Methods for treating inflammatory diseases

Abstract

This disclosure relates to compounds of formula (I) as defined herein, pharmaceutically acceptable salts thereof, and compositions comprising them. Furthermore, the specification also describes methods for treating diseases and disorders disclosed herein using compounds of formula (I), pharmaceutically acceptable salts thereof, and compositions comprising them.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 472,252, filed on 9 June 2023, and U.S. Provisional Application No. 63 / 609,168, filed on 12 December 2023, the entire contents of which are incorporated herein by reference.

[0002] This application relates to the fields of chemistry and biology, and more particularly to compounds of formula (I) as defined herein and their pharmaceutically acceptable salts, as well as compositions comprising the same. Furthermore, the specification also describes methods for treating diseases and disorders disclosed herein using compounds of formula (I), their pharmaceutically acceptable salts, and compositions comprising the same. [Background technology]

[0003] Receptor-interacting protein kinase 2 (RIPK2) is a serine-threonine protein kinase and a downstream signaling molecule for nucleotide-binding oligomerized domain 1 (NODI), NOD2, and Toll-like receptors (TLRs). The RIPK2 protein contains a kinase domain (KD), an intermediate domain (INTD), and a caspase activation and recruitment domain (CARD). The CARD domain of RIPK2 mediates interactions with NODI and NOD2. RIPK2 is expressed in the cytoplasm of antigen-presenting cells, including dendritic cells and macrophages, and is also expressed in T cells and epithelial cells.

[0004] NOD receptors function in the innate immune system, detecting bacterial pathogens by binding to diaminopimelic acid or muramyl dipeptide residues present in bacterial peptidoglycans. Interactions between RIPK2 and NODI, NOD2, and TLRs induce the release of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-12 / 23p40, as well as RIPK2-mediated induction of NF-κ-B-dependent inflammatory responses. RIPK2 activation and dysregulation of the RIPK2-NOD signaling pathway may also play a role in the pathogenesis of various inflammatory diseases. RIPK2 has been reported as a prognostic indicator and candidate therapeutic target for various cancers. [Overview of the project]

[0005] Some embodiments involve compounds of formula (I).

[0006] [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z 1 One or two of them are independently N, and X, Y, and Z 1 The remainder is C,

[0007] [ka] It is either a single bond or a double bond. R x is hydrogen, -NH2, or halogen, Ring A is phenyl or a 5-10 membered heteroaryl. m is 0, 1, 2, 3, or 4. R 1 Each is independent of the others. (i) C1-C6 alkoxys optionally substituted with hydroxyl or phenyl, (ii) C1-C6 deuterated alkoxy, (iii) C1-C6 alkoxyalkyl, (iv) 5-6 member heteroaryls, (v)-N(R 1A )-S(O2)R 1B 、 (vi)-(C=O)NR 1A R 1B 、 (vii) halogen, (viii) cyano, (ix) hydroxyl, (x)-NR A R B 、 (xi) C1-C6 alkyl optionally substituted with one or two substituents independently selected from hydroxyl, and 4- to 8-membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl, (xii) C1-C6 haloalkyl, (xiii) C1-C6 haloalkoxy, (xiv) C3-C6 cycloalkyl, (xv) 4- to 8-membered heterocyclyl optionally substituted with one or two substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl, (xvi)-S(O2)C1-C6 alkyl, or (xvii) 4- to 10-membered heterocyclyloxy optionally substituted with acyl, (xviii) phenyl, R 1A each is independently hydrogen or C1-C6 alkyl, R 1B each is independently, (i) C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, a 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, or a 4- to 10-membered heterocyclyl optionally substituted with -(C=O)OC1-C6 alkyl, (ii) a 5- to 10-membered heteroaryl optionally substituted with one to three substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl, (iii) C3-C6 cycloalkyl groups optionally substituted with one or two substituents independently selected from C1-C6 alkyl groups and C1-C6 hydroxyalkyl groups. (iv) Ethyl enyl, (v) C1-C6 haloalkyl, (vi)-(C=O)OC1-C6 alkyl, 4-10 member heterocyclines, (vii)-NR 1A R 1A ,or (viii) Phenyl, R A is hydrogen or C1-C6 alkyl, R B teeth, (i) Hydrogen, (ii)-S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or C1-C6 alkoxy groups, (iv)-(C=O)C1-C6 alkyl, (v)-(C=O)OC1-C6 alkyl, (vi) A 4- to 8-membered heterocycline optionally substituted with a hydroxyl group, or (vii) Halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 member heteroaryl optionally substituted with C1-C6 alkyl, and C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from -C(=O)C1-C6 alkyl or 4-8 member heterocyclyl optionally substituted with C1-C6 alkyl, (viii) A -(C=O) 5 or 6-membered heteroaryl that is optionally substituted with a C1-C6 alkyl group, R 2 teeth, (i) Hydrogen, (ii) Halogen, (iii) (a) Hydroxyl, (b) Halogen, (c) Phosphate, (d)-NR 2A R 2B , (e) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl groups. (f) 5-6 member heteroaryls optionally substituted with C1-C6 alkyl groups, (g) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or hydroxyalkyl groups, (h)CO2H, (i)C(O)R 2A , (j) C1-C6 alkyl, or (k) Oxo, C1-C6 alkoxys that are optionally substituted with 1 to 3 substituents independently selected from the above, (iv) C1-C6 haloalkoxy, (v) 4-10 member heterocyclyloxy, (vi)-(C=O)NR 2A R 2B , (vii) Hydroxyl, halogen, and -NR 2A R 2B C1-C6 alkyl groups that are optionally substituted with 1 to 3 substituents independently selected from the above. (viii) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl or C1-C6 alkoxy, or (ix)-NR 2A R 2B And, R 2A and R 2B Each of these is independently a C1-C6 alkyl or C1-C6 hydroxyalkyl group that is optionally substituted with hydrogen or hydroxyl. R 3 teeth, (i) C1-C6 thioalkyl, (ii)

[0008] [ka] (iii)

[0009] [ka] (iv) A 4- to 8-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, and C1-C6 alkoxys. (v)NR E R F Or C1-C6 alkyl groups optionally substituted with hydroxyl groups. (vi)-CO2H, (vii)-C(=O)NR E R F , (viii) C1-C6 alkoxys optionally substituted with 4-10 member heterocyclines, (ix) Hydrogen, (x)C1-C6 haloalkyl, (xi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. (xii) C1-C6 alkoxyalkyl, or (xiii) C1-C6 hydroxyalkyl, Z is O or NR 4 And, R 3A teeth, (i) C1-C6 haloalkyl, (ii) C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl groups, (iii) (a) C3-C6 cycloalkyl, (b) A 5-6 member heteroaryl molecule optionally substituted with a C1-C6 alkyl group. (c) Hydroxyl, (d) C1-C6 alkyl, or (e) A 4-6 member heterocyclyl optionally substituted with a 4-6 member heterocyclyl, or a C1-C6 alkyl optionally substituted with a C1-C6 alkoxy. C1-C6 alkyl groups that are optionally substituted, (iv) C1-C6 alkoxyalkyl, (v) C1-C6 hydroxyalkyl, (vi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl, or (vii) A 4-10 member heterocycline optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1-C6 alkoxy. (viii)-N(C1-C6 alkyl)2, R 3B and R 3C Each of these independently consists of a C3-C6 cycloalkyl group, or a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl group, or R 3B and R 3C These, together with the atoms to which they are bonded, form a 4- to 8-membered heterocycline which is optionally substituted with C1-C6 alkyl groups. R 4 is hydrogen or C1-C6 alkyl, and Each R C and R D Each of these is independently a C1-C6 alkyl group that is optionally substituted with hydrogen, -(C=O)C1-C6 alkyl, or oxo. Each R E and R F Each of these is independently either hydrogen or a C1-C6 alkyl group, or R E and R F These atoms, together with the atoms to which they are bonded, form 4- to 8-membered heterocyclines that are optionally substituted with hydroxyls.

[0010] Methods for treating RIPK2-related diseases or disorders in subjects requiring treatment are also provided herein, the methods comprising administering to a subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), or formula (Ii), formula (Ij), formula (Ik), formula (Il), or formula (Im), or any of the aforementioned pharmaceutically acceptable salts), or a pharmaceutical composition comprising an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof of the subject.

[0011] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. Methods and materials are described herein for use in this disclosure, but other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not intended to limit. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated by reference in their entirety unless otherwise specified. In case of any conflict, this specification, including definitions, shall prevail.

[0012] Other features and advantages of this disclosure will become apparent from the following detailed description and drawings, as well as from the claims. [Modes for carrying out the invention]

[0013] Biologics and small molecules targeting pro-inflammatory signaling pathways have been used to successfully treat inflammatory and other diseases in patients, but a significant portion of patients are refractory to existing therapies. Therefore, there is a need for the identification of novel therapeutic molecules that modulate or inhibit these pathways, such as compounds of formula (I) described herein and their pharmaceutically acceptable salts.

[0014] definition To facilitate understanding of the disclosures contained herein, some additional terms are defined below. In general, the nomenclature used herein, as well as the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are well known and commonly used in the art. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications referenced throughout this specification and its accompanying appendices is incorporated herein by reference in their entirety. In case of any conflict, this specification, including its definitions, shall prevail.

[0015] The term "about" when referring to a number or range of numbers means that the number or range referred to is an approximation within, for example, experimental variability and / or statistical experimental error, and therefore the number or range may vary by up to 10% from the explicitly stated number or range.

[0016] The terms “therapeutic dose” or “effective dose” mean an amount of the compound that, when administered to a subject requiring such treatment, is sufficient to (i) treat a disease or disorder as described herein (e.g., RIPK2-related disease or disorder), (ii) reduce, improve or eliminate one or more symptoms of a particular disease or disorder, or (iii) delay the onset of one or more symptoms of a particular disease or disorder as described herein.

[0017] As used herein, the terms “to treat” or “treatment” refer to therapeutic or symptomatic measures. Beneficial or desired clinical outcomes include, but are not limited to, general or partial relief of symptoms associated with the disease or disability, reduction in the degree of disability, stabilization (i.e., non-exacerbating) of the disease or disability, delay or slowing of disease progression, improvement or relief of the disease state (e.g., one or more symptoms of the disease or disability), and remission (whether partial or general), which can be determined by various clinical assessments, including clinical evaluations and self-reports, whether detectable or undetectable. “Treatment” may also mean an extension of survival compared to expected survival without treatment.

[0018] The term “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs in proportion to a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams & Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0019] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting the acidic group-containing compounds described herein with a base to form salts, e.g., ammonium salts, alkali metal salts, e.g., sodium or potassium salts, alkaline earth metal salts, e.g., calcium or magnesium salts, salts of organic bases, e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and amino acids, e.g., arginine, lysine, etc., or by other methods previously determined. Pharmacologically acceptable salts are not particularly limited as long as they are usable for pharmaceutical purposes. Examples of salts formed by the compounds described herein with bases include: salts of the compounds with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts of the compounds with organic bases such as methylamine, ethylamine, and ethanolamine; salts of the compounds with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0020] The term "pharmaceutical composition" refers to a mixture of the compounds described herein with other chemical components such as stabilizers, diluents, dispersants, suspending agents, thickeners, and / or other excipients (collectively referred to herein as "pharmaceutically acceptable excipients"). Pharmaceutical compositions facilitate the administration of compounds to living organisms.

[0021] The term “subject” refers to animals, including but not limited to primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein with respect to mammalian subjects, such as humans. In some embodiments, the subject is human.

[0022] The term "halo" or "halogen" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0023] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, the oxo group bonds to a carbon atom to form a carbonyl group.

[0024] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight or branched chain containing the indicated number of carbon atoms. For example, C 1-10 This indicates that the group may contain 1 to 10 carbon atoms (including those at both ends). Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

[0025] The term "alkenyl" refers to an acyclic hydrocarbon radical that may be a straight or branched chain containing the indicated number of carbon atoms and one or more carbon-carbon double bonds. Non-limiting examples include ethyl enyl and allyl.

[0026] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with a halogen of independently selected proportion.

[0027] The term "hydroxyalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms are substituted with one or more hydroxyl groups as defined herein.

[0028] The term "alkoxy" refers to -O-alkyl radicals (e.g., -OCH3).

[0029] The term "thioalkyl" refers to an alkyl group as defined herein, which is bonded to a molecule via a sulfur atom (e.g., -SCH3).

[0030] The term "haloalkoxy" refers to a haloalkyl group that is bonded to a molecule via an oxygen atom (e.g., -OCF3).

[0031] The term "alkoxyalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms are substituted with one or more alkoxy groups as defined herein.

[0032] As used herein, the term "cyano" refers to the -CN radical.

[0033] As used herein, the term "hydroxyl" refers to the -OH radical.

[0034] As used herein, the term "amino" refers to the -NH2 radical.

[0035] As used herein, the term "phosphoric acid" refers to the -P(=O)2(OH)2 radical.

[0036] As used herein, the term “heteroaryl” refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic group in which at least one ring in the system is aromatic and one or more carbon atoms in at least one ring in the system are substituted with heteroatoms independently selected from the group consisting of N, O, S, B, Si, and P. For example, there may be one, two, or three heteroatoms, or optionally one or two heteroatoms. Heteroaryls may further comprise one or more oxo, N-oxide, S-oxide, and / or S,S-dioxide groups with acceptable valences. In a heteroaryl group having one aromatic ring, the aromatic ring does not need to contain heteroatoms. Non-exclusive examples of heteroaryl groups include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, Examples include tetrazole, pyridine, 2-pyridone, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, triazine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine], and 3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine].

[0037] To clarify, heteroaryls include aromatic lactams, aromatic cyclic ureas, or their vinyl analogs, where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valencies are occupied by non-hydrogen substituents), for example, pyridone (e.g.,

[0038] [ka] ), pyrimidone (for example,

[0039] [ka] ), pyridazinon (for example,

[0040] [ka] ), pyrazinon (for example,

[0041] [ka] ), and imidazolone (for example,

[0042] [ka] ) where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., the oxo group (i.e., "=O") in this specification is a component of a heteroaryl ring).

[0043] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbon group having 3 to 20 carbon atoms. Bicyclic and tricyclic cycloalkyl groups include fused ring systems, spiro ring systems, and crosslinking ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0044] The term "cycloalkoxy" refers to -O-cycloalkyl radicals (e.g., -O-cyclopropyl).

[0045] The term "aryl" refers to a 6- to 20-carbon monocyclic, bicyclic, tricyclic, or polycyclic group in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0046] The term “heterocyclyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic, bicyclic, or tricyclic ring system having 3 to 20 ring atoms, not being aromatic, and containing at least one heteroatom within a ring system selected from the group consisting of N, O, S, B, Si, and P. Bicyclic and tricyclic heterocyclyl groups include fused ring systems, spirocyclic systems, and bridging ring systems. A heterocyclyl group may also be expressed as a “5- to 10-membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9, or 10 atoms, with at least one being a heteroatom. A heterocycle may further contain one or more valence-acceptable oxo, thiocarbonyl, N-oxide, S-oxide, and / or S,S-dioxide groups so that its definition includes oxo and thio systems, e.g., lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. A heterocyclyl group can bond to the rest of the molecule via any carbon atom or via a heteroatom such as nitrogen.Exemplary heterocyclyl groups include, but are not limited to, 1,3-dioxolane, 1,4-dioxolane, maleimide, succinimide, dioxopiperazine, hydantoin, imidazoline, imidazolidine, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidinone, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, and 2-oxop Roridine, pyrrolidinyl, tetrahydrofuryl, thiolanil, pyrazolinil, oxathiolanil, isoxazolidinyl, isothiazolidinyl, pyrrolinil, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanil, sulforanil, thiazolidedionyl, succinimidyl, dihydrofuranol, pyrazolidinonyl, oxazolidinyl, isosazolidinonyl, hydantoinyl, thiohydantoinyl, imidazolidinonyl, oxazolidinyl Nonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinionyl, dioxazolidinethionyl, dioxolanthionyl, oxazolidinethionyl, imidazolidinethionyl, isothiazolidinonyl, piperidinyl, tetrahydropyranil, thianyl, morpholinyl, thiomorpholinyl, dioxanil, piperazinyl, dithianyl, oxazinyl, tetrahydropyranil This includes lahydropyranonil, piperidinonil, dioxanonil, oxazinanonil, morpholinonil, thiomorpholinonil, piperadinonil, tetrahydropyrimidinonil, piperidinedionil, oxazinandionil, dihydropyrimidinedione, tetrahydropyridazinonil, triazinanonil, oxadiadinanonil, dioxazinanonil, morpholindionil, piperazinedionil, piperazinetrionil, triazinandionil, and 2-azaspiro[3.3]heptanil.

[0047] In this context, the term "saturated" refers only to single bonds present between constituent atoms.

[0048] As used herein, when a ring is described as “partially unsaturated,” this means that, provided the ring is not aromatic, the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributable to the ring itself, for example, one or more double or triple bonds between the constituent ring atoms). Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, and dihydrothiophene.

[0049] Where used herein, the symbol

[0050] [ka] This indicates the bonding point of the atom or part to the indicated atom or group in the rest of the molecule.

[0051] Whenever a group is described as "optionally substituted," that group may be unsubstituted or substituted with one or more of the substituents shown. If the group is substituted, the substitution may involve sharing a carbon atom between the parent group and the substitution in order to form a spiro ring. For example, a cyclopropyl-substituted n-butyl group, among other things,

[0052] [ka] Includes.

[0053] To avoid misunderstanding, unless otherwise specified, for rings and cyclic groups (e.g., carbocyclic, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. as described herein) that contain a sufficient number of ring atoms to form a bicyclic or higher-order cyclic system (e.g., tricyclic, polycyclic cyclic systems), such rings and cyclic groups have condensation points where (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 is zero-atom bridges (e.g.,

[0054] [ka] (ii) Represents) (ii) Monocyclic atom (spiro-condensed ring system) (for example,

[0055] [ka] ), or (iii) a continuous array of ring atoms (a bridged ring system in which all bridge lengths are greater than 0 (>0)) (for example,

[0056] [ka] It is understood that this includes those having a fused ring, including those located on the ) surface.

[0057] In addition, any compound or structure provided herein is intended to represent both an unlabeled and an isotope-labeled form of the compound. Compounds in these forms are referred to as “isotope-enriched.” Isotope-enriched compounds have the structure described herein except that one or more atoms are substituted with atoms having a selected atomic mass or mass number.

[0058] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, respectively. 2 H, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I is an example. Various isotope-enriched compounds of this disclosure, for example, 13 C and 14Compounds incorporating radioactive isotopes such as 13C. Such isotope-enriched compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiotherapy for patients.

[0059] The term “isotope-enriched” compounds include “deuterated” compounds as described herein, in which one or more hydrogens are substituted with deuterium, such as hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans. Such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens are substituted with deuterium. In fact, the isotope-enriched compounds of this disclosure can generally be prepared by performing the procedures disclosed in the scheme or in the examples and preparations below, by using readily available isotope-enriched reagents instead of non-isotope-enriching reagents.

[0060] The deuterated enriched compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index, compared to the corresponding non-enriched compounds, due to greater metabolic stability.

[0061] The concentration of heavier isotopes, such as deuterium, can be defined by isotopic enrichment factors. In some embodiments, the positions described as "H" or "hydrogen" in the compounds described herein have hydrogen at their naturally occurring isotopic composition. In some embodiments, the positions described as "H" or "hydrogen" in the compounds described herein have hydrogen enriched with deuterium beyond its naturally occurring isotopic composition; i.e., the compounds are deuterium-enriched compounds. Examples of deurated groups in the compounds described herein, but not limited to, deuterated methine (

[0062] [ka] ), monodeuterated methylene (

[0063] [ka] ) and dideuterated methylene (

[0064] [ka] ), methyl trideuterated (

[0065] [ka] ), trideuterated methoxy(

[0066] [ka] ) are examples. The compounds of this disclosure are further deuterated concentrated compounds at the alpha position of the oxo group, for example,

[0067] [ka] Includes.

[0068] Furthermore, the compounds disclosed comprehensively or specifically herein are intended to include all tautomer forms. Therefore, as an example, the following parts...

[0069] [ka] Compounds containing the following parts

[0070] [ka] This includes tautomer forms containing [the specified compound]. Similarly, pyridinyl or pyrimidinyl moieties described as being optionally substituted with hydroxyl include pyridone or pyrimidone tautomer forms.

[0071] The compounds provided herein may encompass a variety of stereochemical forms. The compounds further include enantiomers (e.g., R and S isomers), diastereomers, and mixtures of enantiomers (e.g., R and S isomers), including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers resulting from structural asymmetry in particular compounds. Unless otherwise indicated, if a disclosed compound is named or indicated by a structure (e.g., a "flat" structure) without specifying its stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, if a disclosed compound is named or indicated by a structure that specifies its stereochemistry (e.g., a structure with "wedge" and / or "wavy" bonds) and has one or more chiral centers, it is understood to represent a specified stereoisomer of the compound.

[0072] Details of one or more embodiments of this disclosure are described in the accompanying drawings and the following description. Other features and advantages of this disclosure will become apparent from the detailed description and the claims.

[0073] The term "RIPK2 inhibitor" as defined herein includes any compound exhibiting RIPK2 inhibitory activity. In some embodiments, RIPK2 inhibitors are selective for RIPK2. Exemplary RIPK2 inhibitors, when measured in the assay described herein, exhibit inhibitory activity (IC) against RIPK2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM. 50 ) can be shown. In some embodiments, RIPK2 inhibitors exhibit inhibitory activity (IC) against RIPK2 less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM when measured in the assay provided herein. 50 ) can be shown.

[0074] Compound of formula (I) RIPK2 mediates inflammatory signaling via NODI, NOD2, and TLRs. However, in vitro inhibition of RIPK2 kinase activity alone does not fully predict the suppression of downstream cellular RIPK2 signaling. Rather, interfering with the interaction between RIPK2 and XIAP is necessary to potently reduce inflammatory signaling. In some cases, potent inhibitors of RIPK2 kinase activity lack the ability to disrupt RIPK2 / XIAP binding and therefore lack the ability to completely block inflammatory signaling in cells or human subjects. This disclosure is in part based on the discovery that selected compounds described herein exert RIPK2 inhibition by co-inhibiting RIPK2 kinase activity and disrupting the RIPK2 / XIAP interaction, thereby reducing cellular inflammatory signaling.

[0075] Some embodiments involve compounds of formula (I).

[0076] [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z 1One or two of them are independently N, and X, Y, and Z 1 The remainder is C,

[0077] [ka] Each of these is either a single bond or a double bond, R x is hydrogen, -NH2, or halogen, Ring A is phenyl or a 5-10 membered heteroaryl. m is 0, 1, 2, 3, or 4. R 1 Each is independent of the others. (i) C1-C6 alkoxys optionally substituted with hydroxyl or phenyl, (ii) C1-C6 deuterated alkoxy, (iii) C1-C6 alkoxyalkyl, (iv) 5-6 member heteroaryls, (v)-N(R 1A )-S(O2)R 1B , (vi)-(C=O)NR 1A R 1B , (vii) halogen, (viii) Cyano, (ix) Hydroxyl, (x)-NR A R B , (xi) Hydroxyl, and a C1-C6 alkyl group optionally substituted with one or two substituents independently selected from a 4- to 8-membered heterocycline optionally substituted with a hydroxyl or a C1-C6 alkyl group. (xii)C1-C6 haloalkyl, (xiii) C1-C6 haloalkoxy, (xiv)C3-C6 cycloalkyl, (xv) 4- to 8-membered heterocyclines optionally substituted with 1-2 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl. (xvi)-S(O2)C1-C6 alkyl, or (xvii) A 4-10 member heterocyclyloxy that is optionally substituted with an acyl, (xviii) phenyl, R 1A Each of these is independently hydrogen or a C1-C6 alkyl group. R 1B Each is independent of the others. (i) C1-C6 alkyl groups optionally substituted with C3-C6 cycloalkyl groups, 5-6 member heteroaryl groups optionally substituted with C1-C6 alkyl groups, or 4-10 member heterocyclines optionally substituted with -(C=O)OC1-C6 alkyl groups. (ii) A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. (iii) C3-C6 cycloalkyl groups optionally substituted with one or two substituents independently selected from C1-C6 alkyl groups and C1-C6 hydroxyalkyl groups. (iv) Ethyl enyl, (v) C1-C6 haloalkyl, (vi)-(C=O)OC1-C6 alkyl, 4-10 member heterocyclines, (vii)-NR 1A R 1A ,or (viii) Phenyl, R A is hydrogen or C1-C6 alkyl, R B teeth, (i) Hydrogen, (ii)-S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or C1-C6 alkoxy groups, (iv)-(C=O)C1-C6 alkyl, (v)-(C=O)OC1-C6 alkyl, (vi) A 4- to 8-membered heterocyclyl optionally substituted with hydroxyl, or (vii) C1-C6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, and -C(=O)C1-C6 alkyl or a 4- to 8-membered heterocyclyl optionally substituted with C1-C6 alkyl, (viii) -(C=O) a 5- or 6-membered heteroaryl optionally substituted with C1-C6 alkyl, R 2 is (i) hydrogen, (ii) halogen, (iii) (a) hydroxyl, (b) halogen, (c) phosphoric acid, (d) -NR 2A R 2B , (e) a 4- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl, (f) 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, (g) C3-C6 cycloalkyl optionally substituted with hydroxyl or hydroxyalkyl, (h) CO2H, (i) C(O)R 2A , (j) C1-C6 alkoxy, or (k) oxo, and is optionally substituted with 1 to 3 substituents independently selected from the above, (iv) C1-C6 haloalkoxy, (v) Heterocyclyloxy of 4 to 10 members, (vi) -(C=O)NR 2A R 2B , (vii) Hydroxyl, halogen, and -NR 2A R 2B C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from (viii) 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl or C1-C6 alkoxy, or (ix) -NR 2A R 2B wherein, R 2A and R 2B are each independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, or C1-C6 hydroxyalkyl, R 3 is, (i) C1-C6 thioalkyl, (ii)

[0078]

Chem.

[0079] ​​​​​​​​​​​​​​​​​​​​​​​ (x)C1-C6 haloalkyl, (xi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. (xii) C1-C6 alkoxyalkyl, or (xiii) C1-C6 hydroxyalkyl, Z is O or NR 4 And, R 3A teeth, (i) C1-C6 haloalkyl, (ii) C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl groups, (iii) (a) C3-C6 cycloalkyl (b) A 5-6 member heteroaryl molecule optionally substituted with a C1-C6 alkyl group. (c) Hydroxyl, (d) C1-C6 alkyl, or (e) A 4-6 member heterocyclyl optionally substituted with a 4-6 member heterocyclyl, or a C1-C6 alkyl optionally substituted with a C1-C6 alkoxy. C1-C6 alkyl groups that are optionally substituted, (iv) C1-C6 alkoxyalkyl, (v) C1-C6 hydroxyalkyl, (vi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl, or (vii) A 4-10 member heterocycline optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1-C6 alkoxy. (viii)-N(C1-C6 alkyl)2, R 3B and R 3C Each of these independently consists of a C3-C6 cycloalkyl group, or a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl group, or R 3B and R 3CThese, together with the atoms to which they are bonded, form a 4- to 8-membered heterocycline which is optionally substituted with C1-C6 alkyl groups. R 4 is hydrogen or C1-C6 alkyl, and Each R C and R D Each of these is independently a C1-C6 alkyl group that is optionally substituted with hydrogen, -(C=O)C1-C6 alkyl, or oxo. Each R E and R F Each of these is independently either hydrogen or a C1-C6 alkyl group, or R E and R F These atoms, together with the atoms to which they are bonded, form 4- to 8-membered heterocyclines that are optionally substituted with hydroxyls.

[0080] In some embodiments, X is N. In some embodiments, X is C.

[0081] In some embodiments, Y is N. In some embodiments, Y is C.

[0082] In some embodiments, Z 1 In some embodiments, Z 1 C is C.

[0083] In some embodiments, X, Y, and Z 1 One of them is N, and X, Y, and Z 1 The other two of them are C. In some embodiments, X, Y, and Z 1 Two of them are N, X, Y, and Z 1 The other one is C.

[0084] In some embodiments, ring A is a 5- to 10-membered heteroaryl.

[0085] In some embodiments, ring A is a 5-6 member heteroaryl. In some embodiments, ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and pyridonyl.

[0086] In some embodiments, ring A is a 9-10 membered heteroaryl. In some embodiments, ring A is indole, indazole, aza-indole, benzimidazole, benzothiophene, benzoxazole, benzothiazole, benzopyrazole, pyrrolopyrimidine, benzoisoxazole, benzotriazole, purine, quinoline, isoquinoline, quinazoline, quinoxaline, or sinnoline.

[0087] In some embodiments, ring A is phenyl.

[0088] In some embodiments, R X It is hydrogen.

[0089] In some embodiments, R X is a halogen. In some embodiments, R X It is fluoro or chloro.

[0090] In some embodiments, R X It is -NH2.

[0091] R 1 In the original context, "one or more" can refer to 1, 2, 3, 4, or any subrange of integers within that range.

[0092] In some embodiments, one or more R 1 It is a C1-C6 alkoxy that is optionally substituted with hydroxyl or phenyl.

[0093] In some embodiments, one or more R 1 R is a C1-C6 alkoxyalkyl. In some embodiments, R 1 It is a C1-C6 alkoxyalkyl group.

[0094] In some embodiments, one or more R 1 It is a C1-C6 deuterated alkoxy.

[0095] In some embodiments, one or more R 1 is a 5-6 member heteroaryl. In some embodiments, R 1 It is a 5-6 member heteroaryl compound.

[0096] In some embodiments, one or more R 1 is -N(R 1A )-S(O2)R 1B In some embodiments, R 1 is -N(R 1A )-S(O2)R 1B That is the case.

[0097] In some embodiments, one or more R 1 is -(C=O)NR 1A R 1B In some embodiments, R 1 is -(C=O)NR 1A R 1B That is the case.

[0098] In some embodiments, one or more R 1 It is phenyl.

[0099] In some embodiments, one or more R 1 R is phenyl. In some embodiments, 1A It is hydrogen.

[0100] In some embodiments, one or more R 1A is a C1-C6 alkyl group. In some embodiments, one or more R1A is methyl. In some embodiments, R 1A is a C1-C6 alkyl group. In some embodiments, R 1A It is methyl.

[0101] In some embodiments, one or more R 1B is a 4- to 10-membered heterocycline optionally substituted with a C1-C6 alkyl group or a -(C=O)OC1-C6 alkyl group. In some embodiments, one or more R 1B is a 4- to 10-membered heterocycline optionally substituted with a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group, or with a -(C=O)OC1-C6 alkyl group. In some embodiments, one or more R 1B is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. In some embodiments, one or more R 1B is a C1-C6 alkyl group substituted with a 4- to 10-membered heterocycline optionally substituted with a -(C=O)OC1-C6 alkyl group. In some embodiments, R 1B is a 4- to 10-membered heterocycline that is optionally substituted with a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group, or with a -(C=O)OC1-C6 alkyl group. In some embodiments, R 1B is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. In some embodiments, R 1B This is a C1-C6 alkyl group that is optionally substituted with a 4- to 10-membered heterocycline, which is a -(C=O)OC1-C6 alkyl group.

[0102] In some embodiments, one or more R 1B is a C1-C6 alkyl group. In some embodiments, one or more R 1B is methyl. In some embodiments, R 1B is a C1-C6 alkyl group. In some embodiments, R 1B It is methyl.

[0103] In some embodiments, one or more R 1B is a 5-10 member heteroaryl. In some embodiments, one or more R 1B is a 5-6 member heteroaryl. In some embodiments, R 1B is a 5-10 member heteroaryl. In some embodiments, R 1B It is a 5-6 member heteroaryl compound.

[0104] In some embodiments, one or more R 1B is a 5-10 member heteroaryl that is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. In some embodiments, one or more R 1B R is a 5-6 member heteroaryl that is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. In some embodiments, R 1B It is a 5-6 member heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups.

[0105] In some embodiments, one or more R 1B R is a 5-10 member heteroaryl that is optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl that is optionally substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1BR is a 5-6 member heteroaryl that is optionally substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-6 member heteroaryl substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and hydroxyl groups. In some embodiments, R 1B R is a 5-6 member heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and hydroxyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl that is optionally substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl that is optionally substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-6 member heteroaryl that is optionally substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with 1-3 independently selected C1-C6 alkyl groups. In some embodiments, R 1B It is a 5-6 member heteroaryl substituted with 1-3 independently selected C1-C6 alkyl groups.

[0106] In some embodiments, one or more R 1B is a 5-10 member heteroaryl that is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl. In some embodiments, one or more R 1BR is a 5-6 member heteroaryl that is optionally substituted with one or two substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with 1-2 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. In some embodiments, R 1B It is a 5-6 member heteroaryl substituted with 1-2 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups.

[0107] In some embodiments, one or more R 1B R is a 5-10 member heteroaryl that is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl that is optionally substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-6 member heteroaryl that is optionally substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B is a 5-10 member heteroaryl substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-6 member heteroaryl substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with 1-2 substituents independently selected from C1-C6 alkyl and hydroxyl groups. In some embodiments, R 1B R is a 5-6 member heteroaryl substituted with 1-2 substituents independently selected from C1-C6 alkyl and hydroxyl groups. In some embodiments, R 1BR is a 5-10 member heteroaryl that is optionally substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-10 member heteroaryl that is optionally substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B R is a 5-6 member heteroaryl that is optionally substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B is a 5-10 member heteroaryl substituted with 1-2 independently selected C1-C6 alkyl groups. In some embodiments, R 1B It is a 5-6 member heteroaryl substituted with 1-2 independently selected C1-C6 alkyl groups.

