1:2 to give the title compound (6.5 g, crude) as a colorless oil. Step 2A: Preparation of 6-bromo-2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine

[0501] To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (650 mg, crude) in DMF (10 mL) was added K2CO3 (3.15 g, 23.2 mmol) and tetrahydrofuran-3-yl methanesulfonate (2.86 g, 17.2 mmol), and the mixture was stirred at 60 °C for 16 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by C18 column chromatography eluting with MeCN:HO = 20% to 60% to give the title compound (500 mg, 37.4% over two steps) as a gray solid. ESI-MS (M+H) + :296.8. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 5.01 - 4.91 (m, 1H), 4.11 - 4.05 (m, 2H), 4.05 - 3.99 (m, 1H), 3.97 - 3.90 (m, 1H), 2.39 (s, 3H), 2.30 - 2.21 (m, 2H). Step 3A: Preparation of methyl 2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylate

[0502] To a solution of 6-bromo-2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine (480 mg, 1.62 mmol) in MeOH (50 mL) was added Pd(dppf)Cl (237 mg, 0.32 mmol) and TEA (1.64 g, 16.2 mmol), and the mixture was charged with CO three times and stirred under a CO balloon at 80 °C overnight. The mixture was filtered, and the filtrate was concentrated to give the title compound (crude 400 mg, 89.4% yield) as a gray solid. ESI-MS (M+H) + :277.2.

[0503] Step 4A: Preparation of 2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid

[0504] To a solution of 2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylate (crude 400 mg, 1.45 mmol) in THF (8 mL) and HO (4 mL) was added LiOH (174 mg, 7.2 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The aqueous phase was adjusted to pH = 2 with 1 M HCl and purified by C18 column chromatography eluting with MeCN:HO (0.1% FA) = 0% to 15% to give the title compound (270 mg, 70.8%) as a white solid. ESI-MS (M+H) + :263.0. Step 1: Preparation of tert-butyl (2S)-2-methyl-4-(6-(2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate

[0505] To a solution of 2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.38 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (111 mg, 0.38 mmol) in DMF (10 mL) was added DIPEA (147 mg, 1.14 mmol) and HATU (216 mg, 0.57 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title compound (70 mg, 34.1% yield) as a gray solid. ESI-MS (M+H): 538.3. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.06 (s, 1H), 8.21 (d, J = 9.8 Hz, 1H), 7.67 (s, 1H), 7.42 (d, J = 9.9 Hz, 1H), 7.02 (s, 1H), 5.34 (br s, 1H), 4.27 - 4.16 (m, 2H), 4.09 - 4.06 (m, 1H), 3.98 - 3.95 (m, 3H), 3.87 - 3.77 (m, 2H), 3.23 - 3.15 (m, 2H), 2.99 - 2.88 (m, 1H), 2.42 - 2.34 (m, 1H), 2.30 (s, 3H), 2.22 - 2.13 (m, 1H), 1.44 (s, 9H), 1.13 (d, J = 6.7 Hz, 3H). Step 2: Preparation of 2-methyl-N-(6-((S)-3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride

[0506] A solution of tert-butyl (2S)-2-methyl-4-(6-(2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate (70 mg, 0.13 mmol) in 3M HCl / EtOAc (3 mL) was stirred at room temperature for 1 h. The precipitate was filtered, washed with EtOAc (1 mL), and dried under vacuum to give the title compound (50 mg, 82.2% yield) as a yellow solid. ESI-MS (M+H): 438.1. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.77 - 9.68 (m, 2H), 9.25 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.68 (d, J = 9.8 Hz, 1H), 7.34 (s, 1H), 4.38 (t, J = 12.6 Hz, 2H), 3.96 (br s, 2H), 3.88 - 3.75 (m, 2H), 3.45 - 3.30 (m, 3H), 3.22 - 2.87 (m, 3H), 2.46 (s, 3H), 2.39 - 2.30 (m, 1H), 2.19 - 2.07 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H). Example 53. Synthesis of 6-cyclobutoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide HCl salt (Compound 207) [ka] Step 1: Preparation of tert-butyl 4-(6-(6-cyclobutoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate

[0507] To a stirred solution of 6-cyclobutoxy-2-methyl-2H-indazole-5-carboxylic acid (40 mg, 0.14 mmol), tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (40 mg, 0.14 mmol), and DIEA (55 mg, 0.429 mmol) in DMF (1 mL) was added HATU (70 mg, 0.18 mmol) at room temperature. The mixture was stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (25 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude was purified by preparative HPLC (0.1% NH3.HO / CH3CN in water) to give the title product (34 mg, Y: 47.2%) as a yellow solid. ESI-MS (M+H)+: 508.3 Step 2: Preparation of 6-cyclobutoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide HCl salt

[0508] To a solution of tert-butyl 4-(6-(6-cyclobutoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate (20 mg, 0.04 mmol) in EA (2 mL) was added HCl / EA (3 M, 2 mL) at room temperature, and the mixture was warmed to room temperature and stirred for 2 h. After concentration, the solid was washed with EA three times (3 mL × 3) and dried under vacuum to give the title product (9 mg, yield: 60%) as a pale yellow solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.52 (d, J = 8.8 Hz, 2H), 8.25 - 8.15 (m, 2H), 7.00 (s, 1H), 5.02 - 4.98 (m, 1H), 4.25 (s, 3H), 4.05 - 4.00 (m, 4H), 3.48 - 3.43 (m, 4H), 2.68 - 2.59 (m, 2H), 2.36 - 2.25 (m, 2H), 1.99 - 1.81 (m, 2H).ESI-MS (M+H)+:408.1. Example 54. Synthesis of (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide HCl salt (Compound 208) [ka] Step 1: Preparation of tert-butyl (S)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate

[0509] To a solution of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (1 g, 4.545 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (1.3 g, 4.545 mmol) in MeCN (10 mL) was added NMI (1.1 g, 13.635 mmol) and TCFH (1.9 g, 6.815 mmol), and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered to give the title compound (1 g, 45.4% yield) as a gray solid. 1 H NMR (400 MHz, CDCl3) δ 10.94 (s, 1H), 8.72 (s, 1H), 8.53 - 8.50 (m, 1H), 8.00 (s, 1H), 7.09 (s, 1H), 7.03 - 6.98 (m, 1H), 4.49 - 4.22 (m, 2H), 4.20 (s, 3H), 4.03 - 3.94 (m, 2H), 3.48 (br.s, 2H), 3.32 - 3.25 (m, 2H), 3.09 - 3.01 (m, 1H), 1.70 (t, J = 7.0 Hz, 3H), 1.49 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H).ESI-MS (M+H) +:496.0. Step 2: Preparation of (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide HCl salt

