Methods for treating inflammatory diseases

Abstract

This application relates to formula (I) or formula (II) as defined herein. [Case 1] This specification relates to the compounds of TIFF2026520038000189.tif5233, their pharmaceutically acceptable salts, and compositions comprising them. Furthermore, it also describes methods for treating the diseases and disorders disclosed in the specification using the compounds of formula (I) or formula (II), their pharmaceutically acceptable salts, and compositions comprising them.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 472,233, filed on 9 June 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 formulas (I) and (II) as defined herein, as well as pharmaceutically acceptable salts thereof, and compositions comprising them. Furthermore, methods for treating diseases and disorders disclosed herein using compounds of formula (I) and / or formula (II), as well as pharmaceutically acceptable salts thereof, and compositions comprising them are also described. [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 use formula (I) or formula (II)

[0006] [ka] We provide compounds of or pharmaceutically acceptable salts thereof, in which, R 1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy molecules, a 4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl and -(NH)-C1-C6 alkyl molecules, and a -(NH)-4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl molecules. R 1A and R 1B These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R 2Ais selected independently from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl optionally substituted with 1 or 2 halogens, C3-C6 cycloalkyl, halogen, C1-C6 alkyl, and 4- to 10-membered heterocyclyl optionally substituted with 1 or 2 substituents independently selected from C(O)O C1-C6 alkyl, R 2B is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, R 3 is hydrogen or halogen, X is

[0007]

Chemical formula

[0008] Similarly, the Specified Method provides 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.

[0009] Similarly, the Specified Method provides 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0010] 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.

[0011] 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]

[0012] Biologics and small molecules targeting pro-inflammatory signaling pathways are used to successfully treat inflammatory and other diseases in patients; however, 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 formulas (I) and (II) described herein, and their pharmaceutically acceptable salts.

[0013] 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.

[0014] 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 of numbers may vary by up to 10% from the explicitly stated number or range of numbers.

[0015] The term "therapeutic dose" means an amount of the compound that, when administered to a subject requiring such treatment, is sufficient to (i) treat a disease or disorder 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 described herein.

[0016] 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 disorder, reduction in the degree of neurological impairment, stabilization (i.e., non-exacerbating) of the disease or disorder, delay or slowing of disease progression, improvement or relief of the disease state (e.g., one or more symptoms of the disease or disorder), 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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 ethyleneyl and allyl.

[0025] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with a halogen of independently selected proportion.

[0026] 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.

[0027] The term "alkoxy" refers to -O-alkyl radicals (e.g., -OCH3).

[0028] The term "thioalkyl" refers to an alkyl group as defined herein, which is bonded to a molecule via a sulfur atom (e.g., -SCH3).

[0029] The term "haloalkoxy" refers to a haloalkyl group that is bonded to a molecule via an oxygen atom (e.g., -OCF3).

[0030] 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.

[0031] As used herein, the term "cyano" refers to the -CN radical.

[0032] As used herein, the term "hydroxyl" refers to the -OH radical.

[0033] As used herein, the term "amino" refers to the -NH2 radical.

[0034] As used herein, the term "phosphoric acid" refers to the -P(=O)2(OH)2 radical.

[0035] 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. 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, tetrazole, pyridine, 2 Examples include pyridone, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, triazine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 6,7-dihydro-5H-cyclopenta[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].

[0036] 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.,

[0037] [ka] ), pyrimidone (for example,

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

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

[0040] [ka] ), and imidazolone (for example,

[0041] [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).

[0042] 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.

[0043] The term "cycloalkoxy" refers to -O-cycloalkyl radicals (e.g., -O-cyclopropyl).

[0044] 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.

[0045] 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 heterocycloalkyl 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, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidinone, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-Oxopyrrolidine, pyrrolidinyl, tetrahydrofuryl, thiolanil, pyrazolinil, oxathiolanil, isoxazolidinyl, isothiazolidinyl, pyrrolinil, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanil, sulforanil, thiazolidedionyl, succinimidyl, dihydrofuranol, pyrazolidinonyl, oxazolidinyl, isosazolidinonyl, hydantoinyl, thiohydantoinyl, imidazolidinonyl, ox Sazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinionyl, dioxazolidinethionyl, dioxolanthionyl, oxazolidinethionyl, imidazolidinethionyl, isothiazolidinonyl, piperidinyl, tetrahydropyranil, thianyl, morpholinyl, thiomorpholinyl, dioxanil, piperazinyl, dithianyl, oxazinyl, This includes tetrahydropyranonil, piperidinonil, dioxanonil, oxazinanonil, morpholinonil, thiomorpholinonil, piperadinonil, tetrahydropyrimidinonil, piperidinedionil, oxazinandionil, dihydropyrimidinedione, tetrahydropyridazinonil, triazinanonil, oxadiadinanonil, dioxazinanonil, morpholindionil, piperazinedionil, piperazinetrionil, triazinandionil, and 2-azaspiro[3.3]heptanil.

[0046] In this context, the term "saturated" refers only to single bonds present between constituent atoms.

[0047] 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.

[0048] Where used herein, the symbol

[0049] [ka] This indicates the bonding point of the atom or part to the indicated atom or group in the rest of the molecule.

[0050] 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,

[0051] [ka] Includes.

[0052] 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.,

[0053] [ka] (ii) Represents) (ii) Monocyclic atom (spiro-condensed ring system) (for example,

[0054] [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,

[0055] [ka] It is understood that this includes those having a fused ring, including those located on the ) surface.

[0056] In addition, any compound or structure described 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.” An isotope-enriched compound has the structure described herein, except that one or more atoms are substituted with atoms having a selected atomic mass or mass number.

[0057] 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.

[0058] 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.

[0059] The deuterium-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.

[0060] 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 (

[0061] [ka] ), monodeuterated methylene (

[0062] [ka] ) and dideuterated methylene (

[0063] [ka] ), methyl trideuterated (

[0064] [ka] ), trideuterated methoxy(

[0065] [ka] ) are some examples.

[0066] Furthermore, the compounds disclosed comprehensively or specifically herein are intended to include all tautomer forms. Therefore, as an example, the following parts...

[0067] [ka] Compounds containing the following parts

[0068] [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.

[0069] 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.

[0070] 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.

[0071] 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, when measured in the assay provided herein, 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. 50 ) can be shown.

[0072] Compounds of formula (I) and formula (II) 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.

[0073] Some embodiments use formula (I) or formula (II)

[0074] [ka] We provide compounds of or pharmaceutically acceptable salts thereof, in which, R 1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy molecules, a 4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl and -(NH)-C1-C6 alkyl molecules, and a -(NH)-4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl molecules. R 1A and R 1B These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R 2A It is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halogen, C1-C6 alkyl, and 4-10 membered heterocyclyls optionally substituted with one or two substituents independently selected from C(O)O C1-C6 alkyl. R 2B These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. R 3 is hydrogen or halogen, X is

[0075] [ka] Selected from, R 4 is hydrogen or C1-C6 alkyl, R 5 teeth, (i) (a) C3-C6 cycloalkyl groups optionally substituted with 1 to 3 substituents independently selected from halogens or phenyls, (b) Phenyls optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, C1-C6 hydroxyalkyls, and cyanos. (c)-NR A R B , (d) Hydroxyl, (e) halogen, (f) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl, and (g) 5-10 member heteroaryls optionally substituted with 1-3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. C1-C6 alkyl groups that are optionally substituted with 1 to 4 substituents independently selected from the above. (ii) C3-C10 cycloalkyls optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, phenyls optionally substituted with 1 to 2 independently selected halogens and 5 to 10 member heteroaryls, (iii) A 4-10 member heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl, (iv) Phenyls optionally substituted with 1 to 3 substituents independently selected from halogens, nitros, and C1-C6 haloalkyls. (v) A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl groups. (vi) C1-C6 alkoxy, or (vii) C3-C6 cycloalkoxy Selected from, Alternatively, R 4 and R 5These, together with the atoms to which they are bonded, form 5-12 member heterocyclines or 9-10 member heteroaryls, each optionally substituted with phenyl. R A and R B These are independently selected from hydrogen and C1-C6 alkyl groups.

[0076] Some embodiments are given by formula (I)

[0077] [ka] We provide a compound of or a pharmaceutically acceptable salt thereof, in which, R 1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy molecules, a 4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl and -(NH)-C1-C6 alkyl molecules, and a -(NH)-4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl molecules. R 1A and R 1B These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R 2A It is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halogen, C1-C6 alkyl, and 4-10 membered heterocyclyls optionally substituted with one or two substituents independently selected from C(O)O C1-C6 alkyl. R 3 is hydrogen or halogen, X is

[0078] [ka] Selected from, R 4 is hydrogen or C1-C6 alkyl, R 5 teeth, (i) (a) C3-C6 cycloalkyl groups optionally substituted with 1 to 3 substituents independently selected from halogens or phenyls, (b) Phenyls optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, C1-C6 hydroxyalkyls, and cyanos. (c)-NR A R B , (d) Hydroxyl, (e) halogen, (f) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl, and (g) 5-10 member heteroaryls optionally substituted with 1-3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. C1-C6 alkyl groups that are optionally substituted with 1 to 4 substituents independently selected from the above. (ii) C3-C10 cycloalkyls optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, phenyls optionally substituted with 1 to 2 independently selected halogens and 5 to 10 member heteroaryls, (iii) A 4-10 member heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl, (iv) Phenyls optionally substituted with 1 to 3 substituents independently selected from halogens, nitros, and C1-C6 haloalkyls. (v) A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl groups. (vi) C1-C6 alkoxy, or (vii) C3-C6 cycloalkoxy Selected from, Alternatively, R 4 and R 5 These, together with the atoms to which they are bonded, form 5-12 member heterocyclines or 9-10 member heteroaryls, each optionally substituted with phenyl. R A and R B These are independently selected from hydrogen and C1-C6 alkyl groups.

[0079] Some embodiments are given by formula (II)

[0080] [ka] We provide a compound of or a pharmaceutically acceptable salt thereof, in which, R 1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy molecules, a 4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl and -(NH)-C1-C6 alkyl molecules, and a -(NH)-4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl molecules. R 1A and R 1B These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R 2B is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, R 3 is hydrogen or halogen, X is

[0081]

Chemical formula

[0082] Unless otherwise specified, the following selected embodiments describe the substituents of formula (I) and formula (II).

[0083] In some embodiments, R 1 is hydroxyl, -S(O2)C1-C6 alkyl, C1-C6 alkyl optionally substituted with NR 1A R 1B a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, a 4- to inembered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl, -(NH)-C1-C6 alkyl, and a -(NH)-4- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R1 is a 5- to 10-member heteroaryl optionally substituted with 1 to 3 substituents independently selected from hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B is a C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy optionally substituted with 1 to 3 substituents independently selected from hydroxyl, -S(O2)C1-C6 alkyl, NR, a 4- to 10-member heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl, -(NH)-C1-C6 alkyl, and a -(NH)-4- to 10-member heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 1 is a C1-C6 alkyl optionally substituted with hydroxyl, -S(O2)C1-C6 alkyl, a 5- to 10-member heteroaryl optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, halogen and C1-C6 alkyl, -(NH)-C1-C6 alkyl, a 4- to 10-member heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl, and a -(NH)-4- to 10-member heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 1 is a C1-C6 alkyl optionally substituted with hydroxyl, -S(O2)C1-C6 alkyl, a 5- to 10-member heteroaryl optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, halogen and C1-C6 alkyl, -(NH)-C1-C6 alkyl, a 4- to 10-member heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl, and a -(NH)-4- to 10-member heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 1These are 5-6 member heteroaryls substituted with two substituents independently selected from hydroxyl, C1-C6 alkyls optionally substituted with -S(O2)C1-C6 alkyls, C1-C6 thioalkyls, and C1-C6 alkoxys, 4-10 member heterocyclines optionally substituted with halogens and 1-3 substituents independently selected from C1-C6 alkyls and -(NH)-C1-C6 alkyls, and -(NH)-4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyls. In some embodiments, R 1 These are 9-10 member heteroaryls substituted with two substituents independently selected from hydroxyl, C1-C6 alkyls optionally substituted with -S(O2)C1-C6 alkyls, C1-C6 thioalkyls, and C1-C6 alkoxys, 4-10 member heterocyclines optionally substituted with halogens and 1-3 substituents independently selected from C1-C6 alkyls and -(NH)-C1-C6 alkyls, and -(NH)-4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyls. In some embodiments, R 1 These are 5-10 member heteroaryls substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, and -S(O2)C1-C6 alkyl, as well as -(NH)-4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl. In some embodiments, R 1 These are 9-10 member heteroaryls substituted with two substituents independently selected from C1-C6 alkoxys and -S(O2)C1-C6 alkyls, and -(NH)-4-10 member heterocyclines optionally substituted with C1-C6 alkyls. In some embodiments, R 1is a 5- to 6-member heteroaryl substituted with two substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, -S(O2)C1-C6 alkyl, and a 4- to 10-member heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl, and -(NH)-.

[0084] In some embodiments, R 1A and R 1B are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 1A and R 1B are independently selected from hydrogen and C1-C6 alkyl. In some embodiments, R 1A is H and R 1B is C1-C6 alkyl. In some embodiments, R 1A and R 1B are independently selected from C1-C6 alkyl.

[0085] In some embodiments, R 1 is a 9-member heteroaryl. In some embodiments, R 1 is a 9-member heteroaryl bonded to the remainder of formula (I) or (II) via a 5-member ring. In some embodiments, R 1 is a 9-member heteroaryl bonded to the remainder of formula (I) or (II) via a 6-member ring. In some embodiments, R 1 is

[0086]

Chemical formula

[0087]

Chemical formula

[0088] [ka] And in the formula,

[0089] [ka] " indicates a connection point to the rest of equation (I) or (II), R 1 It is optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkoxy, -S(O2)C1-C6 alkyl, and -(NH)-4 to 10-membered heterocyclines, which are optionally substituted with 1 to 3 substituents independently selected from halogens and C1-C6 alkyl.

[0090] In some embodiments, R 1 These are 9-membered heteroaryls substituted with two substituents independently selected from C1-C6 thioalkyls, C1-C6 alkoxys, and -S(O2)C1-C6 alkyls, as well as -(NH)-4 to 10-membered heterocyclines optionally substituted with 1 to 3 substituents independently selected from halogens and C1-C6 alkyls.

[0091] In some embodiments, R 1 These are 5-6 member heteroaryls substituted with two substituents independently selected from C1-C6 thioalkyls, C1-C6 alkoxys, and -S(O2)C1-C6 alkyls, as well as -(NH)-4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyls.

[0092] In some embodiments, when R 1 is substituted with a -(NH)-4- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl, the -(NH)-4- to 10-membered heterocyclyl is substituted with 1 or 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 1 is substituted with a -(NH)-4- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl, the -(NH)-4- to 10-membered heterocyclyl is unsubstituted.

[0093] In some embodiments, R 1 is a 9-membered heteroaryl substituted with 2 substituents independently selected from C1-C6 thioalkyl, C1-C6 alkoxy, and -S(O2)C1-C6 alkyl.

[0094] In some embodiments, R 1 is a 5- to 6-membered heteroaryl substituted with 2 substituents independently selected from C1-C6 thioalkyl, C1-C6 alkoxy, and -S(O2)C1-C6 alkyl.

[0095] In some embodiments, R 2A is hydrogen.

