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

Abstract

The present application relates to compounds of formula (I) as defined herein and pharmaceutically acceptable salts thereof and compositions comprising the same. Also described are methods of treating diseases and conditions disclosed herein using compounds of Formula (I) and pharmaceutically acceptable salts thereof, and compositions comprising the same.

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 comprising the same. Methods of using compounds of formula (I), and pharmaceutically acceptable salts thereof, and compositions comprising the same for treating diseases and disorders disclosed herein 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 receptors (TLRs). The RIPK2 protein includes 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, thereby detecting bacterial pathogens by binding to diaminopimelic acid or muramyl dipeptide residues present in bacterial peptidoglycan. The interaction between RIPK2 and NOD1, and between NOD2 and TLRs, triggers the release of proinflammatory cytokines including TNF-α, IL-6, and IL-12 / 23p40, as well as the induction of RIPK2-mediated NF-κ-B-dependent inflammatory responses. Activation of RIPK2 and dysregulation of the RIPK2-NOD signaling pathway may also play a role in the pathogenesis of various inflammatory diseases. RIPK2 has been reported to be a prognostic marker and candidate therapeutic target for a variety of cancers. Summary of the invention

[0004] Some embodiments provide a compound of formula (I):

[0005]

[0006] or a pharmaceutically acceptable salt thereof, wherein:

[0007] Ring A is phenyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group;

[0008] One of X and Y is N, and the other of X and Y is C;

[0009] Each is a single bond or a double bond, so that the bicyclic ring system of formula (I) is imidazo[1,2-a]pyridine or pyrazolo[1,5-a]pyridine;

[0010] m is 0, 1, 2, 3 or 4;

[0011] Each R 1 Independently selected from the group consisting of:

[0012] (i) halogen,

[0013] (ii) cyano,

[0014] (iii) C1-C6 alkyl optionally substituted by hydroxy, C1-C6 alkoxy or -S(O2)C1-C6 alkyl,

[0015] (iv) C1-C6 haloalkyl,

[0016] (v) C1-C6 haloalkoxy,

[0017] (vi) C3-C6 cycloalkyl,

[0018] (vii) –NR A R B ,

[0019] (viii) a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group,

[0020] (ix) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl,

[0021] (x) – S(O2) C1-C6 alkyl,

[0022] (xi) hydroxyl group,

[0023] (xii) nitro,

[0024] (xiii) –S(O2)C3-C6 cycloalkyl, and

[0025] (xiv) When ring A is phenyl, R 1 Further selected from –S(O2)NR A R A ;

[0026] R A is hydrogen or C1-C6 alkyl;

[0027] R B for

[0028] (i)Hydrogen,

[0029] (ii) –S(O2)C1-C6 alkyl,

[0030] (iii) a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group or a C1-C6 alkoxy group,

[0031] (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl, or

[0032] (v) C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from the following:

[0033] (a) halogen,

[0034] (b) hydroxyl groups,

[0035] (c)-NR C R D ,

[0036] (d) C1-C6 alkoxy,

[0037] (e) C1-C6 haloalkoxy,

[0038] (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group,

[0039] (g) phenyl optionally substituted by C1-C6 alkoxy,

[0040] (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group,

[0041] (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl,

[0042] (k) C1-C6 thioalkyl, and

[0043] (l) – S(=NR E )(=O)C1-C6 alkyl;

[0044] R 2 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0045] R 3 for

[0046] (i) C1-C6 thioalkyl,

[0047] (ii)

[0048] (iii)

[0049] (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl,

[0050] (v) optionally NR E R For a hydroxy-substituted C1-C6 alkyl group,

[0051] (vi) -CO2H,

[0052] (vii) -C(=O)NR E R F ,

[0053] (viii) C1-C6 alkoxy optionally substituted by a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by a C1-C6 alkoxy group,

[0054] (ix) hydrogen;

[0055] Z is O or NR 4 ;

[0056] R 3A is C1-C6 haloalkyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by C3-C6 cycloalkyl;

[0057] R 3B and R 3C Each is independently a C3-C6 cycloalkyl group or a C1-C6 alkyl group optionally substituted by a C3-C6 cycloalkyl group;

[0058] R 4 is hydrogen or C1-C6 alkyl; and

[0059] Each R C and R D Each is independently hydrogen, -C(=O)OC1-C6 alkyl or C1-C6 alkyl optionally substituted by oxo;

[0060] Each R E and R F are each independently hydrogen or C1-C6 alkyl; and

[0061] in

[0062] (i) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is a C1-C6 alkoxy group, R 3 When -S(O2)-C1-C6 alkyl and m is 1, then R 1 Not –NH2 or –NH(C=O)CH3;

[0063] (ii) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is fluorine, NH-(p-methoxybenzyl) or –NH2, the other R1 Not halogen;

[0064] (iii) When X is C, Y is N, ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 When it is –S(O2)-C1-C6 alkyl and m is 1, R 1 It is not fluorine, cyano or unsubstituted C1-C6 alkoxy;

[0065] (iv) When X is C, Y is N, ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is a halogen, the other R 1 is not an unsubstituted C1-C6 alkoxy group;

[0066] (v) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is C1-C6 haloalkoxy, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is –NH2, the other R 1 Not halogen;

[0067] (vi) When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When -S(O2)-C1-C4 alkyl, ring A is phenyl, and m is 1, R 1 It is not halogen, -NH2, cyano or unsubstituted C1-C6 alkoxy;

[0068] (vii) When X is C, Y is N, R 2 is ethoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not -NH2 or unsubstituted alkoxy; and

[0069] (viii) When X is C, Y is N, R 2 is C1-C2 haloalkoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not –NH2; and

[0070] (ix) When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3When the ring A is -S(O2)-C1-C4 alkyl and m is 0, then the ring A is not 1H-indazole or 1H-benzo[d]imidazole.

[0071] In some embodiments, Formula (I) is:

[0072]

[0073] or a pharmaceutically acceptable salt thereof, wherein:

[0074] Ring A is phenyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group;

[0075] One of X and Y is N, and the other of X and Y is C;

[0076] Each is a single bond or a double bond, so that the bicyclic ring system of formula (I) is imidazo[1,2-a]pyridine or pyrazolo[1,5-a]pyridine;

[0077] m is 0, 1, 2 or 3;

[0078] Each R 1 Independently selected from the group consisting of:

[0079] (i) halogen,

[0080] (ii) cyano,

[0081] (iii) a C1-C6 alkyl group optionally substituted by a hydroxy group,

[0082] (iv) C1-C6 haloalkyl,

[0083] (v) C1-C6 haloalkoxy,

[0084] (vi) C3-C6 cycloalkyl,

[0085] (vii) –NR A R B ,

[0086] (viii) a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group, and

[0087] (ix) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl;

[0088] R A is hydrogen or C1-C6 alkyl;

[0089] R B for

[0090] (i)Hydrogen,

[0091] (ii) –S(O2)C1-C6 alkyl,

[0092] (iii) a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group or a C1-C6 alkoxy group,

[0093] (iv) a 4- to 8-membered heterocyclic group optionally substituted by a hydroxy group, or

[0094] (v) C1-C6 alkyl optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, hydroxy, -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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl;

[0095] R 2 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0096] R 3 for

[0097] (i) C1-C6 thioalkyl,

[0098] (ii)

[0099] (iii)

[0100] (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl,

[0101] (v) optionally NR E R F or a hydroxy-substituted C1-C6 alkyl group,

[0102] (vi) -CO2H,

[0103] (vii) -C(=O)NR E R F ,

[0104] (viii) C1-C6 alkoxy optionally substituted by 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by C1-C6 alkoxy group, or

[0105] (ix) hydrogen;

[0106] Z is O or NR 4 ;

[0107] R 3A is C1-C6 haloalkyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by C3-C6 cycloalkyl;

[0108] R 3B and R 3C Each is independently a C3-C6 cycloalkyl group or a C1-C6 alkyl group optionally substituted by a C3-C6 cycloalkyl group;

[0109] R 4 is hydrogen or C1-C6 alkyl; and

[0110] Each R C and R D Each is independently hydrogen or C1-C6 alkyl optionally substituted by oxo;

[0111] Each R E and R F are each independently hydrogen or C1-C6 alkyl; and

[0112] in

[0113] (x) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is a C1-C6 alkoxy group, R 3 When -S(O2)-C1-C6 alkyl and m is 1, then R 1 Not –NH2 or –NH(C=O)CH3;

[0114] (xi) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is fluorine, NH-(p-methoxybenzyl) or –NH2, the other R 1 Not halogen;

[0115] (xii) When X is C, Y is N, Ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 When it is –S(O2)-C1-C6 alkyl and m is 1, R 1 It is not fluorine, cyano or unsubstituted C1-C6 alkoxy;

[0116] (xiii) When X is C, Y is N, Ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is a halogen, the other R 1is not an unsubstituted C1-C6 alkoxy group;

[0117] (xiv) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is C1-C6 haloalkoxy, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is –NH2, the other R 1 Not halogen;

[0118] (xv) When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When -S(O2)-C1-C4 alkyl, ring A is phenyl, and m is 1, R 1 It is not halogen, -NH2, cyano or unsubstituted C1-C6 alkoxy;

[0119] (xvi) When X is C, Y is N, R 2 is ethoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not -NH2 or unsubstituted alkoxy; and

[0120] (xvii) When X is C, Y is N, R 2 is C1-C2 haloalkoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not –NH2; and

[0121] (xviii) When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When the ring A is -S(O2)-C1-C4 alkyl and m is 0, then the ring A is not 1H-indazole or 1H-benzo[d]imidazole.

[0122] 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.

[0123] Also provided herein is a method for treating a RIPK2-related disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0124] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. Methods and materials used in the present disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods and embodiments are illustrative only and are not intended to be limiting. Unless otherwise expressly indicated, all publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0125] Other features and advantages of the disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0126] Biologics and small molecules targeting proinflammatory signaling pathways have been used to successfully treat inflammatory diseases and other diseases in patients, however, a significant portion of patients are refractory to existing therapies. Therefore, there is a need to identify novel therapeutic molecules that modulate or inhibit these pathways, such as compounds of formula (I) and pharmaceutically acceptable salts thereof as described herein.

[0127] definition

[0128] For ease of understanding the disclosure set forth herein, some additional terms are defined below. In general, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meanings as those of ordinary skill in the art to which the disclosure belongs. Each patent, application, disclosed application and other publications mentioned in the entire specification and the attached appendix are incorporated herein by reference in their entirety. In the event of a conflict, this specification (including definitions) shall prevail.

[0129] The term "about" when referring to a number or a numerical range means that the referenced number or numerical range is approximate, e.g., within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary by up to ±10% over the stated number or numerical range.

[0130] The phrase "therapeutically effective amount" means an amount of a compound that, when administered to a subject in need of such treatment, is sufficient to: (i) treat a disease or disorder as described herein (e.g., a RIPK2-associated disease or disorder), (ii) reduce, improve, or eliminate one or more symptoms of a specific disease or disorder, or (iii) delay the onset of one or more symptoms of a specific disease or disorder as described herein.

[0131] As used herein, the term "treat" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, overall or partial alleviation of symptoms associated with a disorder or condition, reduction in the extent of a neurological disorder, a stable (i.e., non-deteriorating) disease or condition state, a delay or slowing of disease progression, an improvement or alleviation of a disease state (e.g., one or more symptoms of a disease or condition), and whether detectable or undetectable relief (whether partial or complete), and can be determined by various clinical assessments including clinical evaluation and self-report. "Treatment" can also mean prolonged survival compared to survival expected when not receiving treatment.

[0132] The term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with human and animal tissues or organs without causing excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., 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.

[0133] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered, and does not eliminate the biological activity and properties of the compound. In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid (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, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acidic group with a base to form a salt (such as an ammonium salt, an alkali metal salt (such as a sodium salt or a potassium salt), an alkaline earth metal salt (such as a calcium salt or a magnesium salt), an organic base (such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine) and a salt with an amino acid (such as arginine, lysine, etc.) or by other methods previously determined. There is no specific limitation on pharmacologically acceptable salts, as long as they can be used in medicine. Examples of salts formed with bases of the compounds described herein include the following: salts thereof with inorganic bases (such as sodium, potassium, magnesium, calcium, aluminum); salts thereof with organic bases (such as methylamine, ethylamine, ethanolamine); salts thereof with basic amino acids (such as lysine, ornithine); and ammonium salts. The salt may be an acid addition salt, which may be specifically exemplified by an acid addition salt using the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and 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; acidic amino acids such as aspartic acid and glutamic acid.

[0134] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "pharmaceutically acceptable excipients", such as stabilizers, diluents, dispersants, suspending agents, thickeners and / or other excipients). Pharmaceutical compositions facilitate administration of the compound to an organism.

[0135] The term "subject" refers to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein with respect to, for example, a mammalian subject (such as a human).

[0136] The term "halo" or "halogen" refers to one of the halogens of group 17 of the periodic table. The term refers in particular to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0137] The term "oxo" refers to a divalent double-bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

[0138] The term "alkyl" refers to a saturated acyclic hydrocarbon group which may be straight or branched chain containing the specified number of carbon atoms.1-10 The indicated groups may have from 1 to 10 (inclusive) carbon atoms in them. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl.

[0139] The term "alkenyl" refers to an acyclic hydrocarbon group which may be straight or branched chain containing the specified number of carbon atoms and one or more carbon-carbon double bonds. Non-limiting examples include vinyl and allyl.

[0140] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogens.

[0141] The term "hydroxyalkyl" refers to an alkyl group as described herein wherein one or more hydrogen atoms are replaced by one or more hydroxy groups as described herein.