[0510] A solution of tert-butyl (S)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (1 g, 2.02 mmol) in 3 M HCl / EtOAc (10 mL) was stirred at room temperature for 2 hours. The precipitate was filtered and washed with EtOAc (1 mL) to give the title compound (740 mg, 85.4%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.79 (d, J = 31.1 Hz, 2H), 8.53 - 8.41 (m, 2H), 8.36 (s, 1H), 7.88 (d, J = 9.9 Hz, 1H), 7.14 (s, 1H), 4.39 (t, J = 14.0 Hz, 2H), 4.30 - 4.23 (m, 2H), 4.15 (s, 3H), 3.53 - 3.10 (m, 5H), 1.48 (t, J = 6.9 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H)..ESI-MS (M+H) +:396.1. Example 55. Synthesis of (S)-6-cyclobutoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide HCl salt (Compound 209) [ka] Step 1: Preparation of tert-butyl (S)-4-(6-(6-cyclobutoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate

[0511] To a solution of 6-cyclobutoxy-2-methyl-2H-indazole-5-carboxylic acid (100 mg, 0.406 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (120 mg, 0.406 mmol) in DMF (6 mL) was added DIEA (157 mg, 1.218 mmol) and HATU (200 mg, 0.528 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC (0.1% NH3.HO / CH3CN in water) to give the title compound (110 mg, 52.3% yield) as a gray solid. ESI-MS (M+H): 522.2 Step 2: Preparation of (S)-6-cyclobutoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxamide HCl salt

[0512] A solution of tert-butyl (S)-4-(6-(6-cyclobutoxy-2-methyl-2H-indazole-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.19 mmol) in 3 M HCl / EtOAc (4 mL) was stirred at room temperature for 2 hours. The precipitate was filtered, washed with EtOAc (1 mL), and dried to give the title compound (66 mg, 82.5% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.00 - 9.84 (m, 2H), 8.51 - 8.43 (m, 2H), 8.36 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 6.94 (s, 1H), 4.99 - 4.90 (m, 1H), 4.46 - 4.35 (m, 2H), 4.15 (s, 3H), 3.59 - 3.48 (m, 1H), 3.42 - 3.28 (m, 3H), 3.19 - 3.08 (m, 1H), 2.60 - 2.54 (m, 2H), 2.26 - 2.15 (m, 2H), 1.90 - 1.81 (m, 1H), 1.73 (d, J = 9.6 Hz, 1H), 1.35 (d, J = 6.2 Hz, 3H).ESI-MS (M+H) +:422.1. Example 56. N-(6-4,7-diazaspiro[2.5]octan-7-ylpyridazin-3-yl)-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide (Compound 210) Starting material: Preparation of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid [ka] Step 1: Preparation of 5-bromo-4-ethoxypyridin-2-amine

[0513] To a mixture of 2-amino-5-bromopyridin-4-ol (20.8 g, 110.05 mmol) and potassium carbonate (30.42 g, 220.09 mmol) in DMF (100 mL) was added iodoethane (20.6 g, 132.06 mmol), and the reaction mixture was stirred at room temperature for 2 days. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was washed with HO (100 mL), brine (100 mL), dried over NaSO, and evaporated to give crude 5-bromo-4-ethoxypyridin-2-amine (11.4 g, Y: 43%), which was used in the next step without purification. 1 H NMR (500 MHz, DMSO-d6) δ 7.80 (s, 1H), 6.01 (s, 1H), 6.00 (br s, 2H) 4.02 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 6.9 Hz, 3H). Step 2: Preparation of 2-amino-5-bromo-4-ethoxy-1-(prop-2-yn-1-yl)pyridin-1-ium bromide

[0514] 5-Bromo-4-ethoxypyridin-2-amine (11.4 g, 52.52 mmol), 3-bromoprop-1-yne (7.5 g, 63.02 mmol), and 2-propanol (200 mL) were added to a round-bottom flask equipped with a rubber septum and vigorously stirred at 80 °C for 6 h. The mixture was then cooled to room temperature, and excess solvent / propargyl bromide was removed under high vacuum. The resulting crude residue, 2-amino-5-bromo-4-ethoxy-1-(prop-2-yn-1-yl)pyridin-1-ium bromide (18.0 g, Y: 86.7%), was used in the next step without purification. 1 H NMR (500 MHz, DMSO-d6) δ 8.53 (br s, 3H), 6.66 (s, 1H), 5.00 (d, J = 2.6 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.82 - 3.67 (m, 1H), 1.38 (t, J = 6.9 Hz, 3H). Step 3: Preparation of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine

[0515] To a stirred solution of sodium hydroxide (2.57 g, 64.28 mmol) in deionized HO (100 mL), 2-amino-5-bromo-4-ethoxy-1-(prop-2-yn-1-yl)pyridin-1-ium bromide (18.0 g, 53.57 mmol) was added over 5 min, and the reaction mixture was stirred at room temperature for 30 min. Immediately after the addition, the solution turned yellow, and a yellow oil began to disperse as a distinct, separate phase. The oil product was then extracted with EtOAc (2 × 60 mL), dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to give 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (15.1 g, Y: 93.9%) as a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J = 2.6 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 6.88 (d, J = 2.6 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.36 (t, J = 6.9 Hz, 3H). Step 4: Preparation of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate

[0516] 6-Bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (15.1 g, 59.19 mmol) was dissolved in MeOH (100 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (966.71 mg, 1.18 mmol) was added, followed by triethylamine (11.98 g, 118.38 mmol). The reaction mixture was transferred to an autoclave and stirred at 130 °C under CO pressure (40 bar) overnight. The MeOH was then evaporated, and the residue was partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried over NaSO and evaporated under reduced pressure to give crude methyl 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (12.5 g, Y: 72.1%), which was used in the next step without purification. 1 H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 7.55 (s, 1H), 6.85 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.24 (s, 3H), 1.33 (t, J = 6.9Hz, 3H). Step 5: Preparation of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid

[0517] A mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (12.5 g, 53.36 mmol) and potassium hydroxide (4.49 g, 80.05 mmol) was stirred overnight in a mixture of methanol (80 mL) and HO (60 mL). The resulting mixture was concentrated under reduced pressure to remove methanol, and the resulting aqueous solution was neutralized to pH = 5 with 1 N HCl to precipitate the carboxylic acid. The solid 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (6.0 g, Y: 48.5%) was isolated by filtration, dried, and used directly in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.52 (s, 1H), 6.81 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H). Starting Material: Preparation of tert-butyl 7-(6-aminopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate [ka] Step 1: Preparation of tert-butyl 7-(6-chloropyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0518] 3,6-Dichloropyridazine (842.11 mg, 5.65 mmol) in anhydrous toluene (10 mL) was treated with 4-Boc-4,7-diazaspiro[2.5]octane (1.2 g, 5.65 mmol) and triethylamine (1.72 g, 16.96 mmol). The reaction mixture was heated under reflux for 16 h, concentrated under reduced pressure, and the residue was purified on SiO (5% MeOH / CHCl / 1% NHOH) to give the title compound tert-butyl 7-(6-chloropyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1.05 g, Y: 57.2%) as a white solid. ESI-MS (M+H): 325.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 9.5, 1H), 7.33 (d, J = 9.5, 1.6 Hz, 1H), 3.55 (m, 2H), 3.4 (s, 2H), 2.93 (m, 2H), 1.37 (s, 9H), 0.87 (m, 2H), 0.77 (m, 2H). Step 2: Preparation of tert-butyl 7-6-[(diphenylmethylidene)-amino]pyridazin-3-yl-4,7-diazaspiro[2.5]-octane-4-carboxylate

