Imidazo(1,2 - 1)pyridine derivatives as RIPK2 inhibitors

Abstract

This application relates to compounds of formula (I) as defined herein, and pharmaceutically acceptable salts thereof, and compositions containing them. Also described are methods of treating the diseases and disorders disclosed herein with compounds of formula (I), and pharmaceutically acceptable salts thereof, and compositions containing them.

Description

Technical Field

[0001] The present application relates to the fields of chemistry and biology, and in particular, to compounds of formula (I) as defined herein, and pharmaceutically acceptable salts thereof, and compositions containing them. Methods of treating the diseases and disorders disclosed herein with the compounds of formula (I), and pharmaceutically acceptable salts thereof, and compositions containing the same are also described.

Background Art

[0002] Receptor-interacting protein kinase 2 (RIPK2) is a serine-threonine protein kinase and a signaling molecule downstream of nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptor (TLR). 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 the interaction with NOD1 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.

[0003] NOD receptors function in the innate immune system and detect bacterial pathogens by binding to diaminopimelic acid or muramyl dipeptide residues present in bacterial peptidoglycan. The interaction between RIPK2 and NOD1, NOD2 and TLR results in the release of inflammatory cytokines including TNF-α, IL-6, and IL-12 / 23p40, and the RIPK2-mediated induction of NF-Κ-B-dependent inflammatory responses. Activation of RIPK2 and dysregulation of the RIPK2-NOD signaling pathway may also be involved in the etiology of various inflammatory diseases. RIPK2 has been reported to be a prognostic indicator and a candidate therapeutic target for various cancers.

Summary of the Invention

[0004] Some embodiments are compounds of formula (I):

Chemical Formula

Chemical formula

Chemical formula

Chemical formula

[0005] In some embodiments, formula (I) is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0006] Also provided herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0007] Also provided herein is a method of treating an RIPK2-related disease or disorder in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising as a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0008] Unless otherwise specified, all technical and scientific terms used in this specification shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Methods and materials are described herein for use in this disclosure, and other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are hereby incorporated by reference in their entirety, unless explicitly stated otherwise. In case of conflict, the present specification, including definitions, will control.

[0009] Other features and advantages of the present disclosure will become apparent from the following detailed description, drawings, and claims.

Mode for Carrying Out the Invention

[0010] Biologics and small molecules targeting inflammatory signaling pathways are used to successfully treat inflammatory and other diseases in patients, but most patients show resistance to existing treatments. Therefore, there is a need to identify novel therapeutic molecules that modulate or inhibit these pathways, such as the compounds of formula (I) described herein and their pharmaceutically acceptable salts.

[0011] Definitions To facilitate understanding of the present disclosure as defined herein, several additional terms are defined below. In general, the nomenclature used herein and the procedures for testing in organic chemistry, drug discovery chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise specified, all technical and scientific terms used herein shall generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Each of the patents, applications, published applications, and other publications referred to throughout this specification and the attached appendix are hereby incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0012] When referring to a number or numerical range, the term "about" means that the recited number or numerical range is within an approximation, e.g., within experimental variations and / or statistical experimental error, and thus the number or numerical range may vary by up to ±10% of the recited number or numerical range.

[0013] The phrase "therapeutically effective amount" means an amount of a compound that, when administered to a subject in need of such treatment, (i) treats a disease or disorder described herein (e.g., a RIPK2-related disease or disorder), (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease or disorder, or (iii) delays the onset of one or more symptoms of a particular disease or disorder described herein.

[0014] As used herein, the terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms associated with a disease or disorder, whether detectable or undetectable, reduction in the degree of a neurological disorder, stabilization (i.e., no worsening) of a disease or disorder, delay or blunting of disease progression, improvement or temporary remission of a disease state (e.g., one or more symptoms of a disease or disorder), and remission (whether partial or complete), as determined by various clinical evaluations including clinical assessment and self-reporting. "Treatment" can also mean prolonging survival as compared to the expected survival in the absence of treatment.

[0015] 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 compatible with the other components of the pharmaceutical formulation and is "pharmaceutically acceptable" in the sense that it can be used in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. See, 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.

[0016] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which the formulation is administered and does not inactivate the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts can be 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, salicylic acid, etc. In some cases, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form salts such as ammonium salts, alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, organic bases such as salts with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, etc., and salts with amino acids such as arginine, lysine, etc., or by other methods determined heretofore. Pharmaceutically acceptable salts are not particularly limited as long as they can be used in medicine. Examples of salts formed by the compounds described herein with bases include the following: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, and ethanolamine, salts 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 the following: 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.

[0017] The term "pharmaceutical composition" refers to a mixture of a compound described herein and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners (collectively referred to herein as "pharmaceutically acceptable excipients"). Pharmaceutical compositions facilitate the administration of the compound to a living being.

[0018] The term "subject" refers to an animal and includes, but is not limited to, primates (e.g., humans), monkeys, cows, 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, for example, humans.

[0019] The term "halo" or "halogen" refers to one of the halogens of 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.

[0020] The term "oxo" refers to a divalent oxygen atom double-bonded (i.e., "=O"). As used herein, an oxo group is bonded to a carbon atom to form a carbonyl.

[0021] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight-chain or branched-chain, containing the indicated number of carbon atoms. For example, C 1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms therein. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

[0022] The term "alkenyl" refers to an acyclic hydrocarbon radical, which may be straight-chain or branched-chain, containing the indicated number of carbon atoms and one or more carbon-carbon double bonds. Non-limiting examples include ethenyl and allyl.

[0023] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are independently replaced by a halogen selected.

[0024] The term "hydroxyalkyl" refers to an alkyl group described herein in which one or more hydrogen atoms are replaced by one or more hydroxyl groups described herein.

[0025] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0026] The term "thioalkyl" refers to an alkyl group described herein that is bonded to the molecule through a sulfur atom (e.g., -SCH3).

[0027] The term "haloalkoxy" refers to a haloalkyl group that is bonded to the molecule through an oxygen atom (e.g., -OCF3).

[0028] The term "alkoxyalkyl" refers to an alkyl group described herein in which one or more hydrogen atoms are replaced by one or more alkoxy groups described herein.

[0029] As used herein, the term "cyano" refers to a -CN radical.

[0030] As used herein, the term "nitro" refers to a -NO2 radical.

[0031] As used herein, the term "hydroxyl" refers to an -OH radical.

[0032] As used herein, the term "amino" refers to a formula -NH2 radical.

[0033] The term "phosphoric acid" as used herein refers to a -P(=O)2(OH)2 radical.

[0034] As used herein, the term "heteroaryl" refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic group in which at least one ring of the system is aromatic and one or more carbon atoms of at least one ring within the system are replaced by heteroatoms independently selected from the group consisting of N, O, S, B, Si, and P. For example, it contains 1, 2 or 3, optionally 1 or 2 heteroatoms. Heteroaryl may further contain one or more oxo groups, N-oxide groups, S-oxide groups, and / or S,S-dioxide groups as valence permits. Non-limiting 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, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, 2-pyridone, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, triazine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 1’,2’-dihydrospiro[cyclopropane-1,3’-pyrrolo[2,3-b]pyridine], and 3’,4’-dihydrospiro[cyclopropane-1,2’-pyrido[3,2-b][1,4]oxazine].

[0035] For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), for example, each ring nitrogen adjacent to a carbonyl is tertiary (i.e., where the oxo group (i.e., "=O") is a component of the heteroaryl ring), pyridone (e.g.,

Chemical Structure

[0036] 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 bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0037] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbon atoms 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, tetrahydronaphthyl, etc.

[0038] The term "heterocyclyl" refers to a saturated, or partially unsaturated, monocyclic, bicyclic, or tricyclic hydrocarbon ring system having 3 to 20 ring atoms, with at least one heteroatom within a ring system selected from the group consisting of N, O, S, B, Si, and P, which is not aromatic. Bicyclic and tricyclic heterocyclyl groups include fused, spiro, and bridged ring systems. The heterocyclyl group can be denoted 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. The heterocycle, to the extent permitted by valency, may further contain one or more oxo, thiocarbonyl, N-oxide, S-oxide, and / or S,S-dioxide groups so that the definition includes oxo- and thio-based systems such as lactam, lactone, cyclic imide, cyclic thioimide, cyclic carbamate. The heterocyclyl group may be attached to the remainder of the molecule via any carbon atom or heteroatom such as nitrogen. Exemplary heterocyclyl groups include 1,3-dioxolane, 1,4-dioxolane, maleimide, succinimide, dioxopiperazine, hydantoin, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxaazolidinonyl, triazolidinonyl,Triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinethionyl, isothiazolidinonyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinandionyl, dihydropyrimidinedione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, triazinandionyl, and 2-azaspiro[3.3]heptanyl are included, but not limited to these.

[0039] The term "saturated", when used in this context, means that only single bonds exist between the constituent atoms.

[0040] As used herein, when a ring is described as "partially unsaturated", it means that, provided the ring is not aromatic, the ring has one or more additional degrees of unsaturation (in addition to the degrees of unsaturation arising from 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, dihydrothiophene, and the like.

[0041] As used herein, a wavy line represents the point of attachment of an atom or moiety to an atom or group shown in the remainder of the molecule.

[0042] When a group is described as "optionally substituted", it always means that the group may be unsubstituted or substituted with one or more of the indicated substituents. When a group is substituted, the substitution may involve sharing of carbon atoms between the parent group and the substituent to form a spiro ring. For example, an n-butyl group substituted with cyclopropyl may include, inter alia,

Chemical formula

[0043] To avoid misunderstanding and unless otherwise specified, for rings and cyclic groups (e.g., carbocycles, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc.) containing a sufficient number of ring atoms to form a bicyclic or higher-order ring system (e.g., tricyclic, polycyclic ring system), such rings and cyclic groups have condensation points located (i) on adjacent ring atoms (e.g., [x.x.0] ring system (where 0 represents zero atom bridges) (e.g.,

Chemical formula

Chemical formula

Chemical formula

[0044] Furthermore, any compound or structure provided herein is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. These forms of the compound are referred to as "isotopically enriched". An isotopically enriched compound has the structure depicted herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number.