[0142] The term "alkoxy" refers to an -O-alkyl group (eg, -OCH3).

[0143] The term "thioalkyl" refers to an alkyl group as described herein attached to the molecule via a sulfur atom (eg, -SCH3).

[0144] The term "haloalkoxy" refers to a haloalkyl group attached to the molecule via an oxygen atom (eg, -OCF3).

[0145] The term "alkoxyalkyl" refers to an alkyl group as described herein wherein one or more hydrogen atoms are replaced by one or more alkoxy groups as described herein.

[0146] As used herein, the term "cyano" refers to a -CN group.

[0147] As used herein, the term "nitro" refers to a -NO2 group.

[0148] As used herein, the term "hydroxyl" refers to an -OH group.

[0149] As used herein, the term "amino" refers to a -NH2 group.

[0150] As used herein, the term "phosphate" refers to a -P(=O)2(OH)2 group.

[0151] As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic or tricyclic group, wherein at least one ring in the system is aromatic; and wherein one or more carbon atoms on at least one ring in the system are replaced by heteroatoms independently selected from the group consisting of N, O, S, B, Si and P. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The heteroaryl group may also contain one or more oxo, N-oxide, S-oxide and / or S,S-dioxide groups, as long as the 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].

[0152] For the purpose of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., ), pyrimidone (e.g., ), pyridazinones (e.g., ), pyrazinones (e.g. ) and imidazolones (e.g. ) wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (ie, the oxo group (ie, "=O") herein is an integral part of a heteroaryl ring).

[0153] 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 cycloalkyls include fused rings, spirocyclic and bridged ring systems. Non-limiting examples of cycloalkyls include cyclopropyl, cyclohexyl, spiro[2.3]hexyl and bicyclo[1.1.1]pentyl.

[0154] The term "aryl" refers to a monocyclic, bicyclic, tricyclic or polycyclic group of 6-20 carbon atoms, wherein 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.

[0155] The term "heterocyclyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic, bicyclic or tricyclic ring system having 3 to 20 ring atoms, which is not aromatic and has at least one heteroatom selected from the group consisting of N, O, S, B, Si and P in the ring system. Bicyclic and tricyclic heterocyclic groups include fused rings, spirocyclic and bridged ring systems. Heterocyclic groups can be represented as "5 to 10 membered heterocyclic groups", which are ring systems containing 5, 6, 7, 8, 9 or 10 atoms (at least one of which is a heteroatom). The heterocycle may also contain one or more oxo, thiocarbonyl, N-oxide, S-oxide and / or S, S-dioxide groups, as long as the valence permits, so that the definition includes oxo systems and sulphur systems, such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. The heterocyclic group can be bonded to the rest of the molecule through any carbon atom or through a heteroatom (such as nitrogen). Exemplary heterocyclic groups include, but are not limited to, 1,3-dioxolane, 1,4-dioxolane, maleimide, succinimide, dioxopiperazine, hydantoin, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidone, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, pyrrolidinone, tetrahydrofuran yl, thiolanyl, pyrazolyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidinonyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantoinyl, thiohydantoinyl, imidazolidinonyl, oxazolidinyl, thiazolidinonyl, oxathiolano ... thiolanonyl), dioxolanonyl, dioxazolidinone, oxadiazolidinone, triazolidinone, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinylthionyl, isothiazolidinone, piperidinyl, tetrahydropyranyl, thienyl, morpholinyl, thiomorpholinyl, dioxane 1-azaspiro[3.3]heptyl.

[0156] As used herein and hereinbefore, the term "saturated" means that only single bonds exist between the constituent atoms.

[0157] As used herein, when a ring is described as "partially unsaturated", it means that the ring has one or more additional unsaturations (in addition to the unsaturation attributed to the ring itself; for example, one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0158] As used herein, a wavy line depicts the point of attachment of an atom or moiety to the designated atom or group in the rest of the molecule.

[0159] Whenever a group is described as "optionally substituted", the group may be unsubstituted or substituted with one or more of the specified substituents. When a group is substituted, the substitution may include sharing a carbon atom between the parent group and the substituent to form a spirocycle. For example, n-butyl substituted with cyclopropyl includes wait.

[0160] For the avoidance of doubt, and unless otherwise indicated, with respect to rings and cyclic groups (e.g., carbocycles, aryls, cycloalkyls, heterocyclyls, heteroaryls, etc., as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic systems), it is to be understood that such rings and cyclic groups encompass those having fused rings, including those wherein the point of fusion is located between: (i) adjacent ring atoms (e.g., a [xx0] ring system, where 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro-fused ring system) (e.g., ), or (iii) a continuous array of ring atoms (a bridged ring system with all bridge lengths > 0) (e.g. ).

[0161] In addition, any compound or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. 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.

[0162] Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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. Various isotopically enriched compounds of the present disclosure, for example, in which radioactive isotopes such as 13 C and 14 Such isotopically enriched compounds are useful in metabolic studies, reaction kinetics studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays or radiotherapy of patients.

[0163] The term "isotopically enriched" compound includes "deuterated" compounds as described herein, in which one or more hydrogens are replaced by deuterium, such as hydrogen on a carbon atom. Such compounds exhibit enhanced metabolic resistance and can therefore be used to increase the half-life of any compound when administered to a mammal (particularly a human). Such compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium. In fact, the isotopically enriched compounds of the present disclosure can generally be prepared by replacing non-isotopically enriched reagents with readily available isotopically enriched reagents by executing the procedures disclosed in the scheme or in the embodiments and preparations described below.

[0164] Deuterium-enriched compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties involving distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability relative to the corresponding unenriched compounds, such as increased in vivo half-life, reduced dosage requirements and / or improved therapeutic index.

[0165] The concentration of heavier isotopes, such as deuterium, can be defined by an isotopic enrichment factor. In some embodiments, positions labeled "H" or "hydrogen" in the compounds described herein have hydrogen in its naturally abundant isotopic composition. In some embodiments, positions labeled "H" or "hydrogen" in the compounds described herein have hydrogen enriched in deuterium and above its naturally abundant isotopic composition, i.e., the compounds are deuterium-enriched compounds. Examples of deuterated groups in the compounds described herein include, but are not limited to, deuteromethine. Monodeuterated methylene and dideuterated methylene Trideuterated methyl Trideuterated methoxy The compounds of the present disclosure also include deuterium-enriched compounds at the alpha position of the oxo group, such as

[0166] Furthermore, compounds disclosed generally or specifically herein are intended to include all tautomeric forms. Thus, for example, a compound containing part The compounds include some Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxy encompasses pyridone or pyrimidone tautomeric forms.

[0167] Compounds provided herein may encompass various stereochemical forms. Compounds also encompass mixtures of enantiomers (e.g., R and S isomers), diastereomers, and enantiomers (e.g., R and S isomers), including racemic mixtures and mixtures of diastereomers, and single enantiomers and diastereomers produced due to the structural asymmetry of some compounds. Unless otherwise indicated, when disclosed compounds are named or depicted by structures (e.g., "planar" structures) that do not specify stereochemistry, and have one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, when disclosed compounds are named or depicted by structures (e.g., structures with "wedge-shaped bonds" and / or "virtual bonds") that specify stereochemistry and have one or more chiral centers, it is understood to represent the indicated stereoisomers of the compound.

[0168] The 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 become apparent from the description and the claims.

[0169] "RIPK2 inhibitors" as defined herein include any compound that exhibits RIPK2 inhibitory activity. In some embodiments, the RIPK2 inhibitor is selective for RIPK2. Exemplary RIPK2 inhibitors may exhibit an inhibitory activity (IC) against RIPK2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in an assay described herein. 50 In some embodiments, the RIPK2 inhibitor can exhibit an inhibitory activity (IC) against RIPK2 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 an assay provided herein. 50 ).

[0170] Compound of formula (I)

[0171] Some embodiments provide a compound of formula (I):

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein:

[0174] Ring A is phenyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group;

[0175] One of X and Y is N, and the other of X and Y is C;

[0176] Each is a single bond or a double bond, so that the bicyclic ring system of formula (I) is imidazo[1,2-a]pyridine or pyrazolo[1,5-a]pyridine;

[0177] m is 0, 1, 2, 3 or 4;

[0178] Each R 1 Independently selected from the group consisting of:

[0179] (i) halogen,

[0180] (ii) cyano,

[0181] (iii) C1-C6 alkyl optionally substituted by hydroxy, C1-C6 alkoxy or -S(O2)C1-C6 alkyl,

[0182] (iv) C1-C6 haloalkyl,

[0183] (v) C1-C6 haloalkoxy,

[0184] (vi) C3-C6 cycloalkyl,

[0185] (vii) –NR A R B ,

[0186] (viii) a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group,

[0187] (ix) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl,

[0188] (x) – S(O2) C1-C6 alkyl,

[0189] (xi) hydroxyl group,

[0190] (xii) nitro,

[0191] (xiii) –S(O2)C3-C6 cycloalkyl, and

[0192] (xiv) When ring A is phenyl, R 1 Further selected from –S(O2)NR A R A ;

[0193] R A is hydrogen or C1-C6 alkyl;

[0194] R B for

[0195] (i)Hydrogen,

[0196] (ii) –S(O2)C1-C6 alkyl,

[0197] (iii) a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group or a C1-C6 alkoxy group,

[0198] (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl, or

[0199] (v) C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from the following:

[0200] (a) halogen,

[0201] (b) hydroxyl groups,

[0202] (c)-NR C R D ,

[0203] (d) C1-C6 alkoxy,

[0204] (e) C1-C6 haloalkoxy,

[0205] (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group,

[0206] (g) phenyl optionally substituted by C1-C6 alkoxy,

[0207] (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group,

[0208] (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl,

[0209] (k) C1-C6 thioalkyl, and

[0210] (l) – S(=NR E )(=O)C1-C6 alkyl;

[0211] R 2 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0212] R 3 for

[0213] (i) C1-C6 thioalkyl,

[0214] (ii)

[0215] (iii)

[0216] (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl,

[0217] (v) optionally NR E R F or a hydroxy-substituted C1-C6 alkyl group,

[0218] (vi) -CO2H,

[0219] (vii) -C(=O)NR E R F ,

[0220] (viii) C1-C6 alkoxy optionally substituted by a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by a C1-C6 alkoxy group,

[0221] (ix) hydrogen;

[0222] Z is O or NR 4 ;

[0223] R 3A is C1-C6 haloalkyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by C3-C6 cycloalkyl;

[0224] R 3B and R 3C Each is independently a C3-C6 cycloalkyl group or a C1-C6 alkyl group optionally substituted by a C3-C6 cycloalkyl group;

[0225] R 4 is hydrogen or C1-C6 alkyl; and

[0226] Each R C and R D Each is independently hydrogen, -C(=O)OC1-C6 alkyl or C1-C6 alkyl optionally substituted by oxo;

[0227] Each R E and R F are each independently hydrogen or C1-C6 alkyl; and

[0228] in

[0229] When X is C, Y is N, and ring A is 4-pyridyl, R 2is a C1-C6 alkoxy group, R 3 When -S(O2)-C1-C6 alkyl and m is 1, then R 1 Not –NH2 or –NH(C=O)CH3;

[0230] When X is C, Y is N, and ring A is 4-pyridyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is fluorine, NH-(p-methoxybenzyl) or –NH2, the other R 1 Not halogen;

[0231] When X is C, Y is N, and ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 When it is –S(O2)-C1-C6 alkyl and m is 1, R 1 It is not fluorine, cyano or unsubstituted C1-C6 alkoxy;

[0232] When X is C, Y is N, and ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is a halogen, the other R 1 is not an unsubstituted C1-C6 alkoxy group;

[0233] When X is C, Y is N, and ring A is 4-pyridyl, R 2 is C1-C6 haloalkoxy, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is –NH2, the other R 1 Not halogen;

[0234] When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When -S(O2)-C1-C4 alkyl, ring A is phenyl, and m is 1, R 1 It is not halogen, -NH2, cyano or unsubstituted C1-C6 alkoxy;

[0235] When X is C, Y is N, R 2 is ethoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not -NH2 or unsubstituted alkoxy; and

[0236] When X is C, Y is N, R 2 is C1-C2 haloalkoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not –NH2; and

[0237] When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When the ring A is -S(O2)-C1-C4 alkyl and m is 0, then the ring A is not 1H-indazole or 1H-benzo[d]imidazole.

[0238] In some embodiments, X is C, Y is N, and the bicyclic ring system of formula (I) is imidazo[1,2-a]pyridine.

[0239] In some embodiments, X is N, Y is C, and the bicyclic ring system of formula (I) is pyrazolo[1,5-a]pyridine.

[0240] In some embodiments, ring A is a 5-10 membered heteroaryl. In some embodiments, ring A is selected from the group consisting of indazolyl, indolyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl. In some embodiments, ring A is indazolyl.

[0241] In some embodiments, ring A is a 5-6 membered heteroaryl. In some embodiments, ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyridonyl.

[0242] 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.

[0243] In some embodiments, Ring A is Where R 1A Independently selected from R 1 In some embodiments, Ring A is Where R 1A Independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 .

[0244] In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A , R 1B and R 1C Each independently selected from R 1 .

[0245] In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 .

[0246] In some embodiments, Ring B is pyridonyl.In some embodiments, Ring A is selected from the group consisting of 4-pyridonyl, 5-pyridonyl, and 6-pyridonyl.

[0247] In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is 1-pyrazolyl (i.e., pyrazolyl is attached to the remainder of Formula (I) at the 1-nitrogen 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 oxazolone.