[0519] tert-Butyl 7-(6-chloropyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (949.7 mg, 2.92 mmol), diphenylmethanimine (582.9 mg, 3.22 mmol), Pd(dba) (133.87 mg, 146.2 μmol), 1-[2-(diphenylphosphanyl)naphthalen-1-yl]naphthalen-2-yldiphenylphosphane (182.06 mg, 292.39 μmol), and cesium carbonate (1.91 g, 5.85 mmol) were suspended in dioxane (20.0 mL), and the suspension was stirred overnight at 100° C. The resulting reaction mixture was cooled to room temperature and then filtered through Celite, and the precipitate was washed with ethyl acetate (30 mL). The filtrate was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Hex / EtOAc 2 / 1 as eluent) to give pure tert-butyl 7-6-[(diphenylmethylidene)-amino]pyridazin-3-yl-4,7-diazaspiro[2.5]octane-4-carboxylate (1.0 g, Y: 72.8%). 1 H NMR (500 MHz, DMSO-d6) δ 7.71-7.65 (m, 2H), 7.60-7.55 (m, 1H), 7.53-7.47 (m, 2H), 7.34 (s, 3H), 7.18-7.09 (m, 3H), 6.90-6.85 (m, 1H), 3.55-3.47 (m, , 2H), 3.46-3.39 (m, , 2H), 2.55-2.53 (m, 2H) 1.40 (s, 9H), 0.90-0.85 (m, 2H), 0.78-0.72 (m, 2H). Step 3: Preparation of tert-butyl 7-(6-aminopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0520] tert-Butyl 7-6-[(diphenylmethylidene)amino]pyridazin-3-yl-4,7-diazaspiro[2.5]octane-4-carboxylate (999.51 mg, 2.13 mmol) was dissolved in THF (10 mL). 2-Hydroxy-1,2,3-propanetricarboxylic acid monohydrate (2 M; 2.24 g, 10.64 mmol) was added to the solution, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was neutralized with saturated aqueous sodium bicarbonate (25 mL), and the mixture was extracted twice with ethyl acetate (2 × 15 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude residue was triturated with MTBE (10 mL), and the precipitate was filtered, washed with MTBE (5 mL), and dried in vacuo to give tert-butyl 7-(6-aminopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (260.0 mg, Y: 38% yield) as a white solid. ESI-MS (M+H)+: 306.2. 1 H NMR (500 MHz,chloroform-d) δ 6.90 (d, J = 9.6 Hz, 1H), 6.81 (d, J = 9.6 Hz, 1H), 4.69 (br s, 2H), 3.71-3.66 (m, 2H), 3.45 - 3.37 (m, 2H), 3.29 (s, 2H), 1.46 (s, 9H), 1.05-0.99 (m, 2H), 0.85-0.80 (m, 2H). N-(6-4,7-diazaspiro[2.5]octan-7-ylpyridazin-3-yl)-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide [ka] Step 1: Preparation of tert-butyl 7-(6-amino-pyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0521] 7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100.0 mg, 454.08 μmol) was suspended in DMF (4 mL), and ethylbis(propan-2-yl)amine (146.41 mg, 1.13 mmol) was added, followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]dimethylazanium; hexafluoro-lambda 5-phosphanide (HATU) (206.75 mg, 543.75 μmol). The resulting mixture was stirred at room temperature for 30 minutes. Then, tert-butyl 7-(6-amino-pyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (138.37 mg, 453.13 μmol) was added in one portion, and the reaction mixture was stirred at room temperature overnight. The precipitate that formed was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried in vacuo to give pure tert-butyl 7-(6-7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-amidopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (88.0 mg, 173.37 μmol, 38.3% yield). ESI-MS (M+H)+: 508.4. Step 2: Preparation of N-(6-4,7-diazaspiro[2.5]octan-7-ylpyridazin-3-yl)-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide

[0522] To a solution of tert-butyl 7-(6-7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-amidopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (87.99 mg, 173.35 μmol) in dichloromethane (20 mL), 2,2,2-trifluoroacetic acid (197.66 mg, 1.73 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The solvent was then evaporated to dryness under reduced pressure. The crude residue was crystallized from MTBE / MeCN (4 / 1, ca. 5 mL) to give N-(6-4,7-diazaspiro[2.5]octan-7-ylpyridazin-3-yl)-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide (64.5 mg, Y: 67.8%) as the TFA salt. ESI-MS (M+H)+: 408.2. 1 H NMR (500 MHz, DMSO-d6): δ 11.01 (s, 1H), 9.51 (br s, 1H), 9.2 (s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 3.55 (s, 2H), 2.43 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H), 1.15-1.05 (m, 2H), 0.98-90 (m, 2H). Example 57. Synthesis of (S)-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride (Compound 211) [ka] Preparation of 2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid [ka] Step 1A: Preparation of tetrahydro-2H-pyran-4-yl methanesulfonate

[0523] To a solution of tetrahydro-2H-pyran-4-ol (5.0 g, 49 mmol) in DCM (50 mL) were added TEA (15 g, 147 mmol) and MsCl (6.8 g, 58.8 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was washed with water and brine, dried over Na SO , and filtered. The crude was purified by silica gel column chromatography eluting with PE: EtOAc = 1:2 to give the title compound (8.3 g, 86.1% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.91 - 4.90 (m, 1H), 3.99 - 3.89 (m, 2H), 3.61 - 3.50 (m, 2H), 3.04 (s, 3H), 2.10 - 2.00 (m, 2H), 1.93 - 1.83 (m, 2H). Step 2A: Preparation of 6-bromo-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine

[0524] To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (500 mg, 2.19 mmol) in DMF (10 mL) was added K2CO3 (0.92 g, 6.6 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (800 mg, 4.8 mmol), and the mixture was stirred at 75 °C for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organics were washed, brined, dried over Na2SO4, and filtered. The filtrate was concentrated, and the crude was extracted with MeCN:H2O. = Purification by C18 column chromatography eluting with 20% to 60% gave the title compound (400 mg, 58.8% yield) as a grey solid. ESI-MS (M+H) + :310.8. Step 3A: Preparation of methyl 2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylate

[0525] To a solution of 6-bromo-2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine (400 mg, 1.29 mmol) in MeOH (50 mL) was added Pd(dppf)Cl (141 mg, 0.2 mmol) and TEA (1.0 g, 10 mmol), and the mixture was charged with CO three times and stirred under a CO balloon at 80 °C overnight. The mixture was filtered, and the filtrate was concentrated to give the title compound (600 mg, crude) as a gray solid. ESI-MS (M+H) + :290.9 Step 4A: Preparation of 2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid

[0526] To a solution of methyl 2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylate (600 mg, crude) in THF (8 mL) and HO (4 mL) was added LiOH (200 mg, 8 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The aqueous phase was adjusted to pH = 2 with 1 M HCl and purified by C18 column chromatography eluting with MeCN:HO (FA) = 0% to 15% to give the title compound (70 mg, 19.7% yield over two steps) as a white solid. ESI-MS (M+H) + :277.0. Step 1: Preparation of tert-butyl (S)-2-methyl-4-(6-(2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate

[0527] To a solution of 2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid (60 mg, 0.22 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (60 mg, 0.20 mmol) in DMF (1.5 mL) was added DIPEA (100 mg, 0.775 mmol) and HATU (120 mg, 0.31 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC (0.05% FA / CHCN in water) to give the title compound (10 mg, 8.8% yield) as a gray solid, ESI-MS (M+H): 552.2. Step 2: Preparation of (S)-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide hydrochloride

[0528] A solution of tert-butyl (S)-2-methyl-4-(6-(2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate (10 mg, 0.022 mmol) in 3M HCl / EtOAc (2 mL) was stirred at room temperature for 1 h. The precipitate was filtered, washed with EtOAc (1 mL), and dried to give the title compound (5.5 mg, 63.0% yield) as a yellow solid, ESI-MS (M+H)+: 452.2. 1H NMR (400 MHz, MeOD-d4) δ 9.16 (s, 1H), 8.57 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 5.12 (br s, 1H), 4.51 - 4.42 (m, 2H), 3.94 (br s, 2H), 3.73 - 3.57 (m, 5H), 3.48 - 3.37 (m, 2H), 2.52 (s, 3H), 2.21 (br s, 2H), 1.92 (br s, 2H), 1.29 (br s, 3H). Example 58. Synthesis of 2-methyl-N-(6-((S)-3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide (Compounds 212 and 213) [ka] Step 1: Preparation of 2-methyl-N-(6-((S)-3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide

[0529] 2-Methyl-N-(6-((S)-3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide (20 mg) was obtained by SFC to give title compound 212 (7 mg, 35%) as a white solid and compound 213 (7.64 mg, 38.2%) as a gray solid. ESI-MS (M+H)+: 438.1. compound 212 1H NMR (400 MHz, MeOD-d4) δ 8.89 (s, 1H), 8.19 (d, J = 9.8 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J = 9.9 Hz, 1H), 6.79 (s, 1H), 5.28 - 5.21 (m, 1H), 4.11 - 3.96 (m, 5H), 3.89 - 3.79 (m, 1H), 2.98 (d, J = 10.0 Hz, 1H), 2.87 - 2.73 (m, 3H), 2.51 - 2.44 (m, 1H), 2.41 - 2.23 (m, 5H), 1.06 (d, J = 6.3 Hz, 3H). compound 213 1 H NMR (400 MHz, MeOD-d4) δ 8.98 (s, 1H), 8.29 (d, J = 9.6 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 6.88 (s, 1H), 5.38 - 5.26 (m, 1H), 4.19 - 4.02 (m, 5H), 3.99 - 3.86 (m, 1H), 3.09 - 3.02 (m, 1H), 2.97 - 2.81 (m, 3H), 2.55 (dd, J = 24.4, 13.2 Hz, 1H), 2.48 - 2.29 (m, 5H), 1.16 (d, J = 6.1 Hz, 3H). Example 59. Synthesis of 8-ethyl-2-methyl-N-{6-[(3S)-3-methylpiperazin-1-yl]pyridazin-3-yl}imidazo[1,2-a]pyrazine-6-carboxamide (Compound 214) Starting Material: Preparation of 8-Ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxamide [ka] Step 1: Preparation of 5-bromo-3-ethylpyrazin-2-amine

[0530] 3-Ethylpyrazin-2-amine (10.73 g, 87.13 mmol) and pyridine (7.58 g, 95.84 mmol, 7.75 mL) were mixed in CHCl (200 mL), bromine (14.62 g, 91.48 mmol, 4.69 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The resulting mixture was then washed with water and brine and evaporated under reduced pressure to give pure 5-bromo-3-ethylpyrazin-2-amine (15.8 g, Y: 80.8%). 1 H NMR (500 MHz, chloroform-d) δ 7.93 (s, 1H), 4.61 (br s, 2H), 2.62 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). Step 2: Preparation of 6-bromo-8-ethyl-2-methylimidazo[1,2-a]pyrazine

[0531] To a mixture of 4-methylbenzene-1-sulfonic acid hydrate (1.49 g, 7.82 mmol) and pyridine (618.53 mg, 7.82 mmol, 630.0 μL) in i-PrOH (100 mL) was added 5-bromo-3-ethylpyrazin-2-amine (15.8 g, 78.2 mmol) and 1-bromo-2,2-dimethoxypropane (16.46 g, 89.93 mmol, 12.16 mL), and the reaction mixture was heated to 90 °C for 4 h. The resulting mixture was diluted with DCM, washed with saturated sodium bicarbonate solution, dried (NaSO), and concentrated under reduced pressure to give pure 6-bromo-8-ethyl-2-methylimidazo[1,2-a]pyrazine (16.0 g, Y: 85.2%). ESI-MS (M+H): 240.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.13 (s, 1H), 3.11 (q, J = 7.4 Hz, 2H), 2.50 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H). Step 3: Preparation of methyl 8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxylate

[0532] 6-Bromo-8-ethyl-2-methylimidazo[1,2-a]pyrazine (5.0 g, 20.82 mmol), triethylamine (2.53 g, 24.98 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1.7 g, 2.08 mmol) were dissolved in dry MeOH (200 mL). The reaction mixture was heated at 125 °C for 48 h in a high pressure vessel under CO pressure (20 atm). The solvent was evaporated, and the mixture was poured into water (250 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL), and the organics were dried over NaSO and evaporated to dryness to give pure 8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxylate (4.0 g, Y: 87.6%). ESI-MS(M+H)+:220.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.97 (s, 1H), 3.88 (s, 3H), 3.12 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H). Step 4: Preparation of 8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxamide

[0533] Methyl 8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxylate (400.0 mg, 1.82 mmol) was dissolved in NH / MeOH (10 mL) and the reaction mixture was sealed and heated to 90° C. overnight. After workup with EtOAc, pure 8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxamide (300.0 mg, Y: 80.4%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 3.09 (q, J = 7.5 Hz, 2H), 2.37 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H). 8-ethyl-2-methyl-N-{6-[(3S)-3-methylpiperazin-1-yl]pyridazin-3-yl}imidazo[1,2-a]pyrazine-6-carboxamide, [ka] Step 1: Preparation of tert-butyl (2S)-4-(6-chloropyridazin-3-yl)-2-methylpiperazine-1-carboxylate