[0096] In some embodiments, R 2A is halogen. In some embodiments, R 2A is fluoro or chloro. In some embodiments, R 2A is bromo.

[0097] In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2Ais a C1-C3 alkyl group. In some embodiments, R 2A It is methyl.

[0098] In some embodiments, R 2A is a C1-C6 haloalkyl. In some embodiments, R 2A is a C1-C3 haloalkyl. In some embodiments, R 2A It is trifluoromethyl.

[0099] In some embodiments, R 2A is a C1-C6 hydroxyalkyl group. In some embodiments, R 2A is a C1-C3 hydroxyalkyl group. In some embodiments, R 2A It is hydroxyethyl.

[0100] In some embodiments, R 2B It is hydrogen.

[0101] In some embodiments, R 2B is a C1-C6 alkyl group. In some embodiments, R 2B is a C1-C3 alkyl group. In some embodiments, R 2B It is methyl.

[0102] In some embodiments, R 2B R is a C1-C6 haloalkyl. In some embodiments, R 2B R is a C1-C3 haloalkyl. In some embodiments, R 2B It is trifluoromethyl.

[0103] In some embodiments, R 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.

[0104] In some embodiments, R 3 It is hydrogen.

[0105] In some embodiments, R 3 is a halogen. In some embodiments, R 3 is fluoro or chloro. In some embodiments, R 3 It is Bromo.

[0106] In some embodiments, X is

[0107] [ka] That is the case.

[0108] In some embodiments, X is

[0109] [ka] That is the case.

[0110] In some embodiments, X is

[0111] [ka] That is the case.

[0112] In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 It is methyl.

[0113] In some embodiments, R 4 It is hydrogen.

[0114] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R BThese are phenyl, benzyl, C1-C6 alkyl, and phenyl, which are optionally substituted with hydroxyl, 4- to 10-membered heterocyclines, which are optionally substituted with 1-3 substituents independently selected from phenyl, benzyl, C1-C6 alkyl, and phenyl, which are optionally substituted with C1-C6 alkyl, and C1-C6 alkyl, which are optionally substituted with 1-3 substituents independently selected from 5- to 10-membered heteroaryls, which are optionally substituted with 1-3 substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0115] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B These are phenyl, benzyl, C1-C6 alkyl, and phenyl, which are optionally substituted with hydroxyl, 4-10 member heterocyclyls, which are optionally substituted with 1-3 substituents independently selected from phenyl, benzyl, C1-C6 alkyl, and phenyl, which are optionally substituted with C1-C6 alkyl; 5-10 member heteroaryls, which are optionally substituted with 1-3 substituents independently selected from halogens and C1-C6; and C1-C6 alkyls, which are optionally substituted with 1-3 substituents independently selected from 5-9 member heteroaryls, which are optionally substituted with 1-3 substituents independently selected from halogens, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0116] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R BThese are phenyl, benzyl, C1-C6 alkyl, and phenyl, which are optionally substituted with hydroxyl, 4-10 member heterocyclyls, which are optionally substituted with 1-3 substituents independently selected from phenyl, benzyl, C1-C6 alkyl, and phenyl, which are optionally substituted with C1-C6 alkyl, and C1-C6 alkyls, which are optionally substituted with 1 or 2 substituents independently selected from 5-9 member heteroaryls, which are optionally substituted with 1-3 substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0117] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B These are phenyl, benzyl, C1-C6 alkyl, and phenyl, which are optionally substituted with hydroxyl, 4- to 8-membered heterocyclines, which are optionally substituted with one or two substituents independently selected from phenyl, which are optionally substituted with C1-C6 alkyl, and C1-C6 alkyl, and C1-C6 alkyl, which are optionally substituted with one or two substituents independently selected from 5- to 9-membered heteroaryls, which are optionally substituted with one or two substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0118] In some embodiments, R 5 The C1-C6 alkyl group is methyl.

[0119] In some embodiments, R 5 This is a C3-C10 cycloalkyl group that is optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyl groups, and phenyl groups optionally substituted with 1 to 2 independently selected halogens.

[0120] In some embodiments, R 5This is a C3-C10 cycloalkyl group substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, and phenyl groups optionally substituted with 1 to 2 independently selected halogens.

[0121] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B These are phenyl, benzyl, C1-C6 alkyl, and phenyl that are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are optionally substituted with 1 to 3 substituents independently selected from phenyl, which are optionally substituted with C1-C6 alkyl, and C1-C6 alkyl, which are optionally substituted with 1 to 3 substituents independently selected from 5 to 10-membered heteroaryls that are optionally substituted with 1 to 3 substituents independently selected from halogens and C1-C6 alkyl.

[0122] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B These are phenyl, benzyl, C1-C6 alkyl, and phenyl that are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are optionally substituted with 1 to 3 substituents independently selected from phenyl, which are optionally substituted with C1-C6 alkyl, and which are C1-C6 alkyl, which are optionally substituted with 1 to 3 substituents independently selected from 5 to 10-membered heteroaryls that are optionally substituted with 1 to 3 substituents independently selected from halogens and C1-C6 alkyl.

[0123] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R BThese are phenyl, benzyl, C1-C6 alkyl, and phenyl that are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are 4- to 10 member heterocyclines optionally substituted with 1 to 3 substituents independently selected from these, and C1-C6 alkyls optionally substituted with 1 or 2 substituents independently selected from 5- to 10 member heteroaryls optionally substituted with halogens and C1-C6 alkyls.

[0124] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B These are phenyl, benzyl, C1-C6 alkyl, and phenyl that are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are 4- to 8-membered heterocyclines optionally substituted with one or two substituents independently selected from these, and C1-C6 alkyls optionally substituted with one or two substituents independently selected from halogens and C1-C6 alkyls, which are 5- to 10-membered heteroaryls optionally substituted with one or two substituents independently selected from these.

[0125] In some embodiments, R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B The C1-C6 alkyl groups are 4- to 8-membered heterocyclines substituted with one or two substituents independently selected from phenyl, benzyl, C1-C6 alkyl, and phenyl substituted with C1-C6 alkyl groups, as well as C1-C6 alkyl groups substituted with 5- to 10-membered heteroaryl groups substituted with one or two substituents independently selected from halogens and C1-C6 alkyl groups.

[0126] In some embodiments, R 5C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B These are phenyl, benzyl, C1-C6 alkyl, and phenyl that are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are optionally substituted with C1-C6 alkyl, which are 4- to 8-membered heterocyclines optionally substituted with one or two substituents independently selected from these, and C1-C6 alkyls optionally substituted with one or two substituents independently selected from halogens and C1-C6 alkyls, which are 5- to 10-membered heteroaryls optionally substituted with one or two substituents independently selected from these, which are 5- to 10-membered heteroaryls.

[0127] In some embodiments, R 5 is benzyl, and phenyl is optionally substituted with 1 to 3 independently selected halogens. In some embodiments, R 5 is benzyl, and phenyl is substituted with 1 to 3 independently selected halogens. In some embodiments, R 5 It is benzyl.

[0128] In some embodiments, R 5 The C1-C6 alkyl group is methyl.

[0129] In some embodiments, R 5 This is a C3-C10 cycloalkyl group that is optionally substituted with 1 to 3 substituents independently selected from phenyl, which is optionally substituted with hydroxyl, C1-C6 alkyl, and 1 to 2 independently selected halogens.

[0130] In some embodiments, R 5 This is a C3-C10 cycloalkyl group substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, and phenyl groups optionally substituted with 1 to 2 independently selected halogens.

[0131] In some embodiments, R 5This is a C3-C6 cycloalkyl group substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyl groups, and phenyl groups optionally substituted with 1 to 2 independently selected halogens.

[0132] In some embodiments, R 5 This is a C3-C6 cycloalkyl group substituted with one or two substituents independently selected from halogens, hydroxyls, C1-C6 alkyl groups, and phenyl groups optionally substituted with one or two independently selected halogens.

[0133] In some embodiments, R 5 It is a C3-C6 cycloalkyl that is substituted with two independently selected halogens.

[0134] In some embodiments, R 5 is a C3-C10 cycloalkyl group. In some embodiments, R 5 It is a C3-C6 cycloalkyl group.

[0135] In some embodiments, R 5 It is a 4- to 10-membered heterocycline that is optionally substituted with 1 to 3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl.

[0136] In some embodiments, R 5 It is a 4- to 10-membered heterocycline substituted with 1 to 3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl.

[0137] In some embodiments, R 5 It is a 4- to 10-membered heterocycline substituted with one or two substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl.

[0138] In some embodiments, R 5 It is a 4- to 8-membered heterocycline substituted with one or two substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl.

[0139] In some embodiments, R 5 It is a 4- to 8-membered heterocycline substituted with phenyl.

[0140] In some embodiments, R 5 It is a heterocycline with 4 to 8 members.

[0141] In some embodiments, R 5 This is a phenyl compound that is optionally substituted with 1 to 3 substituents independently selected from halogens, nitros, and C1-C6 haloalkyls.

[0142] In some embodiments, R 5 This is a phenyl compound substituted with 1 to 3 substituents independently selected from halogens, nitros, and C1-C6 haloalkyls.

[0143] In some embodiments, R 5 This is a phenyl compound substituted with one or two substituents independently selected from halogens, nitros, and C1-C6 haloalkyls.

[0144] In some embodiments, R 5 It is a 5-10 member heteroaryl that is optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl groups.

[0145] In some embodiments, R 5 R is a 5-10 member heteroaryl substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl groups. In some embodiments, R 5It is a 5-10 member heteroaryl substituted with 1-3 substituents independently selected from halogens and methyl groups.

[0146] In some embodiments, R 5 R is a 5-10 member heteroaryl substituted with one or two substituents independently selected from halogens and C1-C6 alkyl groups. In some embodiments, R 5 It is a 5- to 10-membered heteroaryl substituted with one or two substituents independently selected from halogens and methyl groups.

[0147] In some embodiments, R 5 R is a 5-6 member heteroaryl substituted with one or two substituents independently selected from halogens and C1-C6 alkyl groups. In some embodiments, R 5 It is a 5-6 member heteroaryl substituted with one or two substituents independently selected from halogens and methyl groups.

[0148] In some embodiments, R 5 is a C1-C6 alkoxy. In some embodiments, R 5 R is a C1-C3 alkoxy. In some embodiments, R 5 It is methoxy.

[0149] In some embodiments, R 5 It is a C3-C6 cycloalkoxy.

[0150] In some embodiments, R 4 and R 5 These, together with the atoms to which they are bonded, form a 5-12 member heterocycline that is optionally substituted with phenyl. In some embodiments, R 4 and R 5 These, together with the atoms to which they are bonded, form a phenyl-substituted 5-12 member heterocycline. In some embodiments, R 4 and R5 These atoms, together with the atoms to which they are bonded, form a 5- to 12-membered heterocycline.

[0151] In some embodiments, R 4 and R 5 These, together with the atoms to which they are bonded, form a 9-10 member heteroaryl that is optionally substituted with phenyl. In some embodiments, R 4 and R 5 These, together with the atoms to which they are bonded, form a phenyl-substituted 9-10 member heteroaryl. In some embodiments, R 4 and R 5 These atoms, together with the atoms to which they are bonded, form a 9-10 member heteroaryl group.

[0152] In some embodiments, R A It is hydrogen.

[0153] 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.

[0154] In some embodiments, R B It is hydrogen.

[0155] 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.

[0156] In some embodiments, formula (I) is (Ia)

[0157] [ka] or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, formula (I) is (Ib)

[0159] [ka] or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, formula (I) is (Ic)

[0161] [ka] or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, formula (I) is (Id)

[0163] [ka] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, formula (I) is (Ie)

[0165] [ka] or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, formula (I) is (If)

[0167] [ka] or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, formula (I) is (Ig)

[0169] [ka] or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, formula (I) is (Ih)

[0171] [ka] or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, formula (I) is (Ii)

[0173] [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1C It is a C1-C6 alkoxy that is optionally substituted with a hydroxyl group. R 1D It is a -S(O2)-C1-C6 alkyl group, R 2A1 These are C1-C3 alkyl or C3-C4 cycloalkyl, R 5A This is a phenyl molecule optionally substituted with a halogen or a C1-C6 alkyl group, or a 5-6 member heteroaryl group optionally substituted with a halogen or a C1-C6 alkyl group.

[0174] In some embodiments, formula (I) is (Ij)

[0175] [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1EIt is a 5-10 member heteroaryl substituted with two substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy which are optionally substituted with hydroxyl, and -S(O2)C1-C6 alkyl. R 2A1 These are C1-C3 alkyl or C3-C4 cycloalkyl, Ring B is (i) a phenyl molecule optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, C1-C6 hydroxyalkyls, and cyanos; or (ii) a 5-6 member heteroaryl molecule optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. Here, -(CH3) 0-1 The symbol is intended to indicate the presence or absence of a methyl group; if a methyl group is not present, a hydrogen atom is present in its place.

[0176] In some embodiments, equation (II) is (II-a)

[0177] [ka] or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, equation (II) is (II-b)

[0179] [ka] or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, equation (II) is (II-c)

[0181] [ka] or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, equation (II) is (II-d)

[0183] [ka] or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, equation (II) is (II-e)

[0185] [ka] or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, equation (II) is (II-f)

[0187] [ka] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, formula (I) is (Ig)

[0189] [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1C It is a C1-C6 alkoxy that is optionally substituted with a hydroxyl group. R 1D is -S(O2)-C1-C6 alkyl, and R 5A This is a phenyl molecule optionally substituted with a halogen or a C1-C6 alkyl group, or a 5-6 member heteroaryl group optionally substituted with a halogen or a C1-C6 alkyl group.

[0190] In some embodiments, formula (I) is (Ih)

[0191] [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1E This is a 5-10 member heteroaryl substituted with two substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy which are optionally substituted with hydroxyl, and -S(O2)C1-C6 alkyl, and also, Ring B is (i) a phenyl molecule optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, C1-C6 hydroxyalkyls, and cyanos; or (ii) a 5-6 member heteroaryl molecule optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. Here, -(CH3) 0-1 The symbol is intended to indicate the presence or absence of a methyl group; if a methyl group is not present, a hydrogen atom is present in its place.

[0192] In some embodiments, formula (I) is,

[0193] [ka] Or selected from the group consisting of any of the pharmaceutically acceptable salts thereof.

[0194] In some embodiments, formula (I) is,

[0195] [ka]

[0196] [ka] or selected from the group consisting of pharmaceutically acceptable salts thereof.

[0197] In some embodiments, formula (I) is,

[0198] [ka] or selected from the group consisting of pharmaceutically acceptable salts thereof.

[0199] In some embodiments, formula (II) is,

[0200] [ka] Or selected from the group consisting of any of the pharmaceutically acceptable salts thereof.

[0201] In some embodiments, formula (II) is,

[0202] [ka] Or selected from the group consisting of any of the pharmaceutically acceptable salts thereof.

[0203] In some embodiments, formula (II) is,

[0204] [ka] or selected from the group consisting of pharmaceutically acceptable salts thereof.

[0205] The compounds of formula (I) and their pharmaceutically acceptable salts do not include the compounds exemplified in PCT application PCT / US2023 / 024988, or their pharmaceutically acceptable salts.

[0206] In some embodiments, the compounds of formula (I) and formula (II) include the compounds of Examples 1 to 194 and their pharmaceutically acceptable salts. In some embodiments, the compounds of Examples 1 to 194 are in free base form. In some embodiments, the compounds of Examples 1 to 194 are in salt form, for example, pharmaceutically acceptable salt form.