[0248] In some embodiments, Ring A is a 5-10 membered heterocyclyl. In some embodiments, Ring A is a 5-6 membered heterocyclyl. In some embodiments, Ring A is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, pyrazolinyl, imidazolinyl, piperidinyl, tetrahydropyranyl, and morpholinyl.

[0249] In some embodiments, Ring A is pyrrolidinyl. In some embodiments, Ring A is 1-pyrrolidinyl (i.e., the pyrrolidinyl is attached to the remainder of Formula (I) at the 1-nitrogen). In some embodiments, Ring A is morpholinyl. In some embodiments, Ring A is 1-morpholinyl (i.e., the morpholinyl is attached to the remainder of Formula (I) at the 1-nitrogen).

[0250] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A and R 1B Each independently selected from R 1 In some embodiments, Ring A is Where R 1A , R 1B and R 1C Each independently selected from R 1 .

[0251] In some embodiments, 1-3 R 1 In some embodiments, 1 or 2 R 1 In some embodiments, one R 1 In some embodiments, one R 1 In some embodiments, one R 1 For chlorine.

[0252] In some embodiments, an R 1 It is cyano.

[0253] In some embodiments, one or both R 1is independently a C1-C6 alkyl group optionally substituted with hydroxy, C1-C6 alkoxy or -S(O2)C1-C6 alkyl. 1 is a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 alkoxy group or a -S(O2)C1-C6 alkyl group. 1 is a C1-C6 alkyl group substituted with a hydroxyl group. 1 is a C1-C3 alkyl group substituted with a hydroxyl group. 1 is hydroxymethyl or hydroxyethyl. In some embodiments, one R 1 In some embodiments, one R 1 is a C1-C6 alkyl group substituted with a C1-C6 alkoxy group. 1 is a C1-C3 alkyl group substituted with a C1-C6 alkoxy group. 1 is a C1-C6 alkyl group substituted with a methoxy group. 1 is a C1-C6 alkyl substituted with -S(O2)C1-C6 alkyl. 1 is a C1-C6 alkyl group substituted with -S(O2)CH3 alkyl. 1 is an unsubstituted C1-C6 alkyl. 1 is an unsubstituted C1-C3 alkyl. 1 It is methyl or ethyl.

[0254] In some embodiments, one or both R 1 is independently C1-C6 haloalkyl. 1 is C1-C6 haloalkyl. 1 is C1-C3 haloalkyl. 1 It is trifluoromethyl.

[0255] In some embodiments, one or both R 1 is independently C1-C6 haloalkoxy. 1 is C1-C6 haloalkoxy. 1 is C1-C3 haloalkoxy. 1 It is trifluoromethoxy.

[0256] In some embodiments, one or both R 1is independently C3-C6 cycloalkyl. 1 is a C3-C6 cycloalkyl group. 1 It is cyclopropyl.

[0257] In some embodiments, one or both R 1 is independently a C1-C6 alkoxy group optionally substituted with a hydroxyl group or a phenyl group. 1 is a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group. 1 is a C1-C6 alkoxy group substituted with a hydroxyl group. 1 is a C1-C6 alkoxy group substituted with a hydroxyl group. 1 is a C1-C3 alkoxy group substituted with a hydroxyl group. 1 is -O(CH2)3OH. In some embodiments, one R 1 is a C1-C6 alkoxy group substituted with a phenyl group. 1 is a C1-C3 alkoxy group substituted with a phenyl group. 1 It is –OCH2-phenyl.

[0258] In some embodiments, one or both R 1 is independently unsubstituted C1-C6 alkoxy. 1 is an unsubstituted C1-C6 alkoxy group. 1 is independently unsubstituted C1-C6 alkoxy. 1 is an unsubstituted C1-C3 alkoxy group. 1 It is a methoxy group.

[0259] In some embodiments, an R 1 is a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from the group consisting of hydroxyl, C1-C6 alkyl and C1-C6 haloalkyl. 1 is a 4-8 membered heterocyclic group substituted by one substituent selected from the group consisting of hydroxyl, C1-C6 alkyl and C1-C6 haloalkyl. 1 It is a 4- to 8-membered heterocyclic group substituted by two substituents independently selected from the group consisting of a hydroxy group, a C1-C6 alkyl group and a C1-C6 haloalkyl group.

[0260] In some embodiments, an R1 It is a 4-8 membered heterocyclic group substituted by a hydroxy group.

[0261] In some embodiments, an R 1 is a 4-8 membered heterocyclyl substituted by a C1-C6 alkyl group. 1 is a 4-8 membered heterocyclyl substituted by a C1-C3 alkyl group. 1 It is a 4-8 membered heterocyclic group substituted by a methyl group.

[0262] In some embodiments, an R 1 is a 4-8 membered heterocyclyl substituted with a C1-C6 haloalkyl. 1 is a 4-8 membered heterocyclyl substituted with a C1-C3 haloalkyl. 1 It is a 4-8 membered heterocyclic group substituted by a trifluoromethyl group.

[0263] In some embodiments, an R 1 is a 4-8 membered heterocyclic group substituted by hydroxyl and C1-C6 alkyl. 1 is a 4-8 membered heterocyclyl substituted by hydroxyl and C1-C3 alkyl. 1 It is a 4-8 membered heterocyclic group substituted by hydroxy and methyl.

[0264] In some embodiments, an R 1 is a 4-8 membered heterocyclic group substituted by hydroxyl and C1-C6 haloalkyl. 1 is a 4-8 membered heterocyclyl substituted with hydroxyl and C1-C3 haloalkyl. 1 It is a 4-8 membered heterocyclic group substituted by hydroxy and trifluoromethyl.

[0265] In some embodiments, an R 1 is a 4-8 membered heterocyclic group substituted by C1-C6 alkyl and C1-C6 haloalkyl. 1 is a 4-8 membered heterocyclic group substituted by C1-C3 alkyl and C1-C3 haloalkyl. 1 It is a 4-8 membered heterocyclic group substituted by a methyl group or a trifluoromethyl group.

[0266] In some embodiments, an R 1 is a 4-8 membered heterocyclyl substituted with two hydroxyl groups. 1 is a 4-8 membered heterocyclyl substituted by two independently selected C1-C6 alkyl groups.1 is a 4-8 membered heterocyclyl substituted by two independently selected C1-C3 alkyl groups. 1 is a 4-8 membered heterocyclyl substituted by two independently selected C1-C6 haloalkyl groups. 1 is a 4-8 membered heterocyclyl substituted by two independently selected C1-C3 haloalkyl groups.

[0267] In some embodiments, an R 1 is piperidinyl substituted with hydroxy. 1 is 2-azaspiro[3.3]heptan-2-yl substituted with hydroxy. 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. 1 It is 4-methylpiperazin-1-yl.

[0268] In some embodiments, an R 1 is an unsubstituted 4-8 membered heterocyclyl. 1 is morpholinyl or 2,6-diazaspiro[3.3]heptan-2-yl. In some embodiments, one R 1 In some embodiments, one R 1 It is 2,6-diazaspiro[3.3]heptane-2-yl.

[0269] In some embodiments, an R 1 is -S(O2)C1-C6 alkyl. 1 is -S(O2)C1-C3 alkyl. In some embodiments, one R 1 It is –S(O2)CH3.

[0270] In some embodiments, an R 1 It is hydroxyl.

[0271] In some embodiments, an R 1 For –NR A R B .

[0272] In some embodiments, an R 1 For nitro.

[0273] In some embodiments, an R 1 It is –S(O2)C3-C6 cycloalkyl.

[0274] In some embodiments, when Ring A is phenyl, R 1 Further selected from –S(O2)NR A R A In some embodiments, when Ring A is phenyl, R 1 –S(O2)NR A R A .

[0275] In some embodiments, R A For hydrogen.

[0276] In some embodiments, R A is C1-C6 alkyl. A It is methyl.

[0277] In some embodiments, R A is hydrogen and R B for

[0278] (i)Hydrogen,

[0279] (ii) –S(O2)C1-C6 alkyl,

[0280] (iii) a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group or a C1-C6 alkoxy group,

[0281] (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl, or

[0282] (v) C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from the following:

[0283] (a) halogen,

[0284] (b) hydroxyl groups,

[0285] (c)-NR C R D ,

[0286] (d) C1-C6 alkoxy,

[0287] (e) C1-C6 haloalkoxy,

[0288] (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group,

[0289] (g) phenyl optionally substituted by C1-C6 alkoxy,

[0290] (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group,

[0291] (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl,

[0292] (k) C1-C6 thioalkyl, and

[0293] (l) – S(=NR E )(=O)C1-C6 alkyl.

[0294] In some embodiments, R A is hydrogen and R B is selected from the group consisting of: (ii) -S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl optionally substituted by hydroxy or C1-C6 alkoxy, (iv) 4-8 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from hydroxy and C1-C6 haloalkyl, and (v) C1-C6 alkyl optionally substituted by 1-4 substituents independently selected from halogen, hydroxy, -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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0295] In some embodiments, R A is a C1-C6 alkyl group and R B is selected from the group consisting of: (ii) -S(O2)C1-C6 alkyl, (iii) C3-C6 cycloalkyl optionally substituted by hydroxy or C1-C6 alkoxy, (iv) 4-8 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from hydroxy and C1-C6 haloalkyl, and (v) C1-C6 alkyl optionally substituted by 1-4 substituents independently selected from halogen, hydroxy, -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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0296] In some embodiments, R B is -S(O2)C1-C6 alkyl. B is -S(O2)C1-C3 alkyl. B It is –S(O2)(CH2)2CH3.

[0297] In some embodiments, R B is a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group or a C1-C6 alkoxy group. B is a C3-C6 cycloalkyl group substituted with a hydroxyl group. B is cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with hydroxyl. B is a C3-C6 cycloalkyl substituted by a C1-C6 alkoxy group. B is a C3-C6 cycloalkyl substituted by a C1-C3 alkoxy group. B is a cyclobutyl group substituted with a C1-C3 alkoxy group. B is cyclobutyl substituted with methoxy. B It is an unsubstituted C3-C6 cycloalkyl group.

[0298] In some embodiments, R B is a 4-8 membered heterocyclyl group optionally substituted by 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl. B is a 4-8 membered heterocyclyl substituted by 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl. B is a 4-8 membered heterocyclic group substituted by hydroxyl and C1-C6 haloalkyl. B is a 4-8 membered heterocyclyl substituted by a C1-C6 haloalkyl. B is a 4-8 membered heterocyclyl substituted with trifluoromethyl. B is a 4-8 membered heterocyclyl substituted with a hydroxyl group. B is an unsubstituted 4-8 membered heterocyclyl. B It is a morpholinyl group.

[0299] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1 to 4 substituents independently selected from the following:

[0300] (a) halogen,

[0301] (b) hydroxyl groups,

[0302] (c)-NR C R D ,

[0303] (d) C1-C6 alkoxy,

[0304] (e) C1-C6 haloalkoxy,

[0305] (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group,

[0306] (g) phenyl optionally substituted by C1-C6 alkoxy,

[0307] (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group,

[0308] (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl,

[0309] (k) C1-C6 thioalkyl, and

[0310] (l) – S(=NR E )(=O)C1-C6 alkyl.

[0311] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1 to 3 substituents independently selected from the following:

[0312] (a) halogen,

[0313] (b) hydroxyl groups,

[0314] (c)-NR C R D ,

[0315] (d) C1-C6 alkoxy,

[0316] (e) C1-C6 haloalkoxy,

[0317] (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group,

[0318] (g) phenyl optionally substituted by C1-C6 alkoxy,

[0319] (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group,

[0320] (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl,

[0321] (k) C1-C6 thioalkyl, and

[0322] (l) – S(=NR E )(=O)C1-C6 alkyl.

[0323] In some embodiments, R Bis a C1-C6 alkyl group optionally substituted by two substituents independently selected from the following:

[0324] (a) halogen,

[0325] (b) hydroxyl groups,

[0326] (c)-NR C R D ,

[0327] (d) C1-C6 alkoxy,

[0328] (e) C1-C6 haloalkoxy,

[0329] (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group,

[0330] (g) phenyl optionally substituted by C1-C6 alkoxy,

[0331] (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group,

[0332] (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl,

[0333] (k) C1-C6 thioalkyl, and

[0334] (l) – S(=NR E )(=O)C1-C6 alkyl.

[0335] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by one of the following:

[0336] (a) halogen,

[0337] (b) hydroxyl groups,

[0338] (c)-NR C R D ,

[0339] (d) C1-C6 alkoxy,

[0340] (e) C1-C6 haloalkoxy,

[0341] (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group,

[0342] (g) phenyl optionally substituted by C1-C6 alkoxy,

[0343] (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group,

[0344] (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl,

[0345] (k) C1-C6 thioalkyl, and

[0346] (l) – S(=NR E )(=O)C1-C6 alkyl.

[0347] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-4 substituents independently selected from the following: 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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0348] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-3 substituents independently selected from the following: 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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0349] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-2 substituents independently selected from the following: 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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0350] In some embodiments, R B is C1-C6 alkyl optionally substituted by halogen, hydroxy, -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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0351] In some embodiments, R B is a C1-C6 alkyl group substituted with 1-4 halogens. B is C1-C3 alkyl substituted by 1-4 halogens. B is a C1-C3 alkyl group substituted with 1-3 halogens. B is a C1-C6 alkyl group substituted with 1-3 halogens and hydroxyl groups. B It is a C1-C3 alkyl group substituted by 1 to 3 halogens and hydroxyl groups.

[0352] In some embodiments, R B is propyl substituted by 1-2 halogens and hydroxyl. B is ethyl, propyl or butyl each substituted with 1-3 halogens. B is propyl or butyl each substituted by 1 to 3 fluorine groups and one hydroxyl group.