[0534] To a solution of 3,6-dichloropyridazine (5.0 g, 33.56 mmol) in DMF (100 mL) was added ethyl bis(propan-2-yl)-amine (4.54 g, 35.16 mmol, 6.12 mL) and tert-butyl (2S)-2-methylpiperazine-1-carboxylate (6.4 g, 31.96 mmol). The reaction mixture was heated to 90 °C for 17 h, cooled to room temperature, and then partitioned between ethyl acetate (200 mL) and HO (100 mL). The aqueous layer was extracted with ethyl acetate (2 × 80 mL), and the combined organic layers were washed with HO (200 mL), brine (200 mL), dried (NaSO), filtered, and the solvent was removed under reduced pressure to give the crude product. Purification by flash silica chromatography gave the desired tert-butyl (2S)-4-(6-chloropyridazin-3-yl)-2-methylpiperazine-1-carboxylate (5.88 g, Y: 56%). ESI-MS (M+H)+: 313.2 Step 2: Preparation of tert-butyl (2S)-4-(6-{8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-amido}pyridazin-3-yl)-2-methylpiperazine-1-carboxylate

[0535] 8-Ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxamide (118.57 mg, 580.57 μmol), tert-butyl (2S)-4-(6-chloro-pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (199.76 mg, 638.63 μmol), tris((1E,4E)-1,5-diphenylpenta-1,4-diene-3- (2S)-4-(6-8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-amidopyridazin-3-yl)-2-methyl-piperazine-1-carboxylate (200.0 mg, Y: 61.6%) was obtained after evaporation and HPLC. ESI-MS (M+H)+: 481.4. Step 3: Preparation of 8-ethyl-2-methyl-N-{6-[(3S)-3-methylpiperazin-1-yl]pyridazin-3-yl}imidazo[1,2-a]pyrazine-6-carboxamide; trifluoroacetic acid

[0536] tert-Butyl (2S)-4-(6-8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-amidopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (0.2 g, 0.42 mmol) was dissolved in a mixture of DCM (1 mL) and TFA (1 mL), and the reaction mixture was stirred overnight at room temperature. After complete evaporation and HPLC, pure 8-ethyl-2-methyl-N-6-[(3S)-3-methylpiperazin-1-yl]pyridazin-3-ylimidazo[1,2-a]pyrazine-6-carboxamide (117.9 mg, Y: 58%) was obtained as the trifluoroacetate salt. ESI-MS (M+H): 381.2. 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.25 (s, 1H), 9.05 (s, 1H), 8.75 (s, 1H), 8.32 (d, J = 9.8 Hz, 1H), 8.07 (s, 1H), 7.58 (d, J = 9.8 Hz, 1H), 4.36 (d, J = 13.2 Hz, 2H), 3.46-3.35 (m, 2H), 3.29 - 3.07 (m, 4H), 3.00 (q, J = 7.6 Hz, 1H), 2.45 (s, 3H), 1.43 (t, J = 7.6 Hz, 3H), 1.28 (d, J = 6.1 Hz, 3H). Example 60. Synthesis of (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide HCl salt (Compound 215) [ka] Step 1: Preparation of ethyl 2-bromo-5-ethoxyisonicotinate.

[0537] To a mixture of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in EtOH (30 mL) was added EtONa (2.8 g, 54.6 mmol). The mixture was stirred at 65 °C for 16 h. After cooling to room temperature, SOCl (3.0 mL, 4.9 g, 41.3 mmol) was added to the reaction mixture. The reaction mixture was stirred for 2 days. After concentration, the residue was diluted with EA (100 mL), washed with water and brine, and dried over NaSO. After concentration, the crude product was purified by silica gel column (PE / EA = 5:1) to give the title product (3.0 g, Y: 80.5%) as a white solid. ESI-MS (M+H): 273.9. Step 2: Preparation of ethyl 5-ethoxy-2-(prop-1-yn-1-yl) isonicotinate.

[0538] A mixture of 2-bromo-5-ethoxyisonicotinate (0.36 g, 1.3 mmol), trimethyl(prop-1-yn-1-yl)silane (0.16 g, 1.4 mmol), CuI (76 mg, 0.4 mmol), Pd(PPh3)4 (150 mg, 0.13 mmol), TEA (0.56 mL, 3.9 mmol), and TBAF (1.0 M, 1.3 mL, 1.3 mmol) in toluene (10 mL) was stirred at room temperature for 5 h. The reaction mixture was diluted with EA (200 mL), washed with brine and water, and dried over Na2SO4. After concentration, the residue was purified by silica gel column (PE / EA = 3:1) to give the title product (100 mg, Y: 33%) as a yellow solid. ESI-MS (M+H): 234.1. 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.64 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H), 2.06 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H). Steps 3 and 4: Preparation of ethyl 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylate.

[0539] A mixture of 5-ethoxy-2-(prop-1-yn-1-yl)isonicotinate (160 mg, 0.67 mmol) and O-(mesitylsulfonyl)hydroxylamine (740 mg, 3.4 mmol) in trichloromethane (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was diluted with DMF (5 mL). KCO (180 mg, 1.3 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture was diluted with EA (120 mL), washed with brine and water, and dried over NaSO. After concentration, the crude product was purified by silica gel column (PE / EA = 3:1) to give the title product (100 mg, Y: 60%) as a colorless oil. ESI-MS (M+H): 249.0. Step 5: Preparation of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid.

[0540] To a mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylate (100 mg, 0.4 mmol) in THF / water (10 mL, 2:1) was added LiOH.HO (50 mg, 1.2 mmol). The mixture was stirred at room temperature for 2 hours. After concentration, the residue was adjusted to pH=5 with 1 M HCl. The crude was purified by preparative HPLC to give the title product (80 mg, Y: 90%) as a colorless oil. ESI-MS (M+H): 221.0. 1 H NMR (400 MHz, CDCl3) δ 8.38 - 8.24 (m, 2H), 6.48 (s, 1H), 4.26 (q, J = 6.9 Hz, 2H), 2.49 (s, 3H), 1.59 (t, J = 6.9 Hz, 3H). Step 6: Preparation of tert-butyl (S)-4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate.

[0541] To a mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.45 mmol) in DMF (5 mL) was added tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (146 mg, 0.5 mmol), DIEA (116 mg, 0.9 mmol), and HATU (190 mg, 0.5 mmol). The mixture was stirred at room temperature for 5 hours, quenched with water (20 mL), and extracted with EA (60 mL × 2). The organic layers were combined and dried over Na2SO4. After concentration, the residue was purified by silica gel column (PE / EA = 2:1) to give the title product (100 mg, 45%) as a yellow solid. ESI-MS (M+H): 496.1. Step 7: Preparation of (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide HCl salt.