[0045] 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, 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. The compounds of the present disclosure can be made with various isotopes enriched, for example, 13 C and 14 C and other radioisotopes incorporated. Compounds enriched with such isotopes are useful in metabolic studies, in kinetic studies, in 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 the radioactive treatment of patients.

[0046] The term "isotopically enriched" compound as described herein includes "deuterated" compounds in which one or more hydrogens are replaced with deuterium, such as hydrogens on a carbon atom. Such compounds show increased resistance to metabolism and are therefore useful in extending 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 replaced with deuterium. In fact, the isotopically enriched compounds of the present disclosure can generally be prepared by replacing readily available isotopically enriched reagents with non-isotopically enriched reagents and carrying out the procedures disclosed in the schemes or examples and preparations described below.

[0047] The deuterium-enriched compounds of the present disclosure can improve the DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosing requirements and / or improved therapeutic index relative to the corresponding non-enriched compound).

[0048] The concentration of a heavier isotope such as deuterium can be defined by an isotope enrichment factor. In some embodiments, the positions noted as "H" or "hydrogen" in the compounds described herein have hydrogen with its isotopic composition at natural abundance. In some embodiments, the positions described as "H" or "hydrogen" in the compounds described herein have hydrogen enriched in deuterium above its isotopic composition at natural abundance, i.e., the compound is a deuterium-enriched compound. Examples of deuterium groups in the compounds described herein include deuteromethine (

Chem.

Chem.

Chem.

Chem.

Chem.

[0049] In addition, compounds generally or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: [Chemical formula] compounds containing are intended to include the tautomeric forms containing the moiety: [Chemical formula] Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted by hydroxyl include pyridone or pyrimidinone tautomeric forms.

[0050] The compounds provided herein may include various stereochemical forms. The compounds also 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, which result from the structural asymmetry in a particular compound. Unless otherwise indicated, when a disclosed compound is named or illustrated by structure without specifying a stereochemical structure (e.g., a "flat" structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, when a disclosed compound is named or illustrated by a structure that specifies a stereochemical structure (e.g., a structure having a "wedge" and / or "dash" bond) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0051] Details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and from the claims.

[0052] As used herein, "RIPK2 inhibitor" includes any compound that exhibits RIPK2 inhibitory activity. In some embodiments, the RIPK2 inhibitor is selective for RIPK2. Exemplary RIPK2 inhibitors have an inhibitory activity (IC 50 ) 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 as measured in the assays described herein against RIPK2. In some embodiments, the RIPK2 inhibitor has an inhibitory activity (IC 50 ) of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in the assays provided herein against RIPK2.

[0053] Compounds of formula (I) Some embodiments provide a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0054] X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 is -S(O2)-C1-C4 alkyl, ring A is phenyl, and when m is 1, R 1 is not halogen, -NH2, cyano, or unsubstituted C1-C6 alkoxy, X is C, Y is N, R 2 is ethoxy, R 3 is -S(O2)-C1-C4 alkyl, and when m is 2, and when one R 1 is halogen, then the other R 1 is not -NH2 or unsubstituted alkoxy, and X is C, Y is N, R 2 is C1-C2 haloalkoxy, R 3 is -S(O2)-C1-C4 alkyl, and when m is 2, and when one R 1 is halogen, then the other R 1 is not -NH2, and X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 is -S(O2)-C1-C4 alkyl, and when m is 0, then ring A is not 1H-indazole or 1H-benzo[d]imidazole.]

[0055] In some embodiments, X is C, Y is N, and the bicyclic ring structure of formula (I) is imidazo[1,2-a]pyridine.

[0056] In some embodiments, X is C, Y is N, and the bicyclic ring structure of formula (I) is pyrazolo[1,5-a]pyridine.

[0057] In some embodiments, ring A is a 5- to 10-membered heteroaryl. In some embodiments, ring A is selected from the group consisting of indazolyl, indolyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, quinolinyl, or isoquinolinyl. In some embodiments, ring A is indazolyl.

[0058] In some embodiments, ring A is a 5- to 6-membered heteroaryl. In some embodiments, ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridonyl.

[0059] In some embodiments, ring A is pyridinyl. In some embodiments, ring A is 2-pyridinyl or 3-pyridinyl. In some embodiments, ring A is 4-pyridinyl.

[0060] In some embodiments, ring A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0061] In some embodiments, ring A is

Chemical formula

Chemical formula

[0062] In some embodiments, ring A is pyridonyl. In some embodiments, ring A is selected from the group consisting of 4-pyridonyl, 5-pyridonyl, and 6-pyridonyl.

[0063] In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is 1-pyrazolyl (i.e., the pyrazolyl is linked to the remainder of formula (I) at the nitrogen in the 1-position). In some embodiments, ring A is 3-pyrazolyl. In some embodiments, ring A is 4-pyrazolyl. In some embodiments, ring A is 5-pyrazolyl. In some embodiments, ring A is oxazololonyl.

[0064] In some embodiments, ring A is a 5- to 10-membered heterocyclyl. In some embodiments, ring A is a 5- to 6-membered heterocyclyl. In some embodiments, ring A is selected from the group consisting of pyrrolidinyl, tetrahydrofuryl, pyrazolinyl, imidazolinyl, piperidinyl, tetrahydropyranyl, and morpholinyl.

[0065] In some embodiments, ring A is pyrrolidinyl. In some embodiments, ring A is 1-pyrrolidinyl (i.e., the pyrrolidinyl is linked to the remainder of formula (I) at the nitrogen in the 1-position). In some embodiments, ring A is morpholinyl. In some embodiments, ring A is 1-morpholinyl (i.e., the morpholinyl is linked to the remainder of formula (I) at the nitrogen in the 1-position).

[0066] In some embodiments, ring A is phenyl. In some embodiments, ring A is

Chemical formula

Chemical formula

[0067] In some embodiments, one to three R 1 are independently halogen. In some embodiments, one or two R 1 are independently halogen. In some embodiments, one R 1 is halogen. In some embodiments, one R 1 is fluoro. In some embodiments, one R 1 is chloro.

[0068] In some embodiments, one R 1 is cyano.

[0069] In some embodiments, one or two R 1 are independently C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, or -S(O2)C1-C6 alkyl. In some embodiments, one R 1 is C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, or -S(O2)C1-C6 alkyl. In some embodiments, one R 1 is C1-C6 alkyl substituted by hydroxyl. In some embodiments, one R 1 is C1-C3 alkyl substituted by hydroxyl. In some embodiments, one R 1 is hydroxymethyl or hydroxyethyl. In some embodiments, one R 1 is hydroxypropyl. In some embodiments, one R 1is C1-C6 alkyl substituted with C1-C6 alkoxy. In some embodiments, one R 1 is C1-C3 alkyl substituted with C1-C6 alkoxy. In some embodiments, one R 1 is C1-C6 alkyl substituted with methoxy. In some embodiments, one R 1 is C1-C6 alkyl substituted with -S(O2)C1-C6 alkyl. In some embodiments, one R 1 is C1-C6 alkyl substituted with -S(O2)CH3 alkyl. In some embodiments, one R 1 is unsubstituted C1-C6 alkyl. In some embodiments, one R 1 is unsubstituted C1-C3 alkyl. In some embodiments, one R 1 is methyl or ethyl.

[0070] In some embodiments, one or two Rs 1 are independently C1-C6 haloalkyl. In some embodiments, one R 1 is C1-C6 haloalkyl. In some embodiments, one R 1 is C1-C3 haloalkyl. In some embodiments, one R 1 is trifluoromethyl.

[0071] In some embodiments, one or two Rs 1 are independently C1-C6 haloalkoxy. In some embodiments, one R 1 is C1-C6 haloalkoxy. In some embodiments, one R 1 is C1-C3 haloalkoxy. In some embodiments, one R 1 is trifluoromethoxy.

[0072] In some embodiments, one or two Rs 1 are independently C3-C6 cycloalkyl. In some embodiments, one R 1is C3-C6 cycloalkyl. In some embodiments, one R 1 is cyclopropyl.

[0073] In some embodiments, one or two Rs 1 are independently C1-C6 alkoxy optionally substituted by hydroxyl or phenyl. In some embodiments, one R 1 is C1-C6 alkoxy optionally substituted by hydroxyl or phenyl. In some embodiments, one or two Rs 1 are C1-C6 alkoxy substituted by hydroxyl. In some embodiments, one R 1 is C1-C6 alkoxy substituted by hydroxyl. In some embodiments, one R 1 is C1-C3 alkoxy substituted by hydroxyl. In some embodiments, one R 1 is -O(CH2)3OH. In some embodiments, one R 1 is C1-C6 alkoxy substituted by phenyl. In some embodiments, one R 1 is C1-C3 alkoxy substituted by phenyl. In some embodiments, one R 1 is -OCH2-phenyl.

[0074] In some embodiments, one or two Rs 1 are independently unsubstituted C1-C6 alkoxy. In some embodiments, one R 1 is unsubstituted C1-C6 alkoxy. In some embodiments, two Rs 1 are independently unsubstituted C1-C6 alkoxy. In some embodiments, one R 1 is unsubstituted C1-C3 alkoxy. In some embodiments, one R 1 is methoxy.

[0075] In some embodiments, one R 1is a 4- to 8-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with 1 substituent selected from the group consisting of hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with 2 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl.

[0076] In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with hydroxyl.

[0077] In some embodiments, one R E is a 4- to 8-membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with C1-C3 alkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with methyl.

[0078] In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with C1-C6 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with C1-C3 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with trifluoromethyl.

[0079] In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with hydroxyl and C1-C6 alkyl. In some embodiments, one R 1is a 4- to 8-membered heterocyclyl substituted with hydroxyl and C1-C3 alkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with hydroxyl and methyl.

[0080] In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with hydroxyl and C1-C6 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with hydroxyl and C1-C3 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with hydroxyl and trifluoromethyl.

[0081] In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with C1-C6 alkyl and C1-C6 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with C1-C3 alkyl and C1-C3 haloalkyl. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with methyl and trifluoromethyl.

[0082] In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with two hydroxyls. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with two independently selected C1-C6 alkyls. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with two independently selected C1-C3 alkyls. In some embodiments, one R 1 is a 4- to 8-membered heterocyclyl substituted with two independently selected C1-C6 haloalkyls. In some embodiments, one R 1is a 4- to 8-membered heterocyclyl in which two independently selected C1-C3 are substituted with haloalkyl.