[0108] In some embodiments, one or more R 1B is a 5-10 member heteroaryl that is optionally substituted with a C1-C6 alkyl, hydroxyl, or C1-C6 hydroxyalkyl group. In some embodiments, one or more R 1B R is a 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl, hydroxyl, or C1-C6 hydroxyalkyl group. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with a C1-C6 alkyl, hydroxyl, or C1-C6 hydroxyalkyl group. In some embodiments, R 1B It is a 5-6 member heteroaryl substituted with a C1-C6 alkyl, hydroxyl, or C1-C6 hydroxyalkyl group.

[0109] In some embodiments, R 1B is a 5-10 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. In some embodiments, R 1B is a 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. In some embodiments, R 1Bis a 5-10 member heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R 1B is a 5-6 member heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R 1B R is a 5-10 member heteroaryl substituted with C1-C6 alkyl and hydroxyl groups. In some embodiments, R 1B These are 5-6 member heteroaryls substituted with C1-C6 alkyl and hydroxyl groups.

[0110] In some embodiments, one or more R 1B is a C3-C6 cycloalkyl group that is optionally substituted with one or two substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl groups. In some embodiments, one or more R 1B is a C3-C6 cycloalkyl substituted with one or two substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl groups. In some embodiments, one or more R 1B is a C3-C6 cycloalkyl substituted with a C1-C6 alkyl group. In some embodiments, one or more R 1B is a C3-C6 cycloalkyl substituted with a C1-C6 hydroxyalkyl group. In some embodiments, R 1B is a C3-C6 cycloalkyl group that is optionally substituted with one or two substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl groups. In some embodiments, R 1B is a C3-C6 cycloalkyl substituted with one or two substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl groups. In some embodiments, R 1B is a C3-C6 cycloalkyl substituted with a C1-C6 alkyl group. In some embodiments, R 1B is a C3-C6 cycloalkyl substituted with a C1-C6 hydroxyalkyl group. In some embodiments, one or more R 1Bis a C3-C6 cycloalkyl group. In some embodiments, R 1B It is a C3-C6 cycloalkyl group.

[0111] In some embodiments, one or more R 1B It is ethyl enyl.

[0112] In some embodiments, one or more R 1B is a C1-C6 haloalkyl. In some embodiments, one or more R 1B is a C1-C3 haloalkyl. In some embodiments, one or more R 1B is difluoromethyl or trifluoromethyl. In some embodiments, R 1B R is a C1-C6 haloalkyl. In some embodiments, R 1B R is a C1-C3 haloalkyl. In some embodiments, R 1B It is either difluoromethyl or trifluoromethyl.

[0113] In some embodiments, one or more R 1B is a 4- to 10-membered heterocycline that is optionally substituted with a -(C=O)OC1-C6 alkyl group. In some embodiments, one or more R 1B is a 4- to 10-membered heterocycline substituted with -(C=O)OC1-C6 alkyl. In some embodiments, one or more R 1B is a 4- to 6-membered heterocycline substituted with -(C=O)OC1-C6 alkyl. In some embodiments, R 1B is a 4- to 10-membered heterocycline that is optionally substituted with a -(C=O)OC1-C6 alkyl group. In some embodiments, R 1B is a 4- to 10-membered heterocycline substituted with -(C=O)OC1-C6 alkyl. In some embodiments, R 1B is a 4- to 6-membered heterocycline substituted with -(C=O)OC1-C6 alkyl. In some embodiments, R 1BR is a 4-10 member heterocycline. In some embodiments, R 1B It is a heterocycline with 4 to 6 members.

[0114] In some embodiments, one or more R 1B -NR 1A R 1A In some embodiments, R 1B -NR 1A R 1A That is the case.

[0115] In some embodiments, one or more R 1B R is phenyl. In some embodiments, 1B It is phenyl.

[0116] In some embodiments, one or more R 1 is a halogen. In some embodiments, R 1 It is fluoro or chloro.

[0117] In some embodiments, one or more R 1 It is cyano.

[0118] In some embodiments, one or more R 1 It is hydroxyl.

[0119] In some embodiments, one or more R 1 -NR A R B That is the case.

[0120] In some embodiments, one or more R 1 It is a C1-C6 alkyl group.

[0121] In some embodiments, one or more R 1This is a C1-C6 alkyl group that is optionally substituted with hydroxyl and 1-2 substituents optionally selected independently from 4- to 8-membered heterocyclines optionally substituted with hydroxyl or C1-C6 alkyl groups.

[0122] In some embodiments, R A It is hydrogen.

[0123] In some embodiments, R A is a C1-C6 alkyl group. In some embodiments, R A is a C1-C3 alkyl group. In some embodiments, R A It is methyl.

[0124] In some embodiments, R B It is hydrogen.

[0125] In some embodiments, R B is a -S(O2)C1-C6 alkyl group. In some embodiments, R B is a -S(O2)C1-C3 alkyl group. In some embodiments, R B It is -S(O2)CH3.

[0126] In some embodiments, R B R is a C3-C6 cycloalkyl that is optionally substituted with a hydroxyl or C1-C6 alkoxy. In some embodiments, R B is a C3-C6 cycloalkyl substituted with a hydroxyl or C1-C6 alkoxy. In some embodiments, R B is a C3-C6 cycloalkyl group substituted with hydroxyl. In some embodiments, R B is a C3-C6 cycloalkyl substituted with a C1-C6 alkoxy. In some embodiments, R B It is a C3-C6 cycloalkyl group.

[0127] In some embodiments, R Bis a -(C=O)C1-C6 alkyl group. In some embodiments, R B is a -(C=O)C1-C3 alkyl group. In some embodiments, R B This is -(C=O)CH3.

[0128] In some embodiments, R B is a -(C=O)OC1-C6 alkyl group. In some embodiments, R B is a -(C=O)OC1-C3 alkyl group. In some embodiments, R B The formula is -(C=O)OCH3.

[0129] In some embodiments, R B is a 4- to 8-membered heterocycline that is optionally substituted with a hydroxyl group. In some embodiments, R B R is a 4- to 8-membered heterocycline substituted with a hydroxyl group. In some embodiments, R B It is a heterocycline with 4 to 8 members.

[0130] In some embodiments, R B is halogen, hydroxyl, -NR C R D The C1-C6 alkyl group is optionally substituted with 1 to 4 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 member heteroaryl optionally substituted with C1-C6 alkyl, and 4-8 member heterocyclyl optionally substituted with -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0131] In some embodiments, R B is halogen, hydroxyl, -NR C R DThese are C1-C6 alkyl groups substituted with 1 to 4 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl groups optionally substituted with C1-C6 alkoxy, 5-6 member heteroaryl groups optionally substituted with C1-C6 alkyl, and 4-8 member heterocyclyl groups optionally substituted with -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0132] In some embodiments, R B is halogen, hydroxyl, -NR C R D The C1-C6 alkyl group is substituted with three substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 member heteroaryl optionally substituted with C1-C6 alkyl, and 4-8 member heterocyclyl optionally substituted with -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0133] In some embodiments, R B is halogen, hydroxyl, -NR C R D The C1-C6 alkyl group is substituted with one or two substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 member heteroaryl optionally substituted with C1-C6 alkyl, and 4-8 member heterocyclyl optionally substituted with -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0134] In some embodiments, R B is halogen, hydroxyl, -NR C R DThese are C1-C6 alkoxys, C1-C6 haloalkoxys, C3-C6 cycloalkyls, phenyls optionally substituted with C1-C6 alkoxys, 5-6 member heteroaryls optionally substituted with C1-C6 alkyls, or C1-C6 alkyls optionally substituted with -C(=O)C1-C6 alkyls or 4-8 member heterocyclines optionally substituted with C1-C6 alkyls.

[0135] In some embodiments, R B is a C1-C6 alkyl group. In some embodiments, R B is a C1-C3 alkyl group. In some embodiments, R B It is methyl.

[0136] In some embodiments, R 1B It is a -(C=O) 5 or 6-membered heteroaryl that is optionally substituted with a C1-C6 alkyl group.

[0137] In some embodiments, R A and R B In some embodiments, R A and R B They are different. In some embodiments, R A and R B Each of these is methyl. In some embodiments, R A and R B Each of them is hydrogen.

[0138] In some embodiments, one or more R 1 is a C1-C6 alkyl group optionally substituted with a hydroxyl group or a 4- to 8-membered heterocycline optionally substituted with a hydroxyl group. In some embodiments, one or more R 1 is a C1-C6 alkyl group substituted with a hydroxyl group or a 4- to 8-membered heterocycline optionally substituted with a hydroxyl group. In some embodiments, R 1is a C1-C6 alkyl group optionally substituted with a hydroxyl group or a 4- to 8-membered heterocycline optionally substituted with a hydroxyl group. In some embodiments, R 1 is a C1-C6 alkyl group substituted with a hydroxyl group or a 4- to 8-membered heterocycline optionally substituted with a hydroxyl group. In some embodiments, R 1 R is a C1-C6 alkyl group substituted with hydroxyl. In some embodiments, R 1 is a C1-C6 alkyl group substituted with a 4- to 8-membered heterocycline optionally substituted with a hydroxyl group. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 is a C1-C3 alkyl group. In some embodiments, R 1 It is methyl.

[0139] In some embodiments, one or more R 1 is a C1-C6 haloalkyl. In some embodiments, one or more R 1 is a C1-C3 haloalkyl. In some embodiments, one or more R 1 is difluoromethyl or trifluoromethyl. In some embodiments, R 1 R is a C1-C6 haloalkyl. In some embodiments, R 1 R is a C1-C3 haloalkyl. In some embodiments, R 1 It is either difluoromethyl or trifluoromethyl.

[0140] In some embodiments, one or more R 1 is a C1-C6 haloalkoxy. In some embodiments, one or more R 1 is a C1-C3 haloalkoxy. In some embodiments, one or more R 1 is difluoromethoxy or trifluoromethoxy. In some embodiments, R 1 is a C1-C6 haloalkoxy. In some embodiments, R1 is a C1-C3 haloalkoxy. In some embodiments, R 1 It is difluoromethoxy or trifluoromethoxy.

[0141] In some embodiments, one or more R 1 is a C3-C6 cycloalkyl group. In some embodiments, R 1 It is a C3-C6 cycloalkyl group.

[0142] In some embodiments, one or more R 1 is a 4- to 8-membered heterocycline that is optionally substituted with 1 to 2 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl. In some embodiments, one or more R 1 is a 4- to 8-membered heterocycline that is optionally substituted with hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, or -(C=O)OC1-C6 alkyl. In some embodiments, one or more R 1 It is a 4- to 8-membered heterocycline that is optionally substituted with two substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl.

[0143] In some embodiments, R 1 R is a 4- to 8-membered heterocycline that is optionally substituted with 1 to 2 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl. In some embodiments, R 1 R is a 4- to 8-membered heterocycline that is optionally substituted with hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, or -(C=O)OC1-C6 alkyl. In some embodiments, R 1It is a 4- to 8-membered heterocycline that is optionally substituted with two substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl.

[0144] In some embodiments, R 1 R is a 4- to 8-membered heterocycline substituted with a hydroxyl group. In some embodiments, R 1 is a 4- to 8-membered heterocycline substituted with a C1-C6 alkyl group. In some embodiments, R 1 R is a 4- to 8-membered heterocycline substituted with a C1-C6 haloalkyl group. In some embodiments, R 1 R is a 4- to 8-membered heterocycline substituted with -(C=O)OC1-C6 alkyl. In some embodiments, R 1 It is a heterocycline with 4 to 8 members.

[0145] In some embodiments, one or more R 1 is a -S(O2)C1-C6 alkyl group. In some embodiments, one or more R 1 is a -S(O2)C1-C3 alkyl group. In some embodiments, one or more R 1 is -S(O2)CH3. In some embodiments, R 1 is a -S(O2)C1-C6 alkyl group. In some embodiments, R 1 is a -S(O2)C1-C3 alkyl group. In some embodiments, R 1 It is -S(O2)CH3.

[0146] In some embodiments, one or more R 1 is a 4-10 member heterocyclyloxy that is optionally substituted with an acyl. In some embodiments, one or more R 1 is a 4-10 member heterocyclyloxy substituted with an acyl. In some embodiments, one or more R 1R is a 4-10 member heterocyclyloxy. In some embodiments, R 1 R is a 4-10 member heterocyclyloxy that is optionally substituted with an acyl. In some embodiments, R 1 R is a 4-10 member heterocyclyloxy substituted with an acyl. In some embodiments, R 1 It is a heterocyclyloxy with 4 to 10 members.

[0147] In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 3 or 4.

[0148] In some embodiments, m is 0.

[0149] In some embodiments, m is 1.

[0150] In some embodiments, m is 2.

[0151] In some embodiments, m is 3.

[0152] In some embodiments, m is 4.

[0153] In some embodiments, R 2 It is hydrogen.

[0154] In some embodiments, R 2 is a halogen. In some embodiments, R 2 It is chloro or fluoro.

[0155] In some embodiments, R 2 teeth, (a) Hydroxyl, (b) Hello, (c) Phosphate, (d)-NR 2A R 2B, (e) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl groups. (f) 5-6 member heteroaryls optionally substituted with C1-C6 alkyl groups, and (g) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or hydroxyalkyl groups, (h)CO2H, (i)C(O)R 2A , (j) C1-C6 alkyl, or (k) Oxo It is a C1-C6 alkoxy that is optionally substituted with 1 to 3 substituents independently selected from the base.

[0156] In some embodiments, R 2 teeth, (a) Hydroxyl, (b) Halogen, (c) Phosphate, (d)-NR 2A R 2B , (e) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl groups. (f) 5-6 member heteroaryls optionally substituted with C1-C6 alkyl groups, and (g) C3-C6 cycloalkyl groups optionally substituted with hydroxyl groups It is a C1-C6 alkoxy substituted with one or two substituents independently selected from the given molecule.

[0157] In some embodiments, R 2 teeth, (a) Hydroxyl, (b) Halogen, (c) Phosphate, (d)-NR 2A R 2B , (e) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl groups. (f) 5-6 member heteroaryls optionally substituted with C1-C6 alkyl groups, and (g) C3-C6 cycloalkyl groups optionally substituted with hydroxyl groups It is a C1-C6 alkoxy substituted with three substituents independently selected from the given molecule.

[0158] In some embodiments, R 2 R is a C1-C6 alkoxy substituted with a hydroxyl group. In some embodiments, R 2 R is a C1-C6 alkoxy substituted with hydroxyl and one or two independently selected halogens. In some embodiments, R 2 It is a C1-C6 alkoxy substituted with 1 to 3 independently selected halogens. In some embodiments, R 2 R is a C1-C6 alkoxy substituted with phosphoric acid. In some embodiments, R 2 , NR 2A R 2B It is a C1-C6 alkoxy substituted with R. In some embodiments, 2 R is a C1-C6 alkoxy substituted with a 4-10 member heterocyclyl which is optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl. In some embodiments, R 2R is a C1-C6 alkoxy substituted with a 4-10 member heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl. In some embodiments, R 2 R is a C1-C6 alkoxy substituted with a 5-6 member heteroaryl which is optionally substituted with a C1-C6 alkyl group. In some embodiments, R 2 is a C1-C6 alkoxy substituted with a 5-6 member heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R 2 is a C1-C6 alkoxy substituted with a 5-6 member heteroaryl group. In some embodiments, R 2 is a C1-C6 alkoxy substituted with a C3-C6 cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R 2 R is a C1-C6 alkoxy substituted with a hydroxyl-substituted C3-C6 cycloalkyl group. In some embodiments, R 2 It is a C1-C6 alkoxy substituted with a C3-C6 cycloalkyl group.

[0159] In some embodiments, R 2 is a C1-C6 alkoxy. In some embodiments, R 2 R is a C1-C3 alkoxy. In some embodiments, R 2 It is methoxy.

[0160] In some embodiments, R 2 is a C1-C6 haloalkoxy. In some embodiments, R 2 R is a C1-C3 haloalkoxy. In some embodiments, R 2 It is difluoromethoxy or trifluoromethoxy.

[0161] In some embodiments, R 2R is a 4-10 member heterocyclyloxy. In some embodiments, R 2 R is a 4-6 member heterocyclyloxy. In some embodiments, R 2 It is a heterocyclyloxy with 7 to 10 members.

[0162] In some embodiments, R 2 is -(C=O)NR 2A R 2B That is the case.

[0163] In some embodiments, R 2 These are hydroxyl, halogen, and -NR 2A R 2B It is a C1-C6 alkyl group that is optionally substituted with 1 to 3 substituents independently selected from the above. In some embodiments, R 2 is a C1-C6 alkyl substituted with a halogen. In some embodiments, R 2 -NR 2A R 2B It is a C1-C6 alkyl substituted with R. In some embodiments, 2 is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R 2 R is hydroxyethyl. In some embodiments, 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a C1-C3 alkyl group. In some embodiments, R 2 It is methyl.

[0164] In some embodiments, R 2 R is a 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl or C1-C6 alkoxy. In some embodiments, R 2 R is a 5-6 member heteroaryl substituted with a C1-C6 alkyl or C1-C6 alkoxy. In some embodiments, R 2 is a 5-6 member heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R2 is a 5-6 member heteroaryl substituted with a C1-C6 alkoxy. In some embodiments, R 2 It is a 5-6 member heteroaryl compound.

[0165] In some embodiments, R 2 -NR 2A R 2B In some embodiments, R 2A and R 2B It is hydrogen.

[0166] In some embodiments, R 2A and R 2B Each of these is independently a C1-C6 alkyl or C1-C6 hydroxyalkyl group that is optionally substituted with hydrogen or hydroxyl.

[0167] In some embodiments, one or more R 2A It is hydrogen.

[0168] In some embodiments, one or more R 2A is a C1-C6 alkyl group. In some embodiments, R 2A is a C1-C3 alkyl group. In some embodiments, R 2A It is methyl.

[0169] In some embodiments, one or more R 2A is a C1-C6 hydroxyalkyl group. In some embodiments, one or more R 2A is a C1-C3 hydroxyalkyl group. In some embodiments, one or more R 2A It is hydroxyethyl.

[0170] In some embodiments, one or more R 2B It is hydrogen.

[0171] In some embodiments, one or more R 2Bis a C1-C6 alkyl group. In some embodiments, R 2B is a C1-C3 alkyl group. In some embodiments, R 2B It is methyl.

[0172] In some embodiments, one or more R 2B is a C1-C6 hydroxyalkyl group. In some embodiments, one or more R 2B is a C1-C3 hydroxyalkyl group. In some embodiments, one or more R 2B R is hydroxyethyl. In some embodiments, 2B R is a C1-C6 hydroxyalkyl group. In some embodiments, R 2B R is a C1-C3 hydroxyalkyl group. In some embodiments, R 2B It is hydroxyethyl.

[0173] In some embodiments, R 2 H, OMe,

[0174] [ka] It is selected from the group consisting of the following.

[0175] In some embodiments, R 3 It is a C1-C6 thioalkyl group.

[0176] In some embodiments, R 3 It is -CO2H.

[0177] In some embodiments, R 3 is a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocycline which is optionally substituted with a C1-C6 alkoxy. In some embodiments, R 3 is a C1-C6 alkoxy substituted with a 4- to 10-membered heterocycline optionally substituted with a C1-C6 alkoxy. In some embodiments, R 3is a C1-C6 alkoxy that is optionally substituted with a 4- to 6-membered heterocycline that is optionally substituted with a C1-C6 alkoxy. In some embodiments, R 3 is a C1-C6 alkoxy that is optionally substituted with a 4- to 10-membered heterocycline substituted with a C1-C6 alkoxy. In some embodiments, R 3 It is a C1-C6 alkoxy.

[0178] In some embodiments, R 3 R is a 4- to 8-membered heterocycline that is optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, oxos, and C1-C6 alkoxys. In some embodiments, R 3 R is a 4- to 8-membered heterocycline substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, and C1-C6 alkoxys. In some embodiments, R 3 R is a 4- to 8-membered heterocycline that is optionally substituted with one or two substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, and C1-C6 alkoxys. In some embodiments, R 3 R is a 4- to 8-membered heterocycline optionally substituted with a halogen, hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R 3 It is a heterocycline with 4 to 8 members.

[0179] In some embodiments, R 3 It is hydrogen.

[0180] In some embodiments, R 3 It is oxo.

[0181] In some embodiments, R 3 R is a C1-C6 haloalkyl. In some embodiments, R 3 R is a C1-C3 haloalkyl. In some embodiments, R 3It is difluoromethyl or trifluoromethyl.

[0182] In some embodiments, R 3 is a 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. In some embodiments, R 3 is a 5-6 member heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R 3 is a 5-6 member heteroaryl substituted with methyl. In some embodiments, R 3 It is a 5-6 member heteroaryl compound.

[0183] In some embodiments, R 3 R is a C1-C6 alkoxyalkyl. In some embodiments, R 3 R is a C1-C3 alkoxyalkyl. In some embodiments, R 3 It is methoxyethyl or methoxypropyl.

[0184] In some embodiments, R 3 R is a C1-C6 hydroxyalkyl group. In some embodiments, R 3 R is a C1-C3 hydroxyalkyl group. In some embodiments, R 3 It is hydroxyethyl.

[0185] In some embodiments, R 3 , NR E R F Or a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R 3 , NR E R F Or a C1-C6 alkyl group substituted with hydroxyl. In some embodiments, R 3 , NR E R F It is a C1-C6 alkyl substituted with R. In some embodiments, 3is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3 is a C1-C3 alkyl group. In some embodiments, R 3 It is methyl.

[0186] In some embodiments, R 3 is -C(=O)NR E R F That is the case.

[0187] In some embodiments, R E It is hydrogen.

[0188] In some embodiments, R E is a C1-C6 alkyl group. In some embodiments, R E is a C1-C3 alkyl group. In some embodiments, R E It is methyl.

[0189] In some embodiments, R F It is hydrogen.

[0190] In some embodiments, R F is a C1-C6 alkyl group. In some embodiments, R F is a C1-C3 alkyl group. In some embodiments, R F It is methyl.

[0191] In some embodiments, R E and R F In some embodiments, R E and R F They are different. In some embodiments, R E and R F Each of these is methyl. In some embodiments, R E and R F Each of them is hydrogen.

[0192] In some embodiments, R E and R F These, together with the atoms to which they are bonded, form a 4- to 8-membered heterocycline that is optionally substituted with a hydroxyl group. In some embodiments, R E and R F These, together with the atoms to which they are bonded, form a hydroxyl-substituted 4- to 8-membered heterocycline. In some embodiments, R E and R F These atoms, together with the atoms to which they are bonded, form a 4- to 8-membered heterocycline.

[0193] In some embodiments, R 3 teeth

[0194] [ka] That is the case.

[0195] In some embodiments, R 3A R is a C1-C6 haloalkyl. In some embodiments, R 3A R is a C1-C3 haloalkyl. In some embodiments, R 3A It is difluoromethyl or trifluoromethyl.

[0196] In some embodiments, R 3A is a C3-C6 cycloalkyl that is optionally substituted with a C1-C6 alkyl. In some embodiments, R 3A is a C3-C6 cycloalkyl substituted with a C1-C6 alkyl group. In some embodiments, R 3A is a C3-C6 cycloalkyl group substituted with methyl. In some embodiments, R 3A It is a C3-C6 cycloalkyl group.

[0197] In some embodiments, R 3A teeth, (a) C3-C6 cycloalkyl (b) A 5-6 member heteroaryl molecule optionally substituted with a C1-C6 alkyl group. (c) Hydroxyl, (d) C1-C6 alkyl, or (e) A 4-6 member heterocyclyl optionally substituted with a 4-6 member heterocyclyl, or a C1-C6 alkyl optionally substituted with a C1-C6 alkoxy. These are C1-C6 alkyl groups that are optionally substituted.

[0198] In some embodiments, R 3A teeth, (a) C3-C6 cycloalkyl (b) A 5-6 member heteroaryl molecule optionally substituted with a C1-C6 alkyl group. (c) Hydroxyl, (d) C1-C6 alkyl, or (e) A 4-6 member heterocyclyl optionally substituted with a 4-6 member heterocyclyl, or a C1-C6 alkyl optionally substituted with a C1-C6 alkoxy. It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0199] In some embodiments, R 3A is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. In some embodiments, R 3A is a C1-C6 alkyl group substituted with a 5-6 member heteroaryl group optionally substituted with a C1-C6 alkyl group. In some embodiments, R 3A is a C1-C6 alkyl group substituted with a 5-6 member heteroaryl group which is substituted with a C1-C6 alkyl group. In some embodiments, R 3A is a C1-C6 alkyl group substituted with a 5-6 member heteroaryl group. In some embodiments, R 3A is a C1-C6 alkyl group substituted with a 4- to 6-membered heterocycline optionally substituted with a C1-C6 alkyl group. In some embodiments, R 3Ais a C1-C6 alkyl group substituted with a 4-6 member heterocycline that is substituted with a C1-C6 alkyl group. In some embodiments, R 3A is a C1-C6 alkyl group substituted with a 4-6 member heterocycline. In some embodiments, R 3A is a C1-C6 alkyl group. In some embodiments, R 3A is a C1-C3 alkyl group. In some embodiments, R 3A It is methyl.

[0200] In some embodiments, R 3A R is a C1-C6 alkoxyalkyl. In some embodiments, R 3A R is a C1-C3 alkoxyalkyl. In some embodiments, R 3A It is methoxyethyl or methoxypropyl.

[0201] In some embodiments, R 3A R is a C1-C6 hydroxyalkyl group. In some embodiments, R 3A R is a C1-C3 hydroxyalkyl group. In some embodiments, R 3A It is hydroxyethyl.

[0202] In some embodiments, R 3A is a 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. In some embodiments, R 3A is a 5-6 member heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R 3A is a 5-6 member heteroaryl substituted with methyl. In some embodiments, R 3A It is a 5-6 member heteroaryl compound.

[0203] In some embodiments, R 3AR is a 4-10 member heterocycline that is optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. In some embodiments, R 3A R is a 4-10 member heterocycline substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. In some embodiments, R 3A R is a 4- to 10-membered heterocycline substituted with one or two substituents independently selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. In some embodiments, R 3A R is a 4- to 10-membered heterocycline substituted with a hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R 3A These are heterocyclines with 4 to 10 members.

[0204] In some embodiments, R 3 H, OMe, CF3,

[0205] [ka] It is selected from the group consisting of the following.

[0206] In some embodiments, Z is NR 4 That is the case.

[0207] In some embodiments, R 4 It is hydrogen.

[0208] In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 is a C1-C3 alkyl group. In some embodiments, R 4 It is methyl.

[0209] In some embodiments, Z is O.

[0210] In some embodiments, R 3 teeth

[0211] [ka] That is the case.

[0212] In some embodiments, R 3B R is a C3-C6 cycloalkyl. In some embodiments, R 3B It is cyclopropyl or cyclobutyl.

[0213] In some embodiments, R 3B is a C1-C6 alkyl group that is optionally substituted with a C3-C6 cycloalkyl group. In some embodiments, R 3B is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. In some embodiments, R 3B is a methyl molecule substituted with a C3-C6 cycloalkyl group. In some embodiments, R 3B is a C1-C6 alkyl group. In some embodiments, R 3B is a C1-C3 alkyl group. In some embodiments, R 3B It is methyl.

[0214] In some embodiments, R 3C It is a C3-C6 cycloalkyl group.

[0215] In some embodiments, R 3C is a C1-C6 alkyl group that is optionally substituted with a C3-C6 cycloalkyl group. In some embodiments, R 3C is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. In some embodiments, R 3C is a methyl molecule substituted with a C3-C6 cycloalkyl group. In some embodiments, R 3C is a C1-C6 alkyl group. In some embodiments, R 3Cis a C1-C3 alkyl group. In some embodiments, R 3C It is methyl.

[0216] In some embodiments, R 3B and R 3C In some embodiments, R 3B and R 3C They are different. In some embodiments, R 3B and R 3C Each of these is methyl.

[0217] In some embodiments, R 3B and R 3C These atoms, together with the atoms to which they are bonded, form 4- to 8-membered heterocyclines that are optionally substituted with C1-C6 alkyl groups.

[0218] In some embodiments, R C It is hydrogen.

[0219] In some embodiments, R C R is a C1-C6 alkyl that is optionally substituted with an oxo. In some embodiments, R C R is a C1-C6 alkyl group substituted with an oxo molecule. In some embodiments, R C is an acyl. In some embodiments, R C is a C1-C6 alkyl group. In some embodiments, R C is a C1-C3 alkyl group. In some embodiments, R C It is methyl.

[0220] In some embodiments, R D It is hydrogen.

[0221] In some embodiments, R D R is a C1-C6 alkyl that is optionally substituted with an oxo. In some embodiments, R DR is a C1-C6 alkyl group substituted with an oxo molecule. In some embodiments, R D is an acyl. In some embodiments, R D is a C1-C6 alkyl group. In some embodiments, R D is a C1-C3 alkyl group. In some embodiments, R D It is methyl.

[0222] In some embodiments, formula (I) is (Ia)

[0223] [ka] or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, formula (I) is (Ib)

[0225] [ka] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, formula (I) is (Ic)

[0227] [ka] or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, formula (I) is (Id)

[0229] [ka] or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, formula (I) is (Ie)

[0231] [ka] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, formula (I) is (If)

[0233] [ka] or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, formula (I) is (Ig)

[0235] [ka] or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, formula (I) is (Ih)

[0237] [ka] or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, formula (I) is (Ii)

[0239] [ka] or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, formula (I) is (Ij)

[0241] [ka] or a pharmaceutically acceptable salt thereof, where ring C is morpholine, N-methylmorpholine, pyrrolidinone, imidazole, or pyrrole. In some embodiments, ring C is morpholine. In some embodiments, ring C is N-methylmorpholine. In some embodiments, ring C is pyrrolidinone. In some embodiments, ring C is imidazole. In some embodiments, ring C is pyrrole.

[0242] In some embodiments, formula (I) is (Ik)

[0243] [ka] or a pharmaceutically acceptable salt thereof,

[0244] In the formula, ring C is pyridine or pyrimidine. In some embodiments, ring C is pyridine. In some embodiments, ring C is pyrimidine.

[0245] In some embodiments, formula (I) is (Il)

[0246] [ka] or a pharmaceutically acceptable salt thereof, where ring C is pyridine or pyrimidine. In some embodiments, ring C is pyridine. In some embodiments, ring C is pyrimidine.

[0247] In some embodiments, formula (I) is (Im)

[0248] [ka] or a pharmaceutically acceptable salt thereof, where ring C is morpholine, N-methylmorpholine, pyrrolidinone, imidazole, or pyrrole. In some embodiments, ring C is morpholine. In some embodiments, ring C is N-methylmorpholine. In some embodiments, ring C is pyrrolidinone. In some embodiments, ring C is imidazole. In some embodiments, ring C is pyrrole.

[0249] In some embodiments, formula (I) is (Ij)

[0250] [ka] or a pharmaceutically acceptable salt thereof, where ring C is morpholine, N-methylmorpholine, pyrrolidinone, imidazole, or pyrrole. In some embodiments, ring C is morpholine. In some embodiments, ring C is N-methylmorpholine. In some embodiments, ring C is pyrrolidinone. In some embodiments, ring C is imidazole. In some embodiments, ring C is pyrrole.

[0251] In some embodiments, formula (I) is (Ik)

[0252] [ka] or a pharmaceutically acceptable salt thereof,

[0253] In the formula, ring C is pyridine or pyrimidine. In some embodiments, ring C is pyridine. In some embodiments, ring C is pyrimidine.

[0254] In some embodiments, formula (I) is (Il)

[0255] [ka] or a pharmaceutically acceptable salt thereof, where ring C is pyridine or pyrimidine. In some embodiments, ring C is pyridine. In some embodiments, ring C is pyrimidine.

[0256] In some embodiments, formula (I) is (Im)

[0257] [ka] or a pharmaceutically acceptable salt thereof, where ring C is morpholine, N-methylmorpholine, pyrrolidinone, imidazole, or pyrrole. In some embodiments, ring C is morpholine. In some embodiments, ring C is N-methylmorpholine. In some embodiments, ring C is pyrrolidinone. In some embodiments, ring C is imidazole. In some embodiments, ring C is pyrrole.

[0258] In some embodiments, formula (I) is (In)

[0259] [ka] or a pharmaceutically acceptable salt thereof, where R 1C , R 1D , and R 1E Each of these is an independently selected R 1 That is the case.

[0260] In some embodiments, formula (I) is (Io)

[0261] [ka] or a pharmaceutically acceptable salt thereof, where R 1C , R 1D , and R 1E Each of these is an independently selected R 1 That is the case.

[0262] In some embodiments, formula (I) is (Ip)

[0263] [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1D and R 1E Each of these is an independently selected R 1 And, Q is -NH(SO2)- or -NH(C1-C6 alkyl)-, R 1F , R 1G , and R 1H Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 hydroxyalkyl group, and R 1F , R 1G , and R 1H At least one of them is hydrogen.

[0264] In some embodiments of formula (Ip), R 1D is fluoro or methoxy, R 1E is fluoro or methoxy. In some embodiments of formula (Ip), R 1D is methoxy, and R 1E is fluoro or methoxy. In some embodiments of formula (Ip), R 1D is methoxy, and R 1E It is fluoro.

[0265] In some embodiments of formula (Ip), R 1F R is hydrogen or methyl, 1G and R 1H Each of these is hydrogen. In some embodiments of formula (Ip), R 1F It is methyl.

[0266] In some embodiments of formula (Ip), Q is -NH(SO2)-, the nitrogen atom is attached to the phenyl ring of formula (Ip), and the sulfur atom is attached to the pyrazole ring of formula (Ip).

[0267] In some embodiments of formula (Ip), Q is -NH(C1-C6 alkyl)-, where the nitrogen atom is connected to the phenyl ring of formula (Ip) and the carbon atom is connected to the pyrazole ring of formula (Ip).

[0268] In some embodiments,

[0269] [ka] teeth,

[0270] [ka] It is selected from the group consisting of the following.

[0271] In some embodiments,

[0272] [ka] teeth,

[0273] [ka] It is selected from the group consisting of the following.

[0274] In some embodiments,

[0275] [ka] teeth,

[0276] [ka]

[0277] [ka]

[0278] [ka] It is selected from the group consisting of the following.