[0353] In some embodiments, R B is a C1-C6 alkyl group substituted with 1-3 hydroxyl groups. B is a C2-C5 alkyl group substituted with 1-2 hydroxyl groups. B is ethyl, propyl, butyl, pentyl, each of which is substituted with 1-2 hydroxyl groups. B In some embodiments, R B In some embodiments, R B is a propyl group substituted with two hydroxyl groups. B is a sec-butyl group or an isopentyl group each substituted by a hydroxy group.

[0354] In some embodiments, R B is a C1-C6 alkyl group substituted by 1-4 independently selected C1-C6 alkoxy groups. B is a C2-C5 alkyl group substituted with 1-2 independently selected C1-C3 alkoxy groups. B It is a C2-C6 alkyl group substituted by a methoxy group.

[0355] In some embodiments, R B is a C1-C6 alkyl group substituted by 1-4 independently selected C1-C6 haloalkoxy groups. B is a C1-C6 alkyl group substituted by 1-2 independently selected C1-C3 alkoxy groups. B It is a C1-C6 alkyl group substituted with –OCHF2.

[0356] In some embodiments, R B is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. B is a C1-C6 alkyl group substituted with a cyclopropyl group. B It is a C1-C6 alkyl group substituted by a cyclobutyl group.

[0357] In some embodiments, R B is a C1-C6 alkyl group substituted with a phenyl group, wherein the phenyl group is optionally substituted with a C1-C6 alkoxy group. B is a C1-C3 alkyl group substituted with a phenyl group, which is optionally substituted with a C1-C6 alkoxy group. B is a C1-C6 alkyl group substituted with a phenyl group. B is -CH2-phenyl. In some embodiments, R B is a C1-C6 alkyl group substituted with a phenyl group, wherein the phenyl group is substituted with a C1-C6 alkoxy group. B is a C1-C3 alkyl group substituted with a phenyl group, wherein the phenyl group is substituted with a C1-C6 alkoxy group. B is methyl substituted by phenyl, and the phenyl is substituted by C1-C3 alkoxy. B It is a methyl group substituted by a 4-methoxyphenyl group.

[0358] In some embodiments, R B is a C1-C6 alkyl group substituted with a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted with a C1-C6 alkyl group. B is a C1-C3 alkyl group substituted with a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted with a C1-C6 alkyl group. B is a C1-C6 alkyl group substituted with a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is substituted with a C1-C6 alkyl group. B is a C1-C3 alkyl group substituted with a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is substituted with a C1-C6 alkyl group.B is a C1-C6 alkyl group substituted with a 5-6 membered heteroaryl group. B is a C1-C3 alkyl group substituted with a 5-6 membered heteroaryl group. B is a C1-C3 alkyl group substituted by a pyridinone group, wherein the pyridinone group is optionally substituted by a C1-C3 alkyl group. B is methyl substituted by pyridonyl, wherein the pyridonyl is substituted by methyl. B is a methyl group substituted by an unsubstituted pyridonyl group.

[0359] In some embodiments, R B is a C1-C6 alkyl group substituted by a 4-8 membered heterocyclyl group, wherein the 4-8 membered heterocyclyl group is optionally substituted by -C(=O)C1-C6 alkyl group or C1-C6 alkyl group. B is a C1-C2 alkyl group substituted by a 4-6 membered heterocyclyl group, wherein the 4-6 membered heterocyclyl group is optionally substituted by -C(=O)C1-C6 alkyl group or C1-C6 alkyl group. B is a C1-C2 alkyl group substituted by a 4-6 membered heterocyclyl group, wherein the 4-6 membered heterocyclyl group is selected from the group consisting of 2-oxopiperidin-4-yl, 6-oxopiperidin-3-yl, piperidin-4-yl and 2-oxopyrrolidin-1-yl, each of which is optionally substituted by a methyl group. B is a C1-C2 alkyl group substituted by a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group 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 It is a C1-C2 alkyl group substituted by a 1-acetylpiperidinyl group.

[0360] In some embodiments, R B For optionally being -NR C R D In some embodiments, R B For the C R D In some embodiments, R B For the C R D In some embodiments, R B For the C R D Substituted C2-C3 alkyl.

[0361] In some embodiments, R A and R B In some embodiments, R A and R B In some embodiments, R A and R B In some embodiments, R A and R B One of them is hydrogen, and R A and R B The other one is not hydrogen.

[0362] In some embodiments, R A and R B Each is independently selected from C1-C6 alkyl. A and R B Each is independently selected from C1-C3 alkyl. A and R B Each is a methyl group.

[0363] In some embodiments, R C and R D In some embodiments, R C and R D In some embodiments, R C and R D In some embodiments, R C and R D One of them is hydrogen, and R C and R D The other of is C1-C6 alkyl optionally substituted by oxo. C and R D One of them is hydrogen, and R C and R D The other of is C1-C2 alkyl optionally substituted by oxo. C and R D One of them is hydrogen, and R C and R D In some embodiments, R C and R D Each is an independently selected C1-C6 alkyl group, each optionally substituted with oxo. C and R D Each is an independently selected C1-C6 alkyl group. C and R DIn some embodiments, R C and R D One of them is hydrogen, and R C and R D The other one is -C(=O)OC1-C6 alkyl.

[0364] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-2 substituents independently selected from the following: 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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0365] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-2 substituents independently selected from the following: 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 4-8 membered heterocyclyl substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0366] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-2 substituents independently selected from the following: 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.

[0367] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-2 substituents independently selected from the following: fluorine, hydroxyl, -NR C R D , methoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl optionally substituted by methoxy, 5-6 membered heteroaryl optionally substituted by methyl, and 4-8 membered heterocyclyl optionally substituted by -C(=O)CH3 or methyl.

[0368] In some embodiments, R B is a C1-C6 alkyl group optionally substituted by 1-2 substituents independently selected from the following: fluorine, hydroxyl, -NR C RD , methoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-8 membered heterocyclyl.

[0369] In some embodiments, when R B When it is a substituted C1-C6 alkyl group, the C1-C6 alkyl group may form a spiro ring with a cycloalkyl group or a heterocyclic group. B Freedom to choose The wavy line represents the group with -NR A R B Attachment point of nitrogen atom.

[0370] In some embodiments, R B Selected from the group consisting of:

[0371]

[0372]

[0373] In some embodiments, m is 0.

[0374] In some embodiments, m is 1.

[0375] In some embodiments, m is 1 and R 1 is selected from the group consisting of fluorine, amino and -NHC1-C6 alkyl optionally substituted with hydroxy. In some embodiments, m is 1 and R 1 In some embodiments, m is 1 and R 1 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 It is -NHC1-C6 alkyl substituted by hydroxyl.

[0376] In some embodiments, m is 2.

[0377] In some embodiments, m is 2 and each R 1 R is independently selected from the group consisting of fluoro, amino, and -NHC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxy and C3-C6 cycloalkyl. 1 is selected from the group consisting of fluoro, amino, and -NHC1-C6 alkyl substituted with 1-2 substituents independently selected from hydroxy and C3-C6 cycloalkyl. In some embodiments, m is 2 and each R 1In some embodiments, m is 2 and each R 1 Independently selected from the group consisting of fluoro, amino and -NHC1-C6 alkyl optionally substituted with 2 substituents independently selected from hydroxy and C3-C6 cycloalkyl.

[0378] In some embodiments, m is 3.

[0379] In some embodiments, m is 3, and each R 1 In some embodiments, m is 3, two R 1 are independently selected from fluorine and C1-C6 alkoxy, and the third R 1 is cyano, -NHS(O2)C1-C6 alkyl or -NHC1-C6 alkyl optionally substituted by hydroxy.

[0380] In some embodiments, m is 4.

[0381] In some embodiments, m is 4, and each R 1 In some embodiments, m is 4, two R 1 are independently selected from fluorine and C1-C6 alkoxy, and the remaining two R 1 Independently selected from cyano, -NHS(O2)C1-C6 alkyl or -NHC1-C6 alkyl optionally substituted with hydroxy.

[0382] In some embodiments, R 2 For hydrogen.

[0383] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 For fluorine.

[0384] In some embodiments, R 2 is C1-C6 alkoxy. 2 is C1-C3 alkoxy. 2 In some embodiments, R 2 It is ethoxy.

[0385] In some embodiments, R 2 is C1-C6 haloalkoxy. 2 In some embodiments, R 2 It is 2,2,2-trifluoroethoxy.

[0386] In some embodiments, R 3 For hydrogen.

[0387] In some embodiments, R 3 is C1-C6 thioalkyl. 3 is C3-C4 thioalkyl. 3 for

[0388] In some embodiments, R 3 It is -CO2H.

[0389] In some embodiments, R 3 -C(=O)NR E R F .

[0390] In some embodiments, R 3 For optionally NR E R F or a C1-C6 alkyl group substituted with a hydroxyl group. 3 To be NR E R F or a C1-C6 alkyl group substituted with a hydroxyl group. 3 To be NR E R F In some embodiments, R 3 is a C1-C6 alkyl group optionally substituted with a hydroxyl group. 3 It is an unsubstituted C1-C6 alkyl group.

[0391] In some embodiments, R E and R F In some embodiments, R E and R F In some embodiments, R E and R F In some embodiments, each of R E and R F Each of R is an independently selected C1-C6 alkyl. E and R FIn some embodiments, each of R E and R F One of them is hydrogen, and R E and R F The other of is C1-C6 alkyl. E In some embodiments, R E is C1-C6 alkyl. F In some embodiments, R F It is a C1-C6 alkyl group.

[0392] In some embodiments, R 3 is a C1-C6 alkoxy group optionally substituted by a 4-10 membered heterocyclyl group, wherein the 4-10 membered heterocyclyl group is optionally substituted by a C1-C6 alkoxy group. 3 is a C1-C3 alkoxy group optionally substituted by a 4-10 membered heterocyclyl group, wherein the 4-10 membered heterocyclyl group is optionally substituted by a C1-C6 alkoxy group. 3 is methoxy or ethoxy optionally substituted by a 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted by a C1-C6 alkoxy group. 3 is a C1-C6 alkoxy group substituted by a 4-10 membered heterocyclyl group, wherein the 4-10 membered heterocyclyl group is optionally substituted by a C1-C6 alkoxy group. 3 is a C1-C3 alkoxy group substituted by a 4-6 membered heterocyclyl group, wherein the 4-6 membered heterocyclyl group is optionally substituted by a C1-C6 alkoxy group. 3 is methoxy or ethoxy substituted by a 4-6 membered heterocyclyl, which is optionally substituted by a C1-C3 alkoxy group. 3 is a C1-C3 alkoxy group substituted by an unsubstituted 4-10 membered heterocyclyl group. 3 is a C1-C3 alkoxy group substituted by an unsubstituted 4-6 membered heterocyclyl group. 3 is a C1-C6 alkoxy group substituted by a 4-10 membered heterocyclyl group, wherein the 4-10 membered heterocyclyl group is substituted by a C1-C6 alkoxy group. 3 is a C1-C3 alkoxy group substituted by a 4-6 membered heterocyclyl group, wherein the 4-6 membered heterocyclyl group is substituted by a C1-C6 alkoxy group. 3 is methoxy or ethoxy substituted by a 4-6 membered heterocyclic group, and the 4-6 membered heterocyclic group is optionally substituted by a C1-C3 alkoxy group.

[0393] In some embodiments, R3 is an unsubstituted C1-C6 alkoxy group. 3 is an unsubstituted C1-C3 alkoxy group. 3 In some embodiments, R 3 It is ethoxy.

[0394] In some embodiments, R 3 is a 4-8 membered heterocyclyl group optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl. 3 is a 4-8 membered heterocyclyl substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl. 3 is a 4-8 membered heterocyclic group substituted by one substituent selected from halogen and C1-C6 alkyl. 3 is a 4-8 membered heterocyclyl substituted by 2 substituents independently selected from halogen and C1-C6 alkyl. 3 is a 4-8 membered heterocyclyl substituted by 2 independent halogens. 3 is a 4-8 membered heterocyclyl substituted with 2 fluorine groups. 3 is a 4-8 membered heterocyclyl substituted by 2 independently selected C1-C6 alkyl groups. 3 is a 4-8 membered heterocyclyl substituted by 2 methyl groups. 3 It is an unsubstituted 4-8 membered heterocyclic group.

[0395] In some embodiments, R 3 for

[0396] In some embodiments, Z is O.

[0397] In some embodiments, Z is NR 4 In some embodiments, R 4 In some embodiments, R 4 is C1-C6 alkyl. 4 is C1-C3 alkyl. 4 It is methyl.

[0398] In some embodiments, R 3A is C1-C6 haloalkyl. 3A It is a C3-C4 haloalkyl group.

[0399] In some embodiments, R 3Ais a C3-C6 cycloalkyl group. 3A It is cyclopropyl.

[0400] In some embodiments, R 3A is a C1-C6 alkyl group optionally substituted with a C3-C6 cycloalkyl group. 3A is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. 3A is a C1-C3 alkyl group substituted with a C3-C6 cycloalkyl group. 3A is a C1-C2 alkyl group substituted with a C3-C6 cycloalkyl group. 3A is a C1-C2 alkyl group substituted by a C3-C6 cycloalkyl group, wherein R 3A The C1-C2 alkyl group of R forms a spirocycloalkyl group with a C3-C6 cycloalkyl group. 3A for In some embodiments, R 3A is an unsubstituted C1-C6 alkyl. 3A is an unsubstituted C3-C4 alkyl. 3A In some embodiments, R 3A It is tert-butyl.