[0083] In some embodiments, one R 1 is piperidinyl substituted with hydroxyl. In some embodiments, one R 1 is 2-azaspiro[3.3]heptan-2-yl substituted with hydroxyl. In some embodiments, one R 1 is 2-azaspiro[3.3]heptan-2-yl substituted with hydroxyl and trifluoromethyl. In some embodiments, one R 1 is piperazinyl substituted with methyl. In some embodiments, one R 1 is 4-methylpiperazin-1-yl.

[0084] In some embodiments, one R 1 is an unsubstituted 4- to 8-membered heterocyclyl. In some embodiments, one R 1 is morpholinyl or 2,6-diazaspiro[3.3]heptan-2-yl. In some embodiments, one R 1 is morpholinyl. In some embodiments, one R 1 is 2,6-diazaspiro[3.3]heptan-2-yl.

[0085] In some embodiments, one R1 is -SO2(C1-C6 alkyl). In some embodiments, one R 1 is -S(O2)C1-C3 alkyl. In some embodiments, one R 1 is -S(O2)CH3.

[0086] In some embodiments, one R 1 is hydroxyl.

[0087] In some embodiments, one R 4 is -NR A R B wherein.

[0088] In some embodiments, one R 1 is nitro.

[0089] In some embodiments, one R 1 is -S(O2)C3-C6 cycloalkyl.

[0090] In some embodiments, when ring A is phenyl, R 1 is -S(O2)NR A R A and is further selected from. In some embodiments, when ring A is phenyl, R 1 is -S(O2)NR A R A .

[0091] In some embodiments, R A is hydrogen.

[0092] In some embodiments, R A is C1-C6 alkyl. In some embodiments, R A is methyl.

[0093] In some embodiments, R A is hydrogen and R B is (i) hydrogen, (ii) -S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl optionally substituted by hydroxyl or C1-C6 alkoxy, (iv) 4-8 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl, or (v) (a) halogen, (b) hydroxyl, (c) -NR C R D , (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) C3-C6 cycloalkyl optionally substituted by hydroxyl, (g) phenyl optionally substituted by C1-C6 alkoxy, (h) 5- or 6-membered heteroaryl optionally substituted by C1-C6 alkyl, (j) hydroxyl, -C(=O)C1-C6 alkyl, or 4- to 8-membered heterocyclyl optionally substituted by C1-C6 alkyl, (k) C1-C6 thioalkyl, and (l) -S(=NR E )(=O)C1-C6 alkyl, and is C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of:

[0094] In some embodiments, R A is hydrogen, and R B is (ii) -S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl optionally substituted by hydroxyl or C1-C6 alkoxy, (iv) 4- to 8-membered heterocyclyl optionally substituted by 1 to 2 substituents independently selected from hydroxyl and C1-C6 haloalkyl, and (v) C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted by C1-C6 alkoxy, 5- or 6-membered heteroaryl optionally substituted by C1-C6 alkyl, and -C(=O)C1-C6 alkyl or 4- to 8-membered heterocyclyl optionally substituted by C1-C6 alkyl.

[0095] In some embodiments, R A is C1-C6 alkyl, and R Bis independently selected from (ii) -S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl optionally substituted by hydroxyl or C1-C6 alkoxy, (iv) 4- to 8-membered heterocyclyl optionally substituted by 1 to 2 substituents independently selected from hydroxyl and C1-C6 haloalkyl, and (v) halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, and C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from -C(=O)C1-C6 alkyl or 4- to 8-membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0096] In some embodiments, R B is -S(O2)C1-C6 alkyl. In some embodiments, R B is -S(O2)C1-C3 alkyl. In some embodiments, R B is -S(O2)(CH2)2CH3.

[0097] In some embodiments, R B is C3-C6 cycloalkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, R B is C3-C6 cycloalkyl substituted with hydroxyl. In some embodiments, R B is cyclobutyl, cyclopentyl, or cyclohexyl, each substituted with hydroxyl. In some embodiments, R B is C3-C6 cycloalkyl substituted with C1-C6 alkoxy. In some embodiments, R B is C3-C6 cycloalkyl substituted with C1-C3 alkoxy. In some embodiments, R B is cyclobutyl substituted with C1-C3 alkoxy. In some embodiments, RB is cyclobutyl substituted with methoxy. In some embodiments, R B is unsubstituted C3-C6 cycloalkyl.

[0098] In some embodiments, R B is a 4- to 8-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C1-C6 haloalkyl. In some embodiments, R B is a 4- to 8-membered heterocyclyl substituted with 1 to 2 substituents independently selected from hydroxyl and C1-C6 haloalkyl. In some embodiments, R B is a 4- to 8-membered heterocyclyl substituted with hydroxyl and C1-C6 haloalkyl. In some embodiments, R B is a 4- to 8-membered heterocyclyl substituted with C1-C6 haloalkyl. In some embodiments, R B is a 4- to 8-membered heterocyclyl substituted with trifluoromethyl. In some embodiments, R B is a 4- to 8-membered heterocyclyl substituted with hydroxyl. In some embodiments, R B is unsubstituted 4- to 8-membered heterocyclyl. In some embodiments, R B is morpholinyl.

[0099] In some embodiments, R B is (a) halogen, (b) hydroxyl, (c) -NR C R D , (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) C3-C6 cycloalkyl optionally substituted with hydroxyl, (g) phenyl optionally substituted with C1-C6 alkoxy, (h) 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, (j) Hydroxyl, -C(=O)C1-C6 alkyl, or a 4- to 8-membered heterocyclyl optionally substituted by C1-C6 alkyl, (k) C1-C6 thioalkyl, and (l) -S(=NR E )(=O)C1-C6 alkyl, is C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from

[0100] In some embodiments, R B is (a) halogen, (b) hydroxyl, (c) -NR C R D , (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) C3-C6 cycloalkyl optionally substituted by hydroxyl, (g) phenyl optionally substituted by C1-C6 alkoxy, (h) 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl, (j) hydroxyl, -C(=O)C1-C6 alkyl, or a 4- to 8-membered heterocyclyl optionally substituted by C1-C6 alkyl, (k) C1-C6 thioalkyl, and (l) -S(=NR E )(=O)C1-C6 alkyl, is C1-C6 alkyl optionally substituted by 1 to 3 substituents independently selected from

[0101] In some embodiments, R B is (a) halogen, (b) hydroxyl, (c) -NR C R D , (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) C3-C6 cycloalkyl optionally substituted by hydroxyl, (g) phenyl optionally substituted by C1-C6 alkoxy, (h) 5- or 6-membered heteroaryl optionally substituted by C1-C6 alkyl, (j) hydroxyl, -C(=O)C1-C6 alkyl, or 4- to 8-membered heterocyclyl optionally substituted by C1-C6 alkyl, (k) C1-C6 thioalkyl, and (l) -S(=NR E )(=O)C1-C6 alkyl, and is C1-C6 alkyl optionally substituted by two substituents independently selected from the group consisting of

[0102] In some embodiments, R B is (a) halogen, (b) hydroxyl, (c) -NR C R D , (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) C3-C6 cycloalkyl optionally substituted by hydroxyl, (g) phenyl optionally substituted by C1-C6 alkoxy, (h) 5- or 6-membered heteroaryl optionally substituted by C1-C6 alkyl, (j) hydroxyl, -C(=O)C1-C6 alkyl, or 4- to 8-membered heterocyclyl optionally substituted by C1-C6 alkyl, (k) C1-C6 thioalkyl, and (l) -S(=NR E )(=O)C1-C6 alkyl, and is C1-C6 alkyl optionally substituted by one selected from the group consisting of

[0103] In some embodiments, R B is halogen, hydroxyl, -NR C R D、C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted by C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, and -C(=O)C1-C6 alkyl or 4-8 membered heterocyclyl optionally substituted by C1-C6 alkyl, and is optionally substituted C1-C6 alkyl selected independently from 1 to 4 substituents.

[0104] In some embodiments, R B is halogen, hydroxyl, -NR C R D 、C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted by C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, and -C(=O)C1-C6 alkyl or 4-8 membered heterocyclyl optionally substituted by C1-C6 alkyl, and is optionally substituted C1-C6 alkyl selected independently from 1 to 3 substituents.

[0105] In some embodiments, R B is halogen, hydroxyl, -NR C R D 、C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted by C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, and -C(=O)C1-C6 alkyl or 4-8 membered heterocyclyl optionally substituted by C1-C6 alkyl, and is optionally substituted C1-C6 alkyl selected independently from 1 to 2 substituents.

[0106] In some embodiments, R B is halogen, hydroxyl, -NR C R D, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted by C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, or C1-C6 alkyl optionally substituted by -C(=O)C1-C6 alkyl or 4-8 membered heterocyclyl optionally substituted by C1-C6 alkyl.

[0107] In some embodiments, R B is C1-C6 alkyl substituted with 1-4 halogens. In some embodiments, R B is C1-C3 alkyl substituted with 1-4 halogens. In some embodiments, R B is C1-C3 alkyl substituted with 1-3 halogens. In some embodiments, R B is C1-C6 alkyl substituted with 1-3 halogens and hydroxyl. In some embodiments, R B is C1-C3 alkyl substituted with 1-3 halogens and hydroxyl.

[0108] In some embodiments, R B is propyl substituted with 1-2 halogens and hydroxyl. In some embodiments, R B is ethyl, propyl, or butyl each substituted with 1-3 halogens. In some embodiments, R B is propyl or butyl each substituted with 1-3 fluoros and 1 hydroxyl.

[0109] In some embodiments, R B is C1-C6 alkyl substituted with 1-3 hydroxyls. In some embodiments, R B is C2-C5 alkyl substituted with 1-2 hydroxyls. In some embodiments, R B is ethyl, propyl, butyl, pentyl each substituted with 1-2 hydroxyls. In some embodiments, R Bis hydroxyethyl. In some embodiments, R B is hydroxypropyl. In some embodiments, R B is propyl substituted with two hydroxyls. In some embodiments, R B is sec-butyl or isoamyl each substituted with a hydroxyl.