[0542] To a solution of tert-butyl (S)-4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (50 mg, 0.1 mmol) in EA (2 mL) was added HCl-EA (3 M, 2 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 2 h. After concentration, the residue was purified by preparative HPLC (0.05% HCl / MeCN in water) to give the title compound (20.0 mg, yield: 50%) as a yellow solid. ESI-MS (M+H): 396.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.50 (s, 1H), 9.36 (s, 1H), 8.51 (s, 1H), 8.32 (d, J = 9.7 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J = 9.9 Hz, 1H), 6.56 (s, 1H), 4.36 (t, J = 12.0 Hz, 2H), 4.25 - 4.19 (m, 2H), 3.39 - 3.33 (m, 3H), 3.15 - 3.08 (m, 2H), 2.39 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H), 1.32 (d, J = 6.5 Hz, 3H). Example 61 (S)-2-Methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxamide (Compound 216) [ka] Preparation of tert-butyl (S)-2-methyl-4-(6-(2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate [ka] Step 1A: Preparation of 6-bromo-2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine

[0543] To a mixture of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (1.5 g, 6.6 mmol) in DMF (20 mL) was added NaH (0.48 g, 13.2 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (2.23 g, 9.9 mmol) was added to the mixture and stirred at room temperature for another 16 h. The mixture was diluted with water (20 mL) and extracted with EA (3 × 30 mL). The organic layer was washed with brine (3 × 40 mL) and dried over anhydrous NaSO. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 1:10) to give the title product (1.1 g, 53.8%) as a white solid. ESI-MS (M+H) + :310.9. 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.50 (s, 1H), 7.19 (s, 1H), 4.94 - 4.90 (m, 2H), 2.28 (s, 3H). Step 2A: Preparation of methyl 2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxylate

[0544] To a mixture of 6-bromo-2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine (300 mg, 1 mmol) in MeOH (30 mL) was added Pd(dppf)Cl (143 mg, 0.2 mmol) and TEA (2.7 mL, 0.2 mmol). The mixture was stirred at 60 °C under a CO atmosphere for 20 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title product (crude 240 mg, 84.6%) as a gray solid. ESI-MS (M+H) + :289.1. Step 3A: Preparation of methyl 2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxylic acid

[0545] To a solution of methyl 2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxylate (300 mg, 1 mmol) in THF / HO (8 mL / 4 mL) was added LiOH (100 mg, 4.1 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH = 5 with 1 M HCl. The aqueous layer was extracted with EA (3 x 50 mL). The organic layer was concentrated in vacuo, and the residue was purified by C18 flash (0.1% FA / CH3CN in water) to give the title product (174 mg, 57.8%) as a yellow solid. ESI-MS (M+H) + :275.1. Step 1: Preparation of tert-butyl (S)-2-methyl-4-(6-(2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate

[0546] To a solution of 2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxylic acid (120 mg, 0.44 mmol) and tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (107 mg, 0.36 mmol) in DMF (10 mL) was added HATU (208 mg, 0.54 mmol) and DIEA (0.25 mL, 1.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 × 50 mL). The organic layer was washed with brine (3 × 50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% FA / CHCN in water) to give the title product (90 mg, 37.3%) as a grey solid. ESI-MS (M+H)+: 550.3. 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.95 (s, 1H), 8.14 (s, 1H), 7.67 (s, 1H), 7.41 (d, J = 9.9 Hz, 1H), 7.17 (s, 1H), 4.97 (dd, J = 17.4, 8.7 Hz, 2H), 4.19 (d, J = 12.4 Hz, 2H), 4.08 (d, J = 13.1 Hz, 1H), 3.82 (d, J = 13.3 Hz, 1H), 3.17 (dd, J = 13.0, 3.8 Hz, 2H), 2.97 - 2.90 (m, 1H), 2.31 (s, 3H), 1.43 (s, 9H), 1.12 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxamide

[0547] To a mixture of tert-butyl (S)-2-methyl-4-(6-(2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)piperazine-1-carboxylate (70 mg, 0.13 mmol) in EA (5 mL) was added EA / HCl (5 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% NH.H.sub.2O / CH.sub.3CN in water) to give the title product (20 mg, 34.9%) as a white solid. ESI-MS (M+H)+: 450.2. 1H NMR (400 MHz, MeOD-d4) δ 8.95 (s, 1H), 8.29 (d, J = 9.9 Hz, 1H), 7.59 (s, 1H), 7.37 (d, J = 9.9 Hz, 1H), 7.07 (s, 1H), 4.90 (d, J = 8.2 Hz, 2H), 4.17 (dd, J = 15.1, 6.6 Hz, 2H), 3.10 (d, J = 11.2 Hz, 1H), 2.92 (dd, J = 13.2, 2.9 Hz, 3H), 2.62 (dd, J = 12.8, 10.6 Hz, 1H), 2.38 (s, 3H), 1.17 (d, J = 6.4 Hz, 3H). Example 62. Synthesis of (S)-7-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide HCl salt (Compound 217) [ka] Step 1: Preparation of tert-butyl (S)-4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate

[0548] To a solution of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (2 g, 7.87 mmol) in toluene (40 mL) was added tert-butyl (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylate (2.31 g, 7.87 mmol), Pd(OAc) (176 mg, 0.787 mmol), Xantphos (455 mg, 0.787 mmol), and NaCO (1.31 g, 15.78 mmol). The resulting solution was stirred at 80° C. under an atmosphere of CO for 5 hours. The resulting solution was concentrated under vacuum. The residue was purified by column chromatography (0.1% in water). NH3 Purification by HCl / CHCN gave the title product (2.1 g, Y: 53.8%) as an off-white solid. ESI-MS (M+H)+: 496.2.1 H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 9.11 (s, 1H), 8.36 (d, J = 9.8 Hz, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 7.01 (d, J = 9.9 Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 4.38 - 4.37 (m, 1H), 4.17 - 4.16 (m, 1H), 4.07 - 3.89 (m, 2H), 3.44 - 3.21 (m, 2H), 3.09 - 3.08 (m, 1H), 2.59 (s, 3H), 1.74 (t, J = 7.0 Hz, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H). Step 2: Preparation of (S)-7-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide HCl salt

[0549] To a solution of tert-butyl (S)-4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamido)pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (2.1 g, 4.24 mmol) in EA (10 mL) was added 3 M HCl / EA solution (10 mL), and the resulting solution was stirred at room temperature for 2 h. The precipitate was filtered and dried to give the title product (650 mg, Y: 35.7%) as a yellow solid. ESI-MS (M+H)+: 396.1. 1 H NMR (400 MHz, MeOD-d4) δ 9.18 (s, 1H), 8.53 (d, J = 10.1 Hz, 1H), 8.16 (d, J = 10.2 Hz, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 4.62 - 4.30 (m, 4H), 3.76 - 3.55 (m, 3H), 3.47 - 3.32 (m, 2H), 2.52 (s, 3H), 1.57 (t, J = 7.0 Hz, 3H), 1.46 (d, J = 6.5 Hz, 3H). Example 63. Synthesis of 2-methyl-N-(6-((S)-3-methylpiperazin-1-yl)pyridazin-3-yl)-7-((tetrahydro-2H-pyran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxamide (Compound 218) [ka] Preparation of 2-methyl-7-((tetrahydro-2H-pyran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid [ka] Step 1A: Preparation of tetrahydro-2H-pyran-3-yl methanesulfonate

[0550] To a solution of tetrahydro-2H-pyran-3-ol (150 mg, 1.46 mmol) and TEA (445 mg, 4.4 mmol) in DCM (5 mL) was added MsCl (200 mg, 1.2 mmol), and the reaction mixture was stirred at 0 °C for 2 h. After cooling to room temperature and diluting with water, the mixture was extracted with EA. The combined organics were washed with brine and water, dried over Na SO , and concentrated to give the desired product (250 mg, crude) as a colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 4.77 - 4.68 (m, 1H), 3.89 - 3.80 (m, 1H), 3.73 - 3.59 (m, 3H), 3.04 (s, 3H), 2.13 - 2.02 (m, 1H), 1.99 - 1.86 (m, 2H), 1.65 - 1.55 (m, 1H). Step 2A: Preparation of 6-bromo-2-methyl-7-((tetrahydro-2H-pyran-3-yl)oxy)imidazo[1,2-a]pyridine

[0551] A solution of tetrahy...