[0401] In some embodiments, R 3 for

[0402] In some embodiments, R 3B and R 3C In some embodiments, R 3B and R 3C are different.

[0403] In some embodiments, R 3B is a C3-C6 cycloalkyl group. 3B It is a C3-C4 cycloalkyl group.

[0404] In some embodiments, R 3B is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. 3B is a C1-C3 alkyl group substituted with a C3-C6 cycloalkyl group. 3B is a C1-C2 alkyl group substituted with a C3-C6 cycloalkyl group. 3B is a C1-C2 alkyl group substituted by a C3-C6 cycloalkyl group, wherein R 3BThe C1-C2 alkyl group of R forms a spirocycloalkyl group with a C3-C6 cycloalkyl group. 3B for In some embodiments, R 3B is an unsubstituted C1-C6 alkyl. 3B It is methyl or ethyl.

[0405] In some embodiments, R 3C is a C3-C6 cycloalkyl group. 3C It is a C3-C4 cycloalkyl group.

[0406] In some embodiments, R 3C is a C1-C6 alkyl group substituted with a C3-C6 cycloalkyl group. 3C is a C1-C3 alkyl group substituted with a C3-C6 cycloalkyl group. 3C is a C1-C2 alkyl group substituted with a C3-C6 cycloalkyl group. 3C is a C1-C2 alkyl group substituted by a C3-C6 cycloalkyl group, wherein R 3C The C1-C2 alkyl group of R forms a spirocycloalkyl group with a C3-C6 cycloalkyl group. 3C for In some embodiments, R 3C is an unsubstituted C1-C6 alkyl. 3C It is methyl or ethyl.

[0407] In some embodiments, the compound of formula (I) is of formula (IA):

[0408]

[0409] or a pharmaceutically acceptable salt thereof.

[0410] In some embodiments, the compound of formula (I) is of formula (IB):

[0411]

[0412] or a pharmaceutically acceptable salt thereof.

[0413] In some embodiments, the compound of formula (I) is of formula (IC):

[0414]

[0415] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0416] In some embodiments, the compound of formula (I) is of formula (ID):

[0417]

[0418] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0419] In some embodiments, the compound of formula (I) is of formula (IE):

[0420]

[0421] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0422] In some embodiments, the compound of formula (I) is of formula (IF):

[0423]

[0424] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0425] In some embodiments, the compound of formula (I) is of formula (IG):

[0426]

[0427] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 In some embodiments, the compound of formula (I) is of formula (IH):

[0428]

[0429] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0430] In some embodiments, the compound of formula (I) is of formula (II):

[0431]

[0432] or a pharmaceutically acceptable salt thereof, wherein R1A and R 1B Each independently selected from R 1 .

[0433] In some embodiments, the compound of formula (I) is of formula (IJ):

[0434]

[0435] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0436] In some embodiments, the compound of formula (I) is of formula (IK):

[0437]

[0438] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0439] In some embodiments, the compound of formula (I) is of formula (IL):

[0440]

[0441] or a pharmaceutically acceptable salt thereof.

[0442] In some embodiments, the compound of formula (I) is of formula (IM):

[0443]

[0444] or a pharmaceutically acceptable salt thereof.

[0445] In some embodiments, the compound of formula (I) is of formula (IN):

[0446]

[0447] or a pharmaceutically acceptable salt thereof.

[0448] In some embodiments, the compound of formula (I) is of formula (IO):

[0449]

[0450] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0451] In some embodiments, the compound of formula (I) is of formula (IP):

[0452]

[0453] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0454] In some embodiments, the compound of formula (I) is of formula (IQ):

[0455]

[0456] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0457] In some embodiments, the compound of formula (I) is of formula (IR):

[0458]

[0459] or a pharmaceutically acceptable salt thereof, wherein R 1A and R 1B Each independently selected from R 1 .

[0460] In some embodiments, the compound of formula (I) is of formula (IS):

[0461]

[0462] or a pharmaceutically acceptable salt thereof, wherein R 1A , R 1B and R 1C Each independently selected from R 1 .

[0463] In some embodiments, the compound of formula (I) is of formula (IT):

[0464]

[0465] or a pharmaceutically acceptable salt thereof, wherein R 1A , R 1B and R 1C Each independently selected from R 1 .

[0466] In some embodiments, the compound of formula (I) is of formula (IU):

[0467]

[0468] or a pharmaceutically acceptable salt thereof.

[0469] In some embodiments, the compound of formula (I) is of formula (IV):

[0470]

[0471] or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, the compound of formula (I) is of formula (IW):

[0473]

[0474] or a pharmaceutically acceptable salt thereof.

[0475] In some embodiments, the compound of formula (I) is of formula (IX):

[0476]

[0477] or a pharmaceutically acceptable salt thereof.

[0478] In some embodiments, R 2 is a C1-C6 alkoxy group and R 3 for Where Z is O.

[0479] In some embodiments of Formula (IA), (IB), (IC), (ID), and (IE), R 2 is a C1-C6 alkoxy group and R 3 for Where Z is O and R 3A It is a C1-C6 alkyl group or a C3-C6 cycloalkyl group.

[0480] In some embodiments, m is 2, wherein one R 1 is a halogen and the other R 1 For –NR A R B .

[0481] In some embodiments of Formula (IA) and (IB), m is 2, wherein one R 1 is a halogen and the other R 1 For –NR A R B .

[0482] In some embodiments of Formula (IC), (ID), and (IE), R 1A and R 1B One of them is a halogen, and R 1A and R1B The other one is –NR A R B .

[0483] In some embodiments, m is 2, wherein one R 1 is a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group, and another R 1 For –NR A R B .

[0484] In some embodiments of Formula (IA) and (IB), m is 2, wherein one R 1 is a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group and the other R 1 For –NR A R B .

[0485] In some embodiments of Formula (IC), (ID), and (IE), R 1A and R 1B One of them is a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group, and R 1A and R 1B The other one is –NR A R B .

[0486] In some embodiments, m is 2, wherein one R 1 is a C1-C6 alkyl group optionally substituted by a hydroxy group, and another R 1 For –NR A R B .

[0487] In some embodiments of Formula (IA) and (IB), m is 2, wherein one R 1 is a C1-C6 alkyl group optionally substituted with a hydroxyl group and the other R 1 For –NR A R B .

[0488] In some embodiments of Formula (IC), (ID), and (IE), R 1A and R 1B One of them is a C1-C6 alkyl group optionally substituted by a hydroxyl group, and R 1A and R 1B The other one is –NR A R B .

[0489] In some embodiments, m is 2, wherein one R 1is C1-C6 haloalkyl and the other R 1 For –NR A R B .

[0490] In some embodiments of Formula (IA) and (IB), m is 2, wherein one R 1 is C1-C6 haloalkyl and the other R 1 For –NR A R B .

[0491] In some embodiments of Formula (IC), (ID), and (IE), R 1A and R 1B One of them is C1-C6 haloalkyl, and R 1A and R 1B The other one is –NR A R B .

[0492] In some embodiments, m is 2, wherein one R 1 is a halogen and the other R 1 is a 4- to 8-membered heterocyclic group optionally substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl.

[0493] In some embodiments of Formula (IA) and (IB), m is 2, wherein one R 1 is a halogen and the other R 1 is a 4- to 8-membered heterocyclic group optionally substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl.

[0494] In some embodiments of Formula (IC), (ID), and (IE), R 1A and R 1B One of them is a halogen, and R 1A and R 1B The other one of is a 4-8 membered heterocyclic group optionally substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl.

[0495] In some embodiments of Formula (IA), (IB), (IC), (ID), and (IE), R A and R B All are hydrogen.

[0496] In some embodiments of Formula (IA), (IB), (IC), (ID), and (IE), R Ais hydrogen and R B It is -S(O2)C1-C6 alkyl.

[0497] In some embodiments of Formula (IA), (IB), (IC), (ID), and (IE), R A is hydrogen and R B It is a C3-C6 cycloalkyl group which is optionally substituted by a hydroxy group or a C1-C6 alkoxy group.

[0498] In some embodiments of Formula (IA), (IB), (IC), (ID), and (IE), R A is hydrogen and R B It is a 4- to 8-membered heterocyclic group which is optionally substituted by a hydroxy group.

[0499] In some embodiments of Formula (IA), (IB), (IC), (ID), and (IE), R A is hydrogen and R B is a C1-C6 alkyl group optionally substituted by 1-4 substituents independently selected from the following: 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 4-8 membered heterocyclyl optionally substituted by -C(=O)C1-C6 alkyl or C1-C6 alkyl.

[0500] In some embodiments of Formulas (IA) to (IX), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and Ring A is pyridyl.

[0501] In some embodiments of Formulas (IA) to (IX), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is phenyl.

[0502] In some embodiments of Formulas (IA) to (IX), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, Ring A is phenyl or pyridyl and at least one R 1 For F.

[0503] In some embodiments of Formulas (IA) to (IX), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, Ring A is phenyl or pyridyl and at least one R 1It is a C1-C4 alkoxy group.

[0504] In some embodiments of Formulas (IA) to (IX), R 3 is -S(O2)-tert-butyl, R 2 is -OMe, Ring A is phenyl or pyridyl and at least one R 1 For –NH2

[0505] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and ring A is phenyl.

[0506] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and Ring A is a 6-membered heteroaryl group.

[0507] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and Ring A is pyridyl.

[0508] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and Ring A is pyrimidinyl.

[0509] In some embodiments, R 3 is -S(O2)-tert-butyl, R 2 is -OMe, and Ring A is a 5-membered heteroaryl group.

[0510] In some embodiments, when X is C, Y is N, Ring A is 4-pyridyl, R 2 is a C1-C6 alkoxy group, R 3 When -S(O2)-C1-C6 alkyl and m is 1, then R 1 It is not -NH2 or -NH(C=O)CH3.

[0511] In some embodiments, when X is C, Y is N, Ring A is 4-pyridyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is fluorine, NH-(p-methoxybenzyl) or –NH2, the other R 1 Not halogen.

[0512] In some embodiments, when X is C, Y is N, Ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3When it is –S(O2)-C1-C6 alkyl and m is 1, R 1 It is not fluorine, cyano or unsubstituted C1-C6 alkoxy.

[0513] In some embodiments, when X is C, Y is N, Ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is a halogen, the other R 1 It is not an unsubstituted C1-C6 alkoxy group.

[0514] In some embodiments, when X is C, Y is N, Ring A is 4-pyridyl, R 2 is C1-C6 haloalkoxy, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is –NH2, the other R 1 Not halogen.

[0515] In some embodiments, when X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When -S(O2)-C1-C4 alkyl, ring A is phenyl, and m is 1, R 1 It is not halogen, -NH2, cyano or unsubstituted C1-C6 alkoxy.

[0516] In some embodiments, when X is C, Y is N, R 2 is ethoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 It is not -NH2 or unsubstituted alkoxy.

[0517] In some embodiments, when X is C, Y is N, R 2 is C1-C2 haloalkoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 Not –NH2.

[0518] In some embodiments, when X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When the ring A is -S(O2)-C1-C4 alkyl and m is 0, then the ring A is not 1H-indazole or 1H-benzo[d]imidazole.

[0519] In some embodiments, the compound described herein is not any compound disclosed in He et al., ACS Med. Chem. Lett., Vol. 8, pp. 1048-1053 (2017), which is incorporated herein by reference solely for the purpose of excluding the compounds disclosed therein.

[0520] In some embodiments, the compound described herein is not selected from 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] 6-Chloro-4-[6-[(1,1-dimethylethyl)sulfonyl]-7-ethoxyimidazo[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; 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-methoxyethoxy)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 of any one of the foregoing.

[0521] In some embodiments, the compound of formula I includes 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, such as pharmaceutically acceptable salt form.

[0522] The ability of a test compound to act as an inhibitor of RIPK2 can be demonstrated by the biological assays described herein. 50 The values ​​are shown in Table A.

[0523] Treatment

[0524] The compounds and compositions disclosed herein are effective in modulating the activity of RIPK2. In some embodiments, the compounds and compositions disclosed herein are RIPK2 inhibitors.

[0525] As used herein, the term "RIPK2-associated disease or disorder" refers to a disease or disorder associated with or having a dysregulation of the RIPK2 gene, RIPK2 protein, or any (e.g., one or more) expression, activity, or level thereof (e.g., a dysregulation of the RIPK2 gene, RIPK2 protein, RIPK2 protein domain, or any expression, activity, or level thereof described herein).

[0526] An exemplary sequence of human RIPK2 is shown below (UniParc accession number UPI00001338F2):

[0527] MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLHIHTPLLDSERKDVLREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDVAWPLRFRILHEIALGVNYL HNMTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIE SGWAQNPDERPSFLKCLIELEPVLRTFEEITFLEAVIQLKKTKLQSVSSAIHLCDKKKMELSLNIPVNHGPQEESCGSSQLHENSGSPETSRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAA FCDHKTTPCSSAIINPLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGLQPYPEILVVSRSPSLNLLQNKSM

[0528] Some embodiments provide a method of treating a RIPK2-related disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0529] Some embodiments provide a method of treating a RIPK2-related disease or condition in a subject in need thereof, comprising (a) determining that the subject suffers from a RIPK2-related disease or condition; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0530] Some embodiments provide a method of treating a RIPK2-related disease or disorder in a subject previously determined or diagnosed as having a RIPK2-related disease or disorder, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0531] In some embodiments, the RIPK2-associated disease or disorder is a cardiovascular disease, an allergic disorder, an autoimmune disease, an inflammatory disease, a cardiovascular disease, a fibrotic disease, or a disease associated with abnormal cell growth.