[0110] In some embodiments, R B is C1-C6 alkyl substituted with 1-4 independently selected C1-C6 alkoxys. In some embodiments, R B is C2-C5 alkyl substituted with 1-2 independently selected C1-C3 alkoxys. In some embodiments, R B is C2-C6 alkyl substituted with methoxy.

[0111] In some embodiments, R B is C1-C6 alkyl substituted with 1-4 independently selected C1-C6 haloalkoxys. In some embodiments, R B is C1-C6 alkyl substituted with 1-2 independently selected C1-C3 alkoxys. In some embodiments, R B is C1-C6 alkyl substituted with -OCHF2.

[0112] In some embodiments, R B is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R B is C1-C6 alkyl substituted with cyclopropyl. In some embodiments, R B is C1-C6 alkyl substituted with cyclobutyl.

[0113] In some embodiments, R B is C1-C6 alkyl substituted with phenyl optionally substituted by C1-C6 alkoxy. In some embodiments, R Bis C1-C3 alkyl substituted with phenyl optionally substituted by C1-C6 alkoxy. In some embodiments, R B is C1-C6 alkyl substituted with phenyl. In some embodiments, R B is -CH2-phenyl. In some embodiments, R B is C1-C6 alkyl substituted with phenyl substituted by C1-C6 alkoxy. In some embodiments, R B is C1-C3 alkyl substituted with phenyl substituted by C1-C6 alkoxy. In some embodiments, R B is methyl substituted with phenyl substituted by C1-C3 alkoxy. In some embodiments, R B is methyl substituted with 4-methoxyphenyl.

[0114] In some embodiments, R B is C1-C6 alkyl substituted with 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl. In some embodiments, R B is C1-C3 alkyl substituted with 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl. In some embodiments, R B is C1-C6 alkyl substituted with 5- to 6-membered heteroaryl substituted by C1-C6 alkyl. In some embodiments, R B is C1-C3 alkyl substituted with 5- to 6-membered heteroaryl substituted by C1-C6 alkyl. In some embodiments, R B is C1-C6 alkyl substituted with 5- to 6-membered heteroaryl. In some embodiments, R B is C1-C3 alkyl substituted with 5- to 6-membered heteroaryl. In some embodiments, R B is C1-C3 alkyl substituted with pyridonyl optionally substituted by C1-C3 alkyl. In some embodiments, R B is methyl substituted with pyridonyl substituted by methyl. In some embodiments, R Bis methyl substituted with unsubstituted pyridonyl.

[0115] In some embodiments, R B is C1-C6 alkyl substituted with -C(=O)C1-C6 alkyl or 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R B is C1-C2 alkyl substituted with -C(=O)C1-C6 alkyl or 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R B is C1-C2 alkyl substituted with 4-6 membered heterocyclyl, and the 4-6 membered heterocyclyl is optionally substituted with methyl each, and is selected from the group consisting of 2-oxopiperidin-4-yl, 6-oxopiperidin-3-yl, piperidin-4-yl, and 2-oxopyrrolidin-1-yl. In some embodiments, R B is C1-C2 alkyl substituted with 4-6 membered heterocyclyl, and the 4-6 membered heterocyclyl is selected from the group consisting of unsubstituted 2-oxopiperidin-4-yl, 6-oxopiperidin-3-yl, piperidin-4-yl, and 2-oxopyrrolidin-1-yl. In some embodiments, R B is C1-C2 alkyl substituted with 1-acetylpyridine.

[0116] In some embodiments, R B is C1-C6 alkyl optionally substituted with -NR C R D . In some embodiments, R B is C1-C6 alkyl substituted with -NR C R D . In some embodiments, R B is C2-C6 alkyl substituted with -NR C R D . In some embodiments, R B is C2-C3 alkyl substituted with -NR C R D .

[0117] In some embodiments, R A and R B are the same. In some embodiments, R A and R B are different. In some embodiments, R A and R B are each hydrogen. In some embodiments, one of R A and R B is hydrogen, and the other of R A and R B is not hydrogen.

[0118] In some embodiments, R A and R B are each independently selected C1-C6 alkyl. In some embodiments, R A and R B are each independently selected C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0119] In some embodiments, R C and R D are the same. In some embodiments, R C and R D are different. In some embodiments, R C and R D are each hydrogen. In some embodiments, one of R C and R D is hydrogen, and the other of R C and R D is C1-C6 alkyl optionally substituted with oxo. In some embodiments, one of R C and R D is hydrogen, and the other of R C and R D is C1-C2 alkyl optionally substituted with oxo. In some embodiments, one of R C and R D is hydrogen, and the other of R Cand R D The other of which is acyl. In some embodiments, R C and R D are each independently selected C1-C6 alkyl optionally substituted by oxo. In some embodiments, R C and R D are each independently selected C1-C6 alkyl. In some embodiments, R C and R D are each methyl. In some embodiments, one of R C and R D is hydrogen and the other of R C and R D is -C(=O)OC1-C6 alkyl.

[0120] In some embodiments, R B is C1-C6 alkyl optionally substituted by one or two substituents independently selected from halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted by C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, and -C(=O)C1-C6 alkyl or 4-8 membered heterocyclyl optionally substituted by C1-C6 alkyl.

[0121] In some embodiments, R B is C1-C6 alkyl optionally substituted by one or two substituents independently selected from halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl substituted by C1-C6 alkoxy, 5-6 membered heteroaryl substituted by C1-C6 alkyl, and -C(=O)C1-C6 alkyl or 4-8 membered heterocyclyl substituted by C1-C6 alkyl.

[0122] In some embodiments, RB is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-8 membered heterocyclyl.

[0123] In some embodiments, R B is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from fluoro, hydroxyl, -NR C R D , methoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl optionally substituted with methoxy, 5-6 membered heteroaryl optionally substituted with methyl, and 4-8 membered heterocyclyl optionally substituted with -C(=O)CH3 or methyl.

[0124] In some embodiments, R B is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from fluoro, hydroxyl, -NR C R D , methoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-8 membered heterocyclyl.

[0125] In some embodiments, when R B is substituted C1-C6 alkyl, the C1-C6 alkyl can form a spiro ring with a cycloalkyl group or a heterocyclyl group. In some embodiments, R B is

Chemical formula

[0126] In some embodiments, RB is selected from the group consisting of

Chemical formula

[0127] In some embodiments, n is 1.

[0128] In some embodiments, m is 1, and R

[0129] is selected from the group consisting of -NHC1-C6 alkyl optionally substituted by fluoro, amino, and hydroxyl. In some embodiments, m is 1, and R 1 is fluoro. In some embodiments, m is 1, and R 1 is amino. In some embodiments, m is 1, and R 1 is -NHC1-C6 alkyl optionally substituted by hydroxyl. In some embodiments, m is 1, and R 1 is -NHC1-C6 alkyl substituted by hydroxyl. 1 In some embodiments, m is 2.

[0130] In some embodiments, m is 2, and each R

[0131] is independently selected from the group consisting of -NHC1-C6 alkyl optionally substituted by 1 to 2 substituents independently selected from fluoro, amino, and hydroxyl and C3-C6 cycloalkyl. In some embodiments, m is 2, and each R 1 is independently selected from the group consisting of -NHC1-C6 alkyl substituted by 1 to 2 substituents independently selected from fluoro, amino, and hydroxyl and C3-C6 cycloalkyl. In some embodiments, m is 2, and each R 1 is selected from the group consisting of -NHC1-C6 alkyl substituted by 1 to 2 substituents independently selected from fluoro, amino, and hydroxyl and C3-C6 cycloalkyl. In some embodiments, m is 2, and each R 1is independently selected from the group consisting of -NH C1-C6 alkyl substituted with fluoro, amino, and hydroxyl or C3-C6 cycloalkyl. In some embodiments, m is 2, and each R 1 is independently selected from the group consisting of -NH C1-C6 alkyl optionally substituted with two substituents independently selected from fluoro, amino, and hydroxyl and C3-C6 cycloalkyl.

[0132] In some embodiments, m is 3.

[0133] In some embodiments, m is 3, and each R 1 is independently selected from the group consisting of -NH C1-C6 alkyl optionally substituted with fluoro, cyano, C1-C6 alkoxy, -NHS(O2)C1-C6 alkyl, and hydroxyl. In some embodiments, m is 3, and two Rs 1 are independently selected from fluoro and C1-C6 alkoxy, and the third R 1 is -NH C1-C6 alkyl optionally substituted with cyano, -NHS(O2)C1-C6 alkyl, or hydroxyl.

[0134] In some embodiments, m is 4.

[0135] In some embodiments, m is 4, and each R 1 is independently selected from the group consisting of -NH C1-C6 alkyl optionally substituted with fluoro, cyano, C1-C6 alkoxy, -NHS(O2)C1-C6 alkyl, and hydroxyl. In some embodiments, m is 4, and two Rs 1 are independently selected from fluoro and C1-C6 alkoxy, and the remaining two Rs 1 are independently selected from -NH C1-C6 alkyl optionally substituted with cyano, -NHS(O2)C1-C6 alkyl, or hydroxyl.

[0136] In some embodiments, R2 is hydrogen.

[0137] In some embodiments, R 2 is halogen. In some embodiments, R 2 is chloro. In some embodiments, R 2 is fluoro.

[0138] In some embodiments, R 2 is C1-C6 alkoxy. In some embodiments, R 2 is C1-C3 alkoxy. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is ethoxy.

[0139] In some embodiments, R 2 is C1-C6 haloalkoxy. In some embodiments, R 2 is trifluoromethoxy. In some embodiments, R 2 is 2,2,2-trifluoroethoxy.

[0140] In some embodiments, R 3 is hydrogen.

[0141] In some embodiments, R 3 is C1-C6 thioalkyl. In some embodiments, R 3 is C3-C4 thioalkyl. In some embodiments, R 3 is

Chemical formula

[0142] In some embodiments, R 3 is -CO2H.

[0143] In some embodiments, R 3 is -C(=O)NRE R F is as follows.

[0144] In some embodiments, R 3 is C1-C6 alkyl optionally substituted with NR E R F or hydroxyl. In some embodiments, R 3 is C1-C6 alkyl substituted with NR E R F or hydroxyl. In some embodiments, R 3 is C1-C6 alkyl substituted with NR E R F . In some embodiments, R 3 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R 3 is unsubstituted C1-C6 alkyl.