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: X is N or CR １ and Y is N or CR ２ and Z is N or CR ３ and R １ , R ２ , R ３ , and R ４ are each independently hydrogen, halogen, hydroxy, cyano, COOH, C(O)C １ -C ６ Alkyl, C(O)OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C3-C ６ Cycloalkyloxy, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , NHC(O)C １ -C ６ Alkyl, N(C １ -C ６ alkyl)C(O)C １ -C ６ Alkyl, C(O)NH ２ , C(O)NH(C １ -C ６ alkyl), and C(O)N(C １ -C ６ alkyl) ２ wherein the alkyl, alkenyl, alkynyl, and alkoxy are selected from the group consisting of one or more of halogen, hydroxyl, methoxy, C ３ -C ８ cycloalkyl, or NH ２ optionally replaced by R ５ But hydrogen, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, A is, 【Chemistry 2】 is selected from the group consisting of A is 1 to 4 R ９ optionally replaced by R ６ But C １ -C ３ Alkyl or C １ -C ３ is haloalkyl, R ７ But hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C3-C ６ cycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and C １ -C ６ optionally substituted with 1 to 3 substituents independently selected from alkyl; R ８ But halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, or C3-C ６ is cycloalkyl, Each R ９ are independently selected from halogen, hydroxy, cyano, COOH, C(O)C １ -C ６ Alkyl, C(O)OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyloxy, C ３ -C ８ Cycloalkyl, NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , NHC(O)C １ -C ６ Alkyl, N(C １ -C ６ alkyl)C(O)C １ -C ６ Alkyl, C(O)NH ２ , C(O)NH(C １ -C ６ alkyl), and C(O)N(C １ -C ６ alkyl) ２ wherein the alkyl, alkenyl, alkynyl, and alkoxy are selected from the group consisting of one or more of halogen, hydroxyl, methoxy, C ３ -C ８ cycloalkyl, or NH ２ optionally replaced by B is not attached to formula (I) by a nitrogen atom and has 1 to 6 R １２ or heterocycloalkyl optionally substituted with B is NR １０ R １１ and R １０ However, (CH ２ ) ０－３ Aryl, (CH ２ ) ０－３ Heteroaryl, (CH ２ ) ０－３ heterocycloalkyl (containing at least one nitrogen ring atom), or C １ -C ８ heteroalkyl (containing at least one nitrogen atom), and each R １０ But 1 to 6 R １２ optionally replaced by R １１ But hydrogen, C １－７ Alkyl, C １－７ haloalkyl, or C ３－８ cycloalkyl, or R １０ and R １１ together with the nitrogen atom to which they are attached form a heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1 to 6 R １２ optionally replaced by Each R １２ are independently selected from halogen, hydroxy, cyano, COOH, C(O)C １ -C ６ Alkyl, C(O)OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, (CH ２ ) 0-2 C ３ -C ８ Cycloalkyl, (CH ２ ) 0-2 SO2 C １ -C ６ Alkyl, C １ -C ６ Heteroalkylene C ３ -C ８ Cycloalkyl, OC ３ -C ８ cycloalkyl, 4- to 7-membered monocyclic heterocycloalkyl, C １ -C ６ Heteroalkylene (4- to 7-membered monocyclic heterocycloalkyl), O (4- to 7-membered monocyclic heterocycloalkyl), (CH ２ ) 0-2 (4- to 7-membered monocyclic heterocycloalkyl), NH ２ , NH(C １ -C ６ alkyl), N(C １ -C ６ alkyl) ２ , NHC(O)C １ -C ６ Alkyl, N(C １ -C ６ alkyl)C(O)C １ -C ６ Alkyl, C(O)NH ２ , C(O)NH(C １ -C ６ alkyl), and C(O)N(C １ -C ６ alkyl) ２ wherein the alkyl, alkenyl, alkynyl, and alkoxy are selected from the group consisting of one or more halogen, hydroxyl, or NH ２ and wherein said cycloalkyl and heterocycloalkyl are optionally substituted with one or more of halogen, hydroxyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C １ -C ６ Alkoxy, or NH ２ optionally replaced by, or Two R on the same carbon １２ can be combined as keto (=O), or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 0, 1, or 2 of X, Y, and Z are N.

3. The compound is a compound of formula (Ia): 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

4. The compound is a compound of formula (Ib): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

5. The compound is a compound of formula (Ic): 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

6. The compound is a compound of formula (Id): 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

7. The compound is a compound of formula (Ie): 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

8. The compound is a compound of formula (If), 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

9. R １ , R ２ , R ３ , and R ４ are each independently hydrogen, halogen, C １ -C ６ Alkoxy, and C １ -C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl.

10. R １ , R ２ , R ３ , and R ４ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein each is hydrogen.

11. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12. A is, 【Chemistry 9】 10. The compound of claim 1, selected from the group consisting of:

13. A is R ９ 10. The compound of claim 1, wherein the compound is unsubstituted by:

14. R ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is Me.

15. R ７ But C １ -C ６ Alkyl, C3-C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl or heterocycloalkyl.

16. R ７ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, isopropyl, or cyclobutyl.

17. A is, 【Chemistry 10】 10. The compound of claim 1, selected from the group consisting of:

18. A is, 【Chemistry 11】 13. The compound of claim 12, wherein:

19. A is, 【Chemistry 12】 19. The compound of claim 18, wherein:

20. A is, 【Chemistry 13】 13. The compound of claim 12, wherein:

21. A is, 【Chemistry 14】 21. The compound of claim 20, wherein:

22. A is, 【Chemistry 15】 13. The compound of claim 12, wherein:

23. B is NR １０ R １１ and R １０ and R １１ together with the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1, 2, 3, or 4 R １２ 2. The compound of claim 1, optionally substituted with:

24. R １０ and R １１ together with the nitrogen atom to which they are attached form a monocyclic heterocycloalkyl of 4 to 7 ring atoms containing a total of 1 or 2 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1, 2, 3, or 4 R １２ 24. The compound of claim 23, optionally substituted with, or a pharmaceutically acceptable salt thereof.