[0532] In some embodiments, the RIPK2-related disease or disorder is a type I hypersensitivity (allergic) reaction. In some embodiments, the type I hypersensitivity (allergic) reaction is allergic inflammation. In some embodiments, the allergic inflammation is allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis or atopic dermatitis.

[0533] 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 spondyloarthopathy, non-radioactive spondyloarthopathy, Behcet's disease, dermatomyositis, type 1 diabetes, Goodpasture's syndrome, Graves' disease, Guillain Barre Syndrome, Hashimoto's disease, disease, mixed connective tissue injury, myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, temporal arteritis, or vasculitis. In some embodiments, the autoimmune disease is Crohn's disease, ulcerative colitis, inflammatory bowel disease, or multiple sclerosis. In some embodiments, the autoimmune disease is Crohn's disease. In some embodiments, the autoimmune disease is ulcerative colitis. In some embodiments, the autoimmune disease is inflammatory bowel disease. In some embodiments, the autoimmune disease is multiple sclerosis.

[0534] In some embodiments, the RIPK2-related disease or disorder is a metabolic disease. In some embodiments, the metabolic disease is dysglycemia, type 2 diabetes, non-alcoholic fatty liver disease (including non-alcoholic steatohepatitis) or obesity.

[0535] 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, bursitis, carpal tunnel syndrome, tendinitis, lung inflammation (e.g., chronic obstructive pulmonary disease), pelvic inflammatory disease, transplant rejection, vasculitis, regional enteritis, distal ileitis, regional 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 chorioretinopathy, In some embodiments, the inflammatory disease is inflammatory bowel disease.

[0536] In some embodiments, the RIPK2-associated disease or disorder is a granulomatous inflammatory disease. In some embodiments, the granulomatous inflammatory disease is Wegener's granulomatosis, Churg-Strauss syndrome, relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, primary biliary cirrhosis, hepatic granulomatous disease, Langerhan's granulomatosis, granulomatous enteritis, orofacial granulomatosis, or Peyronie's disease.

[0537] In some embodiments, the RIPK2-associated 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.

[0538] In some embodiments, the RIPK2-associated disease is fatal systemic inflammatory response syndrome, chronic intestinal and skin inflammation, or acute pancreatitis.

[0539] In some embodiments, the RIPK2-associated disease or disorder is a fibrotic disease. In some embodiments, the fibrotic disease is scleroderma, asbestosis, or idiopathic pulmonary fibrosis.

[0540] In some embodiments, the RIPK2-related disease or disorder comprises 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, NPC1, Friedreich's ataxia, spinal muscular atrophy, corticobasal degeneration, progressive supranuclear palsy (PSP), or multiple system atrophy (MSA).

[0541] In some embodiments, the RIPK2-associated disease or disorder is a disease associated with abnormal cell growth. In some embodiments, the disease associated with abnormal cell growth is cancer, including hematological malignancies and solid tumors.

[0542] Hematological malignancies include, but are not limited to, leukemias 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's lymphoma, and multiple myeloma.

[0543] Solid tumors include lung cancer (small cell lung cancer and non-small cell lung cancer), pancreatic cancer, colon cancer, breast cancer, genitourinary system cancer, skin cancer, bone cancer, prostate cancer, liver cancer, brain cancer, laryngeal cancer, gallbladder cancer, rectal cancer, parathyroid cancer, thyroid cancer, adrenal cancer, cancer of nervous tissue, bladder cancer, head and neck cancer, stomach cancer, gastric cancer, bronchial cancer and kidney cancer (e.g., clear cell renal carcinoma), colorectal cancer, clear cell carcinoma, basal cell carcinoma, squamous cell carcinoma, esophageal cancer, metastatic skin cancer, osteosarcoma, Ewing's sarcoma, reticulum cell sarcoma, Kaposi's sarcoma sarcoma), giant cell tumor, islet cell tumor, acute and chronic lymphocytic and granulocytic tumors, hair cell tumor, adenoma, medullary carcinoma, pheochromocytoma, mucosal neuroma, enteric ganglioneuroma, hyperplastic corneal neuroma, marfanoid habitus tumor, Wilms' tumor, seminoma, ovarian tumor, leiomyomata tumor, cervical dysplasia, neuroblastoma, retinoblastoma, myelodysplastic syndrome, rhabdomyosarcoma, astrocytoma, malignant hypercalcemia, polycythemia vera, adenocarcinoma, glioblastoma multiforme, glioma and malignant melanoma.

[0544] In some embodiments, the RIPK2-related disease or disorder is a disease associated with abnormal cell growth that is a non-malignant proliferative disease. In some embodiments, the non-malignant proliferative disease is benign prostatic hypertrophy, restenosis, hyperplasia, synovial proliferative disorder, idiopathic plasma cell lymphadenopathy, or retinopathy.

[0545] In some embodiments, the RIPK2-related disease or disorder is selected from the group consisting of avascular necrosis, calcium pyrophosphate dihydrate crystal deposition disease (pseudogout), Blau syndrome, Ehlers-Danlossyndrome, 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.

[0546] In some embodiments, the RIPK2-related disease or disorder is a cancer associated with chronic inflammation. In some embodiments, cancers associated with chronic inflammation that can be treated (including reducing the likelihood of recurrence) include colitis-related colorectal cancer, gastric cancer, gastric mucosal lymphoma, lung cancer, hepatocellular carcinoma, thyroid cancer, breast cancer, oral cancer, head and neck cancer, nasopharyngeal cancer, endometrial cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, esophageal cancer, skin cancer, and non-Hodgkin's lymphoma.

[0547] Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0548] Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising (a) determining that the subject has inflammatory bowel disease; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0549] Some embodiments provide a method of treating inflammatory bowel disease in a subject previously identified or diagnosed as having inflammatory bowel disease, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0550] Some embodiments provide a method of treating Crohn's disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0551] Some embodiments provide a method of treating Crohn's disease in a subject in need thereof, comprising (a) determining that the subject has Crohn's disease; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0552] 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 an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0553] In some embodiments, the subject is a human.

[0554] Inhibition of RIPK2 activity

[0555] Some embodiments provide a method for inhibiting RIPK2 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the mammalian cell comprises a RIPK2 protein.

[0556] Also provided is a method for inhibiting RIPK2 activity in a mammalian cell comprising RIPK2 protein, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0557] In some embodiments, contact is performed in vitro. In some embodiments, 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 a cell. In some embodiments, contact is performed in vivo, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells with RIPK2 activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a cancer cell.

[0558] In some embodiments, RIPK2 activity is inhibited by about 10% to about 99%, for example, 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.

[0559] As used herein, the term "contacting" refers to bringing together specified moieties in an in vitro system or an in vivo system. For example, "contacting" RIPK2 (e.g., RIPK2 protein) with a compound provided herein includes administering a compound provided herein to a subject (such as a human) having RIPK2 protein, and, for example, introducing a compound provided herein into a sample containing mammalian cells or purified preparations containing RIPK2 protein.

[0560] Pharmaceutical composition

[0561] Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0562] Example

[0563] Materials and methods

[0564] The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes.

[0565] The reaction for preparing the compound provided herein can be carried out in a suitable solvent, and the suitable solvent can be easily selected by a technician in the field of organic synthesis. At the temperature of the reaction (for example, a temperature in the range of the freezing temperature of the solvent to the boiling temperature of the solvent), the suitable solvent may not react with the starting material (reactant), intermediate or product substantially. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to a specific reaction step, a suitable solvent for a specific reaction step can be selected by a technician.

[0566] The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found in, for example, Protecting Group Chemistry, 1st edition, Oxford University Press, 2000; March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, Wiley-Interscience Publication, 2001; and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 74 (11), 1297 (1997).

[0567] Intermediates

[0568] Intermediate 1

[0569]

[0570] 6-(tert-butylsulfonyl)imidazo[1,2-a]pyridine: 6-(tert-butylthio)imidazo[1,2-a]pyridine (3.38 g, 16.4 mmol, prepared as described in U.S. Publication No. US2018 / 0072717, which is incorporated herein by reference in its entirety) was provided in a mixture of methanol (69 mL) and water (23 mL). 3-sulfotrioxide-1-compound (15.1 g, 24.6 mmol) was added and the mixture was stirred at room temperature for 18 h. The suspension was filtered and the solids were removed. The solvent was evaporated. The crude was purified in three rounds using preparative HPLC. The batches were combined to obtain the title compound. [M+H] + =239.3. 1 H NMR(400MHz,DMSO-d6)δppm 9.34(dd,J=1.9,0.9Hz,1H),8.24(s,1H),7.87(d,J=1.3Hz,1H),7.81(d,J=9.4Hz,1H),7.57(dd,J=9.5,1.9Hz,1H),1.31(s,9H).

[0571] 6-(tert-Butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine: 6-(tert-Butylsulfonyl)imidazo[1,2-a]pyridine (2.75 g, 11.5 mmol) and N-iodo-succinimide (3.12 g, 13.8 mmol) were combined in a mixture of methanol (79 mL) and water (31 mL). The mixture was stirred at 24 °C for 20 h. Water and saturated aqueous sodium bicarbonate solution were added and the organic solvent was evaporated. The residue was extracted with dichloromethane and the combined organic phases were filtered and concentrated. The crude product was purified by flash chromatography (silica gel, dichloromethane / ethanol gradient) to give the title compound. [M+H] + =365.2. 1 H NMR (400MHz, DMSO-d6) δppm 8.55 (dd, J = 1.9, 0.9 Hz, 1H), 7.95 (s, 1H), 7.82 (dd, J = 9.5, 0.9 Hz, 1H), 7.54 (dd, J = 9.4, 1.8 Hz, 1H), 1.33 (s, 9H).

[0572] Intermediate 2

[0573]

[0574] 5-(Cyclopropylsulfonyl)-4-methoxypyridine-2-amine: at room temperature, DMEDA (0.160mL, 1.47mmol, 0.5 equivalent) was added to a stirred solution of 5-bromo-4-methoxypyridine-2-amine (0.6g, 2.95mmol, 1.0 equivalent), sodium cyclopropanesulfinate (0.95g, 7.38mmol, 2.5 equivalent) in DMF (6mL), and the reaction mixture was degassed with N2 gas for 10min. Then CuI (0.113g, 0.59mmol, 0.2 equivalent) was added thereto, and nitrogen was degassed again for 10min. The resulting mixture was heated to 120 ° C for 24h. After the reaction was completed (followed by TLC and LCMS), the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM (50mL) and washed twice with saturated NaHCO3 aqueous solution (2x20mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude compound was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 1-5% MeOH / DCM to obtain the title compound. [M+H] + =229.24.

[0575] 6-(Cyclopropylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine: 2-Chloroacetaldehyde (0.223 g, 2.83 mmol, 5.0 equiv) was added to a stirred solution of 5-(cyclopropylsulfonyl)-4-methoxypyridine-2-amine (0.13 g, 0.56 mmol, 1.0 equiv) in EtOH (1.5 mL) at room temperature and then heated to 80 ° C for 4 h. After the reaction was completed (followed by TLC and LCMS), the mixture was cooled to room temperature and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 1-5% MeOH / DCM to obtain the title compound [M+H] - =253.22.

[0576] 6-(Cyclopropylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine: To a stirred solution of 6-(cyclopropylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine (80 mg, 0.31 mmol, 1.0 equiv) in DCM (0.8 mL), MeOH (0.1 mL) was added NIS (85.7 mg, 0.38 mmol, 1.2 equiv) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction mass was concentrated under reduced pressure. The residue thus obtained was diluted with DCM (100 mL) and washed with saturated NaHCO3 aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude compound was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 1-5% MeOH / DCM to obtain the title compound. [M+H] + =379.0; 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),7.56(s,1H),7.71(s,1H),7.31(s,1H),4.00(s,3H),3.12-3.08(m,1H),1.18-1.15(m,2H),1.10-1.08(m,2H).

[0577] Intermediate 3

[0578]

[0579] 5-(tert-Butylthio)-6-methoxypyrazolo[1,5-a]pyridine: A mixture of 5-bromo-6-methoxypyrazolo[1,5-a]pyridine (227 mg, 899.77 μmol, 1 eq), Pd(OAc)2 (4.04 mg, 18.00 μmol, 0.02 eq), dppf (19.95 mg, 35.99 μmol, 0.04 eq) and t-BuONa (129.71 mg, 1.35 mmol, 1.5 eq) in dioxane (5 mL) was degassed and purged 3 times with N2, and then 2-methylpropane-2-thiol (162.29 mg, 1.80 mmol, 202.62 μL, 2 eq) was added. The mixture was stirred at 90 °C for 12 h under N2 atmosphere, and then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=20 / 1 to 10 / 1) to give the title compound. [M+H] + =237.1. 1H NMR (400MHz, DMSO-d6) δppm 8.41 (s, 1H), 7.90 (d, J = 2.4Hz, 1H), 7.85 (s, 1H), 6.60 (d, J = 2.4Hz, 1H), 3.83 (s, 3H), 1.28 (s, 9H).

[0580] 5-(tert-Butylsulfonyl)-6-methoxypyrazolo[1,5-a]pyridine: 5-(tert-Butylthio)-6-methoxypyrazolo[1,5-a]pyridine (188 mg, 715.94 μmol, 1 equivalent) and A mixture of (660.21 mg, 1.07 mmol, 1.5 eq) in MeOH (1.5 mL) and H2O (0.5 mL) was stirred at 25°C under N2 atmosphere for 12 h. The title compound was obtained. [M+H] + =269.0.