[0279] In some embodiments,

[0280] [ka] teeth,

[0281] [ka] It is selected from the group consisting of the following.

[0282] In some embodiments,

[0283] [ka] teeth,

[0284] [ka] It is selected from the group consisting of the following.

[0285] In some embodiments, the compounds of formula (I) include the compounds of Examples 1 to 304 and their pharmaceutically acceptable salts. In some embodiments, the compounds of Examples 1 to 304 are in free base form. In some embodiments, the compounds of Examples 1 to 304 are in salt form, for example, pharmaceutically acceptable salt form.

[0286] The compounds of formula (I) and their pharmaceutically acceptable salts do not include the compounds or their pharmaceutically acceptable salts exemplified in PCT application number PCT / US23 / 24988.

[0287] The ability of test compounds to act as RIPK2 inhibitors can be demonstrated by the biological assays described herein. See, for example, Tables A1 and A.

[0288] Pharmaceutical composition Some embodiments provide pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0289] Treatment method The compounds and compositions disclosed herein are effective in modulating the activity of RIPK2. In some embodiments, the compounds and compositions disclosed herein are RIPK2 inhibitors.

[0290] As used herein, the term “RIPK2-related disease or disorder” refers to a disease or disorder related to, or having a dysregulation of the RIPK2 gene, the RIPK2 protein, or any of the same (e.g., one or more of them) (e.g., a dysregulation of any of the types of the RIPK2 gene, the RIPK2 protein, or the RIPK2 protein domain, or any of the same as described herein).

[0291] An example sequence of human RIPK2 is shown below (UniParc accession number UPI00001338F2): MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLHIHTPLLDSERKDVLREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDVAWPLRFRILHEIALGVNYL HNMTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIE SGWAQNPDERPSFLKCLIELEPVLRTFEEITFLEAVIQLKKTKLQSVSSAIHLCDKKKMELSLNIPVNHGPQEESCGSSQLHENSGSPETSRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAA FCDHKTTPCSSAIINPLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGLQPYPEILVVSRSPSLNLLQNKSM

[0292] Some embodiments provide a method for treating a RIPK2-related disease or disorder in a subject requiring treatment, comprising the step of administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0293] Some embodiments provide a method for treating a RIPK2-related disease or disorder in a subject requiring treatment, comprising: (a) determining or having determined that the subject is suffering from a RIPK2-related disease or disorder; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0294] Some embodiments provide a method for treating a RIPK2-related disease or disorder in a subject requiring treatment, comprising: (a) determining or having determined that the subject has a RIPK2-related disease or disorder; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0295] Some embodiments provide a method for treating a RIPK2-related disorder in a subject previously identified or diagnosed with such disorder, the method comprising administering to the subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, RIPK2-related disorders or conditions include cardiovascular diseases, allergic disorders, autoimmune diseases, inflammatory diseases, cardiovascular diseases, fibrotic diseases, or diseases associated with abnormal cell proliferation (such as cancer).

[0297] In some embodiments, RIPK2-related disease or disorder is a cardiovascular disease.

[0298] In some embodiments, RIPK2-related disorders or conditions are allergic disorders.

[0299] In some embodiments, RIPK2-related disease or disorder is an autoimmune disease.

[0300] In some embodiments, RIPK2-related diseases or disorders are inflammatory diseases.

[0301] In some embodiments, RIPK2-related disease or disorder is a cardiovascular disease.

[0302] In some embodiments, RIPK2-related disorders or conditions are fibrotic disorders.

[0303] In some embodiments, RIPK2-related disease or disorder is a disease associated with abnormal cell proliferation (such as cancer). In some embodiments, RIPK2-related disease or disorder is cancer.

[0304] In some embodiments, RIPK2-related disorders or conditions are type I hypersensitivity (allergic) reactions. In some embodiments, type I hypersensitivity (allergic) reactions are allergic inflammation. In some embodiments, allergic inflammation is allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic and keratoconjunctivitis, or atopic dermatitis.

[0305] In some embodiments, the RIPK2-related disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is Crohn's disease, ulcerative colitis, rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, psoriasis, lupus nephritis, immune thrombocytopenic purpura, Sjögren's syndrome, ankylosing spondylitis, psoriatic arthritis, juvenile dermatomyositis, juvenile rheumatoid arthritis, juvenile spondyloarthritis, non-radiation spondyloarthritis, Behçet's disease, dermatomyositis, type 1 diabetes, Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, mixed connective tissue injury, myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, temporal arteritis, or vasculitis. In some embodiments, the autoimmune disease is Crohn's disease, ulcerative colitis, inflammatory bowel disease, or multiple sclerosis. In some embodiments, the autoimmune disease is Crohn's disease. In some embodiments, the autoimmune disease is ulcerative colitis. In some embodiments, the autoimmune disease is inflammatory bowel disease. In some embodiments, the autoimmune disease is multiple sclerosis.

[0306] In some embodiments, the RIPK2-related disorder or condition is a metabolic disorder. In some embodiments, the metabolic disorder is a blood glucose disorder, type 2 diabetes, non-alcoholic fatty liver disease (including non-alcoholic steatohepatitis), or obesity.

[0307] In some embodiments, RIPK2-related diseases or disorders are inflammatory diseases. In some embodiments, inflammatory diseases include chronic pulmonary inflammatory disease, osteoarthritis, inflammatory arthritis, asthma, early-onset sarcoidosis, sarcoidosis, eczema, allergic eczema, uveitis, reactive arthritis, chronic inflammation, chronic prostatitis, inflammatory bowel disease, glomerulonephritis, bursitis, carpal tunnel syndrome, tendinitis, inflammation of the lungs (e.g., chronic obstructive pulmonary disease), pelvic inflammatory disease, graft rejection, vasculitis, focal enteritis, distal ileitis, localized ileitis, and terminal ileitis, central areolar choroidal dystrophy. These include dystrophy, macular degeneration, retinitis pigmentosa, adult vitreous disease, pattern dystrophy, diabetic retinopathy, BEST disease, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or systemic inflammatory response syndrome. In some embodiments, the inflammatory disease is inflammatory bowel disease.

[0308] In some embodiments, the RIPK2-related disease or disorder is a granulomatous inflammatory disease. In some embodiments, the granulomatous inflammatory disease is Wegener's granulomatosis, Churg-Strauss syndrome, relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, primary biliary cirrhosis, hepatic granulomatosis, Langerhans granulomatosis, granulomatous colitis, orofacial granulomatosis, or Peyronie's disease.

[0309] In some embodiments, the RIPK2-related disease or disorder is a cardiovascular disease. In some embodiments, the cardiovascular disease is atherosclerosis, thrombosis, myocardial infarction, stroke, aortic aneurysm, arterial hypertension, sickle cell attack, or ischemia-reperfusion injury.

[0310] In some embodiments, RIPK2-related disorders include fatal systemic inflammatory response syndrome, chronic intestinal and skin inflammation, or acute pancreatitis.

[0311] In some embodiments, the RIPK2-related disease or disorder is a fibrotic disease. In some embodiments, the fibrotic disease is scleroderma, asbestosis, or idiopathic pulmonary fibrosis.

[0312] In some embodiments, RIPK2-related disorders include neuroinflammation. In some embodiments, RIPK2-related disorders include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Lewy body dementia, Niemann-Pick disease type C1 (NPC1), Friedreich's ataxia, spinal muscular atrophy, corticobasal degeneration, progressive supranuclear palsy (PSP), or multiple system atrophy (MSA).

[0313] In some embodiments, RIPK2-related diseases or disorders are diseases associated with abnormal cell proliferation. In some embodiments, diseases associated with abnormal cell proliferation are cancers, including hematological malignancies and solid tumors.

[0314] Hematological malignancies include, but are not limited to, leukemias such as acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and B-cell chronic lymphocytic leukemia, as well as lymphomas and myelomas such as B-cell lymphoma (e.g., mantle cell lymphoma), T-cell lymphoma (e.g., peripheral T-cell lymphoma), non-Hodgkin lymphoma, and multiple myeloma.

[0315] Solid tumors include lung cancer (small cell lung cancer and non-small cell lung cancer), pancreatic cancer, colon cancer, breast cancer, genitourinary cancer, skin cancer, bone cancer, prostate cancer, liver cancer, brain tumor, laryngeal cancer, gallbladder cancer, rectal cancer, parathyroid cancer, thyroid cancer, adrenal cancer, nerve tissue cancer, bladder cancer, head and neck cancer, stomach cancer, gastric cancer, bronchial cancer, and kidney cancer (e.g., clear cell carcinoma), colorectal cancer, clear cell carcinoma, basal cell carcinoma, squamous cell carcinoma, esophageal cancer, metastatic skin cancer, osteosarcoma, Ewing's sarcoma, reticulum sarcoma, Kaposi's sarcoma, giant cell tumor, islet cell tumor, acute and chronic lymphocytic and granulocytic tumors, hairy cell tumor, adenoma, medullary carcinoma, pheochromocytoma, mucosal neuroma, enteric ganglion neuroma, hyperplastic corneal neuroma, and Marfanoid habitus tumors. Examples of tumors include Wilms' tumor, seminoma, ovarian tumors, leiomyoma, cervical dysplasia, neuroblastoma, retinoblastoma, myelodysplastic syndrome, rhabdomyosarcoma, astrocytoma, malignant hypercalcemia, polycythemia vera, adenocarcinoma, glioblastoma multiforme, glioma, and malignant melanoma.

[0316] In some embodiments, RIPK2-related disorders or disorders are non-malignant proliferative disorders associated with abnormal cell proliferation. In some embodiments, non-malignant proliferative disorders include benign prostatic hyperplasia, restenosis, hyperplasia, synovial proliferative disorders, idiopathic plasmacytic lymphadenopathy, or retinopathy.

[0317] In some embodiments, RIPK2-related diseases or disorders are selected from the group consisting of avascular necrosis, calcium pyrophosphate dihydrate crystal deposition disease (pseudogout), Blau syndrome, Ehlers-Danlos syndrome, fibromyalgia, disease V, giant cell arteritis, gout, Lyme disease, Marfan syndrome, myositis, osteoarthritis, osteogenesis imperfecta, osteoporosis, Paget's disease, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy syndrome, spinal stenosis, and Still's disease.

[0318] In some embodiments, RIPK2-related disease or disorder is a cancer associated with chronic inflammation. In some embodiments, cancers associated with chronic inflammation that can be treated (including reducing the likelihood of recurrence) include colitis-associated colorectal cancer, gastric cancer, gastric mucosal lymphoma, lung cancer, hepatocellular carcinoma, thyroid cancer, breast cancer, oral cancer, head and neck cancer, nasopharyngeal cancer, endometrial cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, esophageal cancer, skin cancer, and non-Hodgkin lymphoma.

[0319] Some embodiments provide a method for treating inflammatory bowel disease in a subject requiring treatment, comprising the step of administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0320] Some embodiments provide a method for treating inflammatory bowel disease in a subject requiring treatment, comprising: (a) determining or having determined that the subject has inflammatory bowel disease; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0321] Some embodiments provide a method for treating inflammatory bowel disease in a subject requiring treatment, comprising: (a) determining or having determined that the subject has inflammatory bowel disease; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0322] Some embodiments provide a method for treating inflammatory bowel disease in a subject previously identified or diagnosed with inflammatory bowel disease, the method comprising administering to the subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0323] Some embodiments provide a method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising the step of administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0324] Some embodiments provide a method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising: (a) determining or having determined that the subject has Crohn's disease; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0325] Some embodiments provide a method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising: (a) determining or having determined that the subject has Crohn's disease; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0326] Some embodiments provide a method for treating Crohn's disease in a subject previously identified or diagnosed with Crohn's disease, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the subject is human.

[0328] Inhibition of RIPK2 activity and XIAP binding Some embodiments provide a method for inhibiting RIPK2 activity in mammalian cells, comprising the step of contacting mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the mammalian cells contain the RIPK2 protein.

[0329] A method is provided for inhibiting RIPK2 activity in mammalian cells containing the RIPK2 protein, the method comprising contacting mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0330] A method is provided for inhibiting the binding of the RIPK2 protein to the XIAP protein in mammalian cells containing the RIPK2 protein, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the contact step is performed in vitro. In some embodiments, the contact step is performed in vivo. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is sufficient to inhibit RIPK2 activity in cells. In some embodiments, the contact step is performed in vivo, and the method includes administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells having RIPK2 activity. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are cancer cells.

[0332] In some embodiments, RIPK2 activity is inhibited by approximately 10% to approximately 99%, for example, approximately 10% to approximately 50%, approximately 25% to approximately 75%, approximately 50% to approximately 99%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 99%, or any value in between.

[0333] As used herein, the term “contact” refers to the bringing together of the indicated parts in an in vitro or in vivo system. For example, “contact” between RIPK2 (e.g., the RIPK2 protein) and the compound provided herein includes the administration of the compound provided herein to a subject such as a human having the RIPK2 protein, as well as the introduction of the compound provided herein into a sample containing, for example, mammalian cells or a purified preparation containing the RIPK2 protein.

[0334] Pharmaceutical composition Some embodiments provide pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0335] Numbered Embodiments Embodiment 1: Compound of formula (I)

[0336] [ka] or a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z 1 One or two of them are independently N, and X, Y, and Z 1 The remainder is C,

[0337] [ka] Each of these is either a single bond or a double bond, R x is hydrogen, -NH2, or halogen, Ring A is phenyl or a 5-10 membered heteroaryl. m is 0, 1, 2, 3, or 4. R 1 Each is independent of the others. (i) C1-C6 alkoxys optionally substituted with hydroxyl or phenyl, (ii) C1-C6 deuterated alkoxy, (iii) C1-C6 alkoxyalkyl, (iv) 5-6 member heteroaryls, (v)-N(R 1A )-S(O2)R 1B , (vi)-(C=O)NR 1A R 1B , (vii) halogen, (viii) Cyano, (ix) Hydroxyl, (x)-NR A R B , (xi) Hydroxyl, and a C1-C6 alkyl group optionally substituted with one or two substituents independently selected from a 4- to 8-membered heterocycline optionally substituted with a hydroxyl or a C1-C6 alkyl group. (xii)C1-C6 haloalkyl, (xiii) C1-C6 haloalkoxy, (xiv)C3-C6 cycloalkyl, (xv) 4- to 8-membered heterocyclines optionally substituted with 1-2 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl. (xvi)-S(O2)C1-C6 alkyl, or (xvii) A 4-10 member heterocyclyloxy that is optionally substituted with an acyl, (xviii) phenyl, R 1A Each of these is independently hydrogen or a C1-C6 alkyl group. R 1B Each is independent of the others. (i) C1-C6 alkyl groups optionally substituted with C3-C6 cycloalkyl groups, 5-6 member heteroaryl groups optionally substituted with C1-C6 alkyl groups, or 4-10 member heterocyclines optionally substituted with -(C=O)OC1-C6 alkyl groups. (ii) A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl groups. (iii) C3-C6 cycloalkyl groups optionally substituted with one or two substituents independently selected from C1-C6 alkyl groups and C1-C6 hydroxyalkyl groups. (iv) Ethyl enyl, (v) C1-C6 haloalkyl, (vi)-(C=O)OC1-C6 alkyl, 4-10 member heterocyclines, (vii)-NR 1A R 1A ,or (viii) Phenyl, R A is hydrogen or C1-C6 alkyl, R B teeth, (i) Hydrogen, (ii)-S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or C1-C6 alkoxy groups, (iv)-(C=O)C1-C6 alkyl, (v)-(C=O)OC1-C6 alkyl, (vi) A 4- to 8-membered heterocycline optionally substituted with a hydroxyl group, or (vii) Halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 member heteroaryl optionally substituted with C1-C6 alkyl, and C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from -C(=O)C1-C6 alkyl or 4-8 member heterocyclyl optionally substituted with C1-C6 alkyl, (viii) A -(C=O) 5 or 6-membered heteroaryl that is optionally substituted with a C1-C6 alkyl group, R 2teeth, (i) Hydrogen, (ii) Halogen, (iii) (a) Hydroxyl, (b) Halogen, (c) Phosphate, (d)-NR 2A R 2B , (e) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl groups. (f) 5-6 member heteroaryls optionally substituted with C1-C6 alkyl groups, (g) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or hydroxyalkyl groups, (h)CO2H, (i)C(O)R 2A , (j) C1-C6 alkyl, or (k) Oxo C1-C6 alkoxys that are optionally substituted with 1 to 3 substituents independently selected from the above, (iv) C1-C6 haloalkoxy, (v) 4-10 member heterocyclyloxy, (vi)-(C=O)NR 2A R 2B , (vii) Hydroxyl, halogen, and -NR 2A R 2B C1-C6 alkyl groups that are optionally substituted with 1 to 3 substituents independently selected from the above. (viii) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl or C1-C6 alkoxy, or (ix)-NR 2A R 2B And, R 2A and R 2BEach of these is independently a C1-C6 alkyl or C1-C6 hydroxyalkyl group that is optionally substituted with hydrogen or hydroxyl. R 3 teeth, (i) C1-C6 thioalkyl, (ii)

[0338] [ka] (iii)

[0339] [ka] (iv) A 4- to 8-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, and C1-C6 alkoxys. (v)NR E R F Or C1-C6 alkyl groups optionally substituted with hydroxyl groups. (vi)-CO2H, (vii)-C(=O)NR E R F , (viii) C1-C6 alkoxys optionally substituted with 4-10 member heterocyclines, (ix) Hydrogen, (x)C1-C6 haloalkyl, (xi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. (xii) C1-C6 alkoxyalkyl, or (xiii) C1-C6 hydroxyalkyl, Z is O or NR 4 And, R 3A teeth, (i) C1-C6 haloalkyl, (ii) C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl groups, (iii) (a) C3-C6 cycloalkyl (b) A 5-6 member heteroaryl molecule optionally substituted with a C1-C6 alkyl group. (c) Hydroxyl, (d) C1-C6 alkyl, or (e) A 4-6 member heterocyclyl optionally substituted with a 4-6 member heterocyclyl, or a C1-C6 alkyl optionally substituted with a C1-C6 alkoxy. C1-C6 alkyl groups that are optionally substituted, (iv) C1-C6 alkoxyalkyl, (v) C1-C6 hydroxyalkyl, (vi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl, or (vii) A 4-10 member heterocycline optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1-C6 alkoxy. (viii)-N(C1-C6 alkyl)2, R 3B and R 3C Each of these independently consists of a C3-C6 cycloalkyl group, or a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl group, or R 3B and R 3C These, together with the atoms to which they are bonded, form a 4- to 8-membered heterocycline which is optionally substituted with C1-C6 alkyl groups. R 4 is hydrogen or C1-C6 alkyl, and Each R C and R D Each of these is independently a C1-C6 alkyl group that is optionally substituted with hydrogen, -(C=O)C1-C6 alkyl, or oxo.

[0340] Each R E and R F Each of these is independently either hydrogen or a C1-C6 alkyl group, or R E and R FThe compound or a pharmaceutically acceptable salt thereof, wherein the atoms to which they are bonded form a 4- to 8-membered heterocycline which is optionally substituted with a hydroxyl group. Embodiment 2.X is N, wherein the compound or a pharmaceutically acceptable salt thereof is described in Embodiment 1.

[0341] Embodiment 3.X is the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein C is C.

[0342] Embodiment 4. A compound according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is N.

[0343] Embodiment 5. A compound according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is C.

[0344] Embodiment 6.Z 1 A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is N.

[0345] Embodiment 7.Z 1 A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein C is C.

[0346] Embodiment 8. A compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 11-membered heteroaryl.

[0347] Embodiment 9. A compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-6 membered heteroaryl.

[0348] Embodiment 10. Ring A is a compound according to any one of Embodiments 1 to 9, selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and pyridonyl, or a pharmaceutically acceptable salt thereof.

[0349] Embodiment 11. A compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring A is a 9- to 10-membered heteroaryl.

[0350] Embodiment 12. A compound according to any one of Embodiments 1 to 8 or 11, or a pharmaceutically acceptable salt thereof, wherein ring A is indole, indazole, aza-indole, benzimidazole, benzothiophene, benzoxazole, benzothiazole, benzopyrazole, pyrrolopyrimidine, benzoisoxazole, benzotriazole, purine, quinoline, isoquinoline, quinazoline, quinoxaline, or sinnoline.

[0351] Embodiment 13: A compound according to any one of Embodiments 1 to 7, wherein ring A is phenyl, or a pharmaceutically acceptable salt thereof.

[0352] Embodiment 14: R x The compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0353] Embodiment 15: R x A compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

[0354] Embodiment 16: R x The compound according to any one of embodiments 1 to 13, wherein is -NH2.

[0355] Embodiment 17: One or more R 1 The compound described in any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, is a C1-C6 alkoxy optionally substituted with hydroxyl or phenyl.

[0356] Embodiment 18: One or more R 1The compound described in any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 alkoxyalkyl.

[0357] Embodiment 19: One or more R 1 The compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is a 5-6 member heteroaryl.

[0358] Embodiment 20: One or more R 1 is -N(R 1A )-S(O2)R 1B The compound described in any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof.

[0359] Embodiment 21: One or more R 1 is -(C=O)NR 1A R 1B The compound described in any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof.

[0360] Embodiment 22: One or more R 1 A compound according to any one of Embodiments 1 to 16, wherein the compound is a halogen, or a pharmaceutically acceptable salt thereof.

[0361] Embodiment 23: One or more R 1 A compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the compound is cyano.

[0362] Embodiment 24: One or more R 1 A compound according to any one of Embodiments 1 to 16, wherein the compound is hydroxyl, or a pharmaceutically acceptable salt thereof.

[0363] Embodiment 25: One or more R 1 ga-NR A R B The compound described in any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof.

[0364] Embodiment 26: One or more R 1 The compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the compound is a hydroxyl molecule and a C1-C6 alkyl molecule optionally substituted with one or two substituents independently selected from a 4- to 8-membered heterocycline optionally substituted with a hydroxyl molecule or a C1-C6 alkyl molecule.

[0365] Embodiment 27: One or more R 1 A compound according to any one of Embodiments 1 to 16, wherein is a C1-C6 haloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0366] Embodiment 28: One or more R 1 A compound according to any one of Embodiments 1 to 16, wherein is a C1-C6 haloalkoxy, or a pharmaceutically acceptable salt thereof.

[0367] Embodiment 29: One or more R 1 A compound according to any one of Embodiments 1 to 16, wherein is a C3-C6 cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0368] Embodiment 30: One or more R 1 The compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, is a 4- to 8-membered heterocycline that is optionally substituted with one or two substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl.

[0369] Embodiment 31: One or more R 1 A compound according to any one of Embodiments 1 to 16, wherein is -S(O2)C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0370] Embodiment 32: One or more R 1A A compound according to any one of Embodiments 1 to 31, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0371] Embodiment 33: One or more R 1A A compound according to any one of Embodiments 1 to 31, wherein the compound is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof. Embodiment 34: One or more R 1B However, C1-C6 alkyls optionally substituted with C3-C6 cycloalkyls, 5-6 member heteroaryls optionally substituted with C1-C6 alkyls, or 4-10 member heterocyclies optionally substituted with -(C=O)OC1-C6 alkyls; 5-10 member heteroaryls optionally substituted with 1-2 substituents independently selected from C1-C6 alkyls, hydroxyls, and C1-C6 hydroxyalkyls; C3-C6 cycloalkyls optionally substituted with 1-2 substituents independently selected from C1-C6 alkyls and C1-C6 hydroxyalkyls; ethyl enyl; C1-C6 haloalkyls; 4-10 member heterocyclies optionally substituted with -(C=O)OC1-C6 alkyls; -NR 1A R 1A ; and a compound according to any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, selected from phenyl.

[0372] Embodiment 35: One or more R 1B The compound according to any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, is a 5- to 10-membered heteroaryl that is optionally substituted with one or two substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl.

[0373] Embodiment 36: One or more R 1B The compound according to any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, is a C3-C6 cycloalkyl group that is optionally substituted with one or two substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl groups.

[0374] Embodiment 37: One or more R 1BThe compound according to any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, is a C3-C6 cycloalkyl group that is optionally substituted with one or two substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl groups.

[0375] Embodiment 38: One or more R 1B A compound according to any one of Embodiments 1 to 33, wherein is ethyl enyl, or a pharmaceutically acceptable salt thereof.

[0376] Embodiment 39: One or more R 1B A compound according to any one of Embodiments 1 to 33, wherein is a C1-C6 haloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0377] Embodiment 40: One or more R 1B The compound according to any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, is a 4- to 10-membered heterocycline optionally substituted with a -(C=O)OC1-C6 alkyl group.

[0378] Embodiment 41: One or more R 1B ga-NR 1A R 1A The compound described in any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof.

[0379] Embodiment 42: R A A compound according to any one of Embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0380] Embodiment 43: R A A compound according to any one of Embodiments 1 to 41, wherein the compound is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0381] Embodiment 44: R B A compound according to any one of Embodiments 1 to 43, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0382] Embodiment 45: R B A compound according to any one of Embodiments 1 to 43, wherein is -S(O2)C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0383] Embodiment 46: R B The compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, wherein the compound is a C3-C6 cycloalkyl group optionally substituted with a hydroxyl group or a C1-C6 alkoxy group.

[0384] Embodiment 47: R B A compound according to any one of Embodiments 1 to 43, wherein is a -(C=O)C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0385] Embodiment 48: R B A compound according to any one of Embodiments 1 to 43, wherein is -(C=O)OC1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0386] Embodiment 49: R B The compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, is a 4- to 8-membered heterocycline optionally substituted with a hydroxyl group.

[0387] Embodiment 50:R B is halogen, hydroxyl, -NR C R D A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, which is a C1-C6 alkyl group optionally substituted with 1 to 4 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 member heteroaryl groups optionally substituted with C1-C6 alkyl, and a C1-C6 alkyl group optionally substituted with 4-8 member heterocyclyl groups optionally substituted with -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0388] Embodiment 51:R BThe compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, which is a -(C=O) 5-membered or 6-membered heteroaryl that is optionally substituted with a C1-C6 alkyl group.

[0389] Embodiment 52: R 2 A compound according to any one of Embodiments 1 to 51, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0390] Embodiment 53:R 2 A compound according to any one of Embodiments 1 to 51, wherein the compound is a halogen, or a pharmaceutically acceptable salt thereof.

[0391] Embodiment 54: R 2 However, hydroxyl, phosphate, -NR 2A R 2B A 4-10 member heterocyclyl, hydroxyl, CO2H, or C(O)R is optionally substituted with 1-3 substituents independently selected from C1-C6 alkoxy, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, and C1-C6 alkoxyalkyl groups. 2A A compound according to any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein the compound is a C3-C6 cycloalkyl group optionally substituted therewith.

[0392] Embodiment 55:R 2 A compound according to any one of Embodiments 1 to 51, wherein is a C1-C6 haloalkoxy, or a pharmaceutically acceptable salt thereof.

[0393] Embodiment 56: R 2 A compound according to any one of Embodiments 1 to 51, wherein is a 4- to 10-membered heterocyclyloxy, or a pharmaceutically acceptable salt thereof.

[0394] Embodiment 57: R 2 -(C=O)NR 2A R 2B The compound described in any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof.

[0395] Embodiment 58:R 2 However, hydroxyl, halogen, and -NR 2A R 2B A compound according to any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, which is a C1-C6 alkyl group optionally substituted with 1 to 3 substituents independently selected from the compound.

[0396] Embodiment 59: R 2 The compound according to any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein the compound is a 5-6 member heteroaryl optionally substituted with a C1-C6 alkyl or C1-C6 alkoxy.

[0397] Embodiment 60:R 2 ga-NR 2A R 2B The compound described in any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof.

[0398] Embodiment 61: One or more R 2A A compound according to any one of Embodiments 1 to 60, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0399] Embodiment 62: One or more R 2A A compound according to any one of Embodiments 1 to 60, wherein the compound is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0400] Embodiment 63: One or more R 2A A compound according to any one of Embodiments 1 to 60, wherein is a C1-C6 hydroxyalkyl compound, or a pharmaceutically acceptable salt thereof.

[0401] Embodiment 64: One or more R 2B A compound according to any one of Embodiments 1 to 63, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0402] Embodiment 65: One or more R 2BA compound according to any one of Embodiments 1 to 63, wherein is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0403] Embodiment 66: One or more R 2B A compound according to any one of Embodiments 1 to 63, wherein is a C1-C6 hydroxyalkyl compound, or a pharmaceutically acceptable salt thereof.

[0404] Embodiment 67:R 2 However, H, OMe,

[0405] [ka] A compound according to any one of Embodiments 1 to 51, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

[0406] Embodiment 68:R 3 A compound according to any one of Embodiments 1 to 67, wherein is a C1-C6 thioalkyl compound, or a pharmaceutically acceptable salt thereof.

[0407] Embodiment 69:R 3 A compound according to any one of Embodiments 1 to 67, wherein -CO2H, or a pharmaceutically acceptable salt thereof.

[0408] Embodiment 70:R 3 The compound according to any one of Embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, wherein the C1-C6 alkoxy is optionally substituted with a 4- to 10-membered heterocycline optionally substituted with a C1-C6 alkoxy.

[0409] Embodiment 71:R 3 The compound according to any one of Embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, is a 4- to 8-membered heterocycline that is optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, oxo, and C1-C6 alkoxy.

[0410] Embodiment 72:R 3 A compound according to any one of Embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0411] Embodiment 73:R 3 A compound according to any one of Embodiments 1 to 67, wherein is a C1-C6 haloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0412] Embodiment 74:R 3 The compound according to any one of Embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, is a 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group.

[0413] Embodiment 75:R 3 A compound according to any one of Embodiments 1 to 67, wherein is a C1-C6 alkoxyalkyl group, or a pharmaceutically acceptable salt thereof.

[0414] Embodiment 76:R 3 A compound according to any one of Embodiments 1 to 67, wherein is a C1-C6 hydroxyalkyl compound, or a pharmaceutically acceptable salt thereof.

[0415] Embodiment 77:R 3 However, NR E R F A compound according to any one of Embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, which is a C1-C6 alkyl group optionally substituted with a hydroxyl group.

[0416] Embodiment 78:R 3 -C(=O)NR E R F The compound described in any one of Embodiments 1 to 67, or a pharmaceutically acceptable salt thereof.

[0417] Embodiment 79:R 3 but

[0418] [ka] The compound described in any one of Embodiments 1 to 67, or a pharmaceutically acceptable salt thereof.

[0419] Embodiment 80:R 3A C1-C6 haloalkyl; C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl; 5-6 member heteroaryl optionally substituted with C1-C6 alkyl, hydroxyl, or C1-C6 alkoxy; or 4-6 member heterocyclyl optionally substituted with 4-6 member heterocyclyl; or C1-C6 alkyl optionally substituted with C1-C6 alkoxy; C1-C6 alkoxy A compound according to any one of Embodiments 1 to 67 or 79, or a pharmaceutically acceptable salt thereof, selected from calkyl; C1-C6 hydroxyalkyl; 5-6 membered heteroaryls optionally substituted with C1-C6 alkyl; 4-10 membered heterocyclyls optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1-C6 alkoxy; or -N(C1-C6 alkyl)2.

[0420] Embodiment 81:R 3A The compound according to any one of Embodiments 1 to 67 or 79, or a pharmaceutically acceptable salt thereof, wherein the compound is a C3-C6 cycloalkyl group optionally substituted with a C1-C6 alkyl group.

[0421] Embodiment 82:R 3A The compound according to any one of Embodiments 1 to 67 or 79, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C6 alkyl optionally substituted with a C3-C6 cycloalkyl, a C1-C6 alkyl, a hydroxyl, a 5-6 membered heteroaryl optionally substituted with a C1-C6 alkoxy, or a 4-6 membered heterocyclyl optionally substituted with a 4-6 membered heterocyclyl, or a C1-C6 alkyl optionally substituted with a C1-C6 alkoxy.

[0422] Embodiment 83:R3A A compound according to any one of embodiments 1 to 67 or 78, wherein is a C1-C6 alkoxyalkyl group, or a pharmaceutically acceptable salt thereof.

[0423] Embodiment 84:R 3A A compound according to any one of Embodiments 1 to 67 or 79, wherein is a C1-C6 hydroxyalkyl compound, or a pharmaceutically acceptable salt thereof.

[0424] Embodiment 85:R 3A The compound according to any one of Embodiments 1 to 67 or 79, or a pharmaceutically acceptable salt thereof, which is a 5-6 member heteroaryl optionally substituted with a C1-C6 alkyl group.

[0425] Embodiment 86:R 3A The compound according to any one of Embodiments 1 to 67 or 79, or a pharmaceutically acceptable salt thereof, is a 4 to 10-membered heterocycline that is optionally substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0426] Embodiment 87: Z is NR 4 A compound according to any one of embodiments 1 to 41 or 47 to 49, or a pharmaceutically acceptable salt thereof.

[0427] Embodiment 88:R 4 A compound according to any one of Embodiments 1 to 41 or 47 to 51, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0428] Embodiment 89:R 4 A compound according to any one of Embodiments 1 to 41 or 47 to 51, wherein the compound is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0429] Embodiment 90: A compound according to any one of Embodiments 1-41 or 47-50, wherein Z is O, or a pharmaceutically acceptable salt thereof.

[0430] Embodiment 91:R 3 but

[0431] [ka] The compound described in any one of Embodiments 1 to 41, or a pharmaceutically acceptable salt thereof.

[0432] Embodiment 92:R 3B A compound according to any one of Embodiments 1 to 41 or 91, wherein is a C3-C6 cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0433] Embodiment 93:R 3B The compound according to any one of Embodiments 1 to 41 or 91, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl group.

[0434] Embodiment 94:R 3C A compound according to any one of Embodiments 1 to 41 or 91 to 93, wherein is a C3-C6 cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0435] Embodiment 95:R 3C The compound according to any one of Embodiments 1 to 41 or 91 to 93, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl group.