[0145] In some embodiments, R E and R F are the same. In some embodiments, R E and R F are different. In some embodiments, R E and R F are each hydrogen. In some embodiments, R E and R F are each independently selected C1-C6 alkyl. In some embodiments, R E and R F are each methyl. In some embodiments, one of R E and R F is hydrogen and the other of R E and R F is C1-C6 alkyl. In some embodiments, R E is hydrogen. In some embodiments, R E is C1-C6 alkyl. In some embodiments, R F is hydrogen. In some embodiments, R F is C1-C6 alkyl.

[0146] In some embodiments, R 3 is C1-C6 alkoxy optionally substituted with a 4-10 membered heterocyclyl optionally substituted with C1-C6 alkoxy. In some embodiments, R 3 is C1-C3 alkoxy optionally substituted with a 4-10 membered heterocyclyl optionally substituted with C1-C6 alkoxy. In some embodiments, R 3 is methoxy or ethoxy optionally substituted with a 4-10 membered heterocyclyl optionally substituted with C1-C6 alkoxy. In some embodiments, R 3 is C1-C6 alkoxy substituted with a 4-10 membered heterocyclyl optionally substituted with C1-C6 alkoxy. In some embodiments, R 3 is C1-C3 alkoxy substituted with a 4-6 membered heterocyclyl optionally substituted with C1-C6 alkoxy. In some embodiments, R 3 is methoxy or ethoxy substituted with a 4-6 membered heterocyclyl optionally substituted with C1-C3 alkoxy. In some embodiments, R 3 is C1-C3 alkoxy substituted with an unsubstituted 4-10 membered heterocyclyl. In some embodiments, R 3 is C1-C3 alkoxy substituted with an unsubstituted 4-6 membered heterocyclyl. In some embodiments, R 3 is C1-C6 alkoxy substituted with a 4-10 membered heterocyclyl substituted with C1-C6 alkoxy. In some embodiments, R 3 is C1-C3 alkoxy substituted with a 4-6 membered heterocyclyl substituted with C1-C6 alkoxy. In some embodiments, R 3 is methoxy or ethoxy substituted with a 4-6 membered heterocyclyl optionally substituted with C1-C3 alkoxy.

[0147] In some embodiments, R 3is unsubstituted C1-C6 alkoxy. In some embodiments, R 3 is unsubstituted C1-C3 alkoxy. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is ethoxy.

[0148] In some embodiments, R 3 is a 4- to 8-membered heterocyclyl optionally substituted by 1 to 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 3 is a 4- to 8-membered heterocyclyl substituted by 1 to 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 3 is a 4- to 8-membered heterocyclyl substituted by 1 substituent independently selected from halogen and C1-C6 alkyl. In some embodiments, R 3 is a 4- to 8-membered heterocyclyl substituted by 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, R 3 is a 4- to 8-membered heterocyclyl substituted by 2 independent halogens. In some embodiments, R 3 is a 4- to 8-membered heterocyclyl substituted by 2 fluorines. In some embodiments, R 3 is a 4- to 8-membered heterocyclyl substituted by 2 independently selected C1-C6 alkyls. In some embodiments, R 3 is a 4- to 8-membered heterocyclyl substituted by 2 methyl groups. In some embodiments, R 3 is unsubstituted 4- to 8-membered heterocyclyl.

[0149] In some embodiments, R 3 is

Chemical formula

[0150] In some embodiments, Z is O.

[0151] In some embodiments, Z is NR 4 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C3 alkyl. In some embodiments, R 4 is methyl.

[0152] In some embodiments, R 3A is C1-C6 haloalkyl. In some embodiments, R 3A is C3-C4 haloalkyl.

[0153] In some embodiments, R 3A is C3-C6 cycloalkyl. In some embodiments, R 3A is cyclopropyl.

[0154] In some embodiments, R 3A is C1-C6 alkyl optionally substituted by C3-C6 cycloalkyl. In some embodiments, R 3A is C1-C6 alkyl substituted by C3-C6 cycloalkyl. In some embodiments, R 3A is C1-C3 alkyl substituted by C3-C6 cycloalkyl. In some embodiments, R 3A is C1-C2 alkyl substituted by C3-C6 cycloalkyl. In some embodiments, R 3A is C1-C2 alkyl substituted by C3-C6 cycloalkyl, and the C1-C2 alkyl of R 3A forms a spirocycloalkyl together with C3-C6 cycloalkyl. In some embodiments, each R 3A is

Chemical formula

[0155] In some embodiments, R 3 is

Chemical formula

[0156] In some embodiments, R 3B and R 3C are the same. In some embodiments, R 3B and R 3C are different.

[0157] In some embodiments, R 3B is C3-C6 cycloalkyl. In some embodiments, R 3B is C3-C4 cycloalkyl.

[0158] In some embodiments, R 3B is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R 3B is C1-C3 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R 3B is C1-C2 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R 3B is C1-C2 alkyl substituted with C3-C6 cycloalkyl, and the C1-C2 alkyl of R 3B forms a spirocycloalkyl together with C3-C6 cycloalkyl. In some embodiments, R 3B is

Chemical formula

[0159] In some embodiments, R 3C is C3-C6 cycloalkyl. In some embodiments, R 3C is C3-C4 cycloalkyl.

[0160] In some embodiments, R 3C is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R 3C is C1-C3 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R 3C is C1-C2 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R 3C is C1-C2 alkyl substituted with C3-C6 cycloalkyl, and the C1-C2 alkyl of R 3C forms a spirocycloalkyl together with the C3-C6 cycloalkyl. In some embodiments, R 3C is

Chemical formula

[0161] In some embodiments, the compound of formula (I) is of formula (I-A):

Chemical formula

[0162] In some embodiments, the compound of formula (I) is of formula (I-B):

Chemical formula

[0163] In some embodiments, the compound of formula (I) is of formula (I-C): [Chemical formula] or a pharmaceutically acceptable salt thereof, and R 1A and R 1B are each independently selected from R 1 .

[0164] In some embodiments, the compound of formula (I) is of formula (I-D): [Chemical formula] or a pharmaceutically acceptable salt thereof, and R 1A and R 1B are each independently selected from R 1 .

[0165] In some embodiments, the compound of formula (I) is of formula (I-E): [Chemical formula] or a pharmaceutically acceptable salt thereof, and R 1A and R 1B are each independently selected from R 1 .

[0166] In some embodiments, the compound of formula (I) is of formula (I-F): [Chemical formula] or a pharmaceutically acceptable salt thereof, and R 1A and R 1B are each independently selected from R 1 .

[0167] In some embodiments, the compound of formula (I) is of formula (I-G): [Chemical formula]

[0168] or a pharmaceutically acceptable salt thereof, R 1A and R 1B are each independently selected from R 1 In some embodiments, the compound of formula (I) is of formula (I-H): [Chemical formula] or a pharmaceutically acceptable salt thereof, R 1A and R 1B are each independently selected from R 1 In some embodiments, the compound of formula (I) is of formula (I-I):

[0169] In some embodiments, the compound of formula (I) is of formula (I-J): [Chemical formula] or a pharmaceutically acceptable salt thereof, R 1A and R 1B are each independently selected from R 1 In some embodiments, the compound of formula (I) is of formula (I-K):

[0170] In some embodiments, the compound of formula (I) is of formula (I-J): [Chemical formula] or a pharmaceutically acceptable salt thereof, R 1A and R 1B are each independently selected from R 1 In some embodiments, the compound of formula (I) is of formula (I-K):

[0171] In some embodiments, the compound of formula (I) is of formula (I-K): [Chemical formula] or a pharmaceutically acceptable salt thereof, R 1A and R 1Bis, independently of each other, R 1 selected from.

[0172] In some embodiments, the compound of formula (I) is of formula (I-L):

Chemical formula

[0173] In some embodiments, the compound of formula (I) is of formula (I-M):

Chemical formula

[0174] In some embodiments, the compound of formula (I) is of formula (I-N):

Chemical formula

[0175] In some embodiments, the compound of formula (I) is of formula (I-O):

Chemical formula

[0176] In some embodiments, the compound of formula (I) is of formula (I-P):

Chemical formula

[0177] In some embodiments, the compound of formula (I) is of formula (I-Q):

Chem.

[0178] In some embodiments, the compound of formula (I) is of formula (I-R):

Chem.

[0179] In some embodiments, the compound of formula (I) is of formula (I-S):

Chem.

[0180] In some embodiments, the compound of formula (I) is of formula (I-T):

Chem.

[0181] In some embodiments, the compound of formula (I) is of formula (I-U):

Chem.

[0182] In some embodiments, the compound of formula (I) is of formula (I-V):

Chemical formula

[0183] In some embodiments, the compound of formula (I) is of formula (I-W):

Chemical formula

[0184] In some embodiments, the compound of formula (I) is of formula (I-X):

Chemical formula

[0185] In some embodiments, R 2 is C1-C6 alkoxy, and R 3 is

Chemical formula

[0186] In some embodiments of formula (I-A), (I-B), (I-C), (I-D), and (I-E), R 2 is C1-C6 alkoxy, and R 3 is

Chemical formula

[0187] In some embodiments, m is 2, where one of the Rs 1 is halogen, and the other R 1 is -NR A R B .

[0188] In some embodiments of formulas (I-A) and (I-B), m is 2, where one of the Rs 1 is halogen, and the other R 1 is -NR A R B .

[0189] In some embodiments of formulas (I-C), (I-D), and (I-E), one of R 1A and R 1B is halogen, and the other one of the Rs 1A and R 1B is -NR A R B .

[0190] In some embodiments, m is 2, where one of the Rs 1 is C1-C6 alkoxy optionally substituted by hydroxyl or phenyl, and the other R 1 is -NR A R B .

[0191] In some embodiments of formulas (I-A) and (I-B), m is 2, where one of the Rs 1 is C1-C6 alkoxy optionally substituted by hydroxyl or phenyl, and the other R 1 is -NR A R B .

[0192] In some embodiments of formulas (I-C), (I-D), and (I-E), one of R 1A and R 1B is C1-C6 alkoxy optionally substituted by hydroxyl or phenyl, and the other R 1A and R 1B is -NRA R B is.