[0581] 5-(tert-butylsulfonyl)-3-iodo-6-methoxypyrazolo[1,5-a]pyridine: To a solution of 5-(tert-butylsulfonyl)-6-methoxypyrazolo[1,5-a]pyridine (200 mg, 745.35 μmol, 1 eq.) in H2O (1 mL) was added NIS (251.53 mg, 1.12 mmol, 1.5 eq.). The resulting mixture was stirred at 20 °C for 12 h, then the mixture was quenched with saturated Na2SO3 (5 mL) and extracted with EtOAc (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc=10 / 1 to 3 / 1) to give the title compound. [M+H] + =394.9. 1 H NMR (400MHz, DMSO-d6) δppm 8.79 (s, 1H), 8.22 (s, 1H), 7.87 (s, 1H), 3.90 (s, 3H), 1.31 (s, 9H).

[0582] Intermediate 4

[0583]

[0584] 5-Bromopyrazolo[1,5-a]pyridin-6-ol: To a solution of 5-bromo-6-methoxypyrazolo[1,5-a]pyridine (500 mg, 1.98 mmol, 1 eq) in DCE (8 mL) was added AlCl3 (1.32 g, 9.91 mmol, 541.53 μL, 5 eq). The mixture was stirred at 80 °C for 1 h, then it was quenched with saturated Na2SO4 (5 mL), neutralized with saturated NaHCO3, and extracted with DCM (3x40 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. [M+H] + =214.8. 1 H NMR (400MHz, DMSO-d6) δppm 10.33 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H).

[0585] 5-Bromo-6-ethoxypyrazolo[1,5-a]pyridine: A mixture of 5-bromopyrazolo[1,5-a]pyridine-6-ol (180.00 mg, 844.95 μmol, 1 eq), KCO (350.33 mg, 2.53 mmol, 3 eq) and iodoethane (171.32 mg, 1.10 mmol, 87.85 μL, 1.3 eq) in DMF (25 mL) was degassed and purged 3 times with N, and then the mixture was stirred at 80 ° C. for 2 h under N atmosphere. The reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (3×10 mL), dried over NaSO, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, petroleum ether / EtOAc=1 / 0 to 4 / 1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm8.51 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 2.4Hz, 1H), 6.52 (d, J = 2.4Hz, 1H), 4.12 (q, J = 6.8Hz, 2H), 1.39 (t, J = 7.2Hz, 3H).

[0586] 5-(tert-Butylthio)-6-ethoxypyrazolo[1,5-a]pyridine: A mixture of 5-bromo-6-ethoxypyrazolo[1,5-a]pyridine (190 mg, 709.30 μmol, 1 eq), 2-methylpropane-2-thiol (108.75 mg, 1.21 mmol, 135.76 μL, 1.7 eq), dppf (15.73 mg, 28.37 μmol, 0.04 eq), Pd(OAc)2 (3.18 mg, 14.19 μmol, 0.02 eq) and t-BuONa (204.50 mg, 2.13 mmol, 3 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C under N2 atmosphere for 12 h. After the reactant was cooled to room temperature, the mixture was diluted with saturated NH4Cl (20 mL) and extracted with EtOAc (4x10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue which was purified by column chromatography (SiO2, petroleum ether / EtOAc=100 / 0 to 80 / 20) to obtain the title compound. [M+H] + =251.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.39 (s, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.85 (s, 1H), 6.59 (d, J = 2.4Hz, 1H), 4.06 (q, J = 6.8Hz, 2H), 1.37 (t, J = 6.8Hz, 3H), 1.29 (s, 9H).

[0587] 5-(tert-Butylsulfonyl)-6-ethoxypyrazolo[1,5-a]pyridine: To a solution of 5-(tert-butylthio)-6-ethoxypyrazolo[1,5-a]pyridine (60 mg, 215.69 μmol, 1 eq.) in MeOH (3 mL) and H2O (1 mL) was added (198.90 mg, 323.54 μmol, 1.5 eq.). The mixture was stirred at 25 °C for 12 h, then it was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. [M+H] + =283.1.

[0588] 5-(tert-butylsulfonyl)-6-ethoxy-3-iodopyrazolo[1,5-a]pyridine: To a solution of 5-(tert-butylsulfonyl)-6-ethoxypyrazolo[1,5-a]pyridine (50 mg, 177.08 μmol, 1 eq) in H2O (0.25 mL) was added NIS (59.76 mg, 265.62 μmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h, then added dropwise to saturated NaHCO3 (10 mL) and extracted with DCM (3x20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=100 / 0 to 80 / 20) to give the title compound. [M+H] + =408.8. 1 H NMR (400MHz, DMSO-d6) δppm 8.77 (s, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 4.15 (q, J = 6.8Hz, 2H), 1.39-1.30 (m, 12H).

[0589] Intermediate 5

[0590]

[0591] 2-((7-methoxyimidazo[1,2-a]pyridin-6-yl)thio)-2-methylpropan-1-ol: A mixture of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (50 mg, 198.19 μmol, 1 eq), KCO (82.17 mg, 594.56 μmol, 3 eq), dppf (10.99 mg, 19.82 μmol, 0.1 eq) and Pd(dba) (9.07 mg, 9.91 μmol, 0.05 eq) in dioxane (1 mL) was degassed and purged with N (3x). 2-Mercapto-2-methylpropan-1-ol (23.15 mg, 218.01 μmol, 1.1 eq) was added, and the mixture was then stirred at 100 °C under N atmosphere for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (DCM / MeOH=100 / 0 to 10 / 1) to give the title compound. LCMS [M+H] + =253.0. 1H NMR(400MHz,DMSO-d6)δppm 8.70(s,1H),7.76(s,1H),7.41(s,1H),6.96(s,1H),4.78(t,J=6.0Hz,1H),3.85(s,3H),3.27(d,J=6.0Hz,2H),1.13(s,6H).

[0592] 6-((1-fluoro-2-methylpropane-2-yl)thio)-7-methoxyimidazo[1,2-a]pyridine: DAST (546.64 μL, 4.14 mmol, 2 eq.) was added to a solution of 2-((7-methoxyimidazo[1,2-a]pyridin-6-yl)thio)-2-methylpropan-1-ol (0.58 g, 2.07 mmol, 1 eq.) in DCM (5 mL) at 0 °C. The mixture was stirred at 25 °C under N2 atmosphere for 16 h. The reaction mixture was quenched at 0 °C by adding saturated NaHCO3 until pH=8, and then extracted with DCM (3x20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (DCM / MeOH=1 / 0 to 95 / 5) to give the title compound. LCMS [M+H] + =255.0. 1 H NMR (400MHz, DMSO-d6) δppm 8.59 (s, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 6.97 (s, 1H), 3.89 (s, 3H), 3.15 (d, J = 18.8Hz, 2H), 1.45 (s, 3H), 1.40 (s, 3H).

[0593] 6-((1-Fluoro-2-methylpropan-2-yl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine: To a solution of 6-((1-fluoro-2-methylpropan-2-yl)thio)-7-methoxyimidazo[1,2-a]pyridine (260 mg, 920.09 μmol, 1 eq) in H2O (3 mL) and MeOH (9 mL) was added Oxone (2.26 g, 3.68 mmol, 4 eq) and the reaction mixture was stirred at 50°C for 16 h. The title compound was obtained and used in the next step without further purification.

[0594] 6-((1-fluoro-2-methylpropane-2-yl)sulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine: To a solution of 6-((1-fluoro-2-methylpropane-2-yl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine (263.4 mg, 919.94 μmol, 1 eq) in H2O (3 mL) was added NIS (310.46 mg, 1.38 mmol, 1.5 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding saturated NaHCO3 at 0 °C until pH = 8 and extracted with DCM (3x20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (DCM / MeOH=1 / 0 to 10 / 1) to give the title compound. LCMS [M+H] + =412.9. 1 H NMR (400MHz, CDCl3) δppm 8.74 (s, 1H), 7.65 (s, 1H), 7.03 (s, 1H), 4.05 (s, 3H), 3.78 (d, J = 15.2Hz, 2H), 1.65 (s, 3H), 1.60 (s, 3H).

[0595] Intermediate 6

[0596]

[0597] 2-((7-methoxyimidazo[1,2-a]pyridin-6-yl)thio)-2-methylpropan-1-ol: A mixture of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (50 mg, 198.19 μmol, 1 eq), KCO (82.17 mg, 594.56 μmol, 3 eq), dppf (10.99 mg, 19.82 μmol, 0.1 eq) and Pd(dba) (9.07 mg, 9.91 μmol, 0.05 eq) in dioxane (1 mL) was degassed and purged with N (3x). 2-Mercapto-2-methylpropan-1-ol (23.15 mg, 218.01 μmol, 1.1 eq) was added, and the mixture was then stirred at 100 °C under N atmosphere for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (DCM / MeOH=100 / 0 to 10 / 1) to give the title compound. LCMS [M+H] + =253.0. 1H NMR(400MHz,DMSO-d6)δppm 8.70(s,1H),7.76(s,1H),7.41(s,1H),6.96(s,1H),4.78(t,J=6.0Hz,1H),3.85(s,3H),3.27(d,J=6.0Hz,2H),1.13(s,6H).

[0598] 2-((7-methoxyimidazo[1,2-a]pyridin-6-yl)thio)-2-methylpropanal: To a solution of 2-((7-methoxyimidazo[1,2-a]pyridin-6-yl)thio)-2-methylpropan-1-ol (2 g, 7.13 mmol, 1 eq) in DCM (30 mL) was added DMP (3.32 mL, 10.70 mmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by the addition of saturated NaHCO (80 mL) and extracted with DCM (3x80 mL). The combined organic layers were dried over NaSO, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (DCM / MeOH=100 / 0 to 93 / 7) to give the title compound. 1 HNMR (400MHz, DMSO-d6) δppm 9.27 (s, 1H), 8.69 (s, 1H), 7.76 (s, 1H), 7.43 (d, J = 0.8Hz, 1H), 6.96 (s, 1H), 3.80 (s, 3H), 1.26 (s, 6H).

[0599] 6-((1,1-difluoro-2-methylpropane-2-yl)thio)-7-methoxyimidazo[1,2-a]pyridine: To a mixture of 2-((7-methoxyimidazo[1,2-a]pyridin-6-yl)thio)-2-methylpropanal (300 mg, 1.08 mmol, 1 eq) in DCM (30 mL) was added DAST (855.07 μL, 6.47 mmol, 6 eq) at -65 °C. The reaction mixture was stirred at 25 °C under N2 atmosphere for 2 h. The reaction mixture was quenched at 0 °C by adding saturated NaHCO3 until pH = 8. The resulting mixture was extracted with DCM (3x40 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (DCM / MeOH=1 / 0 to 4 / 1) to give the title compound. LCMS[M+H] + =272.9. 1H NMR (400MHz, DMSO-d6) δppm 8.76(s,1H),7.83-7.72(m,1H),7.43(s,1H),6.99(s,1H),6.18-5.82(m,1H),3.88(s,3H),1.22(s,6H).

[0600] 6-((1,1-difluoro-2-methylpropane-2-yl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine: To a mixture of 6-((1,1-difluoro-2-methylpropane-2-yl)thio)-7-methoxyimidazo[1,2-a]pyridine (220 mg, 727.10 μmol, 1 eq) in MeOH (15 mL) and H2O (5 mL) was added Oxone (4.47 g, 7.27 mmol, 10 eq). The mixture was stirred at 30 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound, which was used in the next step without further purification. LCMS [M+H] + =305.0.

[0601] 6-((1,1-difluoro-2-methylpropane-2-yl)sulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine: To a mixture of 6-((1,1-difluoro-2-methylpropane-2-yl)sulfonyl)-7-methoxyimidazo[1,2-a]pyridine (200 mg, 591.50 μmol, 1 eq) in MeOH (15 mL) and H2O (5 mL) was added NIS (159.69 mg, 709.80 μmol, 1.2 eq) at 0°C and the mixture was then stirred at 0°C under N2 atmosphere for 2 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3x30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (DCM / MeOH=1 / 0 to 10 / 1) to give the title compound. LCMS [M+H] + =430.8.

[0602] Intermediate 7

[0603]

[0604] 6-Bromo-7-(difluoromethoxy)imidazo[1,2-a]pyridine: A mixture of 5-bromo-4-(difluoromethoxy)pyridin-2-amine (700 mg, 2.64 mmol, 1 eq.), 2-chloroacetaldehyde (1.55 g, 7.91 mmol, 1.28 mL, 3 eq.) and NaHCO3 (664.27 mg, 7.91 mmol, 307.68 μL, 3 eq.) in EtOH (10 mL) was stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=1 / 0 to 1 / 1) to give the title compound. [M+H] + =262.9. 1 H NMR (400MHz, DMSO-d6) δppm 9.46 (s, 1H), 8.25-8.05 (m, 2H), 7.94-7.50 (m, 2H).

[0605] 6-(tert-Butylthio)-7-(difluoromethoxy)imidazo[1,2-a]pyridine: A mixture of 6-bromo-7-(difluoromethoxy)imidazo[1,2-a]pyridine (700 mg, 2.40 mmol, 1 eq), 2-methylpropane-2-thiol (648.02 mg, 7.19 mmol, 809.01 μL, 3 eq), dppf (53.11 mg, 95.80 μmol, 0.04 eq), Pd(OAc)2 (10.75 mg, 47.90 μmol, 0.02 eq) and t-BuONa (690.53 mg, 7.19 mmol, 3 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then it was stirred at 90 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=1 / 0 to 4 / 1) to give the title compound. [M+H] + =273.0. 1 H NMR (400MHz, DMSO-d6) δppm 8.89 (s, 1H), 7.94 (s, 1H), 7.60-7.20 (m, 3H), 1.27 (s, 9H).