[0436] Embodiment 96:R C A compound according to any one of Embodiments 1 to 95, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0437] Embodiment 97:R C A compound according to any one of Embodiments 1 to 95, or a pharmaceutically acceptable salt thereof, wherein the C1-C6 alkyl group is optionally substituted with an oxo group.

[0438] Embodiment 98:R DA compound according to any one of Embodiments 1 to 97, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0439] Embodiment 99:R D A compound according to any one of Embodiments 1 to 97, or a pharmaceutically acceptable salt thereof, wherein the C1-C6 alkyl group is optionally substituted with an oxo group.

[0440] Embodiment 100:R E A compound according to any one of Embodiments 1 to 99, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0441] Embodiment 101:R E A compound according to any one of Embodiments 1 to 99, wherein is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0442] Embodiment 102:R F A compound according to any one of Embodiments 1 to 101, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0443] Embodiment 103:R F A compound according to any one of Embodiments 1 to 101, wherein is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

[0444] Embodiment 104:R E and R F The compound according to any one of Embodiments 1 to 99, or a pharmaceutically acceptable salt thereof, wherein the atoms to which they are bonded form a 4- to 8-membered heterocycline which is optionally substituted with a hydroxyl group.

[0445] Embodiment 105:R 3 H, OMe, CF3,

[0446] [ka] A compound according to any one of Embodiments 1 to 67, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

[0447] Embodiment 106: Formula (I) is (Ia)

[0448] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0449] Embodiment 107: Formula (I) is (Ib)

[0450] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0451] Embodiment 108: Formula (I) is (Ic)

[0452] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0453] Embodiment 109: Formula (I) is (Id)

[0454] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0455] Embodiment 110: Formula (I) is (Ie)

[0456] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0457] Embodiment 111: Equation (I) is (If)

[0458] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0459] Embodiment 112: Formula (I) is (Ig)

[0460] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0461] Embodiment 113: Formula (I) is (Ih)

[0462] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0463] Embodiment 114: Equation (I) is (Ii)

[0464] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0465] Embodiment 115: Formula (I) is (Ij)

[0466] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein ring C is morpholine or N-methylmorpholine.

[0467] Embodiment 116: Formula (I) is (Ik)

[0468] [ka] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein ring C is pyridine or pyrrolidine.

[0469] Embodiment 117:

[0470] [ka] teeth,

[0471] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0472] Embodiment 118:

[0473] [ka] teeth,

[0474] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0475] Embodiment 119:

[0476] [ka] teeth,

[0477] [ka]

[0478] [ka]

[0479] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0480] Embodiment 120:

[0481] [ka] teeth,

[0482] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0483] Embodiment 121:

[0484] [ka] teeth,

[0485] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0486] Embodiment 122: A compound selected from the group consisting of the compounds of Examples 1 to 304, or a pharmaceutically acceptable salt thereof.

[0487] Embodiment 123: A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0488] Embodiment 124: A method for treating a RIPK2-related disease or disorder in a subject requiring treatment for such disease or disorder, comprising the step of administering an effective amount of a compound according to any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 123, to the subject.

[0489] Embodiment 125: The method according to Embodiment 124, wherein the RIPK2-related disease or disorder is a cardiovascular disease, allergic disorder, autoimmune disease, inflammatory disease, cardiovascular disease, fibrous disease, or a disease associated with abnormal cell proliferation.

[0490] Embodiment 126: The method according to Embodiment 124 or 125, wherein the RIPK2-related disease or disorder is an inflammatory disease.

[0491] Embodiment 127: Inflammatory diseases include chronic pulmonary inflammatory disease, osteoarthritis, inflammatory arthritis, asthma, early-onset sarcoidosis, sarcoidosis, eczema, allergic eczema, uveitis, reactive arthritis, chronic inflammation, chronic prostatitis, inflammatory bowel disease, glomerulonephritis, bursitis, carpal tunnel syndrome, tendinitis, inflammation of the lungs (e.g., chronic obstructive pulmonary disease), pelvic inflammatory disease, graft rejection, vasculitis, focal enteritis, distal ileitis, localized ileitis, and terminal ileitis, central areolar choroidal dystrophy The method according to Embodiment 126, wherein the condition is dystrophy, macular degeneration, retinitis pigmentosa, adult vitreous disease, pattern dystrophy, diabetic retinopathy, BEST disease, myopic degeneration, central serous retinopathy, Stargardt disease, cone rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or systemic inflammatory response syndrome.

[0492] Embodiment 128: A method for treating inflammatory bowel disease in a subject requiring treatment for inflammatory bowel disease, comprising the step of administering an effective amount of a compound according to any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 123, to the subject.

[0493] Embodiment 129: A method for treating inflammatory bowel disease in a subject requiring treatment for inflammatory bowel disease, comprising: (a) determining that the subject is suffering from inflammatory bowel disease; and (b) administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 123.

[0494] Embodiment 130: A method for treating inflammatory bowel disease in a subject previously identified or diagnosed with inflammatory bowel disease, the method comprising the step of administering an effective amount of a compound according to any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 123, to the subject.

[0495] Embodiment 131: A method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising the step of administering an effective amount of a compound according to any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 123, to the subject.

[0496] Embodiment 132: A method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising: (a) determining that the subject has Crohn's disease; and (b) administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 123.

[0497] Embodiment 133: A method for treating Crohn's disease in a subject previously identified or diagnosed with Crohn's disease, the method comprising administering an effective amount of a compound according to any one of Embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 123, to the subject.

[0498] Examples material and method The compounds provided herein, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of many possible synthetic routes.

[0499] The reactions for preparing the compounds provided herein may be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction takes place, which may range from the freezing temperature to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of one or more solvents. Depending on the specific reaction step, a solvent suitable for that particular step can be selected by those skilled in the art.

[0500] The preparation of compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1. st Ed.,Oxford University Press,2000;March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,5 thThis can be found in Ed., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J.Chem.Educ., 74(11), 1297 (1997).

[0501] intermediate

[0502] [ka]

[0503] 7-Methoxy-6-(trifluoromethyl)imidazo[1,2-a]pyridine: To a 30 mL vial, 4-methoxy-5-(trifluoromethyl)pyridine-2-amine (0.2 g, 1.04 mmol, 1 equivalent) and chloroacetaldehyde (0.095 mL, 1.35 mmol) in EtOH (6 mL) were added at room temperature under an N2 atmosphere. The vial was sealed and then heated at 80°C for 18 hours, after which it was cooled to room temperature and concentrated under reduced pressure. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The organic layer was washed with brine, dried over Mg₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO₂, 5-15% ethyl acetate / petroleum ether) to obtain the title compound (180 mg, 80%) as a pale yellow solid. [M+H] + =217.1. 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.13(s,1H),8.03(d,J=1.6Hz,1H),7.44-7.44(m,1H),4.09(s,3H).

[0504] 3-Bromo-7-methoxy-6-(trifluoromethyl)imidazo[1,2-a]pyridine: A suspension of 7-methoxy-6-(trifluoromethyl)imidazo[1,2-a]pyridine (120 mg, 0.56 mmol, 1 equivalent), sodium bromide (114 mg, 1.11 mmol, 2 equivalents), and sodium persulfate (132 mg, 0.56 mmol) in MeCN (2.4 mL) was heated at 80°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with HCl (20 mL), and washed with water (3 × 5 mL). The organic layer was separated, dried over Mg₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO₂, 20-30% HCl / petroleum ether) to obtain the title compound (90 mg, 55%) as an off-white solid. [M+H] + =295.2. 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),7.87(s,1H),7.37(s,1H),4.00(s,3H).

[0505] [ka]

[0506] A mixture of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (50 mg, 198.19 μmol, 1 equivalent), K2CO3 (82.17 mg, 594.56 μmol, 3 equivalents), dppf (10.99 mg, 19.82 μmol, 0.1 equivalent), and Pd2(dba)3 (9.07 mg, 9.91 μmol, 0.05 equivalents) in 1 mL of dioxane was degassed and purged with N2 (3×). 2-mercapto-2-methylpropan-1-ol (23.15 mg, 218.01 μmol, 1.1 equivalents) was added, and the mixture was then stirred at 100°C under an N2 atmosphere for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound as a brown solid. LCMS[M+H] + =253.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.70(s,1H),7.76(s,1H),7.41(s,1H),6.96(s,1H),4.78(t,J=6.0Hz,1H),3.85(s,3H),3.27(d,J=6.0Hz,2H),1.13(s,6H).

[0507] 2-((7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-2-methylpropan-1-ol: To a solution of 2-((7-methoxyimidazo[1,2-a]pyridine-6-yl)thio)-2-methylpropan-1-ol (280 mg, 998.68 μmol, 1 equivalent) in MeOH (7 mL) and H2O (7 mL), Oxone® (1.84 g, 3.00 mmol, 3 equivalents) was added at 0°C. The mixture was stirred at 25°C for 12 hours to obtain the title compound as a brown liquid, which was used in the next step without further purification.

[0508] 2-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-2-methylpropan-1-ol (280 mg, 886.29 μmol, 1.0 equivalent) was dissolved in MeOH (7 mL) and H2O (14 mL), to which NIS (299.10 mg, 1.33 mmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 2 hours, and then quenched with saturated NaHSO3 (20 mL) at 25°C. The resulting mixture was diluted with H2O (25 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The obtained crude material was purified by column chromatography (SiO2, petroleum ether / acetate = 100 / 1 to 0 / 1) to obtain the title compound as a brown solid. LCMS[M+H] + =410.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.71(s,1H),7.23(s,1H),4.99(t,J=5.6Hz,1H),3.92(s,3H),3.57(d,J=5.6Hz,2H),1.29(s,6H).

[0509] [ka]

[0510] 3-((7-methoxyimidazo[1,2-a]pyridine-6-yl)thio)-3-methylbutan-1-ol: 3-mercapto-3-methylbutan-1-ol (262.07 mg, 2.18 mmol, 1.1 equivalent) was added under an N2 atmosphere to a solution of 6-iodo-7-methoxyimidazo[1,2-a]pyridine (0.5 g, 1.98 mmol, 1 equivalent), K2CO3 (821.74 mg, 5.95 mmol, 3 equivalents), DPPF (109.87 mg, 198.19 μmol, 0.1 equivalent), and Pd2(dba)3 (90.74 mg, 99.09 μmol, 0.05 equivalents) in 1,4-dioxane (10 mL). The mixture was stirred at 100°C for 12 hours, then diluted with H2O (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 10% MeOH / DCM) to obtain the title compound (283 mg, yield 48%) as a brown oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.66(s,1H),7.77(s,1H),7.42(s,1H),6.96(s,1H),4.38(t,J=7.2Hz,1H) ,3.84(s,3H),3.63-3.56(m,2H),1.65(t,J=7.2Hz,2H),1.21-1.16(m,6H).

[0511] A mixture of 3-((7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-3-methylbutan-1-ol (283 mg, 956.23 μmol, 1 equivalent) and Oxone® (1.76 g, 2.87 mmol, 3 equivalents) in MeOH (6 mL) and H2O (2 mL) was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 12 hours. The reaction mixture containing the title compound (280 mg) was used directly in the next step. [M+H] + =298.9.

[0512] A mixture of 3-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-3-methylbutan-1-ol (280 mg, 938.47 μmol, 1 equivalent) and NIS (316.71 mg, 1.41 mmol, 1.5 equivalents) in MeOH (6 mL) and H2O (4 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 25°C for 1 hour. The reaction mixture was quenched with H2O (10 mL), then diluted with additional water (20 mL), and extracted with ELISA (3 × 20 mL). The aqueous phase was freeze-dried to obtain a residue, which was purified by column chromatography (SiO2, 10% MeOH / DCM) to obtain the title compound (350 mg, yield 79%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.59-8.42(m,1H),8.01-7.86(m,1H),7.37(s,1H),3.99(s,3H),3.56(t,J=6.8Hz,2H),1.84(t,J=6.8Hz,2H),1.33(s,6H).

[0513] [ka]

[0514] 4-Mercapto-4-methylpentan-1-ol: To a solution of 4-mercapto-4-methylpentanoic acid (500 mg, 3.37 mmol, 1 equivalent) in THF (2 mL), LiAlH4 (2.5 M, 2.70 mL, 2 equivalents) was added at 0°C. The mixture was stirred at 20°C for 1 hour, then quenched with siRNA (2 mL), subsequently diluted with H2O (0.5 mL), and extracted with siRNA (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 20 / 1 to 3 / 1) to obtain the title compound (147 mg, yield 29%) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δppm 4.41(t,J=5.6Hz,1H),3.41-3.35(m,2H),1.55-1.50(m,4H),1.31(s,6H).

[0515] A mixture of 4-((7-methoxyimidazo[1,2-a]pyridine-6-yl)thio)-4-methylpentan-1-ol:dioxane (7 mL) containing 4-mercapto-4-methylpentan-1-ol (143.07 mg, 959.23 μmol, 1.1 equivalents), 6-bromo-7-methoxyimidazo[1,2-a]pyridine (220 mg, 872.03 μmol, 1 equivalent), Pd(OAc)2 (19.58 mg, 87.20 μmol, 0.1 equivalents), dppf (96.69 mg, 174.41 μmol, 0.2 equivalents), and Z-BuONa (251.41 mg, 2.62 mmol, 3 equivalents) was degassed and purged three times with N2. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere, then filtered and concentrated under reduced pressure to obtain a residue. This residue was purified by RP-HPLC to obtain the title compound (153 mg, yield 56%) as a brown oil. [M+H] + =281.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.66(s,1H),7.76(s,1H),7.41(s,1H),6.96(s,1H),4.44(t,J=5.2Hz,1H),3.8 4(s,3H),3.44-3.35(m,2H),1.65-1.55(m,2H),1.48-1.41(m,2H),1.17(s,6H).

[0516] 4-((7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-4-methylpentan-1-ol: To a solution of 4-((7-methoxyimidazo[1,2-a]pyridine-6-yl)thio)-4-methylpentan-1-ol (50 mg, 160.49 μmol, 1 equivalent) in MeOH (1.5 mL) and H2O (0.5 mL), Oxone® (592.00 mg, 962.96 μmol, 6 equivalents) was added, and the mixture was stirred at 30°C for 2 hours. The crude title compound (50 mg) was used in the next step without work-up or purification. [M+H]+ =313.0.

[0517] 4-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-4-methylpentan-1-ol: To a solution of 4-((7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-4-methylpentan-1-ol (50 mg, 160.06 μmol, 1 equivalent) in H2O (0.2 mL), NIS (43.21 mg, 192.07 μmol, 1.2 equivalents) was added. The mixture was stirred at 20°C for 2 hours, then quenched with saturated Na2SO3 (1 mL), and subsequently extracted with siRNA (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by RP-HPLC to obtain the title compound (20 mg, yield 26%) as a pale yellow solid. [M+H] + =438.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.72(s,1H),7.28(s,1H),4.46(t,J=5.2Hz,1H),3.92(s,3H ),3.42-3.36(m,2H),1.71-1.65(m,2H),1.51-1.43(m,2H),1.27(s,6H).

[0518] [ka]

[0519] Pd(OAc)2 (13.35 mg, 59.46 μmol, 0.1 equivalent) was added to a mixture of 5-bromo-6-methoxypyrazolo[1,5-a]pyridine (150 mg, 594.56 μmol, 1 equivalent), 2-mercapto-2-methylpropan-1-ol (126.27 mg, 1.19 mmol, 2 equivalents), dppf (65.92 mg, 118.91 μmol, 0.2 equivalents), and t-BuONa (114.28 mg, 1.19 mmol, 2 equivalents) in 2-((6-methoxypyrazolo[1,5-a]pyridine-5-yl)thio)-2-methylpropan-1-ol:1,4-dioxane (5 mL) under an N2 atmosphere. The mixture was stirred at 100°C for 16 hours, then concentrated under reduced pressure, diluted with H2O (30 mL), and extracted with siRNA (3 × 50 mL). The combined organic layer was washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by preparative TLC (SiO2, 50% siRNA / petroleum ether) to obtain the title compound (130 mg, yield 82%) as a yellow solid. [M+H] + =253.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.41(s,1H),7.95-7.88(m,2H),6.59(d,J=2.0Hz,1H),4.84(t,J=6.0Hz,1H),3.85(s,3H),3.31(d,J=3.2Hz,2H),1.18(s,6H).

[0520] 2-((3-iodo-6-methoxypyrazolo[1,5-a]pyridine-5-yl)sulfonyl)-2-methylpropan-1-ol (130 mg, 489.43 μmol, 1 equivalent) was added to a mixture of 2-((6-methoxypyrazolo[1,5-a]pyridine-5-yl)thio)-2-methylpropan-1-ol (3 mL, 489.43 μmol, 1 equivalent) in MeOH (3 mL) and H2O (1 mL). Oxone® (451.33 mg, 734.15 μmol, 1.5 equivalents) was added. The mixture was stirred at 15°C for 12 hours, after which H2O (3 mL) and NIS (164.98 mg, 733.30 μmol, 1.5 equivalents) were added. The resulting mixture was stirred at 15°C for 1 hour, then quenched with saturated Na2SO3 (30 mL), and extracted with DCM (3 × 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-60% siRNA / petroleum ether) to obtain the title compound (130 mg, yield 58%) as a yellow solid. [M+H] + =411.1. 1 H NMR(400MHz,CDCl3)δppm 8.25(s,1H),8.15(s,1H),8.02(s,1H),4.00(s,3H),3.78(s,2H),1.42(s,6H).

[0521] [ka]

[0522] A mixture of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (5 g, 19.82 mmol, 1 equivalent), methyl 3-mercaptopropanoate (2.36 mL, 21.80 mmol, 1.1 equivalent), xanthophos (2.29 g, 3.96 mmol, 0.2 equivalent), and DIPEA (6.90 mL, 39.64 mmol, 2 equivalents) in methyl 3-((7-methoxyimidazo[1,2-a]pyridine-6-yl)thio)propanoate:dioxane (90 mL) was degassed, then purged with N2 (3×), and then Pd2(dba)3 (1.81 g, 1.98 mmol, 0.1 equivalent) was added. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere, then diluted with water (30 mL) and extracted with siRNA (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by column chromatography (SiO2, PE / siRNA = 5 / 1 to 0 / 1) to obtain the title compound as a brown oil. 1 H NMR(400MHz,CDCl3)δppm 8.16(s,1H),7.46(t,J=1.6Hz,1H),7.39(s,1H),6.90(s,1H),3.93(s,3H),3.64(s,3H),3.06(t,J=7.2Hz,2H),2.57(t,J=7.2Hz,2H).

[0523] To a solution of methyl 3-((7-methoxyimidazo[1,2-a]pyridine-6-yl)thio)propanoate (3.75 g, 12.67 mmol, 1 equivalent) in potassium 7-methoxyimidazo[1,2-a]pyridine-6-thiolate:THF (60 mL), t-BuOK (1.99 g, 17.74 mmol, 1.4 equivalents) was added at 0°C. The mixture was stirred at 25°C for 12 hours, and the precipitate was isolated by filtration. The filtered cake was dried in vacuum to obtain the title compound as a brown solid, which was used in the next step without further purification.

[0524] [ka]

[0525] To a solution of potassium 7-methoxyimidazo[1,2-a]pyridine-6-thiolate (2.35 g, 10.76 mmol, 1 equivalent) in 6-((3-chloropropyl)thio)-7-methoxyimidazo[1,2-a]pyridine:DMF (25 mL), Cs2CO3 (10.52 g, 32.29 mmol, 3 equivalents) and 1-bromo-3-chloropropane (1.27 mL, 12.92 mmol, 1.2 equivalents) were added. The mixture was stirred at 80°C for 4 hours, then diluted with H2O (20 mL) and extracted with siRNA (2 × 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 10 / 1) to obtain the title compound as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.57(s,1H),7.71(s,1H),7.39(d,J=1.2Hz,1H),6.98(m,1H),3.88(s,3H),3.75(t,J=6.4Hz,2H),2.94(t,J=7.2Hz,2H),2.00-1.90(m,2H).

[0526] 6-((3-chloropropyl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine: To a solution of 6-((3-chloropropyl)thio)-7-methoxyimidazo[1,2-a]pyridine (1.92 g, 6.73 mmol, 1 equivalent) in MeOH (24 mL) and H2O (8 mL), Oxone® (6.21 g, 10.10 mmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 12 hours, then filtered and concentrated under vacuum. The resulting crude substance was purified by RP-HPLC to obtain the title compound as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.27(s,1H),8.09(s,1H),7.75(d,J=1.6Hz,1H),7.31(s,1H),4.02(s,3H),3.72(t,J=6.4Hz,2H),3.65-3.57(m,2H),2.10-2.01(m,2H).

[0527] [ka]

[0528] 6-(cyclopropylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine: To a solution of 6-((3-chloropropyl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine (238 mg, 741.82 μmol, 90% purity, 1 equivalent) in DMF (1 mL), NaH (59.34 mg, 1.48 mmol, 60% in mineral oil, 2 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours and then quenched with MeOH (1 mL). The mixture was purified by RP-HPLC to obtain the title compound (127 mg, 61% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.07(s,1H),7.96(s,1H),7.54(d,J=1.2Hz,1H),7.19(s,1H),3.98(s,3H),3.13-2.99(m,1H),1.20-1.02(m,4H).

[0529] 6-(cyclopropylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine: To a solution of 6-(cyclopropylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine (127 mg, 453.05 μmol, 90% purity, 1 equivalent) in MeOH (3 mL) and H2O (1 mL), NIS (122.32 mg, 543.66 μmol, 1.2 equivalents) was added. The mixture was stirred at 25°C for 1 hour, then diluted with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain the title compound (107 mg, 56% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.71(s,1H),7.31(s,1H),4.01(s,3H),3.17-3.05(m,1H),1.22-1.15(m,2H),1.14-1.05(m,2H).

[0530] [ka]

[0531] 3-((7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)propan-1-ol: To a solution of 6-((3-chloropropyl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine (50 mg, 155.84 μmol, 90% purity, 1 equivalent) in H2O (1 mL), NaOH (6.23 mg, 155.84 μmol, 1 equivalent) was added. The mixture was stirred at 25°C for 1 hour, then concentrated under reduced pressure to obtain a residue, which was purified by RP-HPLC to obtain the title compound (5 mg, yield 11%) as a yellow solid. [M+H] + =271.1. 1 H NMR(400MHz,CDCl3)δppm 8.78(s,1H),7.62-7.55(m,2H),7.02(s,1H),4.01(s,3H),3.78(t,J=6.4Hz,2H),3.56(t,J=7.6Hz,2H),2.07-2.01(m,2H).

[0532] 3-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)propan-1-ol: A mixture of 3-((7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)propan-1-ol (5 mg, 16.65 μmol, 90% purity, 1 equivalent) and NIS (4.49 mg, 19.98 μmol, 1.2 equivalents) in MeOH (3 mL) and H2O (1 mL) was stirred at 25°C for 1 hour, then diluted with water (10 mL) and extracted with SiO (3 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (7 mg) as a brown oil. [M+H] + =397.0.

[0533] [ka]

[0534] Potassium in 7-methoxy-6-((1-methyl-1H-pyrazole-5-yl)thio)imidazo[1,2-a]pyridine:Dioxane (5 mL) A mixture of 7-methoxyimidazo[1,2-a]pyridine-6-thiolate (250 mg, 1.15 mmol, 1 equivalent), 5-iodo-1-methyl-1H-pyrazole (166.73 mg, 801.59 μmol, 0.7 equivalents), Pd2(dba)3 (104.86 mg, 114.51 μmol, 0.1 equivalent), xanthophos (132.52 mg, 229.02 μmol, 0.2 equivalents), and K2CO3 (474.79 mg, 3.44 mmol, 3 equivalents) was degassed, purged three times with N2, and then stirred at 80°C under an N2 atmosphere for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by RP-HPLC to obtain the title compound (50 mg, yield 15%) as a gray solid. [M+H] + =261.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.22(s,1H),7.74(s,1H),7.55(s,1H),7.38(s,1H),7.02(s,1H),6.57(d,J=1.6Hz,1H),3.90(s,3H),3.89(s,3H).

[0535] A mixture of 7-methoxy-6-((1-methyl-1H-pyrazole-5-yl)sulfonyl)imidazo[1,2-a]pyridine (30.00 mg, 103.72 μmol, 1 equivalent) and Oxone® (191.29 mg, 311.16 μmol, 3 equivalents) in H2O (0.4 mL) and MeOH (1.2 mL) was stirred at 30°C for 24 hours to obtain the title compound (30 mg) as a yellow liquid, which was used in the next step without post-treatment or purification. [M+H] + =293.0.

[0536] A mixture of 3-iodo-7-methoxy-6-((1-methyl-1H-pyrazole-5-yl)sulfonyl)imidazo[1,2-a]pyridine (30 mg, 102.63 μmol, 1 equivalent) and NIS (34.64 mg, 153.94 μmol, 1.5 equivalents) in H2O (0.6 mL) was stirred at 20°C for 2 hours and then quenched with saturated Na2SO3 (1 mL). The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 50 / 1 to 10 / 1) to obtain the title compound (45 mg, 94% yield) as a brown solid. [M+H] + =418.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.76(s,1H),7.74(s,1H),7.64(d,J=2.0Hz,1H),7.25(s,1H),7.08(d,J=2.0Hz,1H),4.04(s,3H),3.86(s,3H).

[0537] [ka]

[0538] A mixture of potassium 7-methoxyimidazo[1,2-a]pyridine-6-thiolate (800 mg, 3.66 mmol, 2.5 equivalents), tert-butyl 4-iodo-1H-pyrazole-1-carboxylate (431.06 mg, 1.47 mmol, 1 equivalent), CS2CO3 (1.43 g, 4.40 mmol, 3 equivalents), and xanthophos (169.62 mg, 293.15 μmol, 0.2 equivalents) in 6-((1H-pyrazole-4-yl)thio)-7-methoxyimidazo[1,2-a]pyridine:1,4-dioxane (20 mL) was degassed, purged three times with N2, and then Pd2(dba)3 (134.22 mg, 146.58 μmol, 0.1 equivalent) was added. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere, then filtered and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-8% MeOH / DCM) to obtain the title compound (120 mg, yield 30%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 13.34(s,1H),8.10(s,1H),7.81(s,1H),7.79-7.60(m,2H),7.33(d,J=1.6Hz,1H),6.97(s,1H),3.90(s,3H).

[0539] 6-((1H-pyrazole-4-yl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine (120 mg, 438.51 μmol, 1 equivalent) was dissolved in MeOH (6 mL) and H2O (2 mL), to which Oxone® (404.37 mg, 657.77 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 12 hours to obtain the title compound (120 mg) as a white solid, which was used in the next step without further purification. [M+H] + =279.0.

[0540] 6-((1H-pyrazole-4-yl)sulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine: To a solution of 6-((1H-pyrazole-4-yl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine (120 mg, 431.21 μmol, 1 equivalent) in MeOH (9 mL) and H2O (6 mL), NIS (145.52 mg, 646.81 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 3 hours, then diluted with water (30 mL) and extracted with RINKAN (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain a residue, which was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (90 mg, yield 47%) as a white solid. [M+H] + =404.9. 1 H NMR(400MHz,DMSO-d6)δppm 13.77(s,1H),8.71(s,1H),8.56(s,1H),8.02(s,1H),7.69(s,1H),7.19(s,1H),3.92(s,3H).

[0541] [ka]

[0542] A mixture of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethane-1-ol (69.86 mg, 559.01 μmol, 39.62 μL, 1.5 equivalents), 2-bromoethanol (69.86 mg, 559.01 μmol, 39.62 μL, 1.5 equivalents), and Cs2CO3 (364.27 mg, 1.12 mmol, 3 equivalents) in DMF (2 mL) was degassed, purged three times with N2, and then stirred at 80°C under an N2 atmosphere for 2 hours. The reaction mixture was diluted with H2O (20 mL), and the resulting mixture was purified by RP-HPLC to obtain the title compound (40 mg, yield 32%) as a brown solid. 1H NMR(400MHz,DMSO-d6)δppm 9.12(s,1H),7.99(s,1H),7.54(d,J=1.2Hz,1H),7.15(s,1H),4.78(t,J=5.2Hz,1H),4.13(t,J=4.8Hz,2H),3.80-3.70(m,2H),1.32(s,9H).

[0543] 2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethane-1-ol (35 mg, 105.58 μmol, 1 equivalent) was dissolved in 2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethane-1-ol (1.5 mL) and H2O (1.5 mL), to which NIS (28.50 mg, 126.69 μmol, 1.2 equivalents) was added. The mixture was stirred at 25°C for 12 hours, and then concentrated under reduced pressure to remove the MeOH. The residue was purified by RP-HPLC to obtain the title compound (33 mg, yield 66%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δppm 8.67(s,1H),7.68(s,1H),7.05(s,1H),4.27(t,J=4.4Hz,2H),3.97(d,J=2.8Hz,2H),3.24-3.18(m,1H),1.46(s,9H).

[0544] [ka]

[0545] To a solution of 2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethyl 4-methylbenzenesulfonate:300 mg, 636.41 μmol, 1 equivalent of 2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethane-1-ol (300 mg, 636.41 μmol, 1 equivalent) in DCM (3 mL), TsCl (89.78 mg, 1.27 mmol, 2 equivalents), DMAP (77.75 mg, 636.41 μmol, 1 equivalent), and Et3N (193.19 mg, 1.91 mmol, 265.74 μL, 3 equivalents) were added. The mixture was stirred at 25°C for 12 hours, then diluted with H2O (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (220 mg) as a yellow solid.

[0546] A mixture of 4-(2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethyl)morpholine:DMF (2 mL) containing 2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethyl 4-methylbenzenesulfonate (60 mg, 103.73 μmol, 1 equivalent), morpholine (18.07 mg, 207.45 μmol, 18.26 μL, 2 equivalents), and Et3N (31.49 mg, 311.18 μmol, 43.31 μL, 3 equivalents) was degassed, purged three times with N2, and then stirred at 80°C under an N2 atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 9 / 1) to obtain the title compound (50 mg, yield 64%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.72(s,1H),7.30(s,1H),4.25(t,J=5.6Hz,2H),3.56(t,J=4.8Hz,4H),3.38-3.29(m,4H),2.72(t,J=5.6Hz,2H),1.34(s,9H).

[0547] [ka]

[0548] 6-(tert-butylsulfonyl)-3-iodo-7-(2-(4-methylpiperazine-1-yl)ethoxy)imidazo[1,2-a]pyridine: A solution of 2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethyl 4-methylbenzenesulfonate (50 mg, 77.80 μmol, 1 equivalent) in THF (3 mL) was mixed with 1-methylpiperazine (38.96 mg, 388.98 μmol, 43.15 μL, 5 equivalents). The mixture was stirred at 60°C for 12 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0~0 / 1) to obtain the title compound (25 mg, yield 51%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.72(s,1H),7.30(s,1H),4.23(t,J=5.2Hz,2H),2.77-2.71(m,2H),2.64-2.54(m,4H),2.31-2.23(m,7H),1.34(s,9H).

[0549] [ka]

[0550] To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (150 mg, 530.86 μmol, 1 equivalent) in MeCN (5 mL), Et3N (161.15 mg, 1.59 mmol, 221.67 μL, 3 equivalents) and tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (186.78 mg, 637.03 μmol, 1.2 equivalents) were added. The mixture was stirred at 80°C for 3 hours, then diluted with water (10 mL) and extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 9 / 1) to obtain the title compound (100 mg, yield 32%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.12(s,1H),7.99(s,1H),7.54(d,J=1.2Hz,1H),7.16(s,1H),4.21(t,J=5.6Hz,2H) ,3.31-3.21(m,4H),2.78-2.70(m,2H),2.49-2.42(m,4H),1.39(s,9H),1.32(s,9H).

[0551] To a solution of tert-butyl 4-(2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethyl)piperazine-1-carboxylate (80 mg, 137.16 μmol, 1 equivalent) in MeOH (5 mL) and H2O (5 mL), NIS (61.72 mg, 274.33 μmol, 2 equivalents) was added. The mixture was stirred at 0°C for 2 hours, then diluted with water (10 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0 to 90 / 10) to obtain the title compound (50 mg, yield 49%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.78(s,1H),8.50(s,1H),7.66(s,1H),4.57(t,J=6.4Hz,2H),4.25(s,2H),3.30-3.24(m,4H),2.77-2.65(m,4H),1.34(s,9H),1.31(s,9H).

[0552] [ka]

[0553] A mixture of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)-N,N-dimethylethane-1-amine:DMF (4 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (130 mg, 460.08 μmol, 1 equivalent), Cs2CO3 (749.51 mg, 2.30 mmol, 5 equivalents), and 2-bromo-N,N-dimethylethane-1-amine hydrobromide (214.35 mg, 920.16 μmol, 2 equivalents) was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0~2 / 3) to obtain the title compound (50 mg, yield 30%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.13(s,1H),7.99(s,1H),7.55(d,J=1.2Hz,1H),7.18(s,1H),4.20(t,J=6.0Hz,2H),2.74(t,J=6.0Hz,2H),2.30(s,6H),1.32(s,9H).

[0554] 2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)-N,N-dimethylethane-1-amine (45 mg, 124.45 μmol, 1 equivalent) in a mixture of 2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)-N,N-dimethylethane-1-amine (30.80 mg, 136.90 μmol, 1.1 equivalents) in MeOH (3 mL) and H2O (1 mL) was mixed with NIS (30.80 mg, 136.90 μmol, 1.1 equivalents) at 0°C, and the mixture was stirred at 0°C under an N2 atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (50 mg, yield 80%) as a yellow oil, which was used in the next step without further purification.

[0555] [ka]

[0556] To a solution of 2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethylmethanesulfonate:MeCN (3 mL) containing 2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethane-1-ol (150 mg, 452.48 μmol, 1 equivalent), Ms2O (157.64 mg, 904.96 μmol, 2 equivalents) and Et3N (137.36 mg, 1.36 mmol, 188.94 μL, 3 equivalents) were added. The mixture was stirred at 40°C for 2 hours, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0~10 / 1) to obtain the title compound (100 mg, yield 53%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.16(s,1H),8.01(d,J=0.8Hz,1H),7.56(d,J=1.2Hz,1H),7.21(s,1H),4.56-4.51(m,2H),4.45-4.39(m,2H),3.25(s,3H),1.32(s,9H).