[0193] In some embodiments, m is 2, where one R 1 is C1-C6 alkyl optionally substituted by hydroxyl, and the other R 1 is -NR A R B is.

[0194] In some embodiments of formulas (I-A) and (I-B), m is 2, where one R 1 is C1-C6 alkyl optionally substituted by hydroxyl, and the other R 1 is -NR A R B is.

[0195] In some embodiments of formulas (I-C), (I-D), and (I-E), one of R 1A and R 1B is C1-C6 alkyl optionally substituted by hydroxyl, and the other R 1A and R 1B is -NR A R B is.

[0196] In some embodiments, m is 2, where one R 1 is C1-C6 haloalkyl, and the other R 1 is -NR A R B is.

[0197] In some embodiments of formulas (I-A) and (I-B), m is 2, where one R 1 is C1-C6 haloalkyl, and the other R 1 is -NR A R B is.

[0198] In some embodiments of formulas (I-C), (I-D), and (I-E), R 1A and R 1BOne of them is C1-C6 haloalkyl, and the other one R 1A and R 1B is -NR A R B .

[0199] In some embodiments, m is 2, wherein one R 1 is halogen, and the other R 1 is a 4- to 8-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl.

[0200] In some embodiments of formulas (I-A) and (I-B), m is 2, wherein one R 1 is halogen, and the other R 1 is a 4- to 8-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl.

[0201] In some embodiments of formulas (I-C), (I-D), and (I-E), one of R 1A and R 1B is halogen, and the other one of R 1A and R 1B is a 4- to 8-membered heterocyclyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl.

[0202] In some embodiments of formulas (I-A), (I-B), (I-C), (I-D), and (I-E), both R A and R B are hydrogen.

[0203] In some embodiments of formulas (I-A), (I-B), (I-C), (I-D), and (I-E), R A is hydrogen, and R B is -S(O2)C1-C6 alkyl.

[0204] In some embodiments of formulas (I-A), (I-B), (I-C), (I-D), and (I-E), R A is hydrogen, and R B is C3-C6 cycloalkyl optionally substituted by hydroxyl or C1-C6 alkoxy.

[0205] In some embodiments of formulas (I-A), (I-B), (I-C), (I-D), and (I-E), R A is hydrogen, and R B is 4- to 8-membered heterocyclyl optionally substituted by hydroxyl.

[0206] In some embodiments of formulas (I-A), (I-B), (I-C), (I-D), and (I-E), R A is hydrogen, and R B is 1 to 4 substituents independently selected from halogen, hydroxyl, -NR C R D , C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted by C1-C6 alkoxy, 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl, and -C(=O)C1-C6 alkyl or 4- to 8-membered heterocyclyl optionally substituted by C1-C6 alkyl, and is C1-C6 alkyl optionally substituted by the selected substituents.

[0207] In some embodiments of formulas (I-A) to (I-X), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is pyridyl.

[0208] In some embodiments of formulas (I-A) to (I-X), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is phenyl.

[0209] In some embodiments of formulas (I-A) to (I-X), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, ring A is phenyl or pyridyl, and at least one of R 1 is F.

[0210] In some embodiments of formulas (I-A) to (I-X), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, ring A is phenyl or pyridyl, and at least one of R 1 is C1-C4 alkoxy.

[0211] In some embodiments of formulas (I-A) to (I-X), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, ring A is phenyl or pyridyl, and at least one of R 1 is -NH2.

[0212] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is phenyl.

[0213] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is a 6-membered heteroaryl.

[0214] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is pyridyl.

[0215] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is pyrimidyl.

[0216] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is a 5-membered heteroaryl.

[0217] In some embodiments, when X is C, Y is N, ring A is 4-pyridyl, R 2 is C1-C6 alkoxy, R 3 is -S(O2)-C1-C6 alkyl, and m is 1, then R 1 is not -NH2 or -NH(C=O)CH3.

[0218] In some embodiments, when X is C, Y is N, ring A is 4-pyridyl, R 2 is C1-C6 alkoxy, R 3 is -S(O2)-C1-C6 alkyl, and m is 2, and one of R 1 is fluoro, NH-(p-methoxybenzyl), or -NH2, then the other R 1 is not halogen.

[0219] In some embodiments, when X is C, Y is N, ring A is phenyl, R 2 is C1-C6 alkoxy, R 3 is -S(O2)-C1-C6 alkyl, and m is 1, then R 1 is not fluoro, cyano, or unsubstituted C1-C6 alkoxy.

[0220] In some embodiments, when X is C, Y is N, ring A is phenyl, R 2 is C1-C6 alkoxy, R 3 is -S(O2)-C1-C6 alkyl, m is 2, and one of R 1 is halogen, then the other R 1 is not unsubstituted C1-C6 alkoxy.

[0221] In some embodiments, X is C, Y is N, ring A is 4-pyridyl, and R 2 is C1-C6 alkoxy, R 3 is -S(O2)-C1-C6 alkyl, m is 2, and when one of R 1 is -NH2, then the other R 1 is not halogen.

[0222] In some embodiments, X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 is -S(O2)-C1-C4 alkyl, ring A is phenyl, and when m is 1, R 1 is not halogen, -NH2, cyano, or unsubstituted C1-C6 alkoxy.

[0223] In some embodiments, X is C, Y is N, R 2 is ethoxy, R 3 is -S(O2)-C1-C4 alkyl, and when m is 2, and when one of R 1 is halogen, then the other R 1 is not -NH2 or unsubstituted alkoxy.

[0224] In some embodiments, X is C, Y is N, R 2 is C1-C2 haloalkoxy, R 3 is -S(O2)-C1-C4 alkyl, and when m is 2, and when one of R 1 is halogen, then the other R 1 is not -NH2.

[0225] In some embodiments, X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 is -S(O2)-C1-C4 alkyl, and when m is 0, then ring A is not 1H-indazole or 1H-benzo[d]imidazole.

[0226] In some embodiments, the compounds described herein are not any of the compounds disclosed in He, et al., ACS Med. Chem. Lett., Vol. 8, pp. 1048-1053 (2017), and are incorporated herein by reference only for the purpose of excluding the compounds disclosed herein.

[0227] In some embodiments, the compounds described herein are 4-[6-[(1,1-dimethylethyl)sulfonyl]-7-methoxyimidazo[1,2-a]pyridin-3-yl]-2-pyridinamine; 3-(2-amino-6-chloro-4-pyridinyl)-6-[(1,1-dimethylethyl)sulfonyl]imidazo[1,2-a]pyridin-7-ol; 3-(2,6-difluoro-4-pyridinyl)-6-[(1,1-dimethylethyl)sulfonyl]-7-ethoxyimidazo[1,2-a]pyridine; 6-chloro-4-[6-[(1,1-dimethylethyl)sulfonyl]-7-methoxyimidazo[1,2-a]pyridin-3-yl]-2-pyridinamine; N-[4-[6-[(1,1-dimethylethyl)sulfonyl]-7-methoxyimidazo[1,2-a]pyridin-3-yl]-2-pyridinyl]acetamide; 4-[6-[(1,1-dimethylethyl)sulfonyl]-7-ethoxyimidazo[1,2-a]pyridin-3-yl]-6-fluoro-2-pyridinamine; 6-chloro-4-[6-[(1,1-dimethylethyl)sulfonyl]-7-ethoxyimidazo[1,2-a]pyridin-3-yl]-2-pyridinamine; 6-chloro-4-[6-[(1,1-dimethylethyl)sulfonyl]-7-(1-methylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-pyridinamine; 6-chloro-4-[6-[(1,1-dimethylethyl)sulfonyl]-7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-2-pyridinamine; 6-chloro-4-[7-(cyclopropyloxy)-6-[(1,1-dimethylethyl)sulfonyl]imidazo[1,2-a]pyridin-3-yl]-2-pyridinamine; 6-chloro-4-[6-[(1,1-dimethylethyl)sulfonyl]-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridin-3-yl]-2-pyridinamine;6-chloro-4-[6-[(1,1-dimethylethyl)sulfonyl]-7-[2-(4-methyl-1-piperazinyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-pyridinamine, and 4-[6-[(1,1-dimethylethyl)sulfonyl]-7-ethoxyimidazo[1,2-a]pyridin-3-yl]-6-fluoro-N-[(4-methoxyphenyl)methyl]-2-pyridinamine, or a pharmaceutically acceptable salt thereof, is not selected from the above, or any of the foregoing.;

[0228] In some embodiments, the compound of formula I comprises the compounds of Examples 1-340 and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the compounds of Examples 1-340 are in free base form. In some embodiments, the compounds of Examples 1-340 are in salt form, e.g., a pharmaceutically acceptable salt form.

[0229] The performance of a test compound acting as a RIPK2 inhibitor can be demonstrated by the biological assays described herein. IC 50 values are shown in Table A. Methods of treatment

[0230] The compounds and compositions disclosed herein are effective for modulating the activity of RIPK2. In some embodiments, the compounds and compositions disclosed herein are RIPK2 inhibitors.

[0231] As used herein, the term "RIPK2-related disease or disorder" refers to a disease or disorder associated with or having dysregulation of the RIPK2-gene, RIPK2-protein, or the expression or activity or level of any of them (e.g., one or more), such as dysregulation of the RIPK2-gene, RIPK2-protein, RIPK2 protein domain, or any of the types of dysregulation of the expression or activity or level of any of them described herein.

[0232] An exemplary sequence of human RIPK2 is shown below (UniParc accession number UPI00001338F2): MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLHIHTPLLDSERKDVLREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDVAWPLRFRILHEIALGVNYLHNMTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIESGWAQNPDERPSFLKCLIELEPVLRTFEEITFLEAVIQLKKTKLQSVSSAIHLCDKKKMELSLNIPVNHGPQEESCGSSQLHENSGSPETSRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAAFCDHKTTPCSSAIINPLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGLQPYPEILVVSRSPSLNLLQNKSM

[0233] Some embodiments provide a method of treating a RIPK2-related disease or disorder in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0234] Some embodiments provide a method of treating a RIPK2-related disease or disorder in a subject in need of treatment thereof, the method comprising: (a) identifying that the subject has a RIPK2-related disease or disorder; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0235] Some embodiments provide a method of treating a RIPK2-related disease or disorder in a subject previously identified or diagnosed as having been treated for a RIPK2-related disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the RIPK2-related disease or disorder is a cardiovascular disease, an allergic disorder, an autoimmune disease, an inflammatory disease, a heart disease, fibrosis, or a disease associated with abnormal cell proliferation.