[0207] 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.

[0208] 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.

[0209] 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).

[0210] An example sequence of human RIPK2 is shown below (UniParc accession number UPI00001338F2): MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLHIHTPLLDSERKDVLREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDVAWPLRFRILHEIALGVNYL HNMTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIE SGWAQNPDERPSFLKCLIELEPVLRTFEEITFLEAVIQLKKTKLQSVSSAIHLCDKKKMELSLNIPVNHGPQEESCGSSQLHENSGSPETSRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAA FCDHKTTPCSSAIINPLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGLQPYPEILVVSRSPSLNLLQNKSM

[0211] 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.

[0212] 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0213] Some embodiments provide a method for treating a RIPK2-related disease or disorder in a subject requiring treatment, comprising the steps of (a) determining 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 containing an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0214] Some embodiments provide a method for treating a RIPK2-related disease or disorder in a subject requiring treatment, comprising the steps of (a) determining 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0215] 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.

[0216] 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, RIPK2-related disorders or conditions are cardiovascular diseases, allergic disorders, autoimmune diseases, inflammatory diseases, cardiovascular diseases, fibrotic diseases, or diseases associated with abnormal cell proliferation.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] In some embodiments, RIPK2-related disorders include fatal systemic inflammatory response syndrome, chronic intestinal and skin inflammation, or acute pancreatitis.

[0225] 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.

[0226] 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).

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0235] Some embodiments provide a method for treating inflammatory bowel disease in a subject requiring treatment, comprising the steps of (a) determining that the subject is suffering from 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.

[0236] Some embodiments provide a method for treating inflammatory bowel disease in a subject requiring treatment, comprising the steps of (a) determining that the subject is suffering from inflammatory bowel disease, and (b) administering to the subject an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0237] 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.

[0238] 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0239] 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.

[0240] 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 the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0241] Some embodiments provide a method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising the steps of (a) determining 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.

[0242] Some embodiments provide a method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising the steps of (a) determining that the subject has Crohn's disease, and (b) administering to the subject an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0243] 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 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.

[0244] 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 the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the subject is human.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] Similarly, pharmaceutical compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient are provided herein.

[0254] Numbered Embodiments Embodiment 1: Formula (I) or Formula (II)

[0255] [ka] A compound of, or a pharmaceutically acceptable salt thereof, wherein, R 1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy molecules, a 4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl and -(NH)-C1-C6 alkyl molecules, and a -(NH)-4-10 member heterocyclil molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl molecules. R 1A and R 1B These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R 2A It is selected from hydrogen, halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halogen, C1-C6 alkyl, and 4- to 10-membered heterocyclies optionally substituted with one or two substituents independently selected from C(O)O C1-C6 alkyl. R 2B These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. R 3 is hydrogen or halogen, X is

[0256] [ka] Selected from, R 4 is hydrogen or C1-C6 alkyl, R 5 teeth, (i) (a) C3-C6 cycloalkyl groups optionally substituted with 1 to 3 substituents independently selected from halogens or phenyls, (b) Phenyls optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, C1-C6 hydroxyalkyls, and cyanos. (c)-NR A R B ; (d) Hydroxyl, (e) halogen, (f) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl, and (g) 5-10 member heteroaryls optionally substituted with 1-3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. C1-C6 alkyl groups that are optionally substituted with 1 to 4 substituents independently selected from the above. (ii) C3-C10 cycloalkyls optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, phenyls optionally substituted with 1 to 2 independently selected halogens and 5 to 10 member heteroaryls, (iii) A 4-10 member heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl, (iv) Phenyls optionally substituted with 1 to 3 substituents independently selected from halogens, nitros, and C1-C6 haloalkyls. (v) A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl groups. (vi) C1-C6 alkoxy, or (vii) C3-C6 cycloalkoxy Selected from, Alternatively, R 4 and R 5 These, together with the atoms to which they are bonded, form 5-12 member heterocyclines or 9-10 member heteroaryls, each optionally substituted with phenyl. R A and R B These are independently a compound selected from hydrogen and C1-C6 alkyl groups, or a pharmaceutically acceptable salt thereof.

[0257] Embodiment 2: R 1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B The compounds described in Embodiment 1, or pharmaceutically acceptable salts thereof, are 5-10 member heteroaryl compounds optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy compounds, halogens, and 4-10 member heterocyclil compounds optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -(NH)-C1-C6 alkyl compounds, as well as -(NH)-4-10 member heterocyclil compounds optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl compounds.

[0258] Embodiment 3: R1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B The compounds described in Embodiment 1 or 2, or pharmaceutically acceptable salts thereof, are 5-10 member heteroaryls substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy compounds, halogens, and 4-10 member heterocyclils substituted with 1-3 substituents independently selected from C1-C6 alkyl and -(NH)-C1-C6 alkyl compounds, and -(NH)-4-10 member heterocyclils substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl compounds.

[0259] Embodiment 4: R 1 is hydroxyl, -S(O2)C1-C6 alkyl, NR 1A R 1B The compounds described in Embodiment 1 or 2, or pharmaceutically acceptable salts thereof, are 9- to 10-membered heteroaryls substituted with two substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy, halogens, and 4- to 10-membered heterocyclines substituted with 1- to 3 substituents independently selected from C1-C6 alkyl and -(NH)-C1-C6 alkyl, and -(NH)-4- to 10-membered heterocyclines substituted with 1- to 3 substituents independently selected from halogens and C1-C6 alkyl.

[0260] Embodiment 5: R 2A The compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0261] Embodiment 6: R 2A The compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

[0262] Embodiment 7: R 2AThe compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 alkyl group.

[0263] Embodiment 8: R 2A The compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, is a C1-C6 haloalkyl compound.

[0264] Embodiment 9: R 2A The compound according to any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 hydroxyalkyl group optionally substituted with one or two halogens.

[0265] Embodiment 10:R 2A The compound according to any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 hydroxyalkyl group substituted with one or two halogens.

[0266] Embodiment 11: R 2A The compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, is a C1-C6 alkoxyalkyl compound.

[0267] Embodiment 12: R 2A The compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is a C3-C6 cycloalkyl compound.

[0268] Embodiment 13: R 2A The compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, is a 4- to 10-membered heterocycline optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyls, and C(O)O C1-C6 alkyls.

[0269] Embodiment 14: R 2AThe compound described in any one of Embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, is a 4- to 10-membered heterocycline substituted with one or two substituents independently selected from a halogen, a C1-C6 alkyl, and a C(O)O C1-C6 alkyl.

[0270] Embodiment 15: R 2B A compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0271] Embodiment 16: R 2B The compound described in any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 alkyl group.

[0272] Embodiment 17: R 2B The compound described in any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 haloalkyl compound.

[0273] Embodiment 18: R 2B The compound described in any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 hydroxyalkyl compound.

[0274] Embodiment 19: R 3 A compound according to any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0275] Embodiment 20:R 3 A compound according to any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

[0276] Embodiment 21:X is

[0277] [ka] A compound according to any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof.

[0278] Embodiment 22:X is

[0279] [ka] A compound according to any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 23:X is

[0281] [ka] A compound according to any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof.

[0282] Embodiment 24: R 4 The compound described in any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 alkyl group.

[0283] Embodiment 25: R 4 The compound described in any one of Embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0284] Embodiment 26: R 4 The compound described in any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0285] Embodiment 27: R 5 These are C3-C6 cycloalkyl, halogen, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and cyano, -NR, which are optionally substituted with 1 to 3 substituents independently selected from halogens or phenyls. A R BA compound according to any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, wherein the compound is a phenyl, benzyl, C1-C6 alkyl, or

[0286] Embodiment 28: R 5 These are C3-C6 cycloalkyl, halogen, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and cyano, -NR, which are optionally substituted with 1 to 3 substituents independently selected from halogens or phenyls. A R B A compound according to any one of Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, wherein the compound is a phenyl, benzyl, C1-C6 alkyl, or

[0287] Embodiment 29: R 5 These are C3-C6 cycloalkyl, halogen, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and cyano, -NR, which are optionally substituted with 1 to 3 substituents independently selected from halogens or phenyls. A R BA compound according to any one of Embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, which is a phenyl, benzyl, C1-C6 alkyl, and 4- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents optionally substituted with phenyl, benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl, and a C1-C6 alkyl optionally substituted with 1 or 2 substituents optionally substituted with 5- to 10-membered heteroaryl, which is optionally substituted with 1 to 3 substituents optionally substituted with halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0288] Embodiment 30:R 5 C3-C6 cycloalkyls optionally substituted with phenyl, 1-3 independently selected halogens, -NR A R B A compound according to any one of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, which is a 4- to 8-membered heterocyclyl optionally substituted with one or two substituents independently selected from phenyl, benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl, and a C1-C6 alkyl optionally substituted with one or two substituents independently selected from 5- to 9-membered heteroaryls optionally substituted with one or two substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0289] Embodiment 31: R 5 The C1-C6 alkyl group is methyl, the compound according to any one of embodiments 27-30, or a pharmaceutically acceptable salt thereof.

[0290] Embodiment 32: R 5The compound according to any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, is a C3-C10 cycloalkyl compound optionally substituted with 1 to 3 substituents optionally substituted with a halogen, a hydroxyl, a C1-C6 alkyl, one or two independently selected halogens, and a phenyl optionally substituted with a 5-10 member heteroaryl.

[0291] Embodiment 33:R 5 The compound according to any one of Embodiments 1 to 26 or 32, or a pharmaceutically acceptable salt thereof, is a C3-C10 cycloalkyl compound substituted with 1 to 3 substituents independently selected from a halogen, a hydroxyl, a C1-C6 alkyl, a phenyl compound optionally substituted with 1 to 2 independently selected halogens and a 5-10 member heteroaryl.

[0292] Embodiment 34: R 5 The compound described in any one of Embodiments 1 to 26 or 32 to 33, or a pharmaceutically acceptable salt thereof, is a C3-C6 cycloalkyl compound substituted with 1 to 3 substituents independently selected from halogens, hydroxyl, C1-C6 alkyl, and phenyl which is optionally substituted with 1 to 2 independently selected halogens.

[0293] Embodiment 35:R 5 The compound described in any one of Embodiments 1 to 26 or 32 to 34, or a pharmaceutically acceptable salt thereof, is a C3-C6 cycloalkyl compound substituted with one or two substituents independently selected from a halogen, a hydroxyl, a C1-C6 alkyl, one or two independently selected halogens, and a phenyl optionally substituted with a 5-10 member heteroaryl.

[0294] Embodiment 36: R 5The compound described in any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, is a 4- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl.

[0295] Embodiment 37: R 5 The compound described in any one of Embodiments 1 to 26 or 36, or a pharmaceutically acceptable salt thereof, is a 4 to 10-membered heterocyclyl substituted with 1 to 3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl.

[0296] Embodiment 38:R 5 The compound described in any one of Embodiments 1 to 26 or 37 to 38, or a pharmaceutically acceptable salt thereof, is a 4 to 8-membered heterocyclyl substituted with 1 to 3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl.

[0297] Embodiment 39: R 5 The compound described in any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, is a phenyl compound optionally substituted with 1 to 3 substituents independently selected from halogens, nitros, and C1-C6 haloalkyls.

[0298] Embodiment 40:R 5 The compound described in any one of Embodiments 1 to 26 or 39, or a pharmaceutically acceptable salt thereof, is a phenyl compound substituted with 1 to 3 substituents independently selected from halogens, nitros, and C1-C6 haloalkyls.

[0299] Embodiment 41: R 5The compound described in any one of Embodiments 1-26 or 39-40, or a pharmaceutically acceptable salt thereof, is a phenyl compound substituted with one or two substituents independently selected from halogens, nitros, and C1-C6 haloalkyls.

[0300] Embodiment 42: R 5 The compound according to any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, is a 5- to 10-membered heteroaryl compound optionally substituted with 1 to 3 substituents independently selected from halogens and C1-C6 alkyl groups.

[0301] Embodiment 43: R 5 The compound according to any one of Embodiments 1 to 26 or 42, or a pharmaceutically acceptable salt thereof, is a 5- to 10-membered heteroaryl substituted with 1 to 3 substituents independently selected from halogens and C1-C6 alkyl groups.

[0302] Embodiment 44: R 5 The compound described in any one of Embodiments 1 to 26 or 43, or a pharmaceutically acceptable salt thereof, is a 5- to 10-membered heteroaryl substituted with one or two substituents independently selected from halogens and C1-C6 alkyl groups.

[0303] Embodiment 45: R 5 The compound described in any one of Embodiments 1-26 or 43-44, or a pharmaceutically acceptable salt thereof, is a 5-6 member heteroaryl substituted with one or two substituents independently selected from halogens and C1-C6 alkyl groups.

[0304] Embodiment 46: R 5 The compound described in any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 alkoxy.

[0305] Embodiment 47: R 5The compound described in any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, is a C3-C6 cycloalkoxy.

[0306] Embodiment 48: R 4 and R 5 The compounds described in any one of Embodiments 1 to 23, or pharmaceutically acceptable salts thereof, which, together with the atoms to which they are bonded, form a 5- to 12-membered heterocycline optionally substituted with phenyl.

[0307] Embodiment 49: R 4 and R 5 The compounds described in any one of Embodiments 1 to 23 or 48, or a pharmaceutically acceptable salt thereof, which, together with the atoms to which they are bonded, form a 5- to 12-membered heterocycline.

[0308] Embodiment 50:R 4 and R 5 The compounds described in any one of Embodiments 1 to 23, or pharmaceutically acceptable salts thereof, wherein they, together with the atoms to which they are bonded, form a 9-10 member heteroaryl that is optionally substituted with phenyl.

[0309] Embodiment 51:R 4 and R 5 The compounds described in any one of Embodiments 1 to 23 or 50, or a pharmaceutically acceptable salt thereof, wherein they combine with the atoms to which they are bonded to form a 9-10 membered heteroaryl group.

[0310] Embodiment 52: R A A compound according to any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0311] Embodiment 53:R A The compound described in any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 alkyl group.

[0312] Embodiment 54: R B A compound according to any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0313] Embodiment 55:R B The compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein is a C1-C6 alkyl group.

[0314] Embodiment 56: Equation (I) is (Ia)

[0315] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0316] Embodiment 57: Equation (I) is (Ib)

[0317] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0318] Embodiment 58: Equation (I) is (Ic)

[0319] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0320] Embodiment 59: Formula (I) is (Id)

[0321] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 60: Equation (I) is (Ie)

[0323] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0324] Embodiment 61: Equation (I) is (If)

[0325] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0326] Embodiment 62: Equation (II) is (II-a)

[0327] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0328] Embodiment 63: Equation (II) is (II-b)

[0329] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0330] Embodiment 64: Equation (II) is (II-c)

[0331] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0332] Embodiment 65: Equation (II) is (II-d)

[0333] [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0334] Embodiment 66: Formula (I) is,

[0335] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of either the compound or a pharmaceutically acceptable salt thereof.

[0336] Embodiment 67: Formula (I) is,

[0337] [ka]

[0338] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of either the compound or a pharmaceutically acceptable salt thereof.

[0339] Embodiment 68: Formula (I) is,

[0340] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of either the compound or a pharmaceutically acceptable salt thereof.