[0557] A mixture of 1-(2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethyl)azetidine-3-ol in MeCN (3 mL) was degassed, purged three times with N2, and then stirred at 80°C under an N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0~3 / 1) to obtain the title compound (50 mg, yield 53%) as a pale yellow solid. 1H NMR(400MHz,CD3OD)δppm 9.05(s,1H),7.84(d,J=0.8Hz,1H),7.52(d,J=1.6Hz,1H),7.03(s,1H),4.38-4.30(m,1H),4. 17(t,J=5.6Hz,2H),3.91-3.82(m,2H),3.24-3.20(m,2H),3.06(t,J=5.6Hz,2H),1.37(s,9H).

[0558] A mixture of 1-(2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethyl)azetidine-3-ol (35 mg, 89.13 μmol, 1 equivalent) and NIS (60.15 mg, 267.38 μmol, 3 equivalents) in 1 mL of 1-(2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethyl)azetidine-3-ol and NIS (60.15 mg, 267.38 μmol, 3 equivalents) in 1 mL of 1-(2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethyl)azetidine-3-ol and H2O (0.2 mL) was stirred at 25°C for 2 hours. The reaction mixture was quenched at 0°C by adding saturated Na2SO3 (5 mL), then diluted with H2O (10 mL), and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 0 / 1 to 3 / 1) to obtain the title compound (30 mg, yield 63%) as a white solid. 1 H NMR(400MHz,CD3OD)δppm 8.69(s,1H),7.67(s,1H),7.16(s,1H),4.48-4.34(m,1H),4.22(t,J=5.6Hz,2 H),3.91-3.81(m,2H),3.24-3.17(m,2H),3.07(t,J=5.6Hz,2H),1.42(s,9H).

[0559] [ka]

[0560] A mixture of tert-butyl 3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)pyrrolidine-1-carboxylate: 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (1.0 g, 3.54 mmol, 1 equivalent), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.33 g, 7.08 mmol, 2.0 equivalents), and CMBP (2.56 g, 10.62 mmol, 3.0 equivalents) in toluene (20 mL) was degassed, purged three times with N2, and then stirred at 110°C under an N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated to obtain a residue, which was purified by preparative TLC (SiO2, DCM / MeOH = 1 / 0~10 / 1) to obtain the title compound (1.5 g, crude) as a red oil. [M+H] + =423.9.

[0561] A mixture of tert-butyl 3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyrrolidine-7-yl)oxy)pyrrolidine-1-carboxylate (1.5 g, 3.54 mmol, 1 equivalent) in 6-(tert-butylsulfonyl)-7-(pyrrolidine-3-yloxy)imidazo[1,2-a]pyrrolidine-7-yl)oxy)pyrrolidine-1-carboxylate (1.5 g, 3.54 mmol, 1 equivalent) in 6-(tert-butylsulfonyl)-TFA (4 mL) and DCM (20 mL) was stirred at 25°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by RP-HPLC and preparative TLC (SiO2, DCM:MeOH:NH3,H2O=1:0:0~8:1:0.001) to obtain the title compound (180 mg, yield 14%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δppm 8.75(s,1H),7.62(d,J=1.2Hz,1H),7.58-7.51(m,1H),6.98(s,1H),5.06-4.95(m,1H),3.34-3.26 (m,1H),3.26-3.19(m,1H),3.11-3.04(m,1H),3.04-2.96(m,1H),2.16-2.01(m,3H),1.42(s,9H).

[0562] 2-(3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)pyrrolidine-1-yl)ethane-1-ol: K2CO3 (126.92 mg, 918.34 μmol, 2.0 equivalents) was added to a solution of 6-(tert-butylsulfonyl)-7-(pyrrolidine-3-yloxy)imidazo[1,2-a]pyridine (165 mg, 459.17 μmol, 1 equivalent) and 2-bromoethane-1-ol (68.86 mg, 551.00 μmol, 39.06 μL, 1.2 equivalents) in MeCN (8 mL). The mixture was stirred at 80°C for 12 hours, then filtered and concentrated to obtain a residue, which was purified by preparative TLC (SiO2, DCM:MeOH:NH3·H2O = 1:0:0~8:1:0.001) to obtain the title compound (150 mg, yield 80%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δppm 8.80-8.66(m,1H),7.64-7.60(m,1H),7.56(s,1H),6.90(s,1H),5.08-4.89(m,1H),3.78-3.60( m,2H),3.38-3.18(m,1H),3.12-2.97(m,2H),2.89-2.81(m,3H),2.5-2.11(m,4H),1.43(s,9H).

[0563] 2-(3-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)pyrrolidine-1-yl)ethane-1-ol: To a solution of 2-(3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)pyrrolidine-1-yl)ethane-1-ol (50 mg, 122.46 μmol, 1 equivalent) in DMF (1.0 mL), NIS (27.55 mg, 122.46 μmol, 3 equivalents) was added. The mixture was stirred at 25°C for 4 hours, then diluted with H2O (20 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by preparative TLC (SiO2, DCM:MeOH:NH3·H2O = 1:0:0~8:1:0.001) to obtain the title compound (40 mg, yield 53%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δppm 8.70(s,1H),7.66(s,1H),6.94(s,1H),5.11-5.01(m,1H),3.81-3.60(m,2H),3.44-3.25(m,1 H),3.14-3.01(m,2H),2.99-2.83(m,3H),2.53-2.36(m,1H),2.24-2.15(m,1H),1.44(s,9H).

[0564] [ka]

[0565] 3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)propan-1-ol: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (100 mg, 353.91 μmol, 1 equivalent) and 3-bromopropan-1-ol (73.78 mg, 530.86 μmol, 48.01 μL, 1.5 equivalents) in MeCN (2 mL), Cs2CO3 (230.62 mg, 707.81 μmol, 2 equivalents) was added. The mixture was stirred at 80°C for 1 hour, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to obtain the title compound (36 mg, yield 29%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δppm 8.75(s,1H),7.64(d,J=1.2Hz,1H),7.58(s,1H),7.12(s,1H),4.30-4.25(m,2H),3.93-3.89(m,2H),2.15-2.11(m,2H),1.43(s,9H).

[0566] A mixture of 3-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)propan-1-ol (36 mg, 103.72 μmol, 1 equivalent) and NIS (28.00 mg, 124.46 μmol, 1.2 equivalents) in MeOH (3 mL) and H2O (1 mL) was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 / 1 to 0 / 1) to obtain the title compound (50 mg, 99% yield) as a pale yellow solid. [M+H] + =438.8. 1H NMR(400MHz,CDCl3)δppm 8.68(s,1H),7.66(s,1H),7.13(s,1H),4.33-4.28(m,2H),3.92(t,J=5.2,2H),2.19-2.11(m,2H),1.45(s,9H).

[0567] [ka]

[0568] A mixture of 6-(tert-butylsulfonyl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-7-ol (50 mg, 176.95 μmol, 1 equivalent) and Cs2CO3 (172.96 mg, 530.86 μmol, 3 equivalents) in 6-(tert-butylsulfonyl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-7-ol (50 mg, 176.95 μmol, 1 equivalent) and Cs2CO3 (172.96 mg, 530.86 μmol, 3 equivalents) was prepared in 2 mL of 6-(tert-butylsulfonyl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-7-ol and Cs2CO3 (172.96 mg, 530.86 μmol, 3 equivalents), to which 1-bromo-2-methoxyethane (29.51 mg, 212.34 μmol, 19.96 μL, 1.2 equivalents) was added. The mixture was degassed, purged three times with N2, and then stirred at 80°C for 1 hour under an N2 atmosphere. The reaction mixture was diluted with H2O (10 mL), extracted with toluene (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (45 mg, yield 73%) as a yellow oil. [M+H] + =313.0. 1 H NMR(400MHz,CDCl3)δppm 8.76(s,1H),7.62(d,J=1.2Hz,1H),7.55(s,1H),7.24-7.03(m,1H),4.28-4.20(m,2H),3.86-3.80(m,2H),3.43(s,3H),1.44(s,9H).

[0569] 6-(tert-butylsulfonyl)-3-iodo-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine (45 mg, 129.65 μmol, 1 equivalent) in MeOH (3 mL) and H2O (1 mL) was mixed with NIS (32.09 mg, 142.61 μmol, 1.1 equivalents). The mixture was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 2 hours. The reaction mixture was diluted with H2O (10 mL), extracted with DCM (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (60 mg, 95% yield) as a yellow solid. [M+H] + =439.0. 1 H NMR(400MHz,CDCl3)δppm 8.72(s,1H),7.69(s,1H),7.07(s,1H),4.28-4.20(m,2H),3.88-3.80(m,2H),3.43(s,3H),1.45(s,9H).

[0570] [ka]

[0571] To a solution of 6-(tert-butylsulfonyl)-7-(oxetane-3-yloxy)imidazo[1,2-a]pyridine:MeCN (8.0 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (300 mg, 1.06 mmol, 1 equivalent), Cs2CO3 (691.86 mg, 2.12 mmol, 2.0 equivalent) and 3-iodooxetane (390.66 mg, 2.12 mmol, 2.0 equivalent) were added. The mixture was stirred at 80°C for 48 hours, then diluted with H2O (20 mL) and extracted with siRNA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 10 / 1) to obtain the title compound (60 mg, yield 16%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 9.18(s,1H),8.01(s,1H),7.56(s,1H),6.80(s,1H),5.48-5.38(m,1H),5.00(t,J=6.8Hz,2H),4.62-4.53(m,2H),1.36(s,9H).

[0572] A mixture of 6-(tert-butylsulfonyl)-3-iodo-7-(oxetane-3-yloxy)imidazo[1,2-a]pyridine (60 mg, 173.99 μmol, 1 equivalent) and NIS (46.97 mg, 208.78 μmol, 1.2 equivalents) in DMF (1.0 mL) was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 2 hours. The reaction mixture was diluted with saturated Na2SO3 (20 mL), filtered, and the title compound (30 mg, yield 36%) was obtained as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 8.53(s,1H),7.74(s,1H),6.95(s,1H),5.51-5.42(m,1H),5.01(t,J=6.8Hz,2H),4.64-4.51(m,2H),1.38(s,9H).

[0573] [ka]

[0574] To a solution of 3-(chloromethyl)oxetane (37.71 mg, 353.91 μmol, 1 equivalent) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (100 mg, 353.91 μmol, 1 equivalent) in 6-(tert-butylsulfonyl)-7-(oxetane-3-ylmethoxy was added Cs2CO3 (345.93 mg, 1.06 mmol, 3 equivalents). The mixture was stirred at 80°C for 12 hours, then diluted with H2O (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, DCM / MeOH = 100 / 1 to 100 / 10) to obtain the title compound (20 mg, yield 16%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H),8.00(s,1H),7.56(s,1H),7.20(s,1H),4.74-4.65(m,2H),4. 47(t,J=6.0Hz,2H),4.34(d,J=6.4Hz,2H),3.48-3.37(m,1H),1.31(s,9H).

[0575] 6-(tert-butylsulfonyl)-3-iodo-7-(oxetane-3-ylmethoxy)imidazo[1,2-a]pyridine: To a solution of 6-(tert-butylsulfonyl)-7-(oxetane-3-ylmethoxy)imidazo[1,2-a]pyridine (17 mg, 47.16 μmol, 1 equivalent) in DMF (0.5 mL), NIS (15.92 mg, 70.75 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 1 hour, then diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated Na2SO3 (4 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 95 / 5) to obtain the title compound (22 mg, 93% yield) as a yellow solid. 1H NMR 400MHz,DMSO-d6)δppm 8.50(s,1H),7.73(s,1H),7.34(s,1H),4.70(dd,J=2.0,6.0Hz,2H),4.47 (t,J=6.0Hz,2H),4.37(d,J=6.4Hz,2H),3.47-3.40(m,1H),1.32(s,9H).

[0576] [ka]

[0577] To a solution of 6-(tert-butylsulfonyl)-7-((3-methyloxetan-3-yl)methoxy)imidazo[1,2-a]pyridine:DMF (6 mL), 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (0.2 g, 707.81 μmol, 1 equivalent) was added to Cs2CO3 (691.86 mg, 2.12 mmol, 3 equivalents) and 3-(chloromethyl)-3-methyloxetane (93.88 mg, 778.59 μmol, 1.1 equivalents). The mixture was stirred at 80°C for 2 hours under an N2 atmosphere, then quenched with water (5 mL) at 25°C. The reaction mixture was then diluted with H2O (2 mL) and extracted with RINKAN (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 100 / 1~2 / 1) to obtain the title compound (140 mg, yield 53%) as a yellow solid. [M+H] + =339.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.17-9.12(m,1H),8.00(s,1H),7.56(d,J=1.2Hz,1H),7.20(s,1H),4.55 -4.49(m,2H),4.33-4.27(m,2H),4.22(s,2H),1.42(s,3H),1.31(s,9H).

[0578] 6-(tert-butylsulfonyl)-3-iodo-7-((3-methyloxetan-3-yl)methoxy)imidazo[1,2-a]pyridine: To a solution of 6-(tert-butylsulfonyl)-7-((3-methyloxetan-3-yl)methoxy)imidazo[1,2-a]pyridine (125 mg, 332.43 μmol, 1 equivalent) in DMF (1.5 mL), NIS (112.19 mg, 498.64 μmol, 1.5 equivalents) was added at 0°C. The mixture was stirred at 0°C for 2 hours under an N2 atmosphere, then quenched with saturated NaHCO3 (5 mL) at 25°C. The reaction mixture was then diluted with H2O (2 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 10 / 1) to obtain the title compound (0.16 g, 93% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.73(s,1H),7.34(s,1H),4.51(d,J=5.6Hz,2H),4.31(d,J=5.6Hz,2H),4.26(s,2H),1.43(s,3H),1.32(s,9H).

[0579] [ka]

[0580] 3-(((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)methyl)oxetan-3-ol: To a solution of (3-hydroxyoxetan-3-yl)methyl-4-methylbenzenesulfonate (457.05 mg, 1.59 mmol, 1.5 equivalents) in DMF (1 mL), Cs2CO3 (1.04 g, 3.19 mmol, 3 equivalents) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (300 mg, 1.06 mmol, 1 equivalent) were added. The mixture was stirred at 80°C for 2 hours and then partitioned between siRNA (30 mL) and H2O (10 mL). The organic phase was separated, washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, DCM / MeOH = 100 / 0~91 / 9) to obtain the title compound (50 mg, yield 12%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.15(s,1H),8.01(s,1H),7.56(s,1H),7.22(s,1H),5.96(s,1H),4.59(d,J=6.8Hz,2H),4.48(d,J=6.4Hz,2H),4.25(s,2H),1.32(s,9H).

[0581] 3-(((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)methyl)oxetan-3-ol: To a solution of 3-(((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)methyl)oxetan-3-ol (50 mg, 132.20 μmol, 1 equivalent) in DMF (1 mL), NIS (29.74 mg, 132.20 μmol, 1 equivalent) was added at 0°C. The mixture was stirred at 25°C for 1 hour, and then partitioned between ELISA (20 mL) and H2O (10 mL). The organic phase was separated, washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (45 mg, yield 66%) as a brown solid. 1H NMR(400MHz,DMSO-d6)δppm 8.51(s,1H),7.74(s,1H),7.36(s,1H),6.01(s,1H),4.58(d,J=6.8Hz,2H),4.49(d,J=6.4Hz,2H),4.29(s,2H),1.34(s,9H).

[0582] [ka]

[0583] (3-methoxyoxetan-3-yl)methylmethanesulfonate: To a solution of (3-methoxyoxetan-3-yl)methanol (500 mg, 4.23 mmol, 1 equivalent) in DCM (10 mL), Et3N (1.07 g, 10.58 mmol, 1.47 mL, 2.5 equivalents) and MsCl (727.27 mg, 6.35 mmol, 491.40 μL, 1.5 equivalents) were added at 0°C. The mixture was stirred at 25°C for 12 hours, then diluted with saturated NaHCO3 (50 mL) at 0°C and extracted with DCM (3 × 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (850 mg) as a yellow oil, which was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δppm 4.75(d,J=7.2Hz,2H),4.55(s,2H),4.44(d,J=7.2Hz,2H),3.40(s,3H),3.08(s,3H).

[0584] To a solution of (3-methoxyoxetan-3-yl)methylmethanesulfonate (850 mg, 4.33 mmol, 1 equivalent) in 6-(tert-butylsulfonyl)-7-((3-methoxyoxetan-3-yl)methoxy)imidazo[1,2-a]pyridine:DMF (15 mL), Cs2CO3 (4.23 g, 13.00 mmol, 3 equivalents) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (244.80 mg, 866.37 μmol, 0.2 equivalents) were added. The mixture was stirred at 60°C for 2 hours, then diluted with H2O (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 95 / 5) to obtain the title compound (200 mg, yield 12%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.15(s,1H),8.01(d,J=0.4Hz,1H),7.56(s,1H),7.27(s,1H),4.61-4.57(m,2H),4.55-4.52(m,2H),4.43(s,2H),3.29(s,3H),1.31(s,9H).

[0585] 6-(tert-butylsulfonyl)-3-iodo-7-((3-methoxyoxetan-3-yl)methoxy)imidazo[1,2-a]pyridine: To a solution of 6-(tert-butylsulfonyl)-7-((3-methoxyoxetan-3-yl)methoxy)imidazo[1,2-a]pyridine (200 mg, 507.87 μmol, 1 equivalent) in DMF (5 mL), NIS (171.39 mg, 761.81 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 2 hours, then quenched with saturated Na₂SO₃ (5 mL) and extracted with ELISA (3 × 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (100 mg) as a yellow solid, which was used in the next step without further purification. 1H NMR(400MHz,DMSO-d6)δppm 8.51(s,1H),7.74(s,1H),7.41(s,1H),4.62-4.58(m,2H),4.54-4.51(m,2H),4.47(s,2H),3.29(s,3H),1.33(s,9H).

[0586] [ka]

[0587] 1-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)-2-methylpropan-2-ol: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (200 mg, 707.81 μmol, 1 equivalent) in DMF (4 mL), K2CO3 (293.47 mg, 2.12 mmol, 3 equivalents) and 2,2-dimethyloxirane (61.24 mg, 849.37 μmol, 75.42 μL, 1.2 equivalents) were added. The mixture was stirred at 100°C for 12 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1~20 / 1) to obtain the title compound (17 mg, yield 7%) as a yellow solid. [M+H] + =327.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H),7.99(d,J=0.8Hz,1H),7.54(d,J=1.6Hz,1H),7.11(s,1H),4.51(s,1H),3.86(s,2H),1.33(s,9H),1.25(s,6H).

[0588] 1-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)-2-methylpropan-2-ol: To a solution of 1-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)-2-methylpropan-2-ol (30 mg, 91.91 μmol, 1 equivalent) in MeOH (2 mL) and H2O (0.5 mL), NIS (31.02 mg, 137.86 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 2 hours, then quenched with saturated Na2SO3 (5 mL) at 0°C, and subsequently extracted with ELISA (3 × 20 mL). The combined organic layers were washed with saturated NaHCO3 (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (30 mg, 65% yield) as a yellow solid, which was used in the next step without purification. [M+H] + =452.8. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.72(s,1H),7.25(s,1H),4.54(s,1H),3.89(s,2H),1.34(s,9H),1.25(s,6H).

[0589] [ka]

[0590] 3-(2-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)ethyl)oxazolidine-2-one: To a solution of 3-(2-chloroethyl)oxazolidine-2-one (150 mg, 902.56 μmol, 1 equivalent) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (255.03 mg, 902.56 μmol, 1 equivalent) in MeCN (10 mL), Cs2CO3 (588.14 mg, 1.81 mmol, 2.0 equivalents) was added. The mixture was stirred at 80°C for 12 hours, then diluted with H2O (20 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM:MeOH = 1 / 0 to 10 / 1) to obtain the title compound (50 mg, yield 15%) as a yellow oil. [M+H] + =368.1.

[0591] 3-(2-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)ethyl)oxazolidine-2-one (40 mg, 108.87 μmol, 1 equivalent) was dissolved in DMF (1.0 mL) and NIS (19.59 mg, 87.09 μmol, 0.8 equivalents) was added. The mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM: MeOH = 1 / 0~10 / 1) to obtain the title compound (30 mg, yield 25%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.74(s,1H),7.35(s,1H),4.30(t,J=5.2Hz,2H),4.28-4.22(m,2H),3.74-3.68(m,2H),3.60-3.56(m,2H),1.33(s,9H).

[0592] [ka]

[0593] (S)-1-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)propan-2-ol: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (200 mg, 707.81 μmol, 1 equivalent) and (S)-2-(benzyloxy)propan-1-ol (352.95 mg, 2.12 mmol, 3 equivalents) in toluene (1 mL), PPh3 (371.30 mg, 1.42 mmol, 2 equivalents) and DIAD (286.25 mg, 1.42 mmol, 274.45 μL, 2 equivalents) were added. The mixture was stirred at 20°C for 2 hours, then diluted with H2O (20 mL) and extracted with SiO (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 10 / 1 to 0 / 1) to obtain the title compound (80 mg, yield 27%) as a yellow solid. [M+H] + =403.1.

[0594] (S)-1-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)propan-2-ol: A solution of (S)-7-(2-(benzyloxy)propoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine (70 mg, 165.21 μmol, 1 equivalent) in DMF (1 mL) was mixed with NIS (40.89 mg, 181.74 μmol, 1.1 equivalents). The mixture was stirred at 20°C for 1 hour, then diluted with H2O (20 mL) and extracted with SiO (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 10 / 1 to 0 / 1) to obtain the title compound (30 mg, yield 31%) as a white solid. 1H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.73(s,1H),7.64-7.53(m,1H),7.38-7.22(m,5H),4.65-4. 57(m,2H),4.18(d,J=4.4Hz,2H),3.98-3.88(m,1H),1.32-1.26(m,12H).

[0595] [ka]

[0596] (R)-1-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)propan-2-ol: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (200 mg, 707.81 μmol, 1 equivalent) and (R)-2-(benzyloxy)propan-1-ol (352.95 mg, 2.12 mmol, 3 equivalents) in toluene (5 mL), CMBP (1.02 g, 4.25 mmol, 6 equivalents) was added. The mixture was stirred at 100 °C for 1 hour, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, siRNA / petroleum ether 0-70%) to obtain the title compound (340 mg, yield 72%) as a brown solid. [M+H] + =403.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H),8.00(s,1H),7.55(d,J=1.2Hz,1H),7.39-7.25(m,4H),7.33-7.21(m,1H), 7.16(s,1H),4.62(s,2H),4.14(d,J=4.0Hz,2H),3.98-3.83(m,1H),1.31-1.27(m,12H).

[0597] (R)-1-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)propan-2-ol: To a solution of (R)-7-(2-(benzyloxy)propoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine (330 mg, 491.92 μmol, 1 equivalent) in methanol (5 mL), NIS (166.01 mg, 737.88 μmol, 1.5 equivalents) and H2O (3 mL) were added. The mixture was stirred at 25°C for 1 hour, then concentrated, diluted with water (30 mL), and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain a residue. This residue was purified by column chromatography (SiO2, siRNA / petroleum ether 0-70%) to obtain the title compound (170 mg, yield 59%) as a yellow solid. [M+H] + =528.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.72(s,1H),7.39-7.22(m,6H),4.63-4.58(m,2H),4.18(d,J=4.8Hz,2H),3.99-3.86(m,1H),1.36-1.24(m,12H).

[0598] [ka]

[0599] (S)-4-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)butan-2-ol: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (100 mg, 353.91 μmol, 1 equivalent) in toluene (1 mL), (S)-butan-1,3-diol (95.68 mg, 1.06 mmol, 3 equivalents), PPh3 (185.65 mg, 707.81 μmol, 2 equivalents), and DIAD (143.13 mg, 707.81 μmol, 137.22 μL, 2 equivalents) were added. The mixture was stirred at 25°C for 12 hours, then filtered and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (50 mg, yield 39%) as a dark brown solid. [M+H] + =327.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.12(s,1H),7.98(s,1H),7.53(d,J=1.2Hz,1H),7.11(s,1H),4.55(d,J=4.4Hz,1H),4.2 5-4.06(m,2H),3.93-3.81(m,1H),1.85-1.73(m,2H),1.31(s,9H),1.12(d,J=6.0Hz,3H).

[0600] (S)-4-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)butan-2-ol: To a solution of (S)-4-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)butan-2-ol (50 mg, 137.86 μmol, 1 equivalent) in DMF (3 mL), NIS (31.02 mg, 137.86 μmol, 1 equivalent) was added. The mixture was stirred at 25°C for 2 hours, then diluted with H2O (10 mL) and extracted with SiO (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~10 / 1) to obtain the title compound (30 mg, yield 43%) as a yellow solid. [M+H]+ =452.8. 1 H NMR(400MHz,CDCl3)δppm 8.49(s,1H),7.71(s,1H),7.25(s,1H),4.57(d,J=4.8Hz,1H),4.25-4.12(m,2 H),3.96-3.78(m,1H),1.84-1.74(m,2H),1.33(s,9H),1.12(d,J=6.0Hz,3H).

[0601] [ka]

[0602] (R)-4-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)butan-2-ol: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (300 mg, 1.06 mmol, 1 equivalent) in toluene (12 mL), DIAD (429.38 mg, 2.12 mmol, 411.67 μL, 2 equivalents), PPh3 (556.95 mg, 2.12 mmol, 2 equivalents), and (R)-butan-1,3-diol (191.37 mg, 2.12 mmol, 2 equivalents) were added. The mixture was stirred at 25°C under an N2 atmosphere for 12 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the title compound (90 mg, yield 23%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.12(s,1H),7.98(s,1H),7.54(d,J=1.2Hz,1H),7.11(s,1H),4.55(d,J=4.8Hz,1H),4.2 3-4.09(m,2H),3.93-3.83(m,1H),1.86-1.71(m,2H),1.31(s,9H),1.12(d,J=6.4Hz,3H).

[0603] (R)-4-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)butan-2-ol: To a solution of (R)-4-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)butan-2-ol (90 mg, 248.15 μmol, 1 equivalent) in DMF (3 mL), NIS (83.74 mg, 372.23 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 3 hours, then diluted with saturated Na2SO3 (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated NaHCO3 (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 10 / 1) to obtain the title compound (65 mg, yield 52%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.72(s,1H),7.25(s,1H),4.57(d,J=4.8Hz,1H),4.31-4.10(m,2 H),3.94-3.82(m,1H),1.85-1.73(m,2H),1.33(s,9H),1.12(d,J=6.0Hz,3H).

[0604] [ka]

[0605] 3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)-2-methylpropan-1-ol: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (200 mg, 786.46 μmol, 1 equivalent), 3-(benzyloxy)-2-methylpropan-1-ol (155.93 mg, 865.10 μmol, 1.1 equivalents), and PPh3 (412.55 mg, 1.57 mmol, 2 equivalents) in toluene (5 mL), DIAD (318.06 mg, 1.57 mmol, 304.94 μL, 2 equivalents) was added, and the mixture was stirred at 100 °C for 12 hours. Water (80 mL) was added, and then the mixture was extracted with SiO2 (2 × 80 mL). The combined organic layers were washed with brine (2 × 80 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography (SiO₂, siRNA / petroleum ether = 0-1 / 0) to obtain the title compound (250 mg, 50% yield) as a brown solid. [M+H] + =417.1.

[0606] A solution of 3-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)-2-methylpropan-1-ol (240 mg, 374.52 μmol, 1 equivalent) and NIS (101.11 mg, 449.42 μmol, 1.2 equivalents) in DMF (2 mL) was stirred at 15°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, SiO2 / petroleum ether = 0-1 / 1) to obtain the title compound (170 mg, yield 75%) as a yellow solid. 1H NMR(400MHz,CDCl3)δppm 8.67(s,1H),7.65(s,1H),7.32(d,J=4.4Hz,4H),7.26-7.20(m,1H),7.10(s,1H),4.53(s,2H),4.24-4.13 (m,1H),4.10-3.99(m,1H),3.57(d,J=6.4Hz,2H),2.42-2.31(m,1H),1.41(s,9H),1.16(d,J=6.8Hz,3H).

[0607] [ka]

[0608] To a solution of 1-(2-chloroethyl)-1H-pyrazole (90.11 mg, 690.12 μmol, 1.3 equivalents) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (150 mg, 530.86 μmol, 1 equivalent) in 7-(2-(1H-pyrazole-1-yl)ethoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (2 mL) of 7-(2H-pyrazole-1-yl)ethoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (150 mg, 530.86 μmol, 1 equivalent), Cs2CO3 (518.89 mg, 1.59 mmol, 3 equivalents) was added. The mixture was stirred at 80°C for 12 hours, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH = 1:0~10:1) to obtain the title compound (80 mg) as a white solid, which was used in the next step without further purification.

[0609] 7-(2-(1H-pyrazole-1-yl)ethoxy)-6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine (64.00 mg, 183.69 μmol, 1 equivalent) in MeOH (5 mL) was mixed with NIS (82.65 mg, 367.37 μmol, 2 equivalents). The mixture was stirred at 0°C for 2 hours, then quenched with saturated Na2SO3 (20 mL) at 0°C, and subsequently extracted with ELISA (60 mL). The combined organic layers were washed with saturated NaHCO3 (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (50 mg) as a yellow oil, which was used in the next step without further purification.

[0610] [ka]

[0611] To a solution of 6-(tert-butylsulfonyl)-7-((1-methyl-1H-pyrazole-3-yl)methoxy)imidazo[1,2-a]pyridine:MeCN (10 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (150 mg, 471.87 μmol, 1 equivalent) and 3-(chloromethyl)-1-methyl-1H-pyrazole (123.23 mg, 943.75 μmol, 2 equivalents), Cs2CO3 (461.24 mg, 1.42 mmol, 3 equivalents) was added. The mixture was stirred at 80°C for 4 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 20 / 1) to obtain the title compound (50 mg, yield 27%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H),7.99(s,1H),7.69(d,J=2.4Hz,1H),7.55(d,J=1.2Hz,1H),7 .30(s,1H),6.35(d,J=2.4Hz,1H),5.15(s,2H),3.84(s,3H),1.28(s,9H).

[0612] 6-(tert-butylsulfonyl)-3-iodo-7-((1-methyl-1H-pyrazole-3-yl)methoxy)imidazo[1,2-a]pyridine (50 mg, 129.15 μmol, 1 equivalent) in MeOH (1 mL) was mixed with NIS (43.59 mg, 193.73 μmol, 1.5 equivalents) at 0°C. The mixture was stirred at 25°C for 2 hours, then quenched with Na2SO3 (20 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with NaHCO3 (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (50 mg, 73% yield) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 8.51(s,1H),7.73(s,1H),7.70-7.68(m,1H),7.44(s,1H),6.35(d,J=2.4Hz,1H),5.19(s,2H),3.84(s,3H),1.29(s,9H).

[0613] [ka]

[0614] To a solution of 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (88.67 mg, 530.86 μmol, 1 equivalent) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (150 mg, 530.86 μmol, 1 equivalent) in 6-(tert-butylsulfonyl)-7-((1-methyl-1H-pyrazole-4-yl)methoxy) in6 mL), Cs2CO3 (518.89 mg, 1.59 mmol, 3 equivalents) was added. The mixture was stirred at 80°C for 12 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 10 / 1) to obtain the title compound (40 mg, yield 19%) as a yellow solid. [M+H] + =349.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.13(s,1H),7.99(s,1H),7.79(s,1H),7.55(d,J=1.2Hz,1H),7.50(s,1H),7.26(s,1H),5.10(s,2H),3.84(s,3H),1.27(s,9H).

[0615] 6-(tert-butylsulfonyl)-3-iodo-7-((1-methyl-1H-pyrazole-4-yl)methoxy)imidazo[1,2-a]pyridine (30 mg, 77.49 μmol, 1 equivalent) was dissolved in MeOH (4 mL) and H2O (1 mL), to which NIS (26.15 mg, 116.24 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 12 hours, then quenched with saturated Na2SO3 (20 mL) at 0°C, and subsequently extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (30 mg, 73% yield) as a white solid, which was used in the next step without further purification. [M+H] + =474.8. 1H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.80(s,1H),7.72(s,1H),7.51(s,1H),7.40(s,1H),5.14(s,2H),3.84(s,3H),1.29(s,9H).

[0616] [ka]

[0617] 5-Bromopyrazolo[1,5-a]pyridine-6-ol: To a solution of 5-bromo-6-methoxypyrazolo[1,5-a]pyridine (500 mg, 1.98 mmol, 1 equivalent) in DCE (8 mL), AlCl3 (1.32 g, 9.91 mmol, 541.53 μL, 5 equivalents) was added. The mixture was stirred at 80°C for 1 hour, then quenched with saturated Na2SO4 (5 mL), neutralized with saturated NaHCO3, and extracted with DCM (120 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (800 mg) as a dark brown solid. [M+H] + =214.8. 1 H NMR(400MHz,DMSO-d6)δppm 10.33(s,1H),8.21(s,1H),8.02(s,1H),7.83(d,J=1.6Hz,1H),6.47(d,J=2.0Hz,1H).

[0618] To a solution of 5-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazole[1,5-a]pyridine:DMF (5 mL), 400 mg, 1.88 mmol, 1 equivalent of 5-bromopyrazole[1,5-a]pyridine-6-ol was added. Cs2CO3 (1.84 g, 5.63 mmol, 3 equivalents) and 2-((tert-butyldimethylsilyl)oxy)ethane-1-ol (583.94 mg, 2.44 mmol, 1.3 equivalents) were added. The mixture was stirred at 80°C for 12 hours, then diluted with brine (20 mL) and extracted with RINKAN (140 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 10 / 1 to 4 / 1) to obtain the title compound (80 mg, yield 10%) as a pale yellow solid. [M+H] + =371.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.55(s,1H),8.09(s,1H),7.91(d,J=2.8Hz,1H),6.52(d,J=2.4Hz,1H),4.16(t,J=4.8Hz,2H),3.97(t,J=4.4Hz,2H),0.87(s,9H),0.09(s,6H).