[0237] In some embodiments, the RIPK2-related disease or disorder is a type I hypersensitivity (allergy) reaction. In some embodiments, the type I hypersensitivity (allergy) reaction is allergic inflammation. In some embodiments, the allergic inflammation is allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic conjunctivitis and vernal catarrh, or atopic dermatitis.

[0238] 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, Sjogren's syndrome, ankylosing spondylitis, psoriatic arthritis, juvenile dermatomyositis, juvenile rheumatoid arthritis, juvenile spondyloarthropathy, non-radiographic axial spondyloarthritis, Behcet's disease, dermatomyositis, type 1 diabetes, Goodpasture syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, mixed connective tissue disease, 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 colitis. In some embodiments, the autoimmune disease is multiple sclerosis.

[0239] In some embodiments, the RIPK2-related disease or disorder is a metabolic disease. In some embodiments, the metabolic disease is hyperglycemia, type 2 diabetes, non-alcoholic fatty liver disease (including non-alcoholic steatohepatitis), or obesity.

[0240] In some embodiments, the RIPK2-related disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disease is a 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, synovitis, carpal tunnel syndrome, tendinitis, lung inflammation (e.g., chronic obstructive pulmonary disease), pelvic inflammatory disease, graft rejection, vasculitis, regional enteritis, distal ileitis, local ileitis, and terminal ileitis, central areolar choroidal dystrophy, macular degeneration, retinitis pigmentosa, adult vitelliform 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.

[0241] 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, polyarteritis nodosa, giant cell arteritis, primary biliary cirrhosis, hepatic granulomatous disease, Langerhans cell granulomatosis, granulomatous enteritis, oral-facial granulomatosis, or Peyronie's disease.

[0242] 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 crisis, or ischemia-reperfusion injury.

[0243] In some embodiments, the RIPK2-related disease is lethal systemic inflammatory response syndrome, chronic enteritis and skin inflammation, or acute pancreatitis.

[0244] In some embodiments, the RIPK2-related disease or disorder is fibrosis. In some embodiments, the fibrosis is scleroderma, asbestosis, or idiopathic pulmonary fibrosis.

[0245] In some embodiments, the RIPK2-related disease or disorder includes neuroinflammation. In some embodiments, the RIPK2-related disease or disorder is Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Lewy body disease, Niemann-Pick disease, type C1 (NPC1), Friedreich's ataxia, spinal muscular atrophy, corticobasal degeneration, progressive supranuclear palsy (PSP), or multiple system atrophy (MSA).

[0246] In some embodiments, the RIPK2-related disease or disorder is a disease associated with abnormal cell proliferation. In some embodiments, the disease associated with abnormal cell proliferation is cancer, including hematologic malignancies and solid tumors.

[0247] Hematologic malignancies include, but are not limited to, leukemia, such as acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, and 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.

[0248] Solid tumors include lung cancer (small cell lung cancer and non-small cell lung cancer), pancreatic cancer, colorectal cancer, breast cancer, genitourinary cancer, skin cancer, bone cancer, prostate cancer, liver cancer, brain cancer, 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 (type) renal cell carcinoma), colorectal cancer, renal clear cell carcinoma, basal cell carcinoma, squamous cell carcinoma, esophageal cancer, metastatic skin cancer, osteosarcoma, Ewing's sarcoma, reticulosarcoma, Kaposi's sarcoma, giant cell tumor, islet cell tumor, acute and chronic lymphocyte and granulocyte tumors, hairy cell tumor, adenoma, medullary carcinoma, pheochromocytoma, mucosal neuroma, enteric ganglioneuroma, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilms tumor, seminoma, ovarian tumor, leiomyosarcoma tumor, cervical dysplasia, neuroblastoma, retinoblastoma, myelodysplastic syndrome, rhabdomyosarcoma, astrocytoma, hypercalcemia of malignancy, polycythemia vera, adenocarcinoma, glioblastoma multiforme, glioma, and malignant melanoma, etc.

[0249] In some embodiments, the RIPK2-related disease or disorder is a non-malignant proliferative disease, a disease associated with abnormal cell proliferation. In some embodiments, the non-malignant proliferative disease is benign prostatic hyperplasia, restenosis, hypertrophy, synovial proliferation disorder, idiopathic plasmacytic lymphadenopathy, or retinopathy.

[0250] In some embodiments, the RIPK2-related disease or disorder is selected from the group consisting of vascular necrosis, calcium pyrophosphate dihydrate crystal deposition disease (pseudogout), Blau syndrome, Ehlers-Danlos syndrome, fibromyalgia, fifth disease, 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.

[0251] In some embodiments, the RIPK2-related disease or disorder is 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 mucosa 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.

[0252] Some embodiments provide a method of treating an inflammatory bowel disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0253] Some embodiments provide a method of treating an inflammatory bowel disease in a subject in need thereof, the method comprising: (a) identifying that the subject has an inflammatory bowel disease; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0254] Some embodiments provide a method of treating an inflammatory bowel disease in a subject previously identified or diagnosed as having an inflammatory bowel disease, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0255] Some embodiments provide a method of treating Crohn's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0256] Some embodiments provide a method of treating Crohn's disease in a subject in need thereof, the method comprising: (a) identifying that the subject has Crohn's disease; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0257] Some embodiments provide a method of treating Crohn's disease in a subject previously identified or diagnosed as having Crohn's disease, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the subject is human.

[0259] Inhibition of RIPK2 activity Some embodiments also provide a method for inhibiting RIPK2 activity in mammalian cells, the method comprising contacting the mammalian cells with a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the mammalian cells comprise RIPK2 protein.

[0260] Also provided is a method for inhibiting RIPK2 activity in mammalian cells comprising RIPK2 protein, the method comprising contacting the mammalian cells with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the contact is performed in vitro. In some embodiments, the contact 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 is performed in vivo and the method comprises administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells with RIPK2 activity. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are cancer cells.

[0262] In some embodiments, RIPK2 activity is inhibited by about 10% to about 99%, such as about 10% to about 50%, about 25% to about 75%, about 50% to about 99%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or any value therebetween.

[0263] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" RIPK2 (e.g., RIPK2 protein) with a compound provided herein includes introducing a compound provided herein into a sample containing a mammalian cell preparation or purified preparation containing RIPK2 protein, in addition to administering a compound provided herein to a subject such as a human having RIPK2 protein.

[0264] Pharmaceutical composition In some embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Examples

[0265] Materials and methods The compounds containing the salts provided by the present invention can be prepared using known organic synthesis techniques and can be synthesized according to any of many possible synthetic routes.

[0266] The reactions for preparing the compounds provided herein can be carried out in a suitable solvent that can be readily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, in the range from the freezing temperature to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, the suitable solvent(s) for that particular reaction step can be selected by those skilled in the art.

[0267] The preparation of the compounds provided herein can 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 chemical properties of protecting groups can be found, for example, in Protecting Group Chemistry, 1st Ed., Oxford University Press, 2000; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997). Intermediate Intermediate 1

Chemical formula

Chem.

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Table 2

Table 3

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Chem.

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Chem.

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Chem.

Chem.

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Table 4

Chem.

Chemical formula

Chemical formula

Chemical formula

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Chem.

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Chem.

Chemical formula

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Chem.

Chem.

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Table 5-1

Table 5-2

Table 5-3

Table 5-4

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Table 5-6

Table 5-7

Table 5-8

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Table 5-63

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Table 7

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Table 8-1

Table 8-2

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Table 8-6

Table 8-7

Table 8-8

Table 8-9

Table 8-10

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Table 10-1

Table 10-2

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Table 11

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Table 12

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Table 13

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Table 14

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Table 15

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Table 17

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Table 18

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[0268] Biological data RIPK2 binding competition assay The ability of a selected compound of formula (I) to inhibit the binding of Alexa647-labeled ATP-competitive kinase inhibitors to the GST-RIPK2 fusion protein was quantified using a TR-FRET-based RIPK2 binding competition assay as described in the following paragraphs.

[0269] A recombinant fusion protein of N-terminal glutathione-S-transferase (GST) and a fragment of human RIPK2 (amino acids 1-310 of accession number O43353) was expressed in baculovirus-infected Sf9 cells and purified via glutathione affinity chromatography for use as the GST-RIPK2 fusion protein. Tracer 199 (catalog number PR9115B) from Life Technologies was used as the Alexa647-labeled ATP-competitive kinase inhibitor.

[0270] For the assay, 50 nL of a 100-fold concentrated solution of each test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both from Greiner Bio-One, Frickenhausen, Germany), and 3 μL of a solution of Tracer 199 (16.7 nM => final concentration in 5 μL assay volume is 10 nM) in aqueous assay buffer (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 orthovanadate, 0.01% (w / v) bovine serum albumin (BSA), 0.005% (w / v) Pluronic F-127 (Sigma)) was added. Next, binding competition was initiated by adding 2 μL of a solution of GST-RIPK2 fusion protein (2.5 nM => final concentration in 5 μL assay volume is 1 nM) and anti-GST-Tb (1.25 nM => final concentration in 5 μL assay volume is 0.5 nM), PerkinElmer's Lumi4®-Tb cryptate conjugate anti-GST antibody (catalog number 61GSTTAH) to the assay buffer.

[0271] The resulting mixture was incubated at 22 °C for 45 minutes to allow complex formation between Tracer 199, the fusion protein, and anti-GST-Tb. Subsequently, the amount of this complex was evaluated by measuring the resonance energy transfer from Tb cryptate to Tracer 199. Thus, the fluorescence emissions at 620 nm and 665 nm after excitation at 337 nm were measured with a TR-FRET reader, e.g., Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or Viewlux (PerkinElmer). The ratio of the emissions at 665 nm and 620 nm was regarded as a measure of the amount of complex. The data were normalized (assay reaction without inhibitor = 0% activity, assay containing all assay components except GST-RIPK2 fusion protein = 100% activity). Usually, test compounds were tested at 11 different concentrations in the range of 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 are in a separately adjusted dilution series and the exact concentrations may vary depending on the pipettor used) on the same microtiter plate, in duplicate for each concentration, and the IC 50 values were calculated using Genedata Screener™ software.