25. B, 【Chemistry 17】 and W is NR １３ or CR １４ R １４ and R １３ But hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, and (CH ２ ) 0-2 C ３ -C ８ cycloalkyl, wherein alkyl, alkenyl, and alkynyl are selected from the group consisting of one or more halogen, hydroxyl, methoxy, or NH ２ and cycloalkyl is optionally substituted with one or more of halogen, hydroxyl, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or NH ２ optionally replaced by Each R １４ are independently H or R １２ and 2. The compound of claim 1, wherein n is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

26. B, [Chemistry 18] 26. The compound of claim 25, wherein:

27. R １３ is H or unsubstituted C １ -C ６ 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

28. B is a bicyclic 6-14 membered heterocycloalkyl containing a total of 1, 2, or 3 nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, said heterocycloalkyl containing 1, 2, 3, or 4 R １２ 25. The compound of claim 24, optionally substituted with: or a pharmaceutically acceptable salt thereof.

29. Each R １２ But independently, C １ -C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

30. R １１ is hydrogen or C １－７ alkyl, and R １０ C containing at least one nitrogen atom １ -C ８ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is heteroalkyl.

31. R １０ contains at least one nitrogen ring atom (CH ２ ) ０－３ heterocycloalkyl, and each R １０ But 1 to 6 R １２ 2. The compound of claim 1, optionally substituted with: 【Request Item 32】 【Chemistry 33-1】 【Chemistry 33-2】 【Chemistry 33-3】 【Chemistry 33-4】 【Chemistry 33-5】 【Chemistry 33-6】 【Chemistry 33-7】 【Chemistry 33-8】 【Chemistry 33-9】 【Chemistry 33-10】 【Chemistry 33-11】 【Chemistry 33-12】 【Chemistry 33-13】 【Chemistry 33-14】 【Chemistry 33-15】 【Chemistry 33-16】 【Chemistry 33-17】 【Chemistry 33-18】 【Chemistry 33-19】 【Chemistry 33-20】 【Chemistry 33-21】 【Chemistry 33-22】 【Chemistry 33-23】 【Chemistry 33-24】 【Chemistry 33-25】 【Chemistry 33-26】 【Chemistry 33-27】 【Chemistry 33-28】 【Chemistry 33-29】 【Chemistry 33-30】 【Chemistry 33-31】 【Chemistry 33-32】 【Chemistry 33-33】 [Chemistry 33-34] [Chemistry 33-35] [Chemistry 33-36] [Chemistry 33-37] [Chemistry 33-38] [Chemistry 33-39] [Chemistry 33-40] [Chemistry 33-41] [Chemistry 33-42] [Chemistry 33-43] [Chemistry 33-44] [Chemistry 33-45] [Chemistry 33-46] [Chemistry 33-47] [Chemistry 33-48] [Chemistry 33-49] [Chemistry 33-50] [Chemistry 33-51] [Chemistry 33-52] 【Chemistry 33-53】 [Chemistry 33-54] 【Chemistry 33-55】 [Chemistry 33-56] [Chemistry 33-57] [Chemistry 33-58] [Chemistry 33-59] [Chemistry 33-60] [Chemistry 33-61] [Chemistry 33-62] [Chemistry 33-63] [Chemistry 33-64] [Chemistry 33-65] [Chemistry 33-66] [Chemistry 33-67] [Chemistry 33-68] [Chemistry 33-69] 【Chemistry 33-70】 【Chemistry 33-71】 【Chemistry 33-72】 【Chemistry 33-73】 [Chemistry 33-74] 【Chemistry 33-75】 [Chemistry 33-76] 【Chemistry 33-77】 【Chemistry 33-78】 [Chemistry 33-79] 【Chemistry 33-80】 【Chemistry 33-81】 【Chemistry 33-82】 【Chemistry 33-83】 [Chemistry 33-84] 【Chemistry 33-85】 【Chemistry 33-86】 【Chemistry 33-87】 【Chemistry 33-88】 【Chemistry 33-89】 【Chemistry 33-90】 【Chemistry 33-91】 【Chemistry 33-92】 【Chemistry 33-93】 [Chemistry 33-94] 【Chemistry 33-95】 【Chemistry 33-96】 【Chemistry 33-97】 【Chemistry 33-98】 【Chemistry 33-99】 【Chemistry 33-100】 【Chemistry 33-101】 【Chemistry 33-102】 【Chemistry 33-103】 【Chemistry 33-104】 【Chemistry 33-105】 【Chemistry 33-106】 【Chemistry 33-107】 【Chemistry 33-108】 【Chemistry 33-109】 【Chemistry 33-110】 【Chemistry 33-111】 【Chemistry 33-112】 【Chemistry 33-113】 【Chemistry 33-114】 【Chemistry 33-115】 【Chemistry 33-116】 【Chemistry 33-117】 【Chemistry 33-118】 【Chemistry 33-119】 【Chemistry 33-120】 【Chemistry 33-121】 【Chemistry 33-122】 【Chemistry 33-123】 [Chemistry 33-124] 【Chemistry 33-125】 【Chemistry 33-126】 【Chemistry 33-127】 【Chemistry 33-128】 【Chemistry 33-129】 【Chemistry 33-130】 【Chemistry 33-131】 or a pharmaceutically acceptable salt thereof.

33. 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, which is a small molecule splicing modulator.

34. 33. A pharmaceutical composition for use in treating a disease associated with a nucleotide repeat expansion, comprising a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

35. 35. The pharmaceutical composition of claim 34, wherein the nucleotide repeat expansion comprises a nucleotide sequence that is repeated two or more times, and the nucleotide sequence is selected from the group consisting of CAG, CAG / CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT / ATTTC, and CCCTCT.

36. 35. The pharmaceutical composition of claim 34, wherein the nucleotide repeat expansion comprises a trinucleotide sequence repeated two or more times, and the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG, and GCN.

37. Dentatorubral-pallidoluysian atrophy, Huntington's disease, spinal-bulbar muscular atrophy, SCA1 (spinocerebellar ataxia type 1), SCA2 (spinocerebellar ataxia type 2), SCA3 (spinocerebellar ataxia type 3 or Machado-Joseph disease), SCA6 (spinocerebellar ataxia type 6), SCA7 (spinocerebellar ataxia type 7), SCA12 (spinocerebellar ataxia type 12), SCA17 (spinocerebellar ataxia type 17), FRAXA (fragile X syndrome), FXTAS (fragile X-associated tremor / ataxia syndrome), FRAXE (fragile XE mental retardation), Baratela-Scott syndrome 34. A pharmaceutical composition for use in the treatment of a disease selected from the group consisting of cerebral palsy, cerebral palsy syndrome, FRDA (Friedreich's ataxia), DM1 (myotonic dystrophy type 1), DM2 (myotonic dystrophy type 2), SCA8 (spinocerebellar ataxia type 8), Fuchs' endothelial corneal dystrophy, Desbuquois dysplasia, amyotrophic lateral sclerosis, and frontotemporal dementia, comprising a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

38. The pharmaceutical composition described in claim 37, wherein the disease is Huntington's disease.

39. The pharmaceutical composition described in claim 37, wherein the disease is myotonic dystrophy 1.

40. The pharmaceutical composition of claim 37, wherein the disease is selected from the group consisting of FRAXA (Fragile X Syndrome), FXTAS (Fragile X-Associated Tremor / Ataxia Syndrome), and FRAXE (Fragile XE Mental Retardation).

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