[0619] 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(tert-butylthio)pyrazolo[1,5-a]pyridine:Dioxane (4 mL) containing 5-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazolo[1,5-a]pyridine (80 mg, 193.89 μmol, 1 equivalent), Pd(OAc)2(870 A mixture of 0.60 μg, 3.88 μmol, 0.02 equivalents of dppf (4.30 mg, 7.76 μmol, 0.04 equivalents) and t-BuONa (55.90 mg, 581.67 μmol, 3 equivalents) was degassed, purged three times with N2, and then 2-methylpropane-2-thiol (52.46 mg, 581.67 μmol, 65.49 μL, 3 equivalents) was added. The mixture was stirred at 90°C under an N2 atmosphere for 5 hours, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / Ã=20 / 1~5 / 1) to obtain the title compound (80 mg, yield 98%) as a yellow solid. [M+H] + =381.2. 1 H NMR(400MHz,DMSO-d6)δppm 8.43(s,1H),7.89(d,J=2.4Hz,1H),7.86(s,1H),6.59(d,J=2.4Hz,1H),4. 10-4.04(m,2H),3.99-3.93(m,2H),1.29(s,9H),0.88(s,9H),0.11(s,6H).

[0620] To a solution of 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(tert-butylthio)pyrazolo[1,5-a]pyridine (80 mg, 189.17 μmol, 1 equivalent) in 2-((5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridine (3 mL MeOH) and H2O (1 mL), Oxone® (174.44 mg, 283.75 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 12 hours, then filtered and concentrated to obtain the title compound (57 mg) as a yellow liquid, which was used directly in the next step. [M+H] + =299.0.

[0621] 2-((5-(tert-butylsulfonyl)-3-iodopyrazolo[1,5-a]pyridine-6-yl)oxy)ethane-1-ol: To a solution of 2-((5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridine-6-yl)oxy)ethane-1-ol (57 mg, 191.05 μmol, 1 equivalent) in H2O (1 mL), NIS (64.47 mg, 286.57 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 1 hour, then quenched with saturated Na2SO3 (10 mL) and extracted with ethyl acetate (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain the title compound (90 mg, yield 99%) as a white solid. [M+H] + =424.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.82(s,1H),8.22(s,1H),7.88(s,1H),4.82(t,J=5.6Hz,1H),4.14(t,J=5.2Hz,2H),3.75(q,J=5.2Hz,2H),1.33(s,9H).

[0622] [ka]

[0623] (S)-1-((5-bromopyrazolo[1,5-a]pyridine-6-yl)oxy)propan-2-ol: To a solution of 5-bromopyrazolo[1,5-a]pyridine-6-ol (600 mg, 2.82 mmol, 1 equivalent) in MeCN (10 mL), Cs2CO3 (2.75 g, 8.45 mmol, 3 equivalents) and (S)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (778.15 mg, 5.63 mmol, 2 equivalents) were added. The mixture was stirred at 25°C for 1 hour, then diluted with H2O (200 mL) and extracted with siRNA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (40 mg) as a yellow solid. [M+H]+ =272.9.

[0624] (S)-1-((5-(tert-butylthio)pyrazolo[1,5-a]pyridine-6-yl)oxy)propan-2-ol: (S)-1-((5-bromopyrazolo[1,5-a]pyridine-6-yl)oxy)propan-2-ol (40 mg, 147.54 μmol, 1 equivalent) and 2-methylpropan-2-thiol (12.67 mg, 140. A mixture of 43 μmol, 15.81 μL, 9.52 e-1 equivalents of Pd(OAc)2 (3.31 mg, 14.75 μmol, 0.1 equivalent), dppf (16.36 mg, 29.51 μmol, 0.2 equivalent), and t-BuONa (42.54 mg, 442.62 μmol, 3 equivalents) was degassed, purged three times with N2, and then stirred at 90°C under an N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 10 / 1 to 0 / 1) to obtain the title compound (35 mg, yield 76%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.42(s,1H),7.89(d,J=2.4Hz,1H),7.85(s,1H),6.59(s,1H),4.86-4.82(m,1H),4.0 5-3.98(m,1H),3.94-3.88(m,1H),3.83-3.77(m,1H),1.29(s,9H),1.23-1.19(m,3H).

[0625] (S)-1-((5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridine-6-yl)oxy)propan-2-ol: To a solution of (S)-1-((5-(tert-butylthio)pyrazolo[1,5-a]pyridine-6-yl)oxy)propan-2-ol (27.61 mg, 88.63 μmol, 1 equivalent) in EtOH (0.9 mL), Oxone® (81.73 mg, 132.94 μmol, 1.5 equivalents) and H2O (0.3 mL) were added. The mixture was stirred at 25°C for 4 hours, filtered, and concentrated under reduced pressure to obtain the title compound (30 mg) as a white solid. [M+H]+ =313.0.

[0626] (S)-1-((5-(tert-butylsulfonyl)-3-iodopyrazolo[1,5-a]pyridine-6-yl)oxy)propan-2-ol: To a solution of (S)-1-((5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridine-6-yl)oxy)propan-2-ol (30 mg, 96.04 μmol, 1 equivalent) in H2O (1 mL), NIS (32.41 mg, 144.05 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 2 hours, then diluted with H2O (20 mL) and extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 10 / 1 to 0 / 1) to obtain the title compound (20 mg, yield 38%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.80(s,1H),8.22(s,1H),7.87(s,1H),4.01-3.90(m,3H),1.33(s,9H),1.21-1.18(m,3H).

[0627] [ka]

[0628] (R)-7-((1-(benzyloxy)propan-2-yl)oxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (300 mg, 1.06 mmol, 1 equivalent) and (S)-1-(benzyloxy)propan-2-ol (176.47 mg, 1.06 mmol, 1 equivalent) in toluene (10 mL), PPh3 (556.96 mg, 2.12 mmol, 2.0 equivalent) and DIAD (429.38 mg, 2.12 mmol, 411.68 μL, 2.0 equivalent) were added. The mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / Â1 = 1 / 0 to 3 / 1) to obtain the title compound (100 mg, yield 21%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 9.13(s,1H),7.98(s,1H),7.66-7.63(m,1H),7.36-7.21(m,6H),4.98- 4.91(m,1H),4.60-4.49(m,2H),3.67-3.58(m,2H),1.33-1.26(m,12H).

[0629] (R)-7-((1-(benzyloxy)propan-2-yl)oxy)-6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine: To a solution of (R)-7-((1-(benzyloxy)propan-2-yl)oxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine (100 mg, 223.60 μmol, 1 equivalent) in DMF (3 mL), NIS (60.37 mg, 268.32 μmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 1 hour under an N2 atmosphere, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 / 0 to 1 / 1) to obtain the title compound (80 mg, yield 61%) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δppm 8.51(s,1H),7.71(s,1H),7.38(s,1H),7.33-7.22(m,5H),5.04-4.95(m,1H),4. 60-4.47(m,2H),3.65(d,J=4.8Hz,2H),1.35-1.31(m,9H),1.29(d,J=6.0Hz,3H).

[0630] [ka]

[0631] (S)-7-((1-(benzyloxy)propan-2-yl)oxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (300 mg, 1.06 mmol, 1 equivalent) in toluene (9 mL), (R)-1-(benzyloxy)propan-2-ol (529.42 mg, 3.19 mmol, 3 equivalents), DIAD (429.38 mg, 2.12 mmol, 411.67 μL, 2 equivalents), and PPh3 (556.95 mg, 2.12 mmol, 2 equivalents) were added. The mixture was stirred at 100°C for 12 hours, then concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 100 / 1 to 0 / 1) to obtain the title compound (120 mg, yield 22%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H),7.99(s,1H),7.39-7.19(m,7H),5.01-4.90(m,1H),4.60-4.52(m,2H),3.70-3.59(m,2H),1.32(s,9H),1.29(d,J=6.4Hz,3H).

[0632] (S)-7-((1-(benzyloxy)propan-2-yl)oxy)-6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine: To a solution of (S)-7-((1-(benzyloxy)propan-2-yl)oxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine (120 mg, 238.51 μmol, 1 equivalent) in DMF (2 mL), NIS (64.39 mg, 286.21 μmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 1 hour, then diluted with H2O (20 mL) and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 100 / 0~0 / 1) to obtain the title compound (60 mg, yield 43%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.51(s,1H),7.72(s,1H),7.38(s,1H),7.34-7.21(m,5H),5.05-4.94(m,1H), 4.63-4.46(m,2H),3.65(d,J=4.8Hz,2H),1.33(s,9H),1.29(d,J=6.0Hz,3H).

[0633] [ka]

[0634] 7-((1-(benzyloxy)cyclopropyl)methoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine: To a solution of (1-(benzyloxy)cyclopropyl)methanol (250 mg, 884.76 μmol, 1 equivalent) in THF (12.5 mL), 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (262.82 mg, 1.33 mmol, 1.5 equivalents) and PPh3 (464.12 mg, 1.77 mmol, 2 equivalents) were added. After purging the mixture three times with N2, DIAD (447.27 mg, 2.21 mmol, 428.83 μL, 2.5 equivalents) was slowly added. The resulting mixture was stirred under an N2 atmosphere at 25°C for 4 hours, then concentrated to obtain a residue, which was purified by RP-HPLC to obtain the title compound (180 mg, yield 44%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.15(s,1H),8.00(s,1H),7.55(s,1H),7.32-7.23(m,5H),7.15(s,1H),4. 72(s,2H),4.35(s,2H),1.35(s,9H),1.01-0.95(m,2H),0.84-0.77(m,2H).

[0635] 7-((1-(benzyloxy)cyclopropyl)methoxy)-6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine: To a solution of 7-((1-(benzyloxy)cyclopropyl)methoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine (180 mg, 390.82 μmol, 1 equivalent) in DMF (3 mL), NIS (105.51 mg, 468.98 μmol, 1.2 equivalents) was added. The reaction mixture was diluted with water (20 mL), extracted with DCM (3 x 10 mL), and then the combined organic layers were washed with saturated Na2SO3 (2 x 15 mL) and saturated NaHCO3 (2 x 10 mL). The combined organic layers were extracted with dimethylammonium phosphate (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (135 mg) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 8.52(s,1H),7.72(s,1H),7.32-7.21(m,6H),4.71(s,2H),4.38(s,2H),1.36(s,9H),1.03-0.96(m,2H),0.83-0.77(m,2H).

[0636] [ka]

[0637] To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yltrifluoromethanesulfonate:DCM (5 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (200 mg, 707.81 μmol, 1 equivalent), DMAP (86.47 mg, 707.81 μmol, 1 equivalent) and Et3N (214.87 mg, 2.12 mmol, 295.55 μL, 3 equivalents) were added at 0°C. After addition, the mixture was stirred at this temperature for 0.25 hours, and then Tf2O (399.40 mg, 1.42 mmol, 233.57 μL, 2 equivalents) was added dropwise at 0°C. The mixture was stirred at 20°C for 12 hours, then filtered and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-6% MeOH / DCM) to obtain the title compound (216 mg, yield 71%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.47(s,1H),8.31(s,1H),7.89(s,1H),7.85(s,1H),1.33(s,9H).

[0638] 6-(tert-butylsulfonyl)-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-a]pyridine:1,4-dioxane (3 mL) and H2O (0.75 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yltrifluoromethanesulfonate (120 mg, 279.53 μmol, 1 equivalent), 1-methyl-4-(4,4,5,5- A mixture of tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (69.79 mg, 335.43 μmol, 1.2 equivalents), Pd(dppf)Cl2 (20.45 mg, 27.95 μmol, 0.1 equivalent), and K2CO3 (115.90 mg, 838.58 μmol, 3 equivalents) was degassed, purged three times with N2, and then stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched with NH4Cl (10 mL) at 0°C, then diluted with HCl (10 mL), and extracted with HCl (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, 0-6% siRNA / petroleum ether) to obtain the title compound (65 mg, yield 66%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.38(s,1H),8.22(s,1H),7.95(s,1H),7.75(s,1H),7.65(s,1H),7.52(s,1H),3.88(s,3H),1.08(s,9H).

[0639] 6-(tert-butylsulfonyl)-3-iodo-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-a]pyridine (60 mg, 169.60 μmol, 1 equivalent) was dissolved in MeOH (2 mL) and NIS (76.32 mg, 339.20 μmol, 2 equivalents) was added. The mixture was stirred at 80°C for 12 hours, then quenched with Na2SO3 (10 mL) at 0°C, subsequently diluted with H2O (10 mL), and extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, 0-8% siRNA / petroleum ether) to obtain the title compound (30 mg, yield 36%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.79(s,1H),7.99(s,1H),7.94(s,1H),7.69(s,1H),7.63(s,1H),3.89(s,3H),1.10(s,9H).

[0640] [ka]

[0641] 6-(tert-butylsulfonyl)-7-(1-(2-methoxyethyl)-1H-pyrazole-4-yl)imidazo[1,2-a]pyridine:1,4-dioxane (3 mL) and H2O (0.3 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yltrifluoromethanesulfonate (150 mg, 310.59 μmol, 1 equivalent), 1-(2-methoxyethyl)-4- A mixture of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (234.91 mg, 931.76 μmol, 3 equivalents), K2CO3 (128.77 mg, 931.76 μmol, 3 equivalents), and Pd(dppf)Cl2 (45.45 mg, 62.12 μmol, 0.2 equivalents) was degassed, purged three times with N2, and then stirred at 80°C under an N2 atmosphere for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0~10 / 1) to obtain the title compound (100 mg, yield 80%) as a yellow solid. [M+H] + =363.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.38(s,1H),8.22(s,1H),8.00(s,1H),7.75(s,1H),7.68(s,1H),7.54(s,1 H),4.29(t,J=5.2Hz,2H),3.69(t,J=5.2Hz,2H),3.24(s,3H),1.07(s,9H).

[0642] 6-(tert-butylsulfonyl)-3-iodo-7-(1-(2-methoxyethyl)-1H-pyrazole-4-yl)imidazo[1,2-a]pyridine (90 mg, 223.48 μmol, 1 equivalent) was dissolved in 6-(tert-butylsulfonyl)-7-(1-(2-methoxyethyl)-1H-pyrazole-4-yl)imidazo[1,2-a]pyridine (2 mL) of MeOH, to which NIS (150.84 mg, 670.45 μmol, 3 equivalents) was added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0~10 / 1) to obtain the title compound (90 mg, yield 74%) as a white solid. [M+H] + =489.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.79(s,1H),8.04(s,1H),7.93(s,1H),7.72(s,1H),7.68-7.61(m,1H), 4.30(t,J=5.2Hz,2H),3.69(t,J=5.2Hz,2H),3.24(s,3H),1.07(s,9H).

[0643] [ka]

[0644] 6-(tert-butylsulfonyl)-7-(1-methyl-1H-pyrazole-3-yl)imidazo[1,2-a]pyridine:dioxane (3 mL) and H2O (0.75 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yltrifluoromethanesulfonate (100 mg, 232.94 μmol, 1 equivalent) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabol A mixture of loran-2-yl)-1H-pyrazole (96.93 mg, 465.88 μmol, 2 equivalents), K2CO3 (96.58 mg, 698.82 μmol, 3 equivalents), Pd2(dba)3 (21.33 mg, 23.29 μmol, 0.1 equivalent), and PCy3 (13.06 mg, 46.59 μmol, 15.10 μL, 0.2 equivalents) was degassed, purged three times with N2, and then stirred at 80°C under an N2 atmosphere for 12 hours. The reaction mixture was quenched with NH4Cl (10 mL) at 0°C, then diluted with H2O (10 mL), and extracted with HCl (3 × 10 mL). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-6% siRNA / petroleum ether) to obtain the title compound (260 mg, yield 73%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.38(s,1H),8.25(s,1H),7.78(s,1H),7.69(d,J=2.0Hz,1H),7.56(s,1H),6.56(d,J=2.0Hz,1H),3.88(s,3H),1.10(s,9H).

[0645] 6-(tert-butylsulfonyl)-3-iodo-7-(1-methyl-1H-pyrazole-3-yl)imidazo[1,2-a]pyridine (50 mg, 141.33 μmol, 1 equivalent) was dissolved in MeOH (2 mL) and H2O (0.5 mL), to which NIS (38.16 mg, 169.60 μmol, 1.2 equivalents) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with NH4Cl (10 mL) at 0°C, then diluted with H2O (10 mL), and extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, 0-6% siRNA / petroleum ether) to obtain the title compound (43 mg, yield 62%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.78(s,1H),7.97(s,1H),7.72(d,J=2.4Hz,1H),7.66(s,1H),6.61(d,J=2.0Hz,1H),3.89(s,3H),1.11(s,9H).

[0646] [ka]

[0647] 6-(tert-butylsulfonyl)-7-(1H-pyrazole-4-yl)imidazo[1,2-a]pyridine:dioxane (2.4 mL) and H2O (0.6 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yltrifluoromethanesulfonate (200 mg, 465.88 μmol, 1 equivalent) and tert-butyl4-(4,4,5,5-tetramethyl A mixture of -1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (274.08 mg, 931.76 μmol, 2 equivalents), K3PO4 (296.67 mg, 1.40 mmol, 3 equivalents), and Pd(dtbpf)Cl2 (30.36 mg, 46.59 μmol, 0.1 equivalent) was degassed, purged with N2, and then stirred at 80°C under an N2 atmosphere for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 99 / 1 to 90 / 10) to obtain the title compound (100 mg, yield 56%) as a yellow solid. [M+H] + =305.2. 1 H NMR(400MHz,DMSO-d6)δppm 13.06-12.86(m,1H),9.39(s,1H),8.22(s,1H),7.98(s,1H),7.75(s,1H),7.72(s,1H),7.54(s,1H),1.05(s,9H).

[0648] 6-(tert-butylsulfonyl)-3-iodo-7-(1H-pyrazole-4-yl)imidazo[1,2-a]pyridine: A mixture of 6-(tert-butylsulfonyl)-7-(1H-pyrazole-4-yl)imidazo[1,2-a]pyridine (50 mg, 131.42 μmol, 1 equivalent) in MeOH (1.2 mL) and H2O (0.4 mL) was mixed with NIS (44.35 mg, 197.13 μmol, 1.5 equivalents) at 0°C. The mixture was then stirred at 20°C for 1 hour, diluted with saturated NaHCO3 (10 mL), and extracted with DCM (3 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 / 0 to 0 / 1) to obtain the title compound (35 mg, yield 56%) as a yellow solid. 1 H NMR(400MHz,CD3OD)δppm 8.98(s,1H),8.05(s,1H),7.87(s,1H),7.84(s,1H),7.62(s,1H),1.15(s,9H).

[0649] [ka]

[0650] 6-(tert-butylsulfonyl)-7-(1H-pyrazole-3-yl)imidazo[1,2-a]pyridine:1,4-dioxane (4 mL) and H2O (1 mL) containing 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yltrifluoromethanesulfonate (400 mg, 931.76 μmol, 1 equivalent), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 A mixture of -yl)-1H-pyrazole (401.77 mg, 1.86 mmol, 2 equivalents), Pd2(dba)3 (85.32 mg, 93.18 μmol, 0.1 equivalent), PCy3 (261.29 mg, 931.76 μmol, 302.07 μL, 1 equivalent), and K2CO3 (386.32 mg, 2.80 mmol, 3 equivalents) was degassed, purged three times with N2, and then stirred at 100°C for 2 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC to obtain the title compound (80 mg, yield 28%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 13.03-12.92(m,1H),9.39(s,1H),8.26(s,1H),7.78(s,1H),7.75(s,1H),7.73(s,1H),7.57(s,1H),6.61(s,1H),1.08(s,9H).

[0651] To a solution of 6-(tert-butylsulfonyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)imidazo[1,2-a]pyridine (130 mg, 427.12 μmol, 1 equivalent) in THF (10 mL), TsOH (110.33 mg, 640.67 μmol, 1.5 equivalents) and DHP (179.64 mg, 2.14 mmol, 195.26 μL, 5 equivalents) were added. The mixture was stirred at 80°C for 2 hours, then concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~95 / 5) to obtain the title compound (70 mg, yield 34%) as a white solid. 1H NMR(400MHz,CDCl3)δppm 9.00(s,1H),7.86(s,1H),7.81(d,J=1.2Hz,1H),7.74(s,1H),7.62(d,J=2.4Hz,1H),6.82(d,J=2.4Hz,1H),5.43(dd,J=8. 8,2.8Hz,1H),4.10-4.04(m,1H),3.75-3.71(m,1H),2.10-2.05(m,2H),1.64-1.62(m,2H),1.56-1.53(m,2H),1.18(s,9H).

[0652] 6-(tert-butylsulfonyl)-3-iodo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)imidazo[1,2-a]pyridine: To a solution of 6-(tert-butylsulfonyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)imidazo[1,2-a]pyridine (70 mg, 144.15 μmol, 1 equivalent) in DMF (1 mL), NIS (162.16 mg, 720.75 μmol, 5 equivalents) was added at 0°C. The mixture was stirred at 0°C for 1 hour, then diluted with H2O (30 mL) and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~9 / 1) to obtain the title compound (60 mg, yield 73%) as a white solid. 1 H NMR(400MHz,CDCl3)δppm 8.95(s,1H),7.92(s,1H),7.87(s,1H),7.63(d,J=2.4Hz,1H),6.84(d,J=2.4Hz,1H),5.44(dd,J=8.8,2.8Hz,1H ),4.14-4.03(m,1H),3.76-3.71(m,1H),2.13-2.07(m,2H),1.72-1.69(m,2H),1.65-1.61(m,2H),1.19(s,9H).

[0653] [ka]

[0654] Methyl 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-carboxylate: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridin-7-yl trifluoromethanesulfonate (510 mg, 1.19 mmol, 1 eq) in MeOH (15 mL) were added Pd(dppf)Cl2 (86.93 mg, 118.80 μmol, 0.1 eq) and Et3N (360.63 mg, 3.56 mmol, 496.06 μL, 3 eq) under N2 atmosphere. The suspension was degassed and purged with CO three times. The mixture was stirred at 80 °C for 12 h under CO (40 Psi), then concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 1 / 0 to 0 / 1) to afford the title compound (220 mg, yield 56%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 3.81 (s, 9H), 1.35 (s, 9H).

[0655] 6-(tert-Butylsulfonyl)imidazo[1,2-a]pyridine-7-carboxylic acid: To a solution of methyl 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-carboxylate (220 mg, 668.15 μmol, 1 eq) in MeOH (4 mL) and H2O (1 mL) was added LiOH·H2O (280. — 38 mg, 6.68 mmol, 10 eq). The mixture was stirred at 50 °C for 12 h, then concentrated under reduced pressure to give a residue, which was purified by RP-HPLC to afford the title compound (170 mg, yield 81%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (s, 1H), 8.07 (s, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.12 (s, 1H), 1.33 (s, 9H).

[0656] To a solution of 6-(tert-butylsulfonyl)-N,N-dimethylimidazo[1,2-a]pyridine-7-carboxamide (DMF) (2 mL), 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-carboxylic acid (80 mg, 255.03 μmol, 1 equivalent) was added: HATU (116.37 mg, 306.04 μmol, 1.2 equivalents), DIEA (98.88 mg, 765.10 μmol, 133.27 μL, 3 equivalents), and Me2NH·HCl (24.96 mg, 306.04 μmol, 1.2 equivalents). The mixture was stirred at 25°C for 2 hours and then quenched with H2O (1 mL). The title compound (55 mg, 63% yield) was obtained as a white solid by purification of the mixture by RP-HPLC. 1 H NMR(400MHz,DMSO-d6)δppm 9.34(s,1H),8.23(s,1H),7.80(s,1H),7.55(s,1H),2.94(s,3H),2.70(s,3H),1.31(m,9H).

[0657] 6-(tert-butylsulfonyl)-3-iodo-N,N-dimethylimidazo[1,2-a]pyridine-7-carboxamide: To a solution of 6-(tert-butylsulfonyl)-N,N-dimethylimidazo[1,2-a]pyridine-7-carboxamide (50 mg, 145.45 μmol, 1 equivalent) in MeOH (2 mL) and H2O (2 mL), NIS (654.48 mg, 2.91 mmol, 20 equivalents) was added. The mixture was stirred at 25°C for 2 hours, then diluted with H2O (10 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 / 0 to 0 / 1) to obtain the title compound (60 mg, yield 85%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.55(s,1H),7.98(s,1H),7.66(s,1H),2.95(s,3H),2.69(s,3H),1.33(s,9H).

[0658] [ka]

[0659] 6-(tert-butylsulfonyl)-N-(2-hydroxyethyl)imidazo[1,2-a]pyridine-7-carboxamide: To a solution of 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-carboxylic acid (70 mg, 223.15 μmol, 1 equivalent) and 2-aminoethane-1-ol (16.36 mg, 267.79 μmol, 16.16 μL, 1.2 equivalents) in DMF (2 mL), HATU (169.70 mg, 446.31 μmol, 2 equivalents) and DIEA (43.26 mg, 334.73 μmol, 58.30 μL, 1.5 equivalents) were added. After stirring the mixture at 20°C for 1 hour, it was purified by RP-HPLC to obtain the title compound (17 mg, yield 21%) as a white solid. [M+H] + =326.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.29(s,1H),8.33-8.25(m,1H),8.23(s,1H),7.80(s,1H),7.61(s,1H),4 .70-4.54(m,1H),3.54-3.46(m,2H),3.26(d,J=6.0Hz,2H),1.34(s,9H).

[0660] 6-(tert-butylsulfonyl)-N-(2-hydroxyethyl)-3-iodoimidazo[1,2-a]pyridine-7-carboxamide: To a solution of 6-(tert-butylsulfonyl)-N-(2-hydroxyethyl)imidazo[1,2-a]pyridine-7-carboxamide (15 mg, 41.49 μmol, 1 equivalent) in MeOH (1.2 mL) and H2O (0.4 mL), NIS (93.35 mg, 414.90 μmol, 10 equivalents) was added at 0°C. The mixture was stirred at 0°C for 1 hour, then diluted with saturated NaHCO3 (3 mL) and extracted with ELISA (3 × 10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (30 mg) as a yellow solid, which was used in the next step without purification. 11H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (s, 1H), 8.33 (t, J = 5.2 Hz, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 4.66 (t, J = 6.0 Hz, 1H), 3.55 - 3.46 (m, 2H), 3.31 - 3.21 (m, 2H), 1.35 (s, 9H).

[0661]

Chem.

[0662] (6-Bromoimidazo[1,2-a]pyridin-7-yl)methanol: A mixture of methyl 6-bromoimidazo[1,2-a]pyridine-7-carboxylate (1 g, 3.53 mmol, 1 eq) in EtOH (10 mL) was degassed and purged three times with N2, then NaBH4 (400.47 mg, 10.59 mmol, 3 eq) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 2 h under a N2 atmosphere, then quenched with 1 N HCl (1 mL) at 0 °C, then diluted with H2O (15 mL) and extracted with EtOAc (×3 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (590 mg, 66% yield) as a white solid, which was used in the next step without purification. [M+H] + = 226.9. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1H), 7.87 (s, 1H), 7.61 - 7.54 (m, 2H), 5.60 (t, J = 5.6 Hz, 1H), 4.55 - 4.49 (m, 2H).

[0663] To a solution of (6-bromoimidazo[1,2-a]pyridin-7-yl)methanol (590 mg, 2.34 mmol, 1 equivalent) in 6-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridin-7-yl)methanol (10 mL) of 6-bromoimidazo:DCM (10 mL), TBSCl (384.20 mg, 2.55 mmol, 313.64 μL, 1.09 equivalents) and imidazole (191.05 mg, 2.81 mmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 20°C for 2 hours, then diluted with H2O (10 mL) and extracted with DCM (3 × 20 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 / 0 to 1 / 1) to obtain the title compound (800 mg, 90% yield) as a white solid. [M+H] + =340.8. 1 H NMR(400MHz,DMSO-d6)δppm 8.94(s,1H),7.89(s,1H),7.61-7.51(m,2H),4.71(s,2H),0.95(s,9H),0.14(s,6H).

[0664] 7-(((tert-butyldimethylsilyl)oxy)methyl)-6-(tert-butylthio)imidazo[1,2-a]pyridine:dioxane (30 mL) contains 6-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[1,2-a]pyridine (300 mg, 791.05 μmol, 1 equivalent), 2-methylpropane-2-thiol (356.71 mg, A mixture of 3.96 mmol, 445.33 μL, 5 equivalents, dppf (87.71 mg, 158.21 μmol, 0.2 equivalents), Pd(OAc)2 (17.76 mg, 79.11 μmol, 0.1 equivalent), and t-BuONa (228.07 mg, 2.37 mmol, 3 equivalents) was degassed, purged three times with N2 at 20°C, and then stirred at 110°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 / 0~0 / 1) to obtain the title compound (193 mg, yield 62%) as a yellow oil. [M+H]+ =351.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.75(s,1H),7.97(s,1H),7.60-7.50(m,2H),4.86(s,2H),1.27(s,9H),0.95(s,9H),0.13(s,6H).

[0665] To a solution of 7-(((tert-butyldimethylsilyl)oxy)methyl)-6-(tert-butylthio)imidazo[1,2-a]pyridine (193 mg, 495.45 μmol, 1 equivalent) in (6 mL)methanol:MeOH, Oxone® (456.87 mg, 743.17 μmol, 1.5 equivalents) was added. The mixture was stirred at 20°C for 2 hours, then concentrated to obtain the title compound (180 mg) as a yellow liquid, which was used in the next step without purification. [M+H] + =268.9.

[0666] (6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridin-7-yl)methanol: To a solution of (6-(tert-butylsulfonyl)imidazo[1,2-a]pyridin-7-yl)methanol (180 mg, 670.81 μmol, 1 equivalent) in H2O (2 mL), NIS (226.38 mg, 1.01 mmol, 1.5 equivalents) was added at 0°C. The mixture was stirred at 20°C for 1 hour, and then partitioned between H2O (5 mL) and DCM (3 × 10 mL). The organic phase was separated, washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 / 0 to 0 / 1) to obtain the title compound (135 mg, yield 51%) as a white solid. [M+H] + =394.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.51(s,1H),7.92-7.83(m,2H),5.64(t,J=5.6Hz,1H),4.89-4.83(m,2H),1.32(s,9H).

[0667] [ka]

[0668] To a solution of 5-bromo-4-methoxypyridine-2-amine (500 mg, 2.46 mmol, 1 equivalent) in methyl 6-bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate:EtOH (50 mL), Na2CO3 (783.03 mg, 7.39 mmol, 3 equivalents) and methyl 3-bromo-2-oxopropanoate (891.39 mg, 4.93 mmol, 524.35 μL, 2 equivalents) were added. The mixture was stirred at 80°C for 12 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~92 / 8) to obtain the title compound (560 mg, yield 36%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.91(s,1H),8.30(s,1H),7.10(s,1H),3.93(s,3H),3.82(s,3H).

[0669] 2-methylpropane-2-thiol (239.15 mg, 2.65 mmol, 298.57 μL, 1.5 equivalents) and methyl 6-bromo-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (5) in 1,4-dioxane (30 mL). A mixture of 60 mg (1.77 mmol, 1 equivalent), Pd2(dba)3 (161.88 mg, 176.78 μmol, 0.1 equivalent), xanthophos (204.58 mg, 353.57 μmol, 0.2 equivalents), and K2CO3 (732.98 mg, 5.30 mmol, 3 equivalents) was degassed, purged three times with N2, and then stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1:0~10:1) to obtain the title compound (510 mg, yield 78%) as a yellow solid. [M+H] +=295.0.

[0670] Methyl 6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-2-carboxylate (510 mg, 1.39 mmol, 1 equivalent) and Oxone® (2.56 g, 4.16 mmol, 3 equivalents) in H2O (5 mL) and MeOH (15 mL) were stirred at 25°C for 12 hours under an N2 atmosphere. The mixture was then filtered and concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (20 mL), extracted with DCM (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 1:0 to 10:1) to obtain the title compound (380 mg, yield 76%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.19(s,1H),8.57(s,1H),7.16(s,1H),3.91(s,3H),3.84(s,3H),1.31(s,9H).

[0671] A mixture of methyl 6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid (380 mg, 1.05 mmol, 1 equivalent) and LiOH·H2O (439.74 mg, 10.48 mmol, 10 equivalents) in H2O (4 mL) and MeOH (16 mL) was stirred at 25°C for 1 hour under an N2 atmosphere. The mixture was concentrated under reduced pressure, the residue was dissolved in H2O (10 mL), the pH was adjusted to 5 with 1N HCl, and then filtered to obtain the title compound (240 mg, yield 66%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.17(s,1H),8.51(s,1H),7.14(s,1H),3.91(s,3H),1.31(s,9H).

[0672] tert-butyl(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-2-yl)carbamate: A mixture of 6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid (240 mg, 691.55 μmol, 1 equivalent), Et3N (83.97 mg, 829.86 μmol, 115.51 μL, 1.2 equivalents), and DPPA (228.38 mg, 829.86 μmol, 179.12 μL, 1.2 equivalents) in toluene (8 mL) and t-BuOH (8 mL) was degassed, purged three times with N2, and then stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 20 / 1) to obtain the title compound (140 mg, 48% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 10.12-9.79(m,1H),9.03(s,1H),7.84(s,1H),6.98(s,1H),3.86(s,3H),1.48(s,9H),1.28(s,9H).

[0673] To a mixture of tert-butyl(6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine-2-yl)carbamate (100 mg, 234.70 μmol, 1 equivalent) in DCM (10 mL), NIS (63.37 mg, 281.64 μmol, 1.2 equivalents) was added at 0°C. The mixture was degassed, purged three times with N2, and then stirred at 0°C under an N2 atmosphere for 0.5 hours. The reaction mixture was quenched with saturated Na2SO3 (10 mL), diluted with H2O (10 mL), extracted with DCM (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (120 mg, 90% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.23(s,1H),8.46(s,1H),7.18(s,1H),3.92(s,3H),1.46(s,9H),1.32(s,9H).