[0341] Embodiment 69: Formula (II) is,

[0342] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of either the compound or a pharmaceutically acceptable salt thereof.

[0343] Embodiment 70: Formula (II) is,

[0344] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of either the compound or a pharmaceutically acceptable salt thereof.

[0345] Embodiment 71: Formula (II) is,

[0346] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of either the compound or a pharmaceutically acceptable salt thereof.

[0347] Embodiment 72: Formula (II) is,

[0348] [ka] A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of either the compound or a pharmaceutically acceptable salt thereof.

[0349] Embodiment 73: A compound selected from the group consisting of the compounds of Examples 1 to 194, or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 74: A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0351] Embodiment 75: 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 described in any one of Embodiments 1 to 73, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 74 to the subject.

[0352] Embodiment 76: The method according to Embodiment 75, 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.

[0353] Embodiment 77: The method according to Embodiment 75 or 76, wherein the RIPK2-related disease or disorder is an inflammatory disease.

[0354] Embodiment 78: 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 77, 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.

[0355] Embodiment 79: 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 73, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 74 to the subject.

[0356] Embodiment 80: 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 73, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 74.

[0357] Embodiment 81: 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 73, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 74, to the subject.

[0358] Embodiment 82: 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 73, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 74, to the subject.

[0359] Embodiment 83: 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 73, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 74.

[0360] Embodiment 84: A method for treating Crohn's disease in a subject previously identified or diagnosed with Crohn's disease, the method comprising the step of administering an effective amount of a compound according to any one of Embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 74, to the subject.

[0361] 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.

[0362] 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.

[0363] 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 th This 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).

[0364] intermediate

[0365] [ka]

[0366] Di-tert-butyl azodicarboxylate (10.52 g, 45.70 mmol, 6 equivalents) was added to a solution of 6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine (1.80 g, 7.62 mmol, 1 equivalent) in 80 mL of di-tert-butyl 1-(6 [M+H] + =467.4. 1H NMR(400MHz,CDCl3)δppm 8.62(s,1H),7.42(s,1H),7.00-6.90(m,1H),6.86(s,1H),3.91(s,3H),1.45(s,18H),1.30(s,9H).

[0367] A mixture of di-tert-butyl 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine dicarboxylate (1 g, 1.93 mmol, 1 equivalent) in 4 M HCl in 6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)hydrazine-1,2-dicarboxylate (1 g, 1.93 mmol, 1 equivalent) was degassed, purged three times with N2, and then stirred at 25°C under an N2 atmosphere for 3 hours. The mixture was concentrated under reduced pressure to obtain the crude title compound (500 mg) as a yellow solid.

[0368] Ethyl 2-formyl-3-oxopropanoate (1.35 g, 9.39 mmol, 5 equivalents) was added to a solution of 6-(tert-butylthio)-3-hydrazineyl-7-methoxyimidazo[1,2-a]pyridine dihydrochloride (500 mg, 1.88 mmol, 1 equivalent) in ethyl 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine dihydrochloride (10 mL) in ethyl 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine dihydrochloride (100 mg, 1.88 mmol, 1 equivalent). The mixture was stirred at 25°C for 12 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-4% MeOH / DCM) to obtain the title compound (518 mg, yield 66%) as a yellow solid. [M+H] + =375.2.

[0369] 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxylic acid: A solution of ethyl 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxylate (518 mg, 1.25 mmol, 90% purity, 1 equivalent) in MeOH (24 mL) and H2O (4 mL) was mixed with LiOH·H2O (522.40 mg, 12.45 mmol, 10 equivalents). The mixture was stirred at 25°C for 12 hours and then concentrated under reduced pressure. The residue was dissolved in water (2 mL) and neutralized with 1 N HCl. The precipitate was isolated by filtration, and the filtration cake was washed with water (3 mL) and dried to obtain the title compound (300 mg, 69% yield) as a pale yellow solid. [M+H] + =347.0. 1 H NMR(400MHz,DMSO-d6)δppm 13.09-12.36(m,1H),8.73(s,1H),8.27(d,J=8.4Hz,2H),7.80(br s,1H),7.14(br s,1H),3.91(s,3H),1.22(s,9H).

[0370] [ka]

[0371] A mixture of tert-butyl(1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-yl)carbamate in t-BuOH (5 mL) containing 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxylic acid (50 mg, 142.41 μmol, purity 98.66%, 1 equivalent) and Et3N (15.85 mg, 156.65 μmol, 21.80 μL, 1.1 equivalents) was degassed, purged three times with N2, and then DPPA (43.11 mg, 156.65 μmol, 33.94 μL, 1.1 equivalents) was added. The mixture was stirred under an N2 atmosphere at 20°C for 30 minutes, then at 90°C for a further 4 hours, and subsequently concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 1-10% MeOH / DCM) to obtain the title compound (80 mg, 40% yield) as a white solid. [M+H] + =418.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.47(s,1H),8.25(s,1H),8.03(s,1H),7.77(s,1H),7.68(s,1H),7.10(s,1H),3.89(s,3H),1.47(s,9H),1.22(s,9H).

[0372] To a solution of tert-butyl(1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-yl)carbamate (110 mg, 237.11 μmol, 90% purity, 1 equivalent) in MeOH (12 mL) and H2O (3 mL), Oxone® (874.61 mg, 1.42 mmol, 6 equivalents) was added. The mixture was stirred at 25°C for 12 hours, then quenched with saturated Na2SO3 (5 mL) and extracted with SiO2 (2 × 10 mL). The combined organic extracts 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 (105 mg, 98% yield) as a white solid. [M+H] + =450.1. 1 H NMR(400MHz,DMSO-d6)δppm 9.51(s,1H),8.73(s,1H),8.10(s,1H),7.84(s,1H),7.78(s,1H),7.27(s,1H),3.93(s,3H),1.47(s,9H),1.29(s,9H).

[0373] A solution of tert-butyl(1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-amine:DCM (2 mL) and TFA (0.4 mL) was stirred at 25°C for 1 hour and then concentrated under reduced pressure. The solid was dissolved in water (5 mL) and extracted with ELISA (2 × 5 mL). Saturated NaHCO3 was then added to the aqueous phase and extracted again with ELISA (2 × 5 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound (40 mg, yield 84%) as a pink solid. [M+H] +=349.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.80(s,1H),7.71(s,1H),7.48-7.40(m,2H),7.24(s,1H),4.31(br s,2H),3.92(s,3H),1.29(s,9H).

[0374] [ka]

[0375] 1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxylic acid (100 mg, 259.81 μmol, 90% purity, 1 equivalent) was dissolved in MeOH (10 mL) and H2O (2.5 mL), to which Oxone® (798.63 mg, 1.30 mmol, 5 equivalents) was added. The mixture was stirred at 25°C for 3 hours, then quenched with saturated Na2SO3 (20 mL) and extracted with siRNA (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by RP-HPLC to obtain the title compound (5.8 mg, 6% yield) as a white solid. [M+H] + =378.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.85(s,1H),8.81(s,1H),8.34(s,1H),8.17(s,1H),7.41(s,1H),4.00(s,3H),1.30(s,9H).

[0376] [ka]

[0377] CH3I (37.23 mg, 262.30 μmol, 16.33 μL, 1.2 equivalents) was added to a mixture of tert-butyl(1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-yl)(methyl)carbamate (100 mg, 218.59 μmol, 1 equivalent) and t-BuOK (36.79 mg, 327.88 μmol, 1.5 equivalents) in THF (10 mL). The mixture was stirred under an N2 atmosphere at 25°C for 1 hour, then diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (60 mg, yield 53%) as a yellow oil. [M+H] + =464.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.77(s,1H),8.36-7.96(m,2H),7.84(s,1H),7.29(s,1H),3.94(s,3H),3.23(s,3H),1.49(s,9H),1.29(s,9H).

[0378] To a mixture of tert-butyl(1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-amine)(methyl)carbamate (60 mg, 116.49 μmol, 1 equivalent) in 1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-yl)(methyl)carbamate (4 mL) in 1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-ylN-methyl-1H-pyrazole-4-amine:DCM (4 mL), TFA (3.07 g, 26.93 mmol, 2 mL, 231.13 equivalents) was added. The mixture was stirred under an N2 atmosphere at 25°C for 1 hour, then diluted with saturated NaHCO3 (20 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (45 mg, 96% yield) as a yellow solid. [M+H]+ =363.9.

[0379] [ka]

[0380] Methyl 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylate: Methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (850 mg, 2.87 mg) in 1,4-dioxane (56 mL) and H2O (14 mL). A mixture of mmol (1 equivalent), 6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine (1.13 g, 2.87 mmol, 1 equivalent), K2CO3 (1.19 g, 8.62 mmol, 3 equivalents), and Pd(dppf)Cl2 (210.36 mg, 287.49 μmol, 0.1 equivalent) was degassed, purged three times with N2, and then stirred at 80°C for 3 hours under an N2 atmosphere. The mixture was diluted with water (100 mL) and extracted with siRNA (3 × 100 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 1-10% MeOH / DCM) to obtain the title compound (340 mg, yield 26%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.84(s,1H),8.17(s,1H),7.45(s,1H),7.30(s,1H),4.18(s,3H),3.94(s,3H),3.89(s,3H),1.33(s,9H).

[0381] 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid: A solution of methyl 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylate (340 mg, 752.85 μmol, 1 equivalent) in MeOH (6 mL) and H2O (1 mL) was mixed with LiOH (315.92 mg, 7.53 mmol, 10 equivalents). The mixture was stirred at 25°C for 2 hours, then diluted with water (2 mL) and acidified with 2N HCl (pH=5) at 0°C. The resulting mixture was diluted with water (100 mL) and extracted with  (3 × 100 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 1-10% MeOH / DCM) to obtain the title compound (200 mg, 61% yield) as a yellow solid. [M+H] + =393.0. 1 H NMR(400MHz,DMSO-d6)δppm 10.00(s,1H),8.57(s,1H),7.50(s,2H),4.19(s,3H),4.06(s,3H),1.35(s,9H).

[0382] The following compounds were prepared following a procedure similar to that described for intermediate 5.

[0383] [Table 1]

[0384] [ka]

[0385] A mixture of 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-amine:DMF (25 mL) containing 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (200 mg, 458.68 μmol, 1 equivalent), DPPA (138.85 mg, 504.55 μmol, 108.90 μL, 1.1 equivalents), and Et3N (139.24 mg, 1.38 mmol, 191.53 μL, 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 concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 1-5% MeOH / DCM) to obtain the title compound (85 mg, 46% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.94(s,1H),7.86(s,1H),7.21(s,1H),5.72(s,1H),5.47(s,2H),3.92(s,3H),3.60(s,3H),1.31(s,9H).

[0386] [ka]

[0387] N-(3-bromo-1-methyl-1H-pyrazole-5-yl)-2-(2-chlorophenyl)acetamide: To a solution of 3-bromo-1-methyl-1H-pyrazole-5-amine (10 mg, 56.81 μmol, 1 equivalent) in DMF (1 mL) at 20°C, DIEA (14.69 mg, 113.63 μmol, 19.79 μL, 2 equivalents) was added dropwise, followed by the dropwise addition of HATU (43.20 mg, 113.63 μmol, 2 equivalents). The mixture was stirred at 20°C for 30 minutes, after which 2-(2-chlorophenyl)acetic acid (9.69 mg, 56.81 μmol, 1 equivalent) was added. The resulting mixture was stirred at 20°C for 16 hours, then diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 0-5% MeOH / DCM) to obtain the title compound (150 mg, yield 72%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 10.40(s,1H),7.46-7.39(m,2H),7.35-7.27(m,2H),6.31(s,1H),3.88(s,2H),3.67(s,3H).

[0388] 2-(2-chlorophenyl)-N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-yl)acetamide: N-(3-bromo-1-methyl-1H-pyrazole-5-yl)-2-(2-chlorophenyl)acetamide (100 mg, 273.90 μmol, 1 equivalent) in dioxane (1 mL), B2Pin A mixture of 2 (83.46 mg, 328.68 μmol, 1.2 equivalents), Pd(dppf)Cl2 (20.04 mg, 27.39 μmol, 0.1 equivalent), dppf (15.18 mg, 27.39 μmol, 0.1 equivalent), and KOAc (80.64 mg, 821.69 μmol, 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 filtered and concentrated under reduced pressure to obtain the title compound (150 mg) as a dark brown solid, which was used in the next step without further purification.

[0389] [ka]

[0390] Methyl 1-(2-(benzyloxy)ethyl)-3-bromo-1H-pyrazole-5-carboxylate: To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (1 g, 4.88 mmol, 1 equivalent) in DMF (2 mL), Cs2CO3 (4.77 g, 14.63 mmol, 3 equivalents) and ((2-bromoethoxy)methyl)benzene (2.62 g, 12.19 mmol, 1.93 mL, 2.5 equivalents) were added. The mixture was stirred at 25°C for 1 hour, then diluted with water (30 mL) at 0°C, and subsequently extracted with RINKAN (3 × 30 mL). The combined organic extracts 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, 0-50% siRNA / petroleum ether) to obtain the title compound (1.1 g, yield 60%) as a colorless oil. [M+H] + =338.8. 1 H NMR(400MHz,CDCl3)δppm 7.34-7.26(m,3H),7.25-7.17(m,2H),6.80(s,1H),4.78(t,J=5.6Hz,2H),4.48(s,2H),3.85-3.78(m,5H).

[0391] Methyl 1-(2-(benzyloxy)ethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate: Methyl 1-(2-(benzyloxy)ethyl)-3-bromo-1H-pyrazole-5-carboxylate (450 mg, 1.19 mmol, 1 equivalent) in dioxane (8 mL), B2Pin2( A mixture of 909.64 mg, 3.58 mmol, 3 equivalents of KOAc (351.56 mg, 3.58 mmol, 3 equivalents), Pd(dppf)Cl2 (87.37 mg, 119.40 μmol, 0.1 equivalent), and dppf (132.39 mg, 238.81 μmol, 0.2 equivalents) was degassed, purged three times with N2, and then stirred at 100°C for 3 hours under an N2 atmosphere. The mixture was filtered, the filter cake was washed with dioxane (3 x 5 mL), and the filtrate was concentrated under reduced pressure to obtain the title compound (900 mg) as a brown oil, which was used in the next step without further purification.

[0392] Methyl 1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-5-carboxylate in dioxane (8 mL) and H2O (2 mL) A mixture of ruboxylate (900 mg, 2.10 mmol, 1 equivalent), 6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine (918.59 mg, 2.10 mmol, 1 equivalent), K2CO3 (869.49 mg, 6.29 mmol, 3 equivalents), and Pd(dppf)Cl2 (153.45 mg, 209.71 μmol, 0.1 equivalent) was degassed and purged three times with N2. The mixture was stirred at 80°C under an N2 atmosphere for 2 hours, then diluted with water (100 mL) and extracted with Â(3 × 100 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, 0-100% siRNA / petroleum ether) to obtain the title compound (680 mg, yield 55%) as a yellow solid. [M+H] + =527.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.89(s,1H),8.20(s,1H),7.47(s,1H),7.30(s,1H),7.25-7.11(m,5H),4.81 (t,J=5.2Hz,2H),4.46(s,2H),3.96-3.88(m,5H),3.86(s,3H),1.29(s,9H).