[0272] THP-1 Dual Cell SEAP and Viability Assay THP1-Dual™ cells (InvivoGen Cat# thpd-nfis) enable simultaneous evaluation of the NF-κB pathway by monitoring the activity of secreted embryonic alkaline phosphatase (SEAP) and the IRF pathway by assessing the activity of secreted luciferase (Lucia). Cells were cultured according to the manufacturer's recommendations. For the assay, the cell concentration was adjusted to 7.14×10 5 cells / mL in assay medium (RPMI1640, 2 mM L-glutamine, 25 mM HEPES, 10% fetal bovine serum (heat-inactivated at 56 °C for 30 minutes), Pen-Strep (100 U / mL)). 35 μL of the cell suspension (approx. 25,000 cells) per well was added to a flat-bottom 384-well plate (white opaque). The plate was centrifuged at 300 g for 2 minutes, and compounds were added in a serial dilution series according to the plate layout (volume approximately 500 nL - 0.0152 nL), and the plate was incubated at 37 °C with 5% CO2 for 30 minutes. A stock solution of L18-MDP was prepared such that when 15 μL was added to each well, it resulted in a final concentration of 10 ng / mL of L18-MDP in each well when 15 μL of assay medium 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 wells. Then, the plate was incubated overnight (20 - 24 hours) at 37 °C in 5% CO2.

[0273] For the SEAP assay: Without disturbing the cells at the bottom of the well, 15 μL of the 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, the optical density (OD) was measured at 620 - 655 nm using a microplate reader (PheraStar FS microplate reader equipped with a protocol for OD 620 - 655 nm).

[0274] Regarding the viability assay: The cell viability was evaluated using the cells remaining on the plate. For this purpose, the CellTiter-Glo buffer and the lyophilized CellTiter-Glo substrate were allowed to equilibrate to room temperature, and the lyophilized CellTiter-Glo substrate was reconstituted according to the manufacturer's recommendations. The same volume (here 35 μL) of CTG was added to each well, and the contents were mixed on an orbital shaker for 2 minutes to induce lysis and then incubated at room temperature for 10 minutes. Subsequently, the luminescence signal was measured with a microplate reader (PheraStar).

[0275] Analysis: The values of the wells with medium alone were subtracted, and the % inhibition at each compound concentration was calculated by comparing with the control treated with DMSO / L18-MDP. The inhibition values + / − SD were fitted by non-linear regression using Prism software (GraphPad PRISM Software), and the IC 50 values were calculated.

[0276] Table A below shows the IC 50 values of the selected compounds of formula (I) measured in the RIPK2 binding competition assay and the THP-1 Dual cell SEAP and viability assays. For the IC 50 values in the RIPK2 competition assay, "A" indicates an IC 50 < 1 nM, "B" indicates an IC 50 of 1 nM ≤ B ≤ 2.5, "C" indicates an IC 50 of 2.5 nM < C ≤ 20, and "D" indicates an IC 50 > 20 nM. For the IC 50 values in the THP assay, "A" indicates an IC 50 < 50 nM, "B" indicates an IC 50 of 50 nM ≤ B ≤ 250, "C" indicates an IC 50 of 250 nM < C ≤ 1,000, and "D" indicates an IC 50 > 1,000 nM.

Table 1-1

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Table 1-3

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Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof. [In the formula, Ring A is phenyl, a 5-10 member heteroaryl, or a 5-10 member heterocycline. One of X and Y is N, and the other of X and Y is C. each 【Chemistry 2】 However, the bicyclic ring structure of formula (I) is either a single bond or a double bond such that it becomes imidazo[1,2-a]pyridine or pyrazolo[1,5-a]pyridine. m is 0, 1, 2, 3, or 4, Each R １ They became independent, (i) Halogen, (ii) Cyano, (iii) Hydroxyl, C1-C6 alkoxy, or -S(O ２ ) C1-C6 alkyl groups that are optionally substituted with C1-C6 alkyl groups, (iv) C1-C6 haloalkyl, (v) C1-C6 haloalkoxy, (vi) C3-C6 cycloalkyl, ())) Ａ ( Ｂ 、 (viiii) C1-C6 alkoxys optionally substituted with hydroxyl or phenyl, A 4- to 8-membered heterocycline optionally substituted with one or two substituents independently selected from the group consisting of (ix)hydroxyl, C1-C6 alkyl, and C1-C6 haloalkyl, (x) - S(O ２ ) C1-C6 alkyl, (xi) hydroxyl, (xi) Nitro, (xiii)-S(O ２ ) Selected from the group consisting of C3-C6 cycloalkyl, and When ring A is phenyl, R １ is further selected from -S(O ２ )NR Ａ R Ａ ; R Ａ However, it is hydrogen or a C1-C6 alkyl group. R Ｂ but, (i) Hydrogen, (ii) - S (O ２ ) C1-C6 alkyl, (iii) C3-C6 cycloalkyl groups optionally substituted with hydroxyl or C1-C6 alkoxy groups. A 4- to 8-membered heterocycline optionally substituted with one or two substituents independently selected from (iv) hydroxyl and C1-C6 haloalkyl, or (v) (a) Halogen, (b) Hydroxyl, (c)-NR Ｃ R Ｄ 、 (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) C3-C6 cycloalkyl groups optionally substituted with hydroxyl groups. (g) Phenyl compounds optionally substituted with C1-C6 alkoxy compounds. (h) 5-6 member heteroaryls optionally substituted with C1-C6 alkyl groups, (j) A 4- to 8-membered heterocycline optionally substituted with a hydroxyl, -C(=O)C1-C6 alkyl, or C1-C6 alkyl. (k) C1-C6 thioalkyls, and (l) - S (= NR Ｅ )(=O)C1-C6 alkyl, which is optionally substituted with 1 to 4 substituents independently selected from C1-C6 alkyl groups, R ２ However, it is hydrogen, halogen, C1-C6 alkoxy, or C1-C6 haloalkoxy. R ３ but, (i) C1-C6 thioalkyl, (ii) 【Transformation 3】 (iii) 【Chemistry 4】 (iv) A 4- to 8-membered heterocycline optionally substituted with one or two substituents independently selected from halogens and C1-C6 alkyl groups. (v) NR Ｅ R Ｆ Or C1-C6 alkyl groups optionally substituted with hydroxyl, (vi)-CO ２ H、 ( ) ( ) ) ( ) ( ) ) Ｅ ( Ｆ 、 (viiii) C1-C6 alkoxys optionally substituted with 4-10 member heterocyclines optionally substituted with C1-C6 alkoxys, (ix) hydrogen, Z is O or NR ４ And, R ３Ａ However, it is a C1-C6 alkyl group that is optionally substituted with a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, or a C3-C6 cycloalkyl group. R ３Ｂ and R ３Ｃ Each of these is independently a C3-C6 cycloalkyl group, or a C1-C6 alkyl group that is optionally substituted by a C3-C6 cycloalkyl group. R ４ However, it is hydrogen or C1-C6 alkyl, and Each R Ｃ and R Ｄ Each of these is a C1-C6 alkyl group that is optionally substituted with hydrogen, -C(=O)OC1-C6 alkyl, or oxo. Each R Ｅ and R Ｆ Each of them is independently hydrogen or a C1-C6 alkyl, and Therefore, (i) X is C, Y is N, ring A is 4-pyridyl, R ２ is a C1-C6 alkoxy, and R ３ ga-S(O ２ ) - C1 to C6 alkyl, and when m is 1, then R １ is, -NH ２ or -NH(C=O)CH ３ Instead, (ii) X is C, Y is N, ring A is 4-pyridyl, R ２ is a C1-C6 alkoxy, and R ３ ga-S(O ２ ) - C1 to C6 alkyl, m is 2, and one R １ is fluoro, -NH-(p-methoxybenzyl), or -NH ２ If that is the case, then the other R １ It is not halogen, (iii) X is C, Y is N, ring A is phenyl, R ２ is a C1-C6 alkoxy, and R ３ ga-S(O ２ ) - C1 to C6 alkyl, and when m is 1, R １ It is not a fluoro, cyano, or unsubstituted C1-C6 alkoxy, (iv) X is C, Y is N, ring A is phenyl, R ２ is a C1-C6 alkoxy, and R ３ ga-S(O ２ ) - C1 to C6 alkyl, m is 2, and one R １ If one is halogen, then the other R １ These are not unsubstituted C1-C6 alkoxy compounds, (v) X is C, Y is N, ring A is 4-pyridyl, R ２ is a C1-C6 haloalkoxy, and R ３ ga-S(O ２ ) - C1 to C6 alkyl, m is 2, and one R １ ga-NH ２ If that is the case, then the other R １ It is not halogen, (vi) X is C, Y is N, R ２ is a C1-C3 alkoxy, and R ３ ga-S(O ２ ) - C1 to C4 alkyl, ring A is phenyl, and m is 1, R １ Halogen, -NH ２ , rather than cyano or unsubstituted C1-C6 alkoxy, (vii) X is C, Y is N, R ２ is ethoxy, R ３ ga-S(O ２ ) - C1 to C4 alkyl, and m is 2, and one R １ If one is halogen, then the other R １ is, -NH ２ Or rather than an unsubstituted alkoxy, (viiii) X is C, Y is N, R ２ is a C1-C2 haloalkoxy, and R ３ ga-S(O ２ ) - C1 to C4 alkyl, and m is 2, and one R １ If one is halogen, then the other R １ is, -NH ２ Rather, and (ix) X is C, Y is N, R ２ is a C1-C3 alkoxy, and R ３ ga-S(O ２ ) -C1-C4 alkyl, and when m is 0, then ring A is not 1H-indazole or 1H-benzo[d]imidazole.

2. A compound selected from Examples 1 to 340, or any pharmaceutically acceptable salt described above.

3. A pharmaceutical composition comprising the compound described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

4. Use of the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a therapeutic agent for a method of treating a RIPK2-related disease or disorder in a subject requiring treatment for a RIPK2-related disease or disorder, wherein the method comprises administering to the subject an effective amount of the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

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