[0674] [ka]

[0675] 3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)-2,2-dimethylpropan-1-ol: To a solution of 2,2-dimethylpropan-1,3-diol (55.29 mg, 530.86 μmol, 1 equivalent) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (150 mg, 530.86 μmol, 1 equivalent) in toluene (3 mL), CMBP (384.37 mg, 1.59 mmol, 3 equivalents) was added. The mixture was stirred at 100°C for 2 hours under an N2 atmosphere, then diluted with water (3 mL) at 25°C, and subsequently extracted with  (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 95 / 5) to obtain the title compound (127 mg, yield 63%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.14-9.09(m,1H),7.98(s,1H),7.53(d,J=1.2Hz,1H),7.09(s,1H),4.55(t,J=5.2Hz 1H),3.84(s,2H),3.31(s,2H),1.31(s,9H),0.96(s,6H).

[0676] 3-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)-2,2-dimethylpropan-1-ol (100 mg, 264.37 μmol, 1 equivalent) was dissolved in DMF (2 mL) and NIS (89.22 mg, 396.55 μmol, 1.5 equivalents) was added. The mixture was stirred under an N2 atmosphere at 25°C for 2 hours, then quenched with saturated Na2SO3 (5 mL) at 25°C. The reaction mixture was then diluted with H2O (3 mL) and extracted with Depositphotos (3 × 10 mL). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (110 mg) as a yellow solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 8.47(s,1H),7.71(s,1H),7.24(s,1H),4.57(s,1H),3.88(s,2H),3.31-3.30(m,2H),1.33(s,9H),0.96(s,6H).

[0677] [ka]

[0678] 2-(((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)methyl)butan-1-ol: A mixture of 2-ethylpropane-1,3-diol (100 mg, 960.18 μmol, 1 equivalent), 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (271.31 mg, 960.18 μmol, 1 equivalent), and CMBP (695.22 mg, 2.88 mmol, 3 equivalents) in toluene (3 mL) was degassed, purged three times with N2, and then stirred at 100°C for 2 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 99 / 1~10 / 90) to obtain the title compound (110 mg, yield 24%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.12(s,1H),7.98(s,1H),7.53(s,1H),7.12(s,1H),4.49(t,J=5.2Hz,1H),4.06(d,J=5.6Hz,2H ),3.52(t,J=5.6Hz,2H),1.80-1.74(m,1H),1.60-1.59(m,2H),1.31(s,9H),0.91-0.89(m,3H).

[0679] A mixture of 2-(((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)methyl)butan-1-ol (100 mg, 205.62 μmol, 1 equivalent) and NIS (55.51 mg, 246.74 μmol, 1.2 equivalents) in DMF (2 mL) was stirred at 25°C for 1 hour. The mixture was then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 99 / 1~86 / 14) to obtain the title compound (70 mg, yield 66%) as a yellow solid. [M+H] + =466.9. 1H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.71(s,1H),7.27(s,1H),4.51(t,J=5.2Hz,1H),4.10-4.00(m,2H),3.52(t ,J=5.2Hz,2H),1.83-1.74(m,1H),1.49-1.43(m,2H),1.33(s,9H),0.91(t,J=7.2Hz,3H).

[0680] [ka]

[0681] (3-(((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)methyl)oxetan-3-yl)methanol: A solution of (3-(bromomethyl)oxetan-3-yl)methanol (200 mg, 1.10 mmol, 1.2 equivalents) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (260.15 mg, 920.67 μmol, 1 equivalent) in MeCN (1 mL) was mixed with Cs2CO3 (899.92 mg, 2.76 mmol, 3 equivalents). The mixture was stirred at 80°C for 2 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~10 / 1) to obtain the title compound (200 mg, yield 55%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.14(s,1H),8.00(s,1H),7.55(d,J=1.2Hz,1H),7.20(s,1H),4.96(t,J=5.6 Hz,1H),4.47-4.37(m,4H),4.30(s,2H),3.76(d,J=5.2Hz,2H),1.29(s,9H).

[0682] (3-(((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)methyl)oxetan-3-yl)methanol: To a solution of (3-(((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)methyl)oxetan-3-yl)methanol (10 mg, 279.33 μmol, 1 equivalent) in MeCN (5 mL), NIS (87.98 mg, 391.06 μmol, 1.4 equivalents) was added. The mixture was stirred at 20°C for 2 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~10 / 1) to obtain the title compound (120 mg, yield 81%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.73(s,1H),7.35(s,1H),4.98(t,J=5.6Hz,1H),4.44-4.40(m,4H),4.34(s,2H),3.76(d,J=5.2Hz,2H),1.31(s,9H).

[0683] [ka]

[0684] 3-((6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-yl)oxy)-2,2-difluoropropan-1-ol: A mixture of 2,2-difluoropropan-1,3-diol (594.96 mg, 5.31 mmol, 5 equivalents), 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (300 mg, 1.06 mmol, 1 equivalent), and CMBP (1.02 g, 4.25 mmol, 4 equivalents) in toluene (8 mL) was degassed, purged three times with N2, and then stirred at 100°C under an N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-100% siRNA / petroleum ether) to obtain the title compound (230 mg, yield 56%) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 9.17(s,1H),8.02(d,J=1.2Hz,1H),7.58(d,J=1.2Hz,1H),7.28(s,1H),5.6 0(t,J=6.4Hz,1H),4.44(t,J=12.0Hz,2H),3.91-3.79(m,2H),1.30(s,9H).

[0685] A mixture of 3-((6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine-7-yl)oxy)-2,2-difluoropropan-1-ol (150 mg, 387.52 μmol, 1 equivalent) and NIS (104.62 mg, 465.03 μmol, 1.2 equivalents) in MeCN (3 mL) was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (200 mg, yield 87%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.76(s,1H),7.42(s,1H),5.62(t,J=5.2Hz,1H),4.48(t,J=12.0Hz,2H),3.91-3.77(m,2H),1.32(s,9H).

[0686] [ka]

[0687] DIAD (153.01 mg, 756.67 μmol, 146.70 μL, 2 equivalents) and PPh3 (198.46 mg, 756.67 μmol, 2 equivalents) were added to a mixture of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (100 mg, 756.67 μmol, 93.81 μL, 2 equivalents) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (106.90 mg, 378.34 μmol, 1 equivalent) in toluene (2 mL). The mixture was stirred at 100°C under N2 for 12 hours, then diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extract was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain the title compound (25 mg, yield 16%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.13(s,1H),8.00(s,1H),7.55(s,1H),7.20(s,1H),4.41(t,J=5.6Hz,1H),4.17(d,J =5.2Hz,2H),4.12-4.03(m,1H),3.90-3.82(m,1H),1.37(s,3H),1.33-1.28(m,12H).

[0688] 6-(tert-butylsulfonyl)-7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-iodoimidazo[1,2-a]pyridine: To a solution of 6-(tert-butylsulfonyl)-7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine (25 mg, 61.07 μmol, 1 equivalent) in DMF (2 mL), NIS (16.49 mg, 73.28 μmol, 1.2 equivalents) was added. The mixture was stirred at 25°C for 2 hours, then quenched with saturated Na2SO3 (20 mL) at 0°C, and subsequently extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (30 mg, yield 89%) as a yellow solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.73(s,1H),7.34(s,1H),4.47-4.38(m,1H),4.21(d,J=4.0Hz,2H ),4.13-4.06(m,1H),3.89-3.81(m,1H),1.37(s,3H),1.33(s,9H),1.31(s,3H).

[0689] [ka]

[0690] To a solution of 2-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-2-methylpropanoic acid:MeCN (5 mL), 2-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-2-methylpropan-1-ol (100 mg, 219.39 μmol, 1 equivalent), NMO (231.55 μL, 2.19 mmol, 10 equivalents), TPAP (23.13 mg, 65.82 μmol, 0.3 equivalents), and H2O (39.53 mg, 2.19 mmol, 39.53 μL, 10 equivalents) were added. The mixture was stirred at 50°C for 2 hours. After 2 hours, the reaction mixture was concentrated under vacuum. The obtained crude material was purified by silica gel chromatography (DCM / MeOH = 1 / 0 to 1 / 1) to obtain the title compound as a dark brown solid.

[0691] To a solution of 2-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-2-methylpropanoic acid (25 mg, 53.04 μmol, 1 equivalent) in 5-(2-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-2-methylpropanoic acid (25 mg, 53.04 μmol, 1 equivalent) in 5-(2 mL)-DMF, CDI (43.00 mg, 265.20 μmol, 5 equivalents) was added at 25°C. The reaction mixture was stirred at room temperature for 1 hour, after which N-hydroxyacetamidine (7.86 mg, 106.08 μmol, 2 equivalents) was added. The resulting mixture was stirred at 80°C for 11 hours. The reaction mixture was quenched by adding H2O (0.5 mL). The obtained crude substance was purified by preparative HPLC (acidic conditions) to obtain the title compound as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.38(s,1H),8.25(s,0.5H),7.75(s,1H),7.20(s,1H),3.66(s,3H),2.34(s,3H),1.82(s,6H).

[0692] [ka]

[0693] 4-Methoxy-5-((1-methylcyclopropyl)sulfonyl)pyridine-2-amine: To a stirred solution of 5-bromo-4-methoxypyridine-2-amine (10 mg, 49.3 μmol, 1.0 equivalent) in DMF (0.5 mL), 1-methylcyclopropane-1-sulfinate sodium salt (17.5 mg, 123 μmol, 2.5 equivalents), CuI (1.88 mg, 10.0 μmol, 0.2 equivalents), and DMEDA (5.50 mg, 25.0 μmol, 0.5 equivalents) were added at room temperature. The reaction mixture was heated at 120 °C for 16 hours, filtered through Celite®, and rinsed with  (10 mL). The filtrate was evaporated under reduced pressure to obtain the title compound (10.0 mg, yield 84%) as a brownish viscous liquid. This compound was used directly in the next step without further purification. [M+H] + =243.1.

[0694] To an ice-cold solution of 4-methoxy-5-((1-methylcyclopropyl)sulfonyl)pyridine-2-amine (10 mg, 41.3 μmol, 1.0 equivalent) in 7-methoxy-6-((1-methylcyclopropyl)sulfonyl)imidazo[1,2-a]pyridine:EtOH (1 mL), 2-chloroacetaldehyde (16.1 mg, 207 μmol, 5.0 equivalent) was added at room temperature. The reaction mixture was stirred at 80°C for 16 hours, and then evaporated under reduced pressure to obtain the title compound (10.0 mg) as a brownish viscous liquid. The compound was used directly in the next step without further purification. [M+H] + =267.3.

[0695] 3-Iodo-7-methoxy-6-((1-methylcyclopropyl)sulfonyl)imidazo[1,2-a]pyridine: To a stirred solution of 7-methoxy-6-((1-methylcyclopropyl)sulfonyl)imidazo[1,2-a]pyridine (12.0 mg, 45.1 μmol, 1.0 equivalent) in acetic acid (1 mL), NIS (12.2 mg, 54.1 μmol, 1.2 equivalents) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour, then diluted with ice-cold water (2 mL) and extracted with ELISA (2 × 5 mL). The combined organic layers were washed with brine (1 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (15.0 mg) as a pale yellow solid. The compound was used directly in the next step without further purification. [M+H] + =393.1.

[0696] [ka]

[0697] A mixture of 6-iodo-7-methoxyimidazo[1,2-a]pyridine (500 mg, 2.20 mmol, 1 equivalent), 2-methylbutane-2-thiol (458.97 mg, 4.40 mmol, 2 equivalents), dppf (244.16 mg, 440.42 μmol, 0.2 equivalents), and t-BuONa (317.44 mg, 3.30 mmol, 1.5 equivalents) in 7-methoxy-6-(tert-pentylthio)imidazo[1,2-a]pyridine:dioxane (10 mL) was mixed with Pd(OAc)2 (49.44 mg, 220.21 μmol, 0.1 equivalents). The mixture was stirred at 90°C under N2 for 12 hours, then saturated NH4Cl (100 mL) was added, and the mixture was extracted with SiO2 (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, 0-8% MeOH / DCM) to obtain the title compound (410 mg, yield 52%) as a brown solid. [M+H] + =251.2. 1H NMR(400MHz,CDCl3)δppm 8.23(s,1H),7.48-7.36(m,2H),6.92(br s,1H),3.91(s,3H),1.56(q,J=7.6Hz,2H),1.23(s,6H),1.02(t,J=7.6Hz,3H)

[0698] 7-Methoxy-6-(tert-pentylsulfonyl)imidazo[1,2-a]pyridine: To a solution of 7-methoxy-6-(tert-pentylthio)imidazo[1,2-a]pyridine (300 mg, 838.80 μmol, 1 equivalent) in MeOH (6 mL) and H2O (2 mL), Oxone® (1.55 g, 2.52 mmol, 3 equivalents) was added, and the mixture was stirred at 15°C for 12 hours. The reaction mixture was used directly in the next step without post-treatment. The marked compound (230 mg, 68% yield) was obtained as a yellow liquid. [M+H] + =283.2.

[0699] 3-iodo-7-methoxy-6-(tert-pentylsulfonyl)imidazo[1,2-a]pyridine: To a mixture of 7-methoxy-6-(tert-pentylsulfonyl)imidazo[1,2-a]pyridine (230 mg, 570.20 μmol, 1 equivalent) in H2O (2 mL), NIS (192.43 mg, 855.30 μmol, 1.5 equivalents) was added, and the mixture was stirred at 15°C for 1 hour. Water (80 mL) was added, and the mixture was extracted with DCM (2 × 80 mL). The combined organic layers were washed with saturated Na2SO3 (2 × 80 mL) and brine (80 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-5% MeOH / DCM) to obtain the title compound (220 mg, yield 90%) as a white solid. [M+H] + =409.1. 1 H NMR(400MHz,CDCl3)δppm 8.70(s,1H),7.68(s,1H),7.13(s,1H),4.01(s,3H),1.83(q,J=7.6Hz,2H),1.38(s,6H),1.02(t,J=7.6Hz,3H).

[0700] [ka]

[0701] To a solution of 2,2-dimethylthiran (1.94 g, 22.03 mmol, 1.5 equivalents) in 2-methyl-1-(1H-pyrazole-1-yl)propane-2-thiol:DMF (20 mL), Cs2CO3 (14.36 g, 44.07 mmol, 3 equivalents) and 1H-pyrazole (1 g, 14.69 mmol, 1 equivalent) were added. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere, filtered, diluted with H2O (100 mL), and extracted with siRNA (3 × 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 100 / 0~4 / 1) to obtain the title compound (260 mg, yield 10%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δppm 7.51(d,J=1.6Hz,1H),7.42(d,J=2.4Hz,1H),6.26(t,J=1.6Hz,1H),4.21(s,2H),1.32(s,6H).

[0702] 7-Methoxy-6-((2-methyl-1-(1H-pyrazole-1-yl)propan-2-yl)thio)imidazo[1,2-a]pyridine:1,4-dioxane (4 mL) containing 2-methyl-1-(1H-pyrazole-1-yl)propan-2-thiol (100 mg, 576.01 μmol, 1 equivalent), 6-bromo-7-methoxyimidazo[1, 2-a] A mixture of pyridine (145.32 mg, 576.01 μmol, 1 equivalent), Pd2(dba)3 (105.49 mg, 115.20 μmol, 0.2 equivalents), K2CO3 (238.82 mg, 1.73 mmol, 3 equivalents), and xanthophos (133.32 mg, 230.40 μmol, 0.4 equivalents) was degassed and purged three times with N2. The mixture was stirred at 100°C under an N2 atmosphere for 12 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-5% MeOH / DCM) to obtain the title compound (115 mg, yield 59%) as a brown oil. 1 H NMR(400MHz,CDCl3)δppm 8.35(s,1H),7.57-7.48(m,3H),7.44(s,1H),6.94(s,1H),6.27(t,J=2.0Hz,1H),4.25(s,2H),3.93(s,3H),1.26(s,6H).

[0703] 7-methoxy-6-((2-methyl-1-(1H-pyrazole-1-yl)propan-2-yl)sulfonyl)imidazo[1,2-a]pyridine: To a mixture of 7-methoxy-6-((2-methyl-1-(1H-pyrazole-1-yl)propan-2-yl)thio)imidazo[1,2-a]pyridine (4 mL MeOH and 1 mL H2O), Oxone® (1.04 g, 1.70 mmol, 6 equivalents) was added. The mixture was stirred at 20°C for 2 hours, then diluted with H2O (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were washed with brine (2 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO₂, 0-15% MeOH / DCM) to obtain the title compound (85 mg, yield 76%) as a yellow oil. 1H NMR(400MHz,CDCl3))δppm 8.76(s,1H),7.64(s,1H),7.57(s,1H),7.46(d,J=2.4Hz,2H),7.08-6.9 8(m,1H),6.27(t,J=2.0Hz,1H),4.56(s,2H),3.98(s,3H),1.40(s,6H).

[0704] 3-Iodo-7-methoxy-6-((2-methyl-1-(1H-pyrazole-1-yl)propan-2-yl)sulfonyl)imidazo[1,2-a]pyridine: To a mixture of 7-methoxy-6-((2-methyl-1-(1H-pyrazole-1-yl)propan-2-yl)sulfonyl)imidazo[1,2-a]pyridine (80 mg, 191.39 μmol, 1 equivalent) in MeCN (8 mL), NIS (34.45 mg, 153.11 μmol, 0.8 equivalents) was added at 0°C. The mixture was stirred at 0°C for 2 hours, then diluted with H2O (10 mL) and extracted with DCM (3 × 20 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (80 mg) as a yellow solid, which was used in the next step without purification. 1 H NMR(400MHz,CDCl3)δppm 8.69(s,1H),7.68(s,1H),7.49-7.43(m,2H),7.08(s,1H),6.26(t,J=2.4Hz,1H),4.56(s,2H),4.00(s,3H),1.43(s,6H).

[0705] [ka]

[0706] A mixture of tert-butyl 4-((7-methoxyimidazo[1,2-a]pyridine-6-yl)thio)-4-methylpiperidine-1-carboxylate:dioxane (20 mL) containing tert-butyl ester (730 mg, 2.84 mmol, 1 equivalent), 6-iodo-7-methoxyimidazo[1,2-a]pyridine (864.74 mg, 2.84 mmol, 1 equivalent), DIPEA (1.10 g, 8.52 mmol, 1.48 mL, 3 equivalents), xanthophos (657.26 mg, 1.14 mmol, 0.4 equivalents), and Pd2(dba)3 (520.09 mg, 567.96 μmol, 0.2 equivalents) was degassed and purged with N2 (3×). The resulting reaction mixture was stirred at 100°C for 12 hours under an N2 atmosphere, then filtered and concentrated under vacuum. The resulting crude substance was purified by column chromatography (SiO2, Depositphotos) to obtain the title compound as a yellow oil. LCMS[M+H] + =378.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.22(s,1H),7.51(d,J=1.2Hz,1H),7.43(s,1H),6.93(s,1H),3.91(s,3H),3.6 5-3.48(m,4H),1.72-1.64(m,2H),1.60-1.51(m,2H),1.45(s,9H),1.26(s,3H).

[0707] To a solution of tert-butyl 4-((7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-4-methylpiperidine-1-carboxylate (400 mg, 953.64 μmol, 1 equivalent) in MeOH (8 mL) and H2O (2 mL), Oxone® (1.17 g, 1.91 mmol, 2 equivalents) was added. The mixture was stirred at 25°C for 12 hours. The marked compound was obtained as a pale yellow liquid and used in the next step without workup or purification. LCMS[M+H] + =410.0.

[0708] A mixture of tert-butyl 4-((3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)sulfonyl)-4-methylpiperidine-1-carboxylate (400 mg, 976.80 μmol, 1 equivalent) and NIS (329.65 mg, 1.47 mmol, 1.5 equivalents) in H2O (2 mL) was stirred at 25°C for 1 hour, and then quenched at 0°C with saturated NaHSO3 (2 mL). The mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The obtained crude material was purified by column chromatography (SiO2, DCM / MeOH = 19 / 1 to 93 / 7) to obtain the title compound as a yellow solid. LCMS[M+H] + =536.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.66(s,1H),7.67(s,1H),7.10-7.03(m,1H),4.19-4.06(m,2H),3.98(s,3 H),2.98-2.86(m,2H),2.21-2.08(m,2H),1.72-1.64(m,2H),1.45(s,12H).

[0709] [ka]

[0710] A mixture of 6-iodo-7-methoxyimidazo[1,2-a]pyridine (500 mg, 1.64 mmol, 1 equivalent), 4-methyltetrahydro-2H-pyran-4-thiol (241.23 mg, 1.64 mmol, 1 equivalent), DIPEA (636.65 mg, 4.93 mmol, 858.02 μL, 3 equivalents), xanthophos (380.03 mg, 656.80 μmol, 0.4 equivalents), and Pd2(dba)3 (300.72 mg, 328.40 μmol, 0.2 equivalents) in 7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)thio)imidazo[1,2-a]pyridine:dioxane (20 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C for 12 hours under an N2 atmosphere, then filtered, diluted with H2O (10 mL), and extracted with siRNA (2 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~92 / 8) to obtain the title compound (340 mg, yield 67%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.70(s,1H),7.77(s,1H),7.42(s,1H),6.98(s,1H),3.84(s,3H),3.80-3.74(m,2H),3.62-3.57(m,2H),1.61-1.53(m,4H),1.24(s,3H).

[0711] 7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)imidazo[1,2-a]pyridine: To a solution of 7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)thio)imidazo[1,2-a]pyridine (310 mg, 1.00 mmol, 1 equivalent) in MeOH (12 mL) and H2O (3 mL), Oxone® (1.23 g, 2.00 mmol, 2 equivalents) was added. The mixture was stirred at 25°C for 12 hours to obtain the title compound (310 mg) as a pale yellow liquid, which was used directly in the next step.

[0712] 3-Iodo-7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)imidazo[1,2-a]pyridine: To a solution of 7-methoxy-6-((4-methyltetrahydro-2H-pyran-4-yl)sulfonyl)imidazo[1,2-a]pyridine (310 mg, 998.81 μmol, 1 equivalent) in H2O (4 mL), NIS (337.08 mg, 1.50 mmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 1 hour, then quenched with saturated Na2SO3 (2 mL), diluted with H2O (10 mL), and extracted with ELISA (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0~93 / 7) to obtain the title compound (320 mg, yield 66%) as a yellow solid. [M+H] + =436.8. 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),7.73(s,1H),7.28(s,1H),3.92(s,3H),3.86-3.81(m,2H),3 .47(t,J=11.2Hz,2H),2.12-2.01(m,2H),1.55-1.46(m,2H),1.41(s,3H).

[0713] [ka]

[0714] A mixture of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (3 g, 11.89 mmol, 1 equivalent), phenylmethanethiol (2.95 g, 23.8 mmol, 2.79 mL, 2 equivalents), Pd2(dba)3 (1.09 g, 1.19 mmol, 0.1 equivalent), xanthophos (1.38 g, 2.38 mmol, 0.2 equivalents), and DIEA (4.61 g, 35.7 mmol, 6.21 mL, 3 equivalents) in 6-(benzylthio)-7-methoxyimidazo[1,2-a]pyridine:1,4-dioxane (30 mL) was degassed, purged three times with N2, and then stirred at 90°C under N2 for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-6% MeOH / DCM) to obtain the title compound (3.0 g, yield 84%) as a brown oil. 1 H NMR(400MHz,CDCl3)δppm 7.86(s,1H),7.44(s,1H),7.28(s,1H),7.24-7.17(m,3H),7.16-7.12(m,2H),6.93(s,1H),4.00(s,2H),3.96(s,3H).

[0715] 7-Methoxyimidazo[1,2-a]pyridine-6-sulfonyl chloride: To a solution of 6-(benzylthio)-7-methoxyimidazo[1,2-a]pyridine (500 mg, 1.66 mmol, 1 equivalent) in DCM (6 mL), H2O (1.2 mL) and sulfuryl chloride (1.57 g, 11.7 mmol, 1.16 mL, 7 equivalents) were added at 0°C. The mixture was stirred at 20°C for 0.5 hours. The marked compound (500 mg) was obtained as a yellow liquid and used directly. [M+H] + =247.1.

[0716] [ka]

[0717] To a solution of tert-butyl 4-(6-methoxypyrazolo[1,5-a]pyridine-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate: 5-bromo-6-methoxypyrazolo[1,5-a]pyridine (462.01 mg, 1.63 mmol, 1 equivalent) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (755 mg, 2.44 mmol, 1.5 equivalents) in dioxane (5 mL) and H2O (1 mL), Pd(dppf)Cl2 (119.11 mg, 162.78 μmol, 0.1 equivalent) and K2CO3 (674.92 mg, 4.88 mmol, 3 equivalents) were added. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere, then filtered and concentrated under vacuum. The resulting crude substance was purified by column chromatography (SiO2, PE / SiO7 = 1 / 0 to 2 / 1) to obtain the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.35(s,1H),7.84(d,J=2.0Hz,1H),7.44(s,1H),6.49(d,J=2.4Hz,1H),5.95(s, 1H),3.98(s,2H),3.82(s,3H),3.50(t,J=5.6Hz,2H),2.41(s,2H),1.43(s,9H).

[0718] A mixture of tert-butyl 4-hydroxy-4-(6-methoxypyrazolo[1,5-a]pyridine-5-yl)piperidine-1-carboxylate (400 mg, 1.09 mmol, 1 equivalent), Mn(dppm)3 (66.09 mg, 109.29 μmol, 0.1 equivalent), and PhSiH3 (236.54 mg, 2.19 mmol, 269.71 μL, 2 equivalents) in iPrOH (10 mL) and DCM (2 mL) was degassed and purged with O2 (3 ×). The reaction mixture was stirred at 25°C for 1 hour under an O2 atmosphere (15 psi), then diluted with H2O (10 mL) and extracted with ELISA (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude material was purified by column chromatography (SiO₂, PE / siRNA = 1 / 0 to 0 / 1) to obtain the title compound as a brown oil. 1 H NMR(400MHz,CDCl3)δppm 8.34(s,1H),7.88(d,J=2.4Hz,1H),7.48(s,1H),6.51(d,J=2.0Hz,1H),4.07- 4.01(m,2H),3.96(s,3H),3.38-3.24(m,2H),2.02-1.92(m,4H),1.48(s,9H).

[0719] A mixture of tert-butyl 4-hydroxy-4-(6-methoxypyrazolo[1,5-a]pyridine-5-yl)piperidine-4-ol:HCl / dioxane (4M, 11.25 mL, 173.70 equivalents) and tert-butyl 4-hydroxy-4-(6-methoxypyrazolo[1,5-a]pyridine-5-yl)piperidine-1-carboxylate (100 mg, 259.06 μmol, 1 equivalent) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under vacuum, and the crude product was used in the next step without further purification. LCMS[M+H] + =248.2.

[0720] To a solution of 4-(6-methoxypyrazolo[1,5-a]pyridine-5-yl)-1-methylpiperidine-4-ol (90 mg, 363.94 μmol, 1 equivalent) in MeOH (5 mL), paraformaldehyde (90.00 mg, 3.00 mmol, 8.23 ​​equivalents) and AcOH (125.01 μL, 2.18 mmol, 6 equivalents) were added at 25°C. The resulting mixture was stirred at 25°C for 1 hour, after which NaBH(OAc)3 (68.61 mg, 1.09 mmol, 3 equivalents) was added. The resulting mixture was stirred at 25°C for 3 hours, then quenched with H2O (0.5 mL) and concentrated under vacuum. The resulting crude substance was used in the next step without further purification. LCMS[M+H] + =262.2.

[0721] 4-(3-iodo-6-methoxypyrazolo[1,5-a]pyridine-5-yl)-1-methylpiperidine-4-ol: To a solution of 4-(6-methoxypyrazolo[1,5-a]pyridine-5-yl)-1-methylpiperidine-4-ol (95 mg, 363.54 μmol, 1 equivalent) in MeOH (10 mL) and H2O (10 mL), NIS (654.33 mg, 2.91 mmol, 8 equivalents) was added. The mixture was stirred at 25°C for 12 hours and then extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 9 / 1) to obtain the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.25(s,1H),8.51(s,1H),7.99(s,1H),7.67(s,1H),3.94-3.85(m,3H),2.85( s,3H),2.84-2.74(m,2H),2.73-2.68(m,2H),2.33(s,2H),1.69-1.52(m,2H).

[0722] [ka]

[0723] To a mixture of tert-butyl 4-(3-bromo-7-methoxyimidazo[1,2-a]pyridine-6-yl)piperidine-4-ol:DCM (2 mL) and tert-butyl 4-(3-bromo-7-methoxyimidazo[1,2-a]pyridine-6-yl)-4-hydroxypiperidine-1-carboxylate (570 mg, 1.20 mmol, 1 equivalent), TFA (4.37 g, 38.37 mmol, 2.85 mL, 31.88 equivalents) was added at 25°C. The mixture was stirred under an N2 atmosphere at 25°C for 1 hour, and then concentrated under reduced pressure to obtain the title compound (200 mg, yield 46%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.30(s,1H),7.53(s,1H),7.07(s,1H),5.58(s,1H),3.90(s,3H),3.16-3.00(m,4H),2.65-2.56(m,2H),1.55-1.42(m,2H).

[0724] 4-(3-bromo-7-methoxyimidazo[1,2-a]pyridine-6-yl)-1-methylpiperidine-4-ol: A mixture of 4-(3-bromo-7-methoxyimidazo[1,2-a]pyridine-6-yl)piperidine-4-ol (200 mg, 551.83 μmol, 1 equivalent) and paraformaldehyde (200 mg, 2.21 mmol, 4 equivalents) in MeCN (4 mL) was mixed with NaBH(OAc)3 (467.82 mg, 2.21 mmol, 4 equivalents) at 0°C. The mixture was stirred at 25°C under an N2 atmosphere for 6 hours, then filtered and concentrated under reduced pressure to obtain the title compound (120 mg, yield 58%) as a yellow oil, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 8.31(s,1H),7.54(s,1H),7.08(s,1H),6.52(s,1H),3.91(s,3H),2.75-2.60(m,6H),2.56(s,3H),1.55-1.40(m,2H).

[0725] [ka]

[0726] 4-(7-methoxyimidazo[1,2-a]pyridine-6-yl)tetrahydro-2H-pyran-4-ol: To a solution of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (1 g, 3.96 mmol, 1 equivalent) in THF (15 mL), i-PrMgCl·LiCl (1.3 M, 9.15 mL, 3 equivalents) was added at -10°C. The mixture was stirred at -10°C for 30 minutes, and then tetrahydro-4H-pyran-4-one (1.19 g, 11.89 mmol, 1.09 mL, 3 equivalents) was added. The resulting mixture was stirred under an N2 atmosphere at 25°C for 2 hours, then quenched with saturated NH4Cl at 0°C, and extracted with ELISA (3 × 100 mL). The combined organic layers were washed with brine (160 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (220 mg, yield 18%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.55(s,1H),7.88(s,1H),7.42(s,1H),7.03(s,1H),5.22(s,1H),3.87(s,3H) ,3.85-3.74(m,2H),3.72-3.62(m,2H),2.46-2.43(m,2H),1.41-1.31(m,2H).

[0727] 4-(3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)tetrahydro-2H-pyran-4-ol: To a solution of 4-(7-methoxyimidazo[1,2-a]pyridine-6-yl)tetrahydro-2H-pyran-4-ol (100.00 mg, 322.22 μmol, 1 equivalent) in MeOH (3 mL) and H2O (2 mL), NIS (108.74 mg, 483.33 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 3 hours, then concentrated, diluted with water (30 mL), and subsequently extracted with  (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain a residue. This residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (50 mg, yield 37%) as a brown solid. [M+H] + =374.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.34(s,1H),7.51(s,1H),7.05(s,1H),5.44(s,1H),3.91(s,3H),3.85-3.62(m,4H),2.67-2.51(m,2H),1.33(d,J=13.2Hz,2H).

[0728] [ka]

[0729] To a solution of 4-(7-methoxyimidazo[1,2-a]pyran-4-yl)tetrahydro-2H-pyran-4-ol (230 mg, 833.75 μmol, 1 equivalent) in 7-methoxy-6-(4-methoxytetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine:DMF (15 mL), t-BuOK (561.33 mg, 5.00 mmol, 6 equivalents) and MeI (236.68 mg, 1.67 mmol, 103.81 μL, 2 equivalents) were added at 0°C. The mixture was stirred at 0°C for 1 hour, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (60 mg, yield 25%) as a yellow solid. [M+H] + =262.9. 1 H NMR(400MHz,CDCl3)δppm 7.95(s,1H),7.50(s,1H),7.44(s,1H),7.13-6.91(m,1H),3.92(s,3H) ,3.89-3.80(m,4H),3.14(s,3H),2.29-2.23(m,2H),2.18-2.02(m,2H).

[0730] 3-iodo-7-methoxy-6-(4-methoxytetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine: To a solution of 7-methoxy-6-(4-methoxytetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine (60 mg, 205.87 μmol, 1 equivalent) in MeOH (4 mL) and H2O (2 mL), NIS (69.47 mg, 308.80 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 3 hours, then concentrated, diluted with water (30 mL), and extracted with siRNA (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound (65 mg, yield 73%) as a white solid, which was used in the next step without further purification. [M+H] + =388.9. 11H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.54 (s, 1H), 7.09 (s, 1H), 3.88 (s, 3H), 3.79 - 3.61 (m, 4H), 3.07 (s, 3H), 2.28 - 2.11 (m, 2H), 2.10 - 2.01 (m, 2H).

[0731]

Chem.