[0393] 1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-5-carboxylic acid: A solution of methyl 1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-5-carboxylate (680 mg, 1.16 mmol, 1 equivalent) in MeOH (6 mL) and H2O (1 mL) was mixed with LiOH·H2O (487.69 mg, 11.62 mmol, 10 equivalents). The mixture was stirred at 25°C for 4 hours, then diluted with water (2 mL), and the pH was adjusted to 5 with 2N HCl at 0°C. The precipitate was isolated by filtration, washed with water (3 × 10 mL), and dried under vacuum to obtain the title compound (500 mg, yield 76%) as a yellow solid. [M+H] + =513.0. 1 H NMR(400MHz,DMSO-d6)δppm 9.91(s,1H),8.15(s,1H),7.35(s,1H),7.29(s,1H),7.24-7.13(m,5H),4.82(t,J=5.2Hz,2H),4.47(s,2H),3.95-3.90(m,5H),1.29(s,9H).

[0394] The following intermediates were prepared following a procedure similar to that described for intermediate 9.

[0395] [Table 2-1]

[0396] [Table 2-2]

[0397] [Table 2-3]

[0398] [ka]

[0399] To a solution of 1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-5-amine:DMF (15 mL), Et3N (106.60 mg, 1.05 mmol, 146.63 μL, 1.2 equivalents) and DPPA (314.08 mg, 1.14 mmol, 246.34 μL, 1.3 equivalents) were added. The mixture was stirred under an N2 atmosphere at 90°C for 12 hours, then concentrated under reduced pressure to obtain a residue. This residue was purified by RP-HPLC to obtain the title compound (180 mg, yield 38%) as a yellow solid. [M+H] + =484.0.

[0400] [ka]

[0401] A mixture of tert-butyl 4-(3-bromo-7-methoxyimidazo[1,2-a]pyridine-6-yl)-4-hydroxypiperidine-1-carboxylate (1.1 g, 2.32 mmol, 1 equivalent) in DCM (10 mL) was mixed with a solution of DAST (3.58 g, 22.20 mmol, 2.93 mL, 9.56 equivalents) in THF (2.5 mL) at -65°C. The mixture was stirred at 25°C for 1 hour under an N2 atmosphere, then quenched with saturated NaHCO3 (20 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, 0-10% MeOH / DCM) to obtain the title compound (70 mg, 6% yield) as a yellow solid. [M+H] + =430.2. 1 H NMR(400MHz,DMSO-d6)δppm 8.05(s,1H),7.58(s,1H),7.17(s,1H),3.99-3.90(m,2H),3.88(s,3H) ,3.18-3.00(m,2H),2.48-2.30(m,2H),1.89-1.79(m,2H),1.45(s,9H).

[0402] To a mixture of tert-butyl 4-(3-bromo-7-methoxyimidazo[1,2-a]pyridine-6-yl)-4-fluoropiperidine-1-carboxylate (70 mg, 147.09 μmol, 1 equivalent) in 3-bromo-6-(4-fluoropiperidine-4-yl)-7-methoxyimidazo[1,2-a]pyridine-6-yl)-4-fluoropiperidine-1-carboxylate (2 mL) in 3-bromo-6-(4-fluoropiperidine-4-yl)-DCM (2 mL), TFA (1.54 g, 13.46 mmol, 1 mL, 91.52 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 (45 mg, yield 84%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 8.03(s,1H),7.58(s,1H),7.17(s,1H),3.92(s,3H),3.09-2.99(m,2H),2. 98-2.88(m,2H),2.60-2.53(m,1H),2.49-2.35(m,1H),1.88-1.76(m,2H).

[0403] A mixture of 3-bromo-6-(4-fluoro-1-methylpiperidine-4-yl)-7-methoxyimidazo[1,2-a]pyridine (45 mg, 123.41 μmol, 1 equivalent), paraformaldehyde (90 mg, 493.63 μmol, 4 equivalents), and AcOH (2.10 g, 34.94 mmol, 2 mL, 283.10 equivalents) in DCM (2 mL) was stirred at 25°C for 1 hour, and then NaBH(OAc)3 (104.62 mg, 493.63 μmol, 4 equivalents) was added at 0°C. The mixture was stirred under an N2 atmosphere at 25°C for 1 hour, then quenched with saturated NaHCO3 (10 mL) and extracted with DCM (3 × 10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (20 mg, yield 43%) as a yellow oil. [M+H] + =344.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.04(s,1H),7.57(s,1H),7.16(s,1H),3.91(s,3H),2.76-2.50(m,4H),2.30-2.15(m,5H),1.83-1.71(m,2H).

[0404] [ka]

[0405] Methyl 3-(6-(4-fluoro-1-methylpiperidine-4-yl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylate:dioxane (1 mL) and water (0.2 mL) containing 3-bromo-6-(4-fluoro-1-methylpiperidine-4-yl)-7-methoxyimidazo[1,2-a]pyridine (0.139 g, 365.57 μmol, 1 gram) A mixture of methyl-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (129.70 mg, 438.68 μmol, 1.2 equivalents), K2CO3 (151.57 mg, 1.10 mmol, 3 equivalents), and Pd(dppf)Cl2 (26.75 mg, 36.56 μmol, 0.1 equivalents) was degassed and purged three times with N2. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 1-10% MeOH / DCM) to obtain the title compound (50 mg, yield 31%) as a dark brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.33(s,1H),8.01(s,1H),7.37(s,1H),7.16(s,1H),4.18(s,3H),3.92(s,3H),3 .88(s,3H),2.80-2.70(m,2H),2.54(s,3H),2.27(s,4H),1.80(t,J=12.4Hz,2H).

[0406] Lithium 3-(6-(4-fluoro-1-methylpiperidine-4-yl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.04 g, 89.68 μmol, 1 equivalent) was dissolved in THF (1 mL) and water (0.2 mL), to which LiOH·H2O (5.27 mg, 125.55 μmol, 1.4 equivalents) was added. The mixture was stirred at 25°C for 1 hour, and then concentrated under reduced pressure to obtain the title compound (30 mg, yield 78%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.39(s,1H),7.78(s,1H),7.09(s,1H),6.69(s,1H),4.13(s,3H),3.91(s,3H), 2.69(d,J=6.8Hz,2H),2.54(s,3H),2.33-2.23(m,4H),1.78(t,J=12.4Hz,2H).

[0407] [ka]

[0408] 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 water (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, 0-30% siRNA / petroleum ether) 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).

[0409] 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(dpm)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 three times with O2. 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, 0-100% siRNA / petroleum ether) 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).

[0410] To a solution of tert-butyl 4-hydroxy-4-(6-methoxypyrazolo[1,5-a]pyridine-5-yl)piperidine-1-carboxylate (500 mg, 1.15 mmol, 1 equivalent) in MeCN (10 mL), NIS (310.85 mg, 1.38 mmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours, then quenched with saturated Na2SO3 (10 mL) at 0°C, and subsequently diluted with ELISA (50 mL). The organic layer was separated, washed with saturated NaHCO3 (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% siRNA / petroleum ether) to obtain the title compound (400 mg, 66% yield) as a white solid. [M+H] + =474.0. 1 H NMR(400MHz,CDCl3)δppm 8.11(s,1H),7.85(s,1H),7.32(s,1H),4.13-3.98(m,2H),3.94(s,3H) ,3.87-3.80(m,1H),3.36-3.23(m,2H),2.13-1.96(m,4H),1.49(s,9H).

[0411] To a solution of tert-butyl 4-hydroxy-4-(3-iodo-6-methoxypyrazolo[1,5-a]pyridine-5-yl)piperidine-1-carboxylate (400 mg, 760.61 μmol, 1 equivalent) in DCM (10 mL), DAST (367.81 mg, 2.28 mmol, 301.48 μL, 3 equivalents) was added dropwise at -78°C under an N2 atmosphere. The mixture was stirred at -40°C under an N2 atmosphere for 2 hours, then quenched with saturated NaHCO3 (20 mL), subsequently diluted with water (40 mL), and extracted with DCM (3 × 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-5% siRNA / petroleum ether) to obtain the title compound (250 mg, 62% yield) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δppm 8.06(s,1H),7.85(s,1H),7.58(s,1H),4.22-3.98(m,2H),3.85(s,3H),3.18(br s,2H),2.68-2.39(m,2H),1.79-1.72(m,2H),1.51(s,9H).

[0412] tert-butyl4-fluoro-4-(6-methoxy-3-(5-(methoxycarbonyl)-1-methyl-1H-pyrazole-3-yl)pyrazolo[1,5-a]pyridine-5-yl)piperidine-1-carboxylate (250 mg) in dioxane (10 mL) and H2O (2.5 mL) A mixture of methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (473.39 μmol, 1 equivalent), methyl 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (209.95 mg, 710.09 μmol, 1.5 equivalents), Pd(dppf)Cl2 (34.64 mg, 47.34 μmol, 0.1 equivalent), and K2CO3 (196.28 mg, 1.42 mmol, 3 equivalents) was degassed and purged three times with N2. The mixture was stirred at 80°C under an N2 atmosphere for 4 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-40% siRNA / petroleum ether) to obtain the title compound (160 mg, yield 62%) as a white solid. 1 H NMR(400MHz,CDCl3)δppm 8.23(s,1H),8.12(s,1H),8.07(s,1H),7.04(s,1H),4.25(s,3H),4.19-4.01(m,2H),3.92(s, 3H),3.86(s,3H),3.29-3.09(m,2H),2.69-2.44(m,2H),1.80(t,J=12.4Hz,2H),1.51(s,9H).

[0413] Methyl 3-(5-(4-fluoropiperidine-4-yl)-6-methoxypyrazolo[1,5-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylate (tert-butyl 4-fluoro-4-(6-methoxy-3-(5-(methoxycarbonyl)-1-methyl-1H-pyrazole-3-yl)pyrazolo[1,5-a]pyridine-5-yl)piperidine-1-carboxylate (160 mg, 295.37 μmol, 1 equivalent) was added to HCl (4 M, 5 mL) in dioxane. The mixture was stirred at 20°C for 1 hour, then concentrated under reduced pressure to obtain the title compound (120 mg, yield 86%) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,MeOH-d4)δppm 8.33(s,1H),8.31(s,1H),8.24(s,1H),7.15(s,1H),4.21(s,3H),3.99(s, 3H),3.92(s,3H),3.51-3.41(m,4H),3.06-2.85(m,2H),2.15-2.11(m,2H).

[0414] To a solution of methyl 3-(5-(4-fluoro-1-methylpiperidine-4-yl)-6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxylate (120 mg, 278.78 μmol, 1 equivalent) in MeOH (5 mL), paraformaldehyde (84.47 mg, 2.79 mmol, 10 equivalents) and HOAc (100.45 mg, 1.67 mmol, 95.75 μL, 6 equivalents) were added. The mixture was stirred at 20°C for 1 hour, after which NaBH3CN (52.56 mg, 836.33 μmol, 3 equivalents) was added. The resulting mixture was stirred at 20°C for 12 hours, then diluted with H2O (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extract was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-12% MeOH / DCM) to obtain the title compound (120 mg, 97% yield) as a white solid. [M+H]+ =402.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.53(s,1H),8.40(s,1H),8.21(s,1H),7.27(s,1H),4.15(s,3H),3.92( s,3H),3.87(s,3H),3.00-2.65(m,6H),2.54(s,3H),2.08-1.92(m,2H).

[0415] Lithium 3-(5-(4-fluoro-1-methylpiperidine-4-yl)-6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxylate (120 mg, 269.04 μmol, 1 equivalent) was dissolved in THF (5 mL) and H2O (1 mL), to which LiOH·H2O (33.87 mg, 807.11 μmol, 3 equivalents) was added. The mixture was stirred at 20°C for 2 hours, then concentrated under reduced pressure to obtain the title compound (100 mg, yield 85%) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δppm 8.23(s,1H),8.16(s,1H),8.14(d,J=1.2Hz,1H),6.90(d,J=1.2Hz,1H),4.19(d,J=0.8Hz,3 H),3.94(s,3H),2.87-2.68(m,4H),2.53-2.44(m,2H),2.36(s,3H),1.83(t,J=12.2Hz,2H).

[0416] [ka]

[0417] 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 for 2 hours under an N2 atmosphere. 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. 1 H 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).

[0418] 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 MeOH (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 MeOH. The residue was purified by RP-HPLC to obtain the title compound (33 mg, 66% yield) 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).

[0419] [ka]

[0420] (R)-7-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine: To a solution of (R)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol (289.33 mg, 1.42 mmol, 2 equivalents) and 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine-7-ol (200 mg, 707.81 μmol, 1 equivalent) in toluene (5 mL), CMBP (1.02 g, 4.25 mmol, 6 equivalents) was added. The mixture was stirred at 100 °C for 12 hours, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-25% siRNA / petroleum ether) to obtain the title compound (240 mg, yield 69%) as a brown solid. [M+H] + =441.1. 1 H NMR(400MHz,DMSO-d6)δppm 9.12(s,1H),7.98(d,J=0.8Hz,1H),7.53(d,J=1.6Hz,1H),7.09(s,1H),4.07-3.91(m,2H),3.75-3.65(m,1H), 3.68-3.55(m,1H),2.11-2.01(m,1H),1.31(s,9H),1.01(d,J=6.8Hz,3H),0.85(s,9H),0.02(d,J=1.0Hz,6H).

[0421] (R)-7-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropoxy)-6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine: To a solution of (R)-7-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropoxy)-6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine (235 mg, 479.95 μmol, 1 equivalent) in DMF (5 mL), NIS (215.96 mg, 959.90 μmol, 2 equivalents) was added. The mixture was stirred at 25°C for 3 hours and then concentrated under reduced pressure. The residue was diluted with saturated Na2SO3 aqueous solution (50 mL) and then extracted with ELISA (3 × 50 mL). The combined organic extracts were washed with saturated Na2CO3 aqueous solution (100 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound (220 mg, 349.47 μmol, yield 73%) as a white solid. [M+H] + =567.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.48(s,1H),7.71(s,1H),7.24(s,1H),4.11-3.94(m,2H),3.79-3.53(m,2H),2.13- 2.01(m,1H),1.33(s,9H),1.01(d,J=6.8Hz,3H),0.85(s,9H),0.02(d,J=1.2Hz,6H).

[0422] The following compounds were prepared following a procedure similar to that described for intermediate 28.

[0423] [Table 3]

[0424] [ka]

[0425] 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).

[0426] 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, 10-20% siRNA / petroleum ether) 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).

[0427] 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, 5-15% siRNA / petroleum ether) 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).

[0428] 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.

[0429] 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 RINKAN (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, 15-100% RINKAN / petroleum ether) 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).

[0430] Methyl 3-(5-(tert-butylsulfonyl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylate:2-((5-(tert-butylsulfonyl)-3-iodopyrazolo[1,5-a]pyridine-6-yl)oxy)ethane-1-ol (0.1 g, 212.14 μmol, 1 equivalent) in dioxane (1 mL) and H2O (0.2 mL), A mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carboxylate (62.72 mg, 212.14 μmol, 1 equivalent), Pd(dppf)Cl2 (155.22 mg, 212.14 μmol, 1 equivalent), and K2CO3 (29.32 mg, 212.14 μmol, 1 equivalent) was degassed, purged three times with N2, and stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was diluted with water (20 mL), extracted with SiO2 (3 × 10 mL), then washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 10-100% RINKAN / petroleum ether) to obtain the title compound (85 mg, yield 83%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δppm 8.77(s,1H),8.23(s,2H),7.06(s,1H),4.27-4.24(m,5H),3.97-3.95(m,2H),3.94(s,1H),1.46(s,9H).

[0431] Lithium 3-(5-(tert-butylsulfonyl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxylate (85 mg, 175.27 μmol, 1 equivalent) was dissolved in THF (2 mL) and H2O (0.2 mL), to which LiOH·H2O (11.03 mg, 262.90 μmol, 1.5 equivalents) was added. The mixture was stirred at 25°C for 1 hour, filtered, and concentrated under reduced pressure to obtain the title compound (65 mg, yield 79%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 8.69(s,1H),8.64(s,1H),8.38(s,1H),6.67(s,1H),4.16-4.13(m,2H),4.11(s,3H),3.76(t,J=4.4Hz,2H),1.33(s,9H).

[0432] The following compounds were prepared following a procedure similar to that described for intermediate 30.

[0433] [Table 4]

[0434] [ka]

[0435] 3-Bromo-1-methyl-1H-pyrazole-5-carboxylic acid: A solution of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (270 mg, 1.23 mmol, 1 equivalent) in THF (4.5 mL) was mixed with a solution of LiOH·H2O (98.28 mg, 2.34 mmol, 1.9 equivalents) in water (4.5 mL) at 25 °C. The resulting mixture was stirred at 50 °C for 30 minutes under an N2 atmosphere, then diluted with water (10 mL) and washed with Â(3 × 10 mL) (the organic extract was discarded). The aqueous phase was acidified to pH=5 with 1N HCl, and the product was extracted with Â(3 × 10 mL). The organic extract containing the product was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (280 mg, 99% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 6.88(s,1H),4.04(s,3H).

[0436] A solution of 3-bromo-1-methyl-1H-pyrazole-5-carboxamide (200 mg, 878.01 μmol, 1 equivalent), benzylamine (282.24 mg, 2.63 mmol, 287.12 μL, 3 equivalents), TCFH (492.70 mg, 1.76 mmol, 2 equivalents), and 1-methylimidazole (216.26 mg, 2.63 mmol, 209.96 μL, 3 equivalents) in N-benzyl-3-bromo-1-methyl-1H-pyrazole-5-carboxamide:MeCN (7 mL) was stirred at 25°C for 2 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by column chromatography (SiO2, 0-20% siRNA / petroleum ether) to obtain the title compound (170 mg, yield 59%) as a white solid. [M+H] + =295.7. 1 H NMR(400MHz,DMSO-d6)δppm 9.08(s,1H),7.42-7.18(m,5H),7.00(s,1H),4.43(d,J=6.0Hz,2H),4.04(s,3H).

[0437] A mixture of (5-(benzylcarbamoyl)-1-methyl-1H-pyrazole-3-yl)boronic acid:dioxane (1 mL) containing N-benzyl-3-bromo-1-methyl-1H-pyrazole-5-carboxamide (90 mg, 275.37 μmol, 1 equivalent), B2Pin2 (139.86 mg, 550.75 μmol, 2 equivalents), KOAc (81.08 mg, 826.12 μmol, 3 equivalents), and PCy3Pd G3 (17.90 mg, 27.54 μmol, 0.1 equivalent) was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by column chromatography (SiO2, 0-100% siRNA / petroleum ether and 0-80% MeOH / DCM) to obtain the title compound (20 mg, 25% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 9.00(t,J=6.0Hz,1H),8.14(s,2H),7.36-7.24(m,5H),7.15(s,1H),4.42(d,J=6.0Hz,2H),4.09(s,3H).

[0438] The following compounds were prepared following a procedure similar to that described for intermediate 32.

[0439] [Table 5]

[0440] [ka]

[0441] Ethyl 6-fluorospiro[2.5]octane-6-carboxylate: To a solution of ethylspiro[2.5]octane-6-carboxylate (200 mg, 1.10 mmol, 1 equivalent) in THF (4 mL), LDA (2 M, 1.37 mL, 2.5 equivalents) was added dropwise at -60°C. After addition, the mixture was stirred at -60°C for 1 hour, and then N-fluorobenzenesulfonimide (415.24 mg, 1.32 mmol, 1.2 equivalents) in THF (2 mL) was added dropwise at -60°C. The resulting mixture was stirred at 0°C for 1 hour, then quenched with saturated NH4Cl (5 mL) at 0°C, and then 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, 0-50% siRNA / petroleum ether) to obtain the title compound (45 mg, yield 14%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δppm 4.28-4.20(m,2H),2.10-1.97(m,4H),1.71-1.53(m,2H),1.36-1.25(m,3H),0.89-0.84(m,2H),0.30-0.21(m,4H).

[0442] 6-Fluorospiro[2.5]octane-6-carboxylic acid: To a solution of ethyl 6-fluorospiro[2.5]octane-6-carboxylate (45 mg, 157.30 μmol, 1 equivalent) in MeOH (2 mL) and H2O (0.5 mL), LiOH.H2O (66.01 mg, 1.57 mmol, 10 equivalents) was added. The mixture was stirred at 50°C for 12 hours, then concentrated under reduced pressure to remove the MeOH. The resulting aqueous mixture was adjusted to pH=2 with 2 M HCl at 0°C, then diluted with H2O (10 mL) and extracted with RINKAN (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 (35 mg) as a yellow oil. 1 H NMR(400MHz,CDCl3)δppm 2.01-1.93(m,4H),1.69-1.62(m,2H),0.92-0.83(m,2H),0.32-0.16(m,4H).

[0443] [ka]

[0444] To a solution of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (100 mg, 505.00 μmol, 1 equivalent) in DMF (3 mL), DHP (212.39 mg, 2.52 mmol, 230.86 μL, 5 equivalents) and TsOH·H2O (48.03 mg, 252.50 μmol, 0.5 equivalents) were added. The mixture was stirred at 100°C for 12 hours, then diluted with water (20 mL) and extracted with  (3 × 20 mL). The combined organic extract was washed with saturated NaHCO3 (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 1-25% alkyl / petroleum ether) to obtain the title compound (100 mg, yield 63%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.64(d,J=4.4Hz,1H),8.30(d,J=8.8Hz,1H),7.56(dd,J=8.4,4.4Hz,1H),5.92(dd,J=9.6,2.0Hz,1H),3.88(d, J=11.2Hz,1H),3.78-3.70(m,1H),2.37-2.31(m,1H),2.04-1.98(m,2H),1.77-1.70(m,1H),1.61-1.56(m,2H).

[0445] tert-butyl((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)methyl)carbamate: 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (90 mg, 287.10 μmol, 1 equivalent) in 1,4-dioxane (2 mL) and H2O (0.2 mL), tert-butyl((trifluoro A mixture of -λ4-boraneyl(methyl)carbamate potassium salt (102.09 mg, 430.64 μmol, 1.5 equivalents), Pd(OAc)2 (6.45 mg, 28.71 μmol, 0.1 equivalent), XPhos (27.37 mg, 57.42 μmol, 0.2 equivalents), and Cs2CO3 (280.62 mg, 861.29 μmol, 3 equivalents) was degassed and purged three times with N2. The resulting mixture was stirred at 100°C for 12 hours under an N2 atmosphere and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 1-40% siRNA / petroleum ether) to obtain the title compound (77 mg, yield 73%) as a yellow oil. [M+H] + =333.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.54-8.53(m,1H),8.18-8.15(m,1H),7.44-7.40(m,1H),7.28-7.20(m ,1H),5.84(dd,J=9.6,2.4Hz,1H),4.54(d,J=5.6Hz,2H),3.91-3.83(m, 1H),3.75-3.69(m,1H),2.42-2.34(m,1H),2.05-2.01(m,8.9Hz,1H),1. 98-1.91(m,1H),1.77-1.69(m,1H),1.58(d,J=3.6Hz,2H),1.39(s,9H).

[0446] A solution of tert-butyl((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-yl)methyl)carbamate (77 mg, 208.49 μmol, 1 equivalent) in (1H-pyrazolo[4,3-b]pyridine-3-yl)methanamine hydrochloride:HCl / dioxane (2 mL) was stirred at 25°C for 1 hour, and then concentrated under reduced pressure to obtain the title compound (34 mg, 99% yield) as a white solid. The substance was used in the next step without purification. 1 H NMR(400MHz,DMSO-d6)δppm 13.75-13.37(m,1H),8.60(dd,J=4.4,1.2Hz,1H),8.48(d,J=2.4Hz,2H),8.1 1(dd,J=8.4,1.2Hz,1H),7.48(dd,J=8.8,4.4Hz,1H),4.46(q,J=5.6Hz,2H).

[0447] The following compounds were prepared following a procedure similar to that described for intermediate 35.

[0448] [Table 6]

[0449] [ka]

[0450] (5-methylisothiazol-3-yl)methaneamine: A mixture of 3-(chloromethyl)-5-methylisothiazol (80 mg, 541.91 μmol, 1 equivalent) in ammonium hydroxide (2 mL) was stirred at 100°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to obtain the title compound (50 mg, crude) as a yellow solid, which was used directly in the next step without purification.

[0451] [ka]

[0452] To a solution of 1-(5-methylthiazole-2-yl)ethane-1-amine (100 mg, 708.26 μmol, 1 equivalent) in 10 mL of 1-(5-methylthiazole-2-yl)ethane-1-amine:MeOH, NH4OAc (666.05 mg, 8.64 mmol, 12.2 equivalents) and NaBH3CN (182.49 mg, 2.90 mmol, 4.1 equivalents) were added. The mixture was stirred at 60°C for 16 hours and then concentrated under reduced pressure. The residue was purified by RP-HPLC to obtain the title compound (50 mg, yield 37%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δppm 7.40(d,J=1.0Hz,1H),4.36(q,J=6.4Hz,1H),2.41(d,J=0.4Hz,3H),1.41(d,J=6.4Hz,3H).

[0453] The following compounds were prepared following a procedure similar to that described for intermediate 38.

[0454] [Table 7]

[0455] [ka]

[0456] (E)-2-methyl-N-((1-methyl-1H-imidazole-4-yl)methylene)propan-2-sulfinamide: To a solution of 1-methyl-1H-imidazole-4-carboaldehyde (500 mg, 4.54 mmol, 1 equivalent) and 2-methylpropan-2-sulfinamide (660.41 mg, 5.45 mmol, 1.2 equivalents) in THF (10 mL), Ti(i-PrO)4 (2.58 g, 9.08 mmol, 2.68 mL, 2 equivalents) was added at 0°C, and the mixture was stirred at 25°C under an N2 atmosphere for 12 hours. The reaction mixture was diluted with water (20 mL), and solid matter was removed by filtration. The filtrate was extracted with ELISA (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-10% MeOH / Â) to obtain the title compound (560 mg, yield 52%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δppm 8.31(s,1H),7.92(s,1H),7.78(s,1H),3.72(s,3H),1.13(s,9H).

[0457] To a solution of (E)-2-methyl-N-((1-methyl-1H-imidazole-4-yl)methylene)propan-2-sulfinamide (560 mg, 2.36 mmol, 1 equivalent) in 2-methyl-N-(1-methyl-1H-imidazole-4-yl)methylene)propan-2-sulfinamide:DCM (13 mL), MeMgBr (3 M, 1.58 mL, 2 equivalents) was added under an N2 atmosphere at -65°C, and the mixture was then stirred under an N2 atmosphere at 25°C for 2 hours. The reaction mixture was quenched with MeOH (20 mL), concentrated under reduced pressure, diluted with siRNA (20 mL), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-7% MeOH / siRNA) to obtain the title compound (300 mg, crude) as a white solid. 1H NMR(400MHz,DMSO-d6)δppm 7.56(s,1H),6.94(s,1H),5.09(d,J=6.0Hz,1H),4.29-4.24(m,1H),3.61(s,3H),1.38(d,J=6.4Hz,3H),1.11(s,9H).

[0458] A solution of 2-methyl-N-(1-(1-methyl-1H-imidazole-4-yl)ethyl)propan-2-sulfinamide (300 mg, 1.31 mmol, 1 equivalent) in 1-(1-methyl-1H-imidazole-4-yl)ethane-1-amine dihydrochloride:HCl / MeOH (4 mL) was stirred at 25°C for 0.5 hours under an N2 atmosphere, and then concentrated under reduced pressure to obtain the title compound (340 mg, crude) as a yellow oil, which was used without purification.

[0459] The following intermediates were prepared following a procedure similar to that described for intermediate 40.

[0460] [Table 8] [Examples]

[0461] [ka]

[0462] To a solution of 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxamide:DMF (2 mL) containing 1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxylic acid (100 mg, 259.81 μmol, 90% purity, 1 equivalent) and benzylamine (41.76 mg, 389.72 μmol, 42.48 μL, 1.5 equivalents), HATU (197.58 mg, 519.63 μmol, 2 equivalents) and DIEA (100.74 mg, 779.44 μmol, 135.76 μL, 3 equivalents) was added. The mixture was stirred at 25°C for 12 hours, then 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, 3-10% MeOH / DCM) to obtain the title compound (70 mg, yield 56%) as a white solid. [M+H] + =436.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.85(t,J=6.0Hz,1H),8.64(s,1H),8.34(s,1H),8.27(s,1H),7.76(s,1H),7.37-7.31( m,4H),7.29-7.22(m,1H),7.13(s,1H),4.48(d,J=5.6Hz,2H),3.90(s,3H),1.22(s,9H).

[0463] N-benzyl-1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxamide (70 mg, 144.65 μmol, 90% purity, 1 equivalent) was added to a solution of N-benzyl-1-(6-(tert-butylthio)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-carboxamide (533.55 mg, 867.89 μmol, 6 equivalents) in MeOH (4 mL) and H2O (1 mL). The mixture was stirred at 25°C for 12 hours, then quenched with saturated Na2SO3 (5 mL) and extracted with ELISA (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 RP-HPLC to obtain the title compound (7.0 mg, yield 10%) as a white solid. [M+H] + =468.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.89(t,J=6.0Hz,1H),8.74(s,1H),8.68(s,1H),8.38(s,1H),7.92(s,1 H),7.39-7.21(m,6H),4.48(d,J=6.0Hz,2H),3.94(s,3H),1.29(s,9H).

[0464] The following compounds were prepared following a procedure similar to that described for Example 1.

[0465] [Table 9]

[0466] [ka]

[0467] 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-N-(2-chlorobenzyl)-1-methyl-1H-pyrazole-5-carboxamide:DMF (1 mL) contains 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (40 mg, 91 mg). A mixture of (74 μmol, 1 equivalent), HATU (52.32 mg, 137.60 μmol, 1.5 equivalents), and DIEA (35.57 mg, 275.21 μmol, 47.94 μL, 3 equivalents) was degassed, purged three times with N2, and then stirred at 25°C for 5 minutes. (2-chlorophenyl)methaneamine (15.59 mg, 110.08 μmol, 13.32 μL, 1.2 equivalents) was added. The resulting mixture was stirred at 25°C under an N2 atmosphere for 2 hours, filtered, and concentrated under reduced pressure. The residue was purified by RP-HPLC to obtain the title compound (4.12 mg, 9% yield) as a white solid. [M+H] + =516.3. 1 H NMR(400MHz,DMSO-d6)δppm 9.87(s,1H),9.23(t,J=5.6Hz,1H),7.99(s,1H),7.48(dd,J=7.2,1.2Hz,1H),7.45-7.40(m,1H),7.38 (s,1H),7.36-7.30(m,2H),7.29(s,1H),4.55(d,J=6.0Hz,2H),4.14(s,3H),3.94(s,3H),1.33(s,9H).