[0732] tert-Butyl 4-(7-ethoxy-3-iodoimidazo[1,2-a]pyridin-6-yl)-4-hydroxypiperidine-1-carboxylate: To tert-butyl 4-(7-ethoxyimidazo[1,2-a]pyridin-6-yl)-4-hydroxypiperidine-1-carboxylate (1.83 g, 5.06 mmol, prepared according to US20180072717A1) in MeOH (20 mL) and water (8 mL) was added N-iodosuccinimide (1.37 g, 6.08 mmol). The mixture was stirred at 20 °C for 30 min, then an aqueous sodium thiosulfate solution (10%) and water were added. The precipitate was collected by filtration, washed with water, and dried to give 2.22 g (89% yield) of the title compound, which was used without further purification. [M+H] + = 488.5. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (s, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 5.52 (s, 1H), 4.03 - 4.19 (m, 2H), 3.73 - 3.98 (m, 2H), 2.97 - 3.28 (m, 2H), 1.42 (s, 9H), 1.30 - 1.39 (m, 5H).

[0733]

Chem.

[0734] A mixture of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (5 g, 19.82 mmol, 1 equivalent), tributyl(1-ethoxyvinyl) stannan (14.32 g, 39.64 mmol, 13.39 mL, 2 equivalents), Pd(dppf)Cl2 (1.45 g, 1.98 mmol, 0.1 equivalent), and CuI (377.45 mg, 1.98 mmol, 0.1 equivalent) in 6-(1-ethoxyvinyl)-7-methoxyimidazo[1,2-a]pyridine:dioxane (50 mL) was degassed, purged three times with N2, and then stirred at 110°C under an N2 atmosphere for 12 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with SiO2 (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-5% MeOH in DCM) to obtain the title compound (4 g, yield 83%) as a brown oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.99-8.36(m,1H),7.68-7.33(m,2H),7.19-6.86(m,1H),4.65(d,J=1.6 Hz,1H),4.47(d,J=1.6Hz,1H),3.92-3.77(m,5H),1.30(t,J=6.8Hz,3H).

[0735] To a solution of 6-(1-ethoxyvinyl)-7-methoxyimidazo[1,2-a]pyridine-6-yl)ethane-1-one:siRNA (20 mL), 6-(1-ethoxyvinyl)-7-methoxyimidazo[1,2-a]pyridine (3.8 g, 15.67 mmol, 1 equivalent) was added, and HCl (12 M, 1.90 mL, 1.46 equivalents) was added. The mixture was stirred at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (4 g) as a brown solid, which was used in the next step without further purification.

[0736] To a solution of 1-(7-methoxyimidazo[1,2-a]pyridine-6-yl)ethane-1-one in DCE (30 mL), AlCl3 (10.52 g, 78.87 mmol, 4.31 mL, 5 equivalents) was added. The mixture was stirred at 80°C for 1 hour. The reaction mixture was quenched by adding saturated Na2SO4.10H2O (20 mL), and then the pH was adjusted to 7 with saturated NaHCO3. The mixture was then extracted with DCM (120 mL), the organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by column chromatography (SiO2, 0-10% MeOH in DCM) to obtain the title compound as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 11.39-11.05(m,1H),9.42-9.13(m,1H),7.90-7.72(m,1H),7.48(s,1H),6.86-6.60(m,1H),2.65(s,3H).

[0737] A mixture of (2-bromoethoxy)(tert-butyl)dimethylsilane (1.34 g, 5.62 mmol, 1.1 equivalent) and 1-(7-hydroxyimidazo[1,2-a]pyridine-6-yl)ethane-1-one (1 g, 5.11 mmol, 1 equivalent) in 10 mL of DMF was mixed with K2CO3 (1.06 g, 7.66 mmol, 1.5 equivalent). The mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with SiO (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (0-50% siRNA in SiO2 and PE) to obtain the title compound (1 g, yield 53%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 8.86(s,1H),7.87(s,1H),7.47(d,J=1.2Hz,1H),7.08-7.01(m,1H),4.23 -4.18(m,2H),4.01-3.98(m,2H),2.60(s,3H),0.86(s,9H),0.06(s,6H).

[0738] t-BuMgCl (2M, 5.38mL, 10 equivalents) was added at 0°C to a solution of 1-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)imidazo[1,2-a]pyridine-6-yl)ethane-1-one (400 mg, 1.08 mmol, 1 equivalent) in THF (20 mL). The mixture was stirred at 0°C under N2. The reaction mixture was quenched at 0°C by adding saturated NH4Cl (10 mL), then diluted with H2O (20 mL), and extracted with ELISA (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-5% MeOH in DCM) to obtain the title compound (50 mg, yield 10%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.50(s,1H),7.81(s,1H),7.35(d,J=1.2Hz,1H),6.89-6.81(m,1H),4.91 ( s,1H),4.11-4.05(m,1H),4.05-3.99(m,1H),3.96-3.92(m,2H),1.66(s,3H),0.89(s,18H),0.09(s,6H).

[0739] 2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-iodoimidazo[1,2-a]pyridine-6-yl)-3,3-dimethylbutan-2-ol: To a solution of 2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)imidazo[1,2-a]pyridine-6-yl)-3,3-dimethylbutan-2-ol (90 mg, 206.31 μmol, 1 equivalent) in DMF (2 mL), NIS (69.63 mg, 309.47 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 0-20% siRNA / petroleum ether) to obtain the title compound (100 mg, yield 84%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.33(s,1H),7.50(s,1H),6.97(s,1H),5.06(s,1H),4.13-4.08(m,1H),4.06- 4.01(m,1H),3.96-3.92(m,2H),1.69(s,3H),0.90-0.86(m,18H),0.08(s,6H).

[0740] [ka]

[0741] A mixture of 5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine (50 mg, 245.10 μmol, 1 equivalent) and 4,4-dimethyloxazolidine-2-one (42.33 mg, 367.66 μmol, 1.5 equivalents) in 3-(6-methoxypyrazolo[1,5-a]pyrimidine)-1,4-dioxane (2 mL) was mixed with BrettPhos Pd G4 (22.56 mg, 24.51 μmol, 0.1 equivalent) and t-BuONa (70.67 mg, 735.31 μmol, 3 equivalents). The mixture was degassed, purged three times with N2, and then stirred at 100°C for 2 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure, diluted with HCl (10 mL), and washed with H₂O (3 × 10 mL). The combined organic phase was washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (43 mg) as a red solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 9.13-8.96(m,1H),8.13(s,1H),6.72-6.64(m,1H),3.96(s,3H),3.94(s,2H),1.21(s,6H).

[0742] 3-(3-iodo-6-methoxypyrazolo[1,5-a]pyrimidine-5-yl)-4,4-dimethyloxazolidine-2-one (30 mg, 114.39 μmol, 1 equivalent) was dissolved in DMF (1 mL) and NIS (30.88 mg, 137.27 μmol, 1.2 equivalents) was added. The mixture was stirred at 20°C for 2 hours and then quenched with saturated Na₂SO₃ (10 mL). The mixture was diluted with ELISA (20 mL), washed with H₂O (3 × 10 mL) and brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-25% siRNA / petroleum ether) to obtain the title compound (40 mg, 72% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δppm 9.10(s,1H),8.22(s,1H),4.28(s,2H),3.88(s,3H),1.22(s,6H).

[0743] [ka]

[0744] 1-(2,4-dimethoxybenzyl)-4-(7-methoxyimidazo[1,2-a]pyridine-6-yl)-1,4-azaphosfinan 4-oxide: 6-iodo-7-methoxyimidazo[1,2-a]pyridine (280 mg, 919.51 μmol, 1 equivalent) and 1-(2,4-dimethoxybenzyl)-1,4-azaphosfinan 4-oxide in DMF (20 mL) A mixture of 4-oxide (550.23 mg, 1.84 mmol, 2 equivalents), Pd(OAc)2 (20.64 mg, 91.95 μmol, 0.1 equivalent), xanthophos (106.41 mg, 183.90 μmol, 0.2 equivalents), and DIPEA (356.52 mg, 2.76 mmol, 480.49 μL, 3 equivalents) was degassed and purged three times with N2. The mixture was stirred at 90°C under an N2 atmosphere for 12 hours, then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-8% MeOH / DCM) to obtain the title compound (320 mg, yield 75%) as a pale yellow solid. [M+H] + =416.2. 1 H NMR(400MHz,DMSO-d6)δppm 8.89-8.80(m,1H),7.95(s,1H),7.48(s,1H),7.25(d,J=8.4Hz,1H),7.12-6.96(m,1H),6.57-6.50(m,2H),3.94(s,3H) ),3.78(s,3H),3.76(s,3H),3.66(s,2H),3.09-2.97(m,2H),2.92-2.82(m,2H),2.48-2.41(m,2H),1.85-1.73(m,2H).

[0745] A mixture of 1-(2,4-dimethoxybenzyl)-4-(7-methoxyimidazo[1,2-a]pyridine-6-yl)-1,4-azaphosfinan 4-oxide (320 mg, 693.27 μmol, 1 equivalent) in 10 mL of TFA was degassed, purged three times with N2, and then stirred at 70°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the title compound (180 mg) as a brown solid, which was used in the next step without further purification.

[0746] A mixture of 4-(7-methoxyimidazo[1,2-a]pyridine-6-yl)-1-methyl-1,4-azaphosfinan 4-oxide (180 mg, 678.61 μmol, 1 equivalent), AcOH (4.20 g, 69.87 mmol, 4 mL, 102.96 equivalents), and paraformaldehyde (360 mg, 2.71 mmol, 4 equivalents) in MeOH (10 mL) was stirred at 25°C for 1 hour, and then NaBH3CN (170.58 mg, 2.71 mmol, 4 equivalents) was added at 0°C. The resulting mixture was stirred at 25°C for 1 hour under an N2 atmosphere, then filtered and concentrated under reduced pressure to obtain a residue. This residue was purified by RP-HPLC to obtain the title compound (150 mg, yield 71%) as a pale yellow oil. [M+H] + =280.2. 1 H NMR(400MHz,DMSO-d6)δppm 8.84-8.78(m,1H),7.94(s,1H),7.47(d,J=0.8Hz,1H),7.06(d,J=4.4Hz,1H),3.91(s,3H) ,3.04-2.85(m,2H),2.81-2.64(m,2H),2.46-2.35(m,2H),2.31(s,3H),1.89-1.74(m,2H).

[0747] 4-(3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-yl)-1-methyl-1,4-azaphosfinan 4-oxide: To a solution of 4-(7-methoxyimidazo[1,2-a]pyridine-6-yl)-1-methyl-1,4-azaphosfinan 4-oxide (110 mg, 393.88 μmol, 1 equivalent) in DCM (10 mL), NIS (88.62 mg, 393.88 μmol, 1 equivalent) was added at 0°C. The mixture was stirred at 0°C for 10 minutes, and then concentrated under reduced pressure to obtain the residue. The crude product was purified by RP-HPLC to obtain the title compound (5 mg) as a white solid.

[0748] [ka]

[0749] A solution of 3-bromo-7-methoxy-6-(trifluoromethyl)imidazo[1,2-a]pyridine (70 mg, 0.237 mmol) and 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68.621 mg, 0.285 mmol) in 1,4-dioxane (1.12 ml) was degassed with nitrogen for 5 minutes, and then Na2CO3 (50.290 mg, 0.474 mmol), PdCl2(dppf)·DCM complex (17.363 mg, 0.024 mmol), and water (0.38 ml) were added to the reaction mixture. The resulting mixture was heated at 100°C for 2 hours, then diluted with water (5 mL) and extracted with 10% MeOH / DCM (2 × 10 mL). The combined organic layer was dried over Mg₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, 40–60% Âx / petroleum ether) to obtain the title compound (65 mg, yield 83%) as an off-white solid. [M+H] + =330.4.

[0750] The following compounds were prepared following a procedure similar to that described for intermediate 70.

[0751] [Table 1-1]

[0752] [Table 1-2]

[0753] [Table 1-3]

[0754] [Table 1-4]

[0755] [ka]

[0756] 3-Bromo-5-(1H-pyrazole-1-yl)aniline: To a solution of 3,5-dibromoaniline (1 g, 3.99 mmol, 1 equivalent) and pyrazole (244 mg, 3.59 mmol, 0.9 equivalents) in DMSO (20 mL), L-proline (83 mg, 717 μmol, 0.18 equivalents), Cs2CO3 (2.34 g, 7.17 mmol, 1.8 equivalents), and CuI (76 mg, 399 μmol, 0.1 equivalents) were added. The mixture was stirred under N2 at 110°C for 36 hours, then diluted with H2O (30 mL) and extracted with SiO2 (3 × 20 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 10 / 1 to 3 / 1) to obtain the title compound (251 mg, yield 24%) as a dark brown solid. [M+H] + =238.1. 1H NMR(400MHz,DMSO-d6)δppm 8.38(d,J=2.4Hz,1H),7.69(s,1H),7.11(t,J=1.6Hz,1H),7.05(t,J=1.6Hz,1H),6.65(t,J=1.6Hz,1H),6.54-6.45(m,1H),5.68(s,2H).

[0757] [ka]

[0758] To a solution of 4-bromo-2-fluoro-6-nitrophenol (0.7 g, 2.97 mmol, 1 equivalent) in 5-bromo-1-fluoro-2-(methoxy-d3)-3-nitrobenzene:DMF (10 mL), CD3I (631 mg, 4.45 mmol, 271 μL, 1.5 equivalents) and K2CO3 (1.23 g, 8.90 mmol, 3 equivalents) were added. The mixture was stirred at 60°C for 1 hour, then diluted with water (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-10% siRNA / petroleum ether) to obtain the title compound (450 mg, yield 54%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δppm 7.73(t,J=2.0Hz,1H),7.50(dd,J=9.6,2.4Hz,1H).

[0759] 5-Bromo-3-fluoro-2-(methoxy-d3)aniline: To a solution of 5-bromo-1-fluoro-2-(methoxy-d3)-3-nitrobenzene (450 mg, 1.60 mmol, 1 equivalent) in EtOH (20 mL) and H2O (12 mL), Zn (1.05 g, 16.0 mmol, 10 equivalents) and NH4Cl (856 mg, 16.0 mmol, 10 equivalents) were added. The mixture was stirred at 80°C for 10 minutes, then cooled to 25°C and stirred for 2 hours. The reaction mixture was quenched with 1N HCl (1 mL), then diluted with water (20 mL), and extracted with DCM (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (347 mg, yield 87%) as a pale yellow oil, which was used without purification. [M+H] + =224.9. 1 H NMR(400MHz,CDCl3)δppm 6.65-6.64(m,3H),6.62(d,J=2.4Hz,1H).

[0760] [ka]

[0761] 5-Bromo-1,3-dihydroisobenzofuran-1-ol: A mixture of 5-bromoisobenzofuran-1(3H)-one (100 mg, 469.42 μmol, 1 equivalent) in MeOH (5 mL) was mixed with NaBH4 (35.52 mg, 938.84 μmol, 2 equivalents) at 0°C. The mixture was degassed, purged with N2 (3 ×), and then stirred at 0°C under an N2 atmosphere for 0.5 hours. The reaction mixture was then quenched with saturated NH4Cl (5 mL) and extracted with ELISA (3 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 7.30(d,J=8.4Hz,1H),7.09-7.05(m,2H),5.67(d,J=5.6Hz,1H),5.25-5.15(m,1H),4.59-4.49(m,1H),4.30-4.22(m,1H).

[0762] [ka]

[0763] 6-Bromo-2,3-dihydrofl[3,2-b]pyridine-3-ol: A solution of 5-bromo-3-hydroxypicolinaldehyde (200 mg, 990.07 μmol, 1 equivalent) in DMSO (10 mL) was mixed with trimethylsulfoxonium iodide (544.72 mg, 2.48 mmol, 2.5 equivalents) and t-BuOK (277.75 mg, 2.48 mmol, 2.5 equivalents). The mixture was stirred at 20°C for 80 minutes, then quenched with saturated NH4Cl (10 mL) at 0°C, followed by dilution with H2O (10 mL) and extraction with siRNA (3 × 30 mL). The combined organic layer was washed with brine (3 × 30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by column chromatography (SiO2, 0-30% siRNA / PE) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δppm 8.22(s,1H),7.62(s,1H),5.96(d,J=6.0Hz,1H),5.17-5.12(m,1H),4.8(dd,J=10.4,6.8Hz,1H),4.35(dd,J=10.4,2.8Hz,1H).

[0764] [ka]

[0765] To a solution of 5-bromo-N1-methylbenzene-1,2-diamine (100 mg, 497.36 μmol, 1 equivalent) in 6-bromo-1-methyl-1H-benzo[d]imidazole-2-amine:MeOH (4 mL), cyanogen bromide (73.17 μL, 994.71 μmol, 2 equivalents) was added. The mixture was stirred at 25°C for 1 hour, then quenched with saturated NaHCO3 (10 mL) at 25°C, diluted with H2O (20 mL), and extracted with siRNA (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound, which was used in the next step without further purification. LCMS[M+H] + =226.1. 1 H NMR(400MHz,CDCl3)δppm 7.24(s,3H),3.55(s,3H).

[0766] [ka]

[0767] 1-Bromo-3,5-difluoro-4-methoxy-2-nitrobenzene: To a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (2 g, 8.97 mmol, 1 equivalent) in H2SO4 (20 mL), KNO3 (934 mg, 9.24 mmol, 1.03 equivalents) was added at 0°C. The mixture was stirred at 25°C for 12 hours, then poured into ice / water (150 mL) and extracted with DCM (3 × 60 mL). The combined organic layer was washed with H2O (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-5% siRNA / petroleum ether) to obtain the title compound (2.15 g, yield 81%) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 7.96(dd,J=10.8,2.4Hz,1H),4.04(s,3H).

[0768] A mixture of 1-bromo-3,5-difluoro-4-methoxy-2-nitroaniline (2 g, 6.72 mmol, 1 equivalent) in 3-bromo-5-fluoro-6-methoxy-2-nitroaniline:NH3 / MeOH (7M, 25 mL) was stirred at 60°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 0-5% siRNA / petroleum ether) to obtain the title compound (1.4 g, yield 71%) as an orange solid. [M+H] + =264.8. 1 H NMR(400MHz,DMSO-d6)δppm 6.99(d,J=10.4Hz,1H),6.35(s,2H),3.81(s,3H).

[0769] A mixture of 3-bromo-5-fluoro-6-methoxy-2-nitroaniline (1.14 g, 3.87 mmol, 1 equivalent), Fe powder (2.16 g, 38.7 mmol, 10 equivalents), and NH4Cl (2.07 g, 38.7 mmol, 10 equivalents) in 6-bromo-4-fluoro-3-methoxybenzene-1,2-diamine:EtOH (15 mL) and H2O (1.5 mL) was degassed, purged three times with N2, and then stirred at 80°C under N2 for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O (30 mL) and extracted with siRNA (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, 10% siRNA / petroleum ether) to obtain the title compound (890 mg, yield 88%) as an orange solid. [M+H] + =234.9. 1 H NMR(400MHz,DMSO-d6)δppm 6.61(d,J=10.4Hz,1H),4.92(s,2H),4.55(s,2H),3.71(s,3H).

[0770] To a solution of 6-bromo-4-fluoro-3-methoxybenzene-1,2-diamine (100 mg, 383 μmol, 1 equivalent) in 4-bromo-6-fluoro-7-methoxy-1H-benzo[d]imidazole:MeOH (1 mL), CH(OMe)3 (61 mg, 574 μmol, 63 μL, 1.5 equivalents) and AcOH (0.2 mL) were added. The mixture was stirred at 80°C for 1 hour and then concentrated under reduced pressure. The mixture was diluted with saturated NaHCO3 (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 40-50% siRNA / petroleum ether) to obtain the title compound (80 mg, yield 77%) as a white solid. [M+H] + =244.9. 1 H NMR(400MHz,DMSO-d6)δppm 13.30-12.91(m,1H),8.29(s,1H),7.43(d,J=12.0Hz,1H),4.36-4.02(m,3H).

[0771] [ka]

[0772] 4-Bromo-6-fluoro-7-methoxy-2-methyl-1H-benzo[d]imidazole:6-bromo-4-fluoro-3-methoxybenzene-1,2-diamine (200 mg, 766 μmol, 1 equivalent) was dissolved in MeOH (2 mL) and AcOH (0.4 mL), to which triethyl orthoacetate (186 mg, 1.15 mmol, 210 μL, 1.5 equivalents) was added. The mixture was stirred at 80°C for 1 hour and then concentrated under reduced pressure. The mixture was diluted with saturated NaHCO3 (20 mL) and extracted with siRNA (3 × 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / siRNA = 1 1 / 9 to 1 / 1) to obtain the title compound (200 mg, 91% yield) as a white solid. [M+H] + =258.8. 1H NMR(400MHz,CDCl3)δppm 7.18(d,J=12.0Hz,1H),4.18(d,J=1.6Hz,3H),2.64(s,3H).

[0773] [ka]

[0774] A mixture of 6-bromo-4-fluoro-3-methoxybenzene-1,2-diamine (500 mg, 1.91 mmol, 1 equivalent) and 2-hydroxyacetic acid (174.72 μL, 2.87 mmol, 1.5 equivalents) in (4-bromo-6-fluoro-7-methoxy-1H-benzo[d]imidazole-2-yl)methanol:4N HCl (6 mL) was stirred at 100°C for 2 hours. The reaction mixture was diluted with 10:1 DCM:MeOH (20 mL) and neutralized with saturated NaHCO3. The resulting mixture was extracted with 10:1 DCM:MeOH (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by column chromatography (SiO2, 5-7% MeOH / DCM) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δppm 13.19-12.63(m,1H),7.37(d,J=11.2Hz,1H),5.68-5.48(m,1H),4.64(d,J=6.0Hz,2H),4.25-3.95(m,3H).

[0775] 4-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-7-methoxy-1H-benzo[d]imidazole: To a solution of (4-bromo-6-fluoro-7-methoxy-1H-benzo[d]imidazole-2-yl)methanol (210 mg, 687.09 μmol, 1 equivalent) in DCM (10 mL), TBSCl (253.61 μL, 2.06 mmol, 3 equivalents) and imidazole (140.33 mg, 2.06 mmol, 3 equivalents) were added. The mixture was stirred at 25°C for 2 hours, then diluted with H2O (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by column chromatography (SiO2, 5-10% siRNA / PE) to obtain the title compound. LCMS[M+H] + =390.9. 1 H NMR(400MHz,DMSO-d6)δppm 13.28-12.73(m,1H),7.40(d,J=11.6Hz,1H),4.81(s,2H),4.32-3.92(m,3H),0.88(s,9H),0.10(s,6H).

[0776] A mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole:dioxane (1 mL) containing 4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-7-methoxy-1H-benzo[d]imidazole (80 mg, 184.93 μmol, 1 equivalent), B2Pin2 (234.80 mg, 924.66 μmol, 5 equivalents), KOAc (54.45 mg, 554.79 μmol, 3 equivalents), and Pd(dppf)Cl2 (13.53 mg, 18.49 μmol, 0.1 equivalents) was degassed and purged with N2 (3×). The reaction mixture was stirred at 100°C for 12 hours under an N2 atmosphere, then filtered and concentrated under vacuum to obtain the title compound, which was used in the next step without further purification.

[0777] [ka]

[0778] N-(2-amino-3-bromo-5-fluoro-6-methoxyphenyl)-3-(benzyloxy)propenamide: To a solution of 6-bromo-4-fluoro-3-methoxybenzene-1,2-diamine (200 mg, 765.78 μmol, 1 equivalent) and Et3N (532.94 μL, 3.83 mmol, 5 equivalents) in DCM (4 mL), a solution of 3-(benzyloxy)propanoyl chloride (197.76 mg, 995.52 μmol, 1.3 equivalents) in DCM (1 mL) was added dropwise at 0°C. The mixture was stirred at 20°C for 30 minutes, then diluted with H2O (30 mL) and extracted with  (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound, which was used in the next step without further purification.

[0779] 2-(2-(benzyloxy)ethyl)-4-bromo-6-fluoro-7-methoxy-1H-benzo[d]imidazole:N-(2-amino-3-bromo-5-fluoro-6-methoxyphenyl)-3-(benzyloxy)propenamide (200 mg, 503.48 μmol, 1 equivalent) was mixed with AcOH (2 mL). The mixture was stirred at 80°C for 1 hour and then neutralized with saturated NaHCO3. The resulting mixture was diluted with H2O (30 mL) and extracted with RINKAN (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by column chromatography (SiO2, 0-30% RINKAN / PE) to obtain the title compound. LCMS[M+H] + =380.9. 1 H NMR(400MHz,CDCl3)δppm 7.31-7.22(m,5H),7.09(d,J=11.6Hz,1H),4.51(s,2H),4.05(br s,3H),3.80(t,J=5.6Hz,2H),3.14(t,J=5.6Hz,2H).

[0780] A mixture of 2-(2-(benzyloxy)ethyl)-6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole:1,4-dioxane (5 mL) containing 2-(2-(benzyloxy)ethyl)-4-bromo-6-fluoro-7-methoxy-1H-benzo[d]imidazole (190 mg, 450.92 μmol, 1 equivalent), B2Pin2 (572.54 mg, 2.25 mmol, 5 equivalents), KOAc (132.76 mg, 1.35 mmol, 3 equivalents), and Pd(dppf)Cl2 (32.99 mg, 45.09 μmol, 0.1 equivalent) was degassed and purged with N2 (3 ×). The reaction mixture was stirred at 100°C for 12 hours under an N2 atmosphere, then filtered and concentrated under vacuum to obtain the title compound, which was used in the next step without further purification.

[0781] [ka]

[0782] 6-Bromo-2,4-difluoro-3-methoxybenzaldehyde: To a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (1 g, 4.48 mmol, 1 equivalent) in THF (5 mL), LDA (2 M, 2.8 mL, 1.24 equivalents) was added under N2 conditions at -78°C. The mixture was stirred at -60°C for 1 hour, after which DMF (475 mg, 6.50 mmol, 500 μL, 1.45 equivalents) was added all at once. The resulting mixture was stirred under N2 conditions at -60°C for 1 hour, then quenched with saturated NH4Cl (50 mL), and subsequently extracted with siRNA (3 × 20 mL). The combined organic layers were w...

Claims

1. Equation (I) 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is X, Y, and Z １ One or two of these are independently N, and X, Y, and Z １ The remainder is C, 【Chemistry 2】 Each of these is either a single bond or a double bond, R ｘ is hydrogen, -NH ２ , or halogen, Ring A is phenyl or a 5-11 member heteroaryl. m is 0, 1, 2, 3, or 4. R １ Each is independent of the others. (i) C1-C6 alkoxys optionally substituted with hydroxyl or phenyl, (ii) C1-C6 deuterated alkoxy, (iii) C1-C6 alkoxyalkyl, (iv) 5-6 member heteroaryl, (v)-N(R １Ａ )-S(O ２ )R １Ｂ 、 (vi)-(C=O)NR １Ａ R １Ｂ 、 (vii) Halogen, (viiii) Cyano, (ix) Hydroxyl, (x)-NR Ａ R Ｂ 、 (xi)hydroxyl, and a C1-C6 alkyl optionally substituted with one or two substituents independently selected from 4- to 8-membered heterocyclines optionally substituted with hydroxyl or C1-C6 alkyl, (xi) C1-C6 haloalkyl, (xiiii) C1-C6 haloalkoxy, (xiv) C3-C6 cycloalkyl, A 4- to 8-membered heterocycline optionally substituted with one or two substituents independently selected from (xv)hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl, (xvi) - S(O ２ ) C1-C6 alkyl, (xvii) A 4- to 10-member heterocyclyloxy that is optionally substituted with an acyl, or (xviiii) phenyl, R １Ａ Each of these is independently hydrogen or a C1-C6 alkyl group. R １Ｂ Each is independent of the others. (i) C1-C6 alkyl groups optionally substituted with C3-C6 cycloalkyl groups, 5-6 member heteroaryl groups optionally substituted with C1-C6 alkyl groups, or 4-10 member heterocyclines optionally substituted with -(C=O)OC1-C6 alkyl groups. (ii) A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl molecules. (iii) C3-C6 cycloalkyl groups optionally substituted with one or two substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl groups, (iv) ethylenyl, (v) C1-C6 haloalkyl, A 4- to 10-membered heterocycline optionally substituted with (vi)-(C=O)OC1-C6 alkyl, (vii)-NR １Ａ R １Ａ ,or (viiii) phenyl, R Ａ is hydrogen or C1-C6 alkyl, R Ｂ teeth, (i) Hydrogen, (ii) - S (O ２ ) C1-C6 alkyl, (iii) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or C1-C6 alkoxy groups. (iv)-(C=O)C1-C6 alkyl, (v)-(C=O)OC1-C6 alkyl, (vi) 4- to 8-membered heterocyclines optionally substituted with hydroxyl groups, (vii) Halogen, hydroxyl, -NR Ｃ R Ｄ , C1-C6 alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl groups optionally substituted with C1-C6 alkoxy, 5-6 membered heteroaryl groups optionally substituted with C1-C6 alkyl, and 4-8 membered heterocyclyl groups optionally substituted with -C(=O)C1-C6 alkyl or C1-C6 alkyl, or (viiii) A C=O 5 or 6-membered heteroaryl that is optionally substituted with a C1-C6 alkyl group, R ２ teeth, (i) Hydrogen, (ii) Halogen, (iii) (a) Hydroxyl, (b) Halogen, (c) Phosphate, (d)-NR ２Ａ R ２Ｂ 、 (e) A 4- to 10-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl, (f) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. (g) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or hydroxyalkyl groups, (h)CO ２ H、 (i)C(O)R ２Ａ 、 (j) C1-C6 alkoxy, or (k) oxo A C1-C6 alkoxy that is optionally substituted with 1 to 3 substituents independently selected from the above, (iv) C1-C6 haloalkoxy, (v) 4-10 member heterocyclyloxy, (vi)-(C=O)NR ２Ａ R ２Ｂ 、 (vii) Hydroxyl, halogen, and -NR ２Ａ R ２Ｂ C1-C6 alkyl groups that are optionally substituted with 1 to 3 substituents independently selected from the above. (viiii) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl or C1-C6 alkoxy, or (ix)-NR ２Ａ R ２Ｂ And, R ２Ａ and R ２Ｂ Each of these is independently a C1-C6 alkyl or C1-C6 hydroxyalkyl group optionally substituted with hydrogen or hydroxyl, R ３ teeth, (i) C1-C6 thioalkyl, (ii) 【Transformation 3】 (iii) 【Chemistry 4】 (iv) A 4- to 8-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, and C1-C6 alkoxys. (v) NR Ｅ R Ｆ Or a C1-C6 alkyl group optionally substituted with a hydroxyl group. (vi)-CO ２ H、 ( ) ( ) ) ( ) ( ) ) Ｅ ( Ｆ 、 (viiii) C1-C6 alkoxys optionally substituted with 4- to 10-membered heterocyclines, (ix) Hydrogen, (x) C1-C6 haloalkyl, (xi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. (xi) C1-C6 alkoxyalkyl, or (xiiii) C1-C6 hydroxyalkyl, Z is O or NR ４ And, R ３Ａ teeth, (i) C1-C6 haloalkyl, (ii) C3-C6 cycloalkyl groups optionally substituted with C1-C6 alkyl groups, (iii) (a) C3-C6 cycloalkyl (b) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. (c) Hydroxyl, (d) C1-C6 alkoxy, or (e) A 4-6 member heterocyclyl optionally substituted with a 4-6 member heterocyclyl, or a C1-C6 alkyl optionally substituted with a C1-C6 alkoxy. C1-C6 alkyl groups that are optionally substituted, (iv) C1-C6 alkoxyalkyl, (v) C1-C6 hydroxyalkyl, (vi) A 5-6 member heteroaryl that is optionally substituted with a C1-C6 alkyl group. (vii) A 4- to 10-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1-C6 alkoxy, or (viiii)-N(C1-C6 alkyl) ２ And, R ３Ｂ and R ３Ｃ Each of these independently consists of a C3-C6 cycloalkyl group, or a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl group, or R ３Ｂ and R ３Ｃ These, together with the atoms to which they are bonded, form a 4- to 8-membered heterocycline which is optionally substituted with C1-C6 alkyl groups. R ４ is hydrogen or C1-C6 alkyl, and Each R Ｃ and R Ｄ Each of these is independently a C1-C6 alkyl group that is optionally substituted with hydrogen, -(C=O)C1-C6 alkyl, or oxo. Each R Ｅ and R Ｆ Each of these is independently either hydrogen or a C1-C6 alkyl group, or R Ｅ and R Ｆ A compound, or a pharmaceutically acceptable salt thereof, which, together with the atoms to which they are bonded, forms a 4- to 8-membered heterocycline that is optionally substituted with a hydroxyl group.

2. Equation (I) is (I - a) 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

3. Equation (I) is (I - b) 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

4. Equation (I) is (I - c) 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

5. Equation (I) is (I - d) 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

6. Equation (I) is (I - e) 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

7. Equation (I) is (I - f) 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

8. Equation (I) is (I - g) 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

9. Equation (I) is (I - i) 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

10. Equation (I) is (I - n) 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, R １Ｃ , R １Ｄ , and R １Ｅ Each of these is an independently selected R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. Equation (I) is (I - o) 【Chemistry 14】 or a pharmaceutically acceptable salt thereof, R １Ｃ , R １Ｄ , and R １Ｅ Each of these is an independently selected R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. Equation (I) is (I - p) 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, in the formula, R １Ｄ and R １Ｅ Each of these is an independently selected R １ And, Q is -NH(SO ２ ) - or -NH(C1-C6 alkyl)-, R １Ｆ , R １Ｇ , and R １Ｈ Each of these is independently hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl, and R １Ｆ , R １Ｇ , and R １Ｈ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of the atoms is hydrogen.

13. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is N or C.

14. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Y is N or C.

15. Z １ A compound according to any one of claims 1 to 5, wherein is N or C, or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 4, wherein ring A is a 5- to 11-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 4, wherein ring A is phenyl, or a pharmaceutically acceptable salt thereof.

18. A compound selected from the group consisting of the compounds of Examples 1 to 304, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

20. A method for treating a RIPK2-related disease or disorder in a subject requiring treatment for such disease or disorder, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 18, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19.

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