[0468] The following compounds were prepared following a procedure similar to that described in Example 4. Detailed chiral analysis data are provided for an example obtained from a racemic material by chiral SFC separation.

[0469] [Table 10-1]

[0470] [Table 10-2]

[0471] Table 10-3

[0472] Table 10-4

[0473] Table 10-5

[0474] Table 10-6

[0475] Table 10-7

[0476] Table 10-8

[0477] Table 10-9

[0478] Table 10-10

[0479] Table 10-11

[0480] Table 10-12

[0481] Table 10-13

[0482] Table 10-14

[0483] Table 10-15

[0484] Table 10-16

[0485] Table 10-17

[0486] Table 10-18

[0487] Table 10-19

[0488] Table 10-20

[0489] Table 10-21

[0490] Table 10-22

[0491] Table 10-23

[0492] Table 10-24

[0493] Table 10-25

[0494] Table 10-26

[0495] Table 10-27

[0496] Table 10-28

[0497] Table 10-29

[0498] Table 10-30

[0499] Table 10-31

[0500] Table 10-32

[0501] [Table 10-33]

[0502] [ka]

[0503] (R)-1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-N-(1-(pyridine-2-yl)ethyl)-1H-pyrazole-5-carboxamide:DMF (2mL) contains 1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl) To a solution of lysine-3-yl)-1H-pyrazole-5-carboxylic acid (40 mg, 77.14 μmol, 1 equivalent), HATU (58.67 mg, 154.29 μmol, 2.0 equivalents), (R)-1-(pyridine-2-yl)ethane-1-amine (18.85 mg, 154.29 μmol, 2 equivalents), and DIEA (29.91 mg, 231.43 μmol, 40.31 μL, 3.0 equivalents) were added. The mixture was stirred at 25°C for 30 minutes, then filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-10% MeOH / DCM) to obtain the title compound (30 mg, crude) as a yellow oil. [M+H] + =617.1.

[0504] (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-(2-hydroxyethyl)-N-(1-(pyridine-2-yl)ethyl)-1H-pyrazole-5-carboxamide (25 mg, 40.54 μmol, 1 equivalent) in DCM (0.5 mL) was mixed with BCl3 (0.5 mL). The mixture was stirred at 25°C for 2 hours, then quenched with saturated NaHCO3 aqueous solution (5 mL) and extracted with ELISA (3 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP-HPLC to obtain the title compound (2.7 mg, yield 13%) as a white solid. [M+H] + =527.1. 1 H NMR(400MHz,DMSO-d6)δppm 9.93(s,1H),9.06(d,J=7.6Hz,1H),8.54(d,J=4.4Hz,1H),8.02(s,1H),7.82-7.73(m,1H),7.48-7.42(m,1H),7.39(s,1H),7.32-7.24(m,2 H),5.18(t,J=7.2Hz,1H),4.94(t,J=5.6Hz,1H),4.58(t,J=5.6Hz,2H),3.94(s,3H),3.86-3.75(m,2H),1.52(d,J=7.2Hz,3H),1.33(s,9H).

[0505] The following compounds were prepared following a procedure similar to that described for Example 142. Example 146 was prepared from the corresponding THP-protected intermediate by treatment with TFA in DCM instead of BCl3.

[0506] [Table 11]

[0507] [ka]

[0508] (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-N-(1-(3-fluoropyridine-2-yl)ethyl)-1-(1-methylazetidine-3-yl)-1H-pyrazole-5-carboxamide (20 mg, 36.00 μmol, 1 equivalent) was added to a solution of (R)-1-(azetidine-3-yl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-N-(1-(3-fluoropyridine-2-yl)ethyl)-1H-pyrazole-5-carboxamide (20 mg, 36.00 μmol, 1 equivalent) in MeOH (2 mL). Formalin (29.21 mg, 359.96 μmol, 26.80 μL, purity 37%, 10 equivalents) was added. The mixture was stirred at 20°C for 1 hour, after which NaBH3CN (4.52 mg, 71.99 μmol, 2 equivalents) was added. The resulting mixture was stirred at 20°C for 12 hours, and then concentrated under reduced pressure. The residue was purified by RP-HPLC to obtain the title compound (2.4 mg, 24% yield) as a white solid. [M+H] + =570.1. 1 H NMR(400MHz,DMSO-d6)δppm 10.14(s,1H),9.09(d,J=7.2Hz,1H),8.41(d,J=4.4Hz,1H),8.05(s,1H),7.79-7.68(m,1H),7.45-7.39(m,2H),7.30(s,1H),5.66(q,J=6 .8Hz,1H),5.44(q,J=7.2Hz,1H),3.95(s,3H),3.75-3.65(m,2H),3.47(q,J=7.2Hz,2H),2.37(s,3H),1.50(d,J=7.2Hz,3H),1.35(s,9H).

[0509] [ka]

[0510] A mixture of N-benzyl-3-methyl-1H-pyrazole-4-carboxamide (100 mg, 792.94 μmol, 1 equivalent), EDCI (304.01 mg, 1.59 mmol, 2 equivalents), HOBt (214.29 mg, 1.59 mmol, 2 equivalents), and DIEA (204.96 mg, 1.59 mmol, 276.23 μL, 2 equivalents) in DMF (1 mL) was cooled to 0°C, and then a solution of benzylamine (169.93 mg, 1.59 mmol, 172.87 μL, 2 equivalents) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at 25°C for 12 hours and then partitioned between SiO (20 mL) and water (10 mL). The organic phase was separated, washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 0-60% siRNA / petroleum ether) to obtain the title compound (140 mg, yield 74%) as a white solid. 1 H NMR(400MHz,CDCl3)δppm 7.73(s,1H),7.43-7.26(m,5H),6.06(s,1H),4.60(d,J=5.6Hz,2H),2.58(s,3H).

[0511] N-benzyl-1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-3-methyl-1H-pyrazole-4-carboxamide:DMF (0.5 mL) contains N-benzyl-3-methyl-1H-pyrazole-4-carboxamide (98.28 mg, 410.93 μmol, 1 equivalent) and 6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine-3-yl) A mixture of cyimidazo[1,2-a]pyridine (180 mg, 410.93 μmol, 1 equivalent), CuI (39.13 mg, 205.47 μmol, 0.5 equivalents), trans-N,N'-dimethylcyclohexane-1,2-diamine (46.76 mg, 328.74 μmol, 0.8 equivalents), and K3PO4 (174.46 mg, 821.86 μmol, 2 equivalents) was degassed and purged three times with N2. The mixture was stirred at 80°C under an N2 atmosphere for 12 hours, and then partitioned between SiO2 (20 mL) and water (10 mL). The organic phase was separated, washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-7% MeOH / DCM) and RP-HPLC to obtain the title compound (2.62 mg, yield 1.3%) as a white solid. [M+H] + =482.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.73(s,1H),8.66(s,1H),8.62(s,1H),7.83(s,1H),7.37-7.31(m,4H),7.29(s,1H) ,7.27-7.22(m,1H),4.45(d,J=6.0(Hz,2H),3.94(s,2H),2.47(s,3H),1.30(s,9H).

[0512] [ka]

[0513] A mixture of 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (20 mg, 50.96 μmol, 1 equivalent), DPPA (16.83 mg, 61.16 μmol, 13.20 μL, 1.2 equivalents), and DIEA (9.88 mg, 76.45 μmol, 13.32 μL, 1.5 equivalents) in toluene (1 mL) and benzyl alcohol (1 mL) was degassed, purged three times with N2, and then stirred at 90°C under an N2 atmosphere for 3 hours (gas generation). The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, 75% HCl / petroleum ether). The obtained substance was purified by RP-HPLC to obtain the title compound (3.07 mg, yield 12%) as a white solid. [M+H] + =498.1. 1 H NMR(400MHz,DMSO-d6)δppm 10.03-9.97(m,1H),9.89(s,1H),8.01(s,1H),7.46-7.34(m,5H),7.26-7.2 3(m,1H),6.66(s,1H),5.20(s,2H),3.93(s,3H),3.75(s,3H),1.32(s,9H).

[0514] The following compounds were prepared following a procedure similar to that described for Example 149.

[0515] [Table 12]

[0516] [ka]

[0517] To a stirred solution of 2-(2-chlorophenyl)acetic acid (13.18 mg, 77.27 μmol, 1.2 equivalents) and HATU (48.97 mg, 128.79 μmol, 2 equivalents) in N-(1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-yl)-2-(2-chlorophenyl)acetamide:DMF (4 mL), DIEA (24.97 mg, 193.18 μmol, 33.65 μL, 3 equivalents) and 1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-amine (25 mg, 64.39 μmol, 90% purity, 1 equivalent) was added. The reaction mixture was stirred under N2 at 25°C for 1 hour, then diluted with water (15 mL) and extracted with ₹ (3 × 15 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 RP-HPLC to obtain the title compound (5.1 mg, yield 16%) as a white solid. [M+H] + =501.9. 1 H NMR(400MHz,DMSO-d6)δppm 10.55(s,1H),8.74(s,1H),8.34(s,1H),7.96(s,1H),7.84(s,1H),7.49-7.39( m,2H),7.35-7.29(m,2H),7.28(s,1H),3.93(s,3H),3.83(s,2H),1.29(s,9H).

[0518] The following compounds were prepared following a procedure similar to that described for Example 152.

[0519] [Table 13-1]

[0520] [Table 13-2]

[0521] [Table 13-3]

[0522] [Table 13-4]

[0523] [Table 13-5]

[0524] [ka]

[0525] To a solution of 1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-yl)-2-phenylpyrrolidine-1-carboxamide:MeCN (1.5 mL), Et3N (26.06 mg, 257.58 μmol, 35.85 μL, 3 equivalents) and N,N'-disuccinimidylcarbonate (26.39 mg, 103.03 μmol, 1.2 equivalents) were added. The mixture was stirred at 20°C for 0.3 hours, after which 2-phenylpyrrolidine was added (18.96 mg, 128.79 μmol, 1.5 equivalents). The resulting mixture was stirred at 20°C for 12 hours, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by RP-HPLC to obtain the title compound (7.42 mg, yield 22%) as a white solid. [M+H] + =523.1. 1H NMR(400MHz,DMSO-d6)δppm 8.75(s,1H),8.63(s,1H),8.11(s,1H),7.87(s,1H),7.77(s,1H),7.3 3-7.28(m,2H),7.26(s,1H),7.22-7.17(m,3H),5.07(d,J=7.6Hz,1H), 3.92(s,3H),3.75-3.69(s,1H),3.59-3.52(m,1H),2.19-2.16(m,1H), 1.94-1.90(m,1H),1.87-1.82(m,1H),1.78-1.73(m,1H),1.28(s,9H).

[0526] Examples 178 and 179 were obtained from racemic mixture 177 by chiral SFC separation.

[0527] [Table 14]

[0528] [ka]

[0529] AcOH (92.81 mg, 1.55 mmol, 88.47 μL, 3 equivalents) was added to a solution of methyl 4-oxo-2-phenylbutanoate (110.02 mg, 515.16 μmol, 1.0 equivalent) and 1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-amine (200 mg, 515.16 μmol, 1 equivalent) in 1-(1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-4-amine (200 mg, 515.16 μmol, 1 equivalent) in 1-(1-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-3-phenylpyrrolidine-2-one:DCE (2 mL). The mixture was stirred at 25°C for 1 hour under an N2 atmosphere, and then NaBH(OAc)3 (338.47 mg, 1.60 mmol, 3.1 equivalents) was added. The mixture was stirred at 25°C for 12 hours, then concentrated under reduced pressure to obtain a residue, which was purified by RP-HPLC to obtain the title compound (40 mg, yield 16%) as an off-white solid. [M+H]+ =493.9. 1 H NMR(400MHz,DMSO-d6)δppm 8.75(s,1H),8.51(s,1H),8.26(s,1H),7.88(s,1H),7.38-7.24(m,6H),3.95(s,1H),3.94-3. 93(m,3H),3.91(s,1H),3.88-3.80(m,1H),2.70-2.62(m,1H),2.35-2.23(m,1H),1.29(s,9H).

[0530] The following compounds were prepared following a procedure similar to that described for Example 180. Examples 182 and 183 were obtained from racemic mixture 180 by chiral SFC separation.

[0531] [Table 15]

[0532] [ka]

[0533] 2-(2-chlorophenyl)-N-(1-methyl-3-(5-((1-methylpiperidine-4-yl)amino)pyridine-3-yl)-1H-pyrazole-5-yl)acetamide: Dioxane (2 mL) and H2O (0.5 mL) containing 2-(2-chlorophenyl)-N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-yl)acetamide (50 mL) A mixture of (g, 133.10 μmol, 1 equivalent), 5-bromo-N-(1-methylpiperidine-4-yl)pyridine-3-amine (47.95 mg, 159.72 μmol, 1.2 equivalents), Pd(dppf)Cl2 (9.74 mg, 13.31 μmol, 0.1 equivalent), and K2CO3 (55.19 mg, 399.30 μmol, 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 filtered and concentrated under reduced pressure to obtain a residue, which was purified by RP-HPLC to obtain the title compound (3.96 mg, yield 7%) as a white solid. [M+H] + =439.1. 1 H NMR(400MHz,DMSO-d6)δppm 10.37(s,1H),8.26(s,1.4H),8.11(s,1H),7.89(s,1H),7.54-7.41(m,2H),7.37-7.28(m,2H),7.22(s,1H),6.64(s,1H),5.83(d,J=7 .2Hz,1H),3.91(s,2H),3.73(s,3H),3.48-3.29(m,1H),2.91-2.80(m,2H),2.39-2.15(m,5H),1.99-1.88(m,2H),1.57-1.39(m,2H).

[0534] The following compounds were prepared following a procedure similar to that described for Example 184.

[0535] [Table 16-1]

[0536] [Table 16-2]

[0537] [Table 16-3]

[0538] [ka]

[0539] N-(1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1H-pyrazole-5-yl)-1-fluorocyclohexane-1-carboxamide:MeCN (3 mL) contains 1-(2-(benzyloxy)ethyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1, 2-a) Pyridine-3-yl)-1H-pyrazole-5-amine (50 mg, 93.06 μmol, 1 equivalent) and 1-fluorocyclohexane-1-carboxylic acid (27.20 mg, 186.11 μmol, 2 equivalents) were mixed with TCFH (52.22 mg, 186.11 μmol, 2 equivalents) and NMI (22.92 mg, 279.17 μmol, 22.25 μL, 3 equivalents). The mixture was stirred at 25°C for 4 hours, then 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 (40 mg, yield 63%) as a colorless oil. [M+H] + =612.4.

[0540] N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine-3-yl)-1-(2-hydroxyethyl)-1H-pyrazole-5-yl)-1-fluorocyclohexane-1-carboxamide (30 mg, 44.14 μmol, 1 equivalent) in DCM (30 mL) was mixed with BCl3 (0.3 mL) at 0°C. The mixture was stirred at 25°C for 0.5 hours, then quenched with saturated NaHCO3 (20 mL) at 0°C, and subsequently extracted with DCM (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 RP-HPLC to obtain the title compound (2.09 mg, yield 9%) as a white solid. [M+H] + =522.0. 1 H NMR(400MHz,DMSO-d6)δppm 10.63-10.21(m,1H),9.93(s,1H),8.04(s,1H),7.27(s,1H),6.80(s,1H),5.82-5.34(m,1H),4.16(t,J=5.6Hz,2H),3.93(s,3 H),3.85-3.77(m,2H),1.96-1.89(m,3H),1.87-1.78(m,1H),1.71-1.65(m,3H),1.59-1.49(m,2H),1.36(s,1H),1.32(s,9H).

[0541] The following compounds were prepared following a procedure similar to that described for Example 193.

[0542] [Table 17]

[0543] Biological data RIPK2 binding competition assay The ability of selected compounds of formulas (I) and (II) to inhibit the binding of Alexa647-labeled ATP competitive kinase inhibitors to the GST-RIPK2 fusion protein was quantified using the TR-FRET-based RIPK2 binding competition assay described in the following paragraphs.

[0544] A recombinant fusion protein of N-terminal glutathione-S-transferase (GST) expressed in baculovirus-infected Sf9 cells, purified via glutathione affinity chromatography, and a fragment of human RIPK2 (amino acids 1-310 of accession number O43353) was used as the GST-RIPK2 fusion protein. Life Technologies' Tracer199 (catalog number PR9115B) was used as the Alexa647-labeled ATP competitive kinase inhibitor.

[0545] For the assay, 50 nL of a 100-fold concentrated solution of each test compound in DMSO was pipetteed into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Flickenhausen, Germany). The assay buffer consisted of: 25 mM Tris / HCl pH 7.5, 10 mM magnesium chloride (MgCl2), 5 mM β-glycerophosphate, 2.5 mM dithiothreitol (DTT), 0.5 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 0.5 mM sodium ortho-vanadate, 0.01% (w / v) bovine serum albumin (BSA), and 0.005% (w / v) Pluronic acid. A 3 μL solution of Tracer199 (16.7 nM ⇒ final concentration of 10 nM in a 5 μL assay volume) was added to F-127 (Sigma). Subsequently, binding competition was initiated by adding a 2 μL solution of GST-RIPK2 fusion protein (2.5 nM ⇒ final concentration of 1 nM in a 5 μL assay volume) and anti-GST-Tb (1.25 nM ⇒ final concentration of 0.5 nM in a 5 μL assay volume) in the assay buffer, along with PerkinElmer's Lumi4®-Tb cryptotate conjugate anti-GST antibody (catalog number 61GSTTAH). The resulting mixture was incubated at 22°C for 45 minutes to allow a complex to form between Tracer199, the fusion protein, and anti-GST-Tb. The amount of this complex was then assessed by measuring the resonance energy transfer from Tb cryptotate to Tracer199. Therefore, fluorescence intensities at 620 nm and 665 nm after excitation at 337 nm were measured using a TR-FRET reader, e.g., Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or Viewlux (PerkinElmer). The ratio of fluorescence intensities at 665 nm to 620 nm was used as an indicator of the complex's volume. Data were normalized (assay reaction without inhibitor = 0% activity, all other assay components excluding the GST-RIPK2 fusion protein = -100% activity). Typically, the test compound is tested on the same microtiter plate at 11 different concentrations ranging from 20 μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM, and 0.07 nM. This dilution series was prepared separately before the assay by serial dilution at the 100-fold concentrated stage in DMSO, and the exact concentration may vary depending on the pipette used), with two consecutive values ​​for each concentration, and IC using Geneda Screener® software. 50 The value was calculated. Table A1 below shows the IC25 of selected compounds of formula (I) measured in the RIPK2 binding competition assay. 50 The values ​​are shown. IC of the RIPK2 competitive assay. 50 Regarding the values, "A" represents ICs with a minimum impedance of 200 nM. 50 This indicates that "B" represents an IC with a impedance of 200nM to 500nM. 50 This indicates that "C" represents ICs with a impedance of over 500nM and less than or equal to 1,000nM. 50 This indicates that "D" represents an IC with a power output exceeding 1,000 nM. 50 This indicates.

[0546] [Table 18]

[0547] RIPK2-XIAP Competitive PPI Assay The ability of selected compounds of formula (I) to inhibit the binding of the His-XIAP(BIR2)-avi fusion protein to the GST-RIPK2 fusion protein was quantified using the TR-FRET-based competitive assay described in the following paragraphs.

[0548] A recombinant fusion protein of N-terminal glutathione-S-transferase (GST) expressed in baculovirus-infected Sf9 cells, purified via glutathione affinity chromatography, and a fragment of human RIPK2 (amino acids 1-310 of accession number O43353) was used as the GST-RIPK2 fusion protein. A recombinant fusion protein of N-terminal 6x histidine (His), a fragment of human XIAP (amino acids 152-231 of accession number P98170), and a C-terminal avi tag, purified via nickel NTA affinity chromatography, expressed in baculovirus-infected Sf9 cells, was used as the His-XIAP(BIR2)-avi fusion protein.

[0549] For the assay, use 25 mM Tris-HCl 7.5, 0.5 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 10 mM magnesium chloride (MgCl2), 2.5 mM dithiothreitol (DTT), 0.01% (w / v) bovine serum albumin (BSA), and 0.005% (w / v) Pluronic acid. Working solutions were prepared using F-127 (Sigma), 0.5 mM sodium ortho-vanadate, 5 mM disodium β-glycerophosphate hydrate (BGP) containing 1 nM GST-RIPK2, 25 nM His-XIAP(BIR2)-avi, 6 nM anti-His-XL665 (Revvity, catalog no. 61HISXLB), and 0.5 nM anti-GST-Tb (Revvity, catalog no. 61GSTTLB). 50 nL of a 100-fold concentrated solution of each test compound in DMSO was dispensed acoustically into a white, low-volume 384-well microtiter plate (Perkin Elmer, catalog no. 6008280). Subsequently, 5 μl of the assay working solution was added.

[0550] The resulting mixture was incubated at 23°C for 120 minutes. Subsequently, the amount of complex formed by GST-RIPK2, XIAP(BIR2)-avi, anti-His-XL665, and anti-GST-Tb was assessed by measuring the resonance energy transfer from Tb cryptotate to XL665. Therefore, using a TR-FRET reader, e.g., Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or Envision (PerkinElmer), fluorescence intensities at 520 nm and 665 nm after excitation at 337 nm were measured. The ratio of fluorescence intensities at 665 nm to 520 nm was used as an indicator of the complex amount. Data were normalized (assay reaction without inhibitor = 0% activity, 50 nM GSK583 = -100% activity). Typically, the test compound is tested on the same microtiter plate at 11 different concentrations ranging from 10 μM to 0.04 nM (10 μM, 2.86 μM, 0.82 μM, 0.23 μM, 67 nM, 19 nM, 5.4 nM, 1.6 nM, 0.4 nM, 0.1 nM, and 0.04 nM. This dilution series was prepared separately before the assay by serial dilution in 100-fold concentrated DMSO solutions, and the exact concentration may vary depending on the pipette used), with two consecutive values ​​for each concentration, and ICs are performed using Collaborative Drug Discovery software. 50 The value was calculated.

[0551] SEAP and viability assay of THP-1 Dual cells THP1-Dual® cells (InvivoGen catalog number thpd-nfis) enable simultaneous evaluation of the NF-κB pathway by monitoring the activity of secretory embryonic alkaline phosphatase (SEAP) and the IRF pathway by assessing the activity of secretory luciferase (Lucia). Cells were cultured according to the manufacturer's recommendations. For the assay, cell concentrations were set to 7.14 × 10⁴ in assay medium (RPMI1640, 2 mM L-glutamine, 25 mM HEPES, 10% fetal bovine serum (thermally inactivated at 56°C for 30 minutes), Pen-Strep (100 U / mL)). 5The cell suspension was adjusted to cells / mL, and 35 μL per well (approximately 25,000 cells) was added to a flat-bottomed 384-well plate (white opaque). The plate was centrifuged at 300 g for 2 minutes, and the compound was added in a serial dilution series (approximately 500 nL to 0.0152 nL) according to the plate layout. The plate was incubated at 37°C under 5% CO2 conditions for 30 minutes. Using assay medium, an L18-MDP stock solution was prepared so that the final concentration of L18-MDP in each well was 10 ng / mL when 15 μL was added to each well. 15 μL of the L18-MDP stock solution was added to each well, while 15 μL of assay medium was added to the negative control well. The plate was then incubated overnight (20-24 hours) at 37°C under 5% CO2 conditions.

[0552] SEAP assay: To avoid disturbing the cells at the bottom of the wells, 15 μL of supernatant was transferred to a clear 384-well flat-bottom plate, and 35 μL of QUANTI-Blue solution was added per well. After incubation at 37°C for 2 hours, absorbance (OD) at 620–655 nm was measured using a microplate reader (PheraStar FS microplate reader with a protocol for OD 620–655 nm).

[0553] Cell viability assay: Cell viability was evaluated using cells remaining in the plate. For this purpose, CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate were equilibrated at room temperature, and the lyophilized CellTiter-Glo substrate was reconstituted according to the manufacturer's recommendations. Equivolutes (35 μL in this case) of CTG were added to each well, and the contents were mixed in an orbital shaker for 2 minutes to induce lysis, followed by incubation at room temperature for 10 minutes. Subsequently, the luminescence signal was measured using a microplate reader (PheraStar).

[0554] analysis The values ​​from the wells containing only the culture medium were subtracted, and the inhibition rate (%) at each compound concentration was calculated relative to the control treated with DMSO / L18-MDP. The inhibition values ​​± SD were fitted using nonlinear regression with Prism software (GraphPad PRISM Software), and IC was calculated. 50 The value was calculated.

[0555] Table A below shows the potency values ​​of selected compounds of formula (I) as measured in RIPK2(KD) / XIAP(BIR2) binding competitive PPI assays, as well as in SEAP and viability assays of THP-1 Dual cells. "nt" indicates that the test was not performed.

[0556] IC for RIPK2(KD) / XIAP(BIR2) competitive PPI assay 50 Regarding the values, "A" represents ICs with a minimum impedance of 10 nM. 50 This indicates that "B" represents an IC with a impedance of 10nM to 100nM. 50 This indicates that "C" represents ICs with a impedance between 100nM and 1000nM. 50 This indicates that "D" represents an IC with a minimum impedance of over 1000 nM. 50 This indicates.

[0557] A in the RIPK2(KD) / XIAP(BIR2) competitive assay max Regarding the value, "A" represents an A of 80% or higher. max This indicates that "B" is less than 80% and 55% or more than A. max This indicates that "C" is less than 55% but more than 30% of A max This indicates that "D" is less than 30% of A max This indicates.

[0558] IC of THP assay 50 Regarding the values, "A" represents ICs with a minimum impedance of 100 nM. 50 This indicates that "B" represents an IC with a impedance of 100nM to 500nM. 50 This indicates that "C" represents ICs with a impedance greater than 500 nM and less than or equal to 2,500 nM. 50 This indicates that "D" represents an IC with a capacitance of over 2,500 nM. 50 This indicates.

[0559] Table 19-1

[0560] Table 19-2

[0561] Table 19-3

[0562] Table 19-4

[0563] Table 19-5

Claims

1. Equation (I) 【Chemistry 1】 A compound of, or a pharmaceutically acceptable salt thereof, wherein, R １ is hydroxyl, -S(O ２ ) C1-C6 alkyl, NR １Ａ R １Ｂ A 5-10 member heteroaryl, a halogen, and a 4-10 member heterocyclil, each optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 thioalkyl, and C1-C6 alkoxy molecules, and a halogen, and a 4-10 member heterocyclil, each optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -(NH)-C1-C6 alkyl molecules, and a -(NH)-4-10 member heterocyclil, each optionally substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl molecules. R １Ａ and R １Ｂ These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. R ２Ａ It is selected from hydrogen, halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, halogen, C1-C6 alkyl, and 4- to 10-membered heterocyclines optionally substituted with one or two substituents independently selected from C(O)O C1-C6 alkyl. R ３ is hydrogen or halogen, X is 【Chemistry 2】 Selected from, R ４ is hydrogen or C1-C6 alkyl, R ５ teeth, (i) (a) C3-C6 cycloalkyl groups optionally substituted with 1 to 3 substituents independently selected from halogens or phenyls, (b) Phenyls optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, C1-C6 hydroxyalkyls, and cyanos. (c)-NR Ａ R Ｂ 、 (d) Hydroxyl, (e) Halogen, (f) 4-10 member heterocyclines optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl, and (g) A 5- to 10-membered heteroaryl molecule optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. A C1-C6 alkyl group that is optionally substituted with 1 to 4 substituents independently selected from the above. (ii) C3-C10 cycloalkyls optionally substituted with 1 to 3 substituents independently selected from halogens, hydroxyls, C1-C6 alkyls, 1 to 2 independently selected halogens, and phenyls optionally substituted with 5 to 10 member heteroaryls, (iii) A 4- to 10-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl. (iv) Phenyls optionally substituted with one to three substituents independently selected from halogens, nitros, and C1-C6 haloalkyls. (v) A 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from halogens and C1-C6 alkyl groups. (vi) C1-C6 alkoxy, or (vii) C3-C6 cycloalkoxy Selected from, Alternatively, R ４ and R ５ These, together with the atoms to which they are bonded, form 5-12 member heterocyclines or 9-10 member heteroaryls, each optionally substituted with phenyl. R Ａ and R Ｂ The compounds selected from hydrogen and C1-C6 alkyl groups, or pharmaceutically acceptable salts thereof, are independently selected.

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

3. Equation (I) is (I - b) 【Chemistry 4】 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 5】 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 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

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

7. Equation (I) is (I - f) 【Transformation 8】 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 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

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

10. Equation (I) is (I - i) 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, in the formula, R １Ｃ This is a C1-C6 alkoxy that is optionally substituted with a hydroxyl group. R １Ｄ Ha - S (O ２ )-C1-C6 alkyl, R ２Ａ１ These are C1-C3 alkyl or C3-C4 cycloalkyl, R ５Ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a phenyl optionally substituted with a halogen or a C1-C6 alkyl group, or a 5-6 member heteroaryl optionally substituted with a halogen or a C1-C6 alkyl group.

11. Equation (I) is (I - j) 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, in the formula, R １Ｅ C1-C6 alkoxy, which is optionally substituted with C1-C6 alkyl, C1-C6 thioalkyl, or hydroxyl, and -S(O ２ ) A 5-10 member heteroaryl substituted with two substituents independently selected from C1-C6 alkyl groups, R ２Ａ１ These are C1-C3 alkyl or C3-C4 cycloalkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is (i) a phenyl optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, C1-C6 hydroxyalkyls, and cyanos, or (ii) a 5-6 member heteroaryl optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys.

12. A compound selected from the group consisting of the compounds of Examples 1 to 194, or a pharmaceutically acceptable salt of any of them.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

14. 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 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13.

15. A method for treating inflammatory bowel disease in a subject requiring treatment for inflammatory bowel disease, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13.

16. 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 claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13.

17. A method for treating inflammatory bowel disease in a subject previously identified or diagnosed with inflammatory bowel disease, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13.

18. 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 according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13.

19. A method for treating Crohn's disease in a subject requiring treatment for Crohn's disease, comprising: (a) determining that the subject is suffering from Crohn's disease; and (b) administering to the subject an effective amount of a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13.

20. A method for treating Crohn's disease in a subject previously identified or diagnosed with Crohn's disease, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13.

Images