[0606] 6-(tert-Butylsulfonyl)-7-(difluoromethoxy)imidazo[1,2-a]pyridine: 6-(tert-Butylthio)-7-(difluoromethoxy)imidazo[1,2-a]pyridine (30 mg, 99.15 μmol, 1 equivalent) and A mixture of (304.77 mg, 495.75 μmol, 5 equiv) in MeOH (3 mL) and H2O (1 mL) was stirred at 25°C under N2 atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. [M+H] + =304.9.

[0607] 6-(tert-Butylsulfonyl)-7-(difluoromethoxy)-3-iodoimidazo[1,2-a]pyridine: To a mixture of 6-(tert-butylsulfonyl)-7-(difluoromethoxy)imidazo[1,2-a]pyridine (30 mg, 98.58 μmol, 1 eq) in MeOH (3 mL) and H2O (1 mL) was added NIS (26.62 mg, 118.30 μmol, 1.2 eq) at 0°C, and the mixture was stirred at 0°C under N2 atmosphere for 1 h. The reaction mixture was quenched with saturated Na2SO3 (10 mL), and then diluted with H2O (10 mL) and extracted with ethyl acetate (2x20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. [M+H] + =430.8. 1 HNMR (400MHz, DMSO-d6) δppm 8.58(s,1H),7.89(s,1H),7.57(s,1H),7.44-7.20(m,1H),1.35(s,9H).

[0608] Intermediate 8

[0609]

[0610] 4-(7-ethoxy-3-iodoimidazo[1,2-a]pyridin-6-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester: To tert-butyl 4-(7-ethoxyimidazo[1,2-a]pyridin-6-yl)-4-hydroxypiperidine-1-carboxylate (1.83 g, 5.06 mmol, prepared according to US20180072717A1) in methanol (20 mL) and water (8 mL) was added N-iodosuccinimide (1.37 g, 6.08 mmol), and the mixture was stirred at 20°C for 30 min. Aqueous sodium thiosulfate solution (10%) and water were added and the precipitate was collected by filtration, washed with water and dried to give the title compound, which was used without further purification. [M+H] + =488.5. 1H NMR(400MHz,DMSO-d6)δppm 8.34(s,1H),7.51(s,1H),7.00(s,1H),5.52(s,1H),4.03-4.19(m,2H) ,3.73-3.98(m,2H),2.97-3.28(m,2H),1.42(s,9H),1.30-1.39(m,5H).

[0611] Intermediate 9

[0612]

[0613] Tert-Butyl 4-(3-(2,6-difluoropyridin-4-yl)-7-ethoxyimidazo[1,2-a]pyridin-6-yl)-4-fluoropiperidine-1-carboxylate: Tert-Butyl 4-(3-(2,6-difluoropyridin-4-yl)-7-ethoxyimidazo[1,2-a]pyridin-6-yl)-4-hydroxypiperidine-1-carboxylate (500 mg, 1.05 mmol) was provided in CH2Cl2 (15 mL) and cooled to -8°C. Bis(2-methoxyethyl)aminosulfur trifluoride solution (2.33 g, 2.00 mL, 50% by weight, 5.27 mmol) was added dropwise and the mixture was allowed to warm to -30°C over 1 h. The mixture was cooled to -78 °C, bis(2-methoxyethyl)aminosulfur trifluoride solution (2.33 g, 2.00 mL, 50% weight, 5.27 mmol) was added dropwise, and the mixture was allowed to warm to room temperature overnight. The mixture was diluted with DCM and saturated sodium bicarbonate aqueous solution at 0 °C and stirred for 10 min. The organic phase was separated, dried and concentrated. The residue was purified by silica gel flash column chromatography using CH2Cl2 / EtOAc / EtOH mixture as eluent to obtain the title compound. [M+H] + =477.5 1 H NMR(400MHz,DMSO-d6)δppm 8.49(s,1H),8.09(s,1H),7.52(s,2H),7.23(s,1H),4.13-4.24(m,2H),3.90-4.09(m,2H),2.93- 3.24(m,2H),2.34-2.56(m,2H),1.88(brt,J=12.42Hz,2H),1.43(s,9H),1.37(t,J=6.97Hz,3H).

[0614] 3-(2,6-Difluoropyridin-4-yl)-7-ethoxy-6-(4-fluoropiperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride (HCl): tert-Butyl 4-(3-(2,6-difluoropyridin-4-yl)-7-ethoxyimidazo[1,2-a]pyridin-6-yl)-4-fluoropiperidine-1-carboxylate (270 mg, 567 μmol) was provided in methanol (2 mL). Hydrogen chloride solution (207 mg, 1.42 mL, 4 M in 1,4-dioxane, 5.67 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the title compound, which was used without further purification. [M+H] + =377.4. 1 H NMR(400MHz,DMSO-d6)δppm 9.16-9.53(m,2H),8.58(s,1H),8.48(s,1H),7.66(s,2H),7.47(s,1H),4.39(q,J=6.84Hz,2H),3. 32-3.43(m,2H),3.05-3.26(m,2H),2.62-2.89(m,2H),2.04-2.17(m,2H),1.51(t,J=6.97Hz,3H).

[0615] 3-(2,6-difluoropyridin-4-yl)-7-ethoxy-6-(4-fluoro-1-methylpiperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride (HCl): 3-(2,6-difluoropyridin-4-yl)-7-ethoxy-6-(4-fluoropiperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride (HCl) (53 mg, 0.13 mmol) was provided in CH2Cl2 (2 mL). Formaldehyde (48 μL, 37 wt % in water, 0.64 mmol) was added followed by sodium triacetoxyborohydride (140 mg, 0.64 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3. The organic phase was separated, dried and concentrated. The residue was purified by flash column chromatography on silica gel using an EtOAc / EtOH mixture as eluent to give the title compound. [M+H] + =391.5. 1HNMR(400MHz,DMSO-d6)δppm 8.48(s,1H),8.08(s,1H),7.51(s,2H),7.22(s,1H),4.22(q,J=6.8Hz,2H),2.73(br dd,J=10.6,3.8Hz,2H),2.52-2.66(m,2H),2.23(m,3H),2.20-2.29(m,2H),1.80-1.90(m,2H),1.41(t,J=6.8Hz,3H).

[0616] Intermediate 10

[0617]

[0618] 7-Methoxyimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester: To a mixture of 6-bromo-7-methoxyimidazo[1,2-a]pyridine (1 g, 3.96 mmol, 1 eq) in MeOH (10 mL) and toluene (10 mL) was added TEA (602 mg, 5.95 mmol, 828 μL, 1.5 eq) and Pd(dppf)Cl2 (290 mg, 396 μmol, 0.1 eq) under N2. The mixture was stirred at 80 °C under CO (40 Psi) atmosphere for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (EtOAc / MeOH=100 / 1 to 94 / 6) to give the title compound. [M+H] + =207.2.

[0619] 2-(7-methoxyimidazo[1,2-a]pyridin-6-yl)propan-2-ol: To a solution of methyl 7-methoxyimidazo[1,2-a]pyridine-6-carboxylate (850 mg, 3.71 mmol, 1 eq.) in THF (30 mL) was added MeMgBr (3M, 6.18 mL, 5 eq.) under N2 atmosphere at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) at 0 °C and extracted with EtOAc (100 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δppm: 8.44(s,1H),7.79(s,1H),7.34(s,1H),6.90(s,1H),5.23(s,1H),3.85(s,3H),1.51(s,6H).

[0620] 2-(3-iodo-7-methoxyimidazo[1,2-a]pyridin-6-yl)propan-2-ol: To a solution of 2-(7-methoxyimidazo[1,2-a]pyridin-6-yl)propan-2-ol (700 mg, 3.05 mmol, 1 eq) in MeOH (18 mL) and H2O (12 mL) was added NIS (893 mg, 3.97 mmol, 1.3 eq) at 0°C. The mixture was stirred at 20°C for 2 h. The mixture was filtered, diluted with saturated Na2SO3 (20 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with saturated NaHCO3 (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. 1 HNMR (400MHz, DMSO-d6) δppm: 8.29 (s, 1H), 7.50 (s, 1H), 7.02 (s, 1H), 5.44 (s, 1H), 3.89 (s, 3H), 1.52 (s, 6H).

[0621] Intermediate 11

[0622]

[0623] 3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester: To 7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (1.58 g, 7.64 mmol) in methanol (30.0 mL) and water (12.0 mL) was added N-iodosuccinimide (2.06 g, 9.17 mmol), and the mixture was stirred at 20°C for 90 min. Aqueous sodium thiosulfate solution (10%) and water were added and the precipitate was collected by filtration, washed with water and dried to give the title compound, which was used without further purification. [M+H] + =333.2. 1 H NMR (400MHz, DMSO-d6) δppm8.56(s,1H),7.64(s,1H),7.15(s,1H),3.89(s,3H),3.85(s,3H).

[0624] 3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid: To methyl 3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-carboxylate (2.05 g, 6.17 mmol) in THF (20 mL) and water (5 mL) was added lithium hydroxide (222 mg, 926 mmol) and the mixture was stirred at 20 °C for 22 h. The suspension was heated to 60 °C and stirred for 1 h without further heating. The mixture was diluted with water, acidified with 1 M aqueous HCl solution and cooled to 0 °C. The precipitate was collected by filtration, washed with water and dried to give the title compound. [M+H] + =319.2. 1 HNMR (400MHz, DMSO-d6) δppm 8.37 (s, 1H), 7.56 (s, 1H), 7.03 (s, 1H), 3.85 (s, 3H).

[0625] 3-iodo-7-methoxy-N,N-dimethylimidazo[1,2-a]pyridine-6-carboxamide: 3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-carboxamide (500 mg, 1.57 mmol) was suspended in DMF (5 mL) and treated with triethylamine (159 mg, 1.57 mmol) and dimethylamine hydrochloride (128 mg, 1.57 mmol), followed by HATU (598 mg, 1.57 mmol) under an argon atmosphere. The mixture was stirred at room temperature for 19 h. The mixture was diluted with EtOAc and water. The organic phase was separated and dried. The solvent was evaporated and the residue was purified by silica gel flash column chromatography using a CH2Cl2 / EtOH mixture as eluent to give the product, which was triturated with water and collected by filtration to give the title compound. [M+H] + =346.3. 1 H NMR (400MHz, DMSO-d6) δppm 8.37(s,1H),7.89(s,1H),7.23(s,1H),3.95(s,3H),3.00(s,3H),2.81(s,3H).

[0626] Intermediate 12

[0627]

[0628] 3-iodo-7-methoxy-N-methylimidazo[1,2-a]pyridine-6-carboxamide: 3-iodo-7-methoxyimidazo[1,2-a]pyridine-6-carboxylic acid (500 mg, 1.57 mmol) was suspended in CH2Cl2 (10 mL), and then DIPEA (0.685 mL, 3.93 mmol), TBTU (757 mg, 2.36 mmol) and methylamine (2M in THF, 1.57 mL, 3.14 mmol) were added. The mixture was stirred at room temperature for 3 days. The mixture was diluted with water. 1M HCl aqueous solution was added, and the mixture was cooled to 0 ° C. The precipitate was collected by filtration and washed with water. The residue was purified by silica gel flash column chromatography using CH2Cl2 / EtOH mixture as eluent to obtain the title compound. [M+H] + =332.3. 1 H NMR (400MHz, DMSO-d6) δppm 8.54 (s, 1H), 8.32 (q, J = 4.6Hz, 1H), 7.62 (s, 1H), 7.15 (s, 1H), 3.95 (s, 3H), 2.83 (d, J = 4.6Hz, 3H).

[0629] Intermediate 13

[0630]

[0631] 2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine: Bis(1,5-cyclooctadiene)dimethoxyiridium (44.8 mg, 0.01 eq., 67.6 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (36.3 mg, 0.02 eq., 135.1 μmol) were dissolved in DCE (10 mL) under argon. The mixture was stirred at room temperature for 10 min. 2,6-Dichloropyridine (1.00 g, 1 eq., 6.76 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.97 g, 1.15 eq., 7.77 mmol) were added and the mixture was stirred at 100 °C under argon for 4 h. The mixture was diluted with EtOAc and brine was added. The organic phase was separated, washed with saturated NaHCO3 solution, dried and filtered. The solvent was evaporated to give a residue. Purification via silica gel biotage chromatography using hexane / EtOAc as eluent provided the title compound. [X+H] + =192.1 (X = (2,6-dichloropyridin-4-yl)boronic acid). 1H NMR (400MHz, DMSO-d6) δppm 7.57 (s, 2H), 1.30 (s, 12H).

[0632] Intermediate 14

[0633]

[0634] 2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine: To a stirred solution of 2,6-difluoropyridine (0.500 g, 4.34 mmol, 1 eq.) in MTBE (5 mL) was added 4,4,4',4' ,5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.25 g, 4.91 mmol, 1.2 equiv.) was added, followed by 1,10-phenanthroline (0.783 g, 0.043 mmol, 0.01 equiv.) and bis(1,5-cyclooctadiene)dimethoxyiridium (28.8 mg, 0.043 mmol, 0.01 equiv.) at room temperature. The reaction mixture was then heated at 70 ° C for 4 h. After the reaction was complete, the reaction mixture was concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel (100-200 mesh) using 5-10% ethyl acetate / petroleum ether to provide the title compound as a 1.6:1.0 mixture of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. [X+H] + =160.1 (X = (difluoropyridyl)boronic acid).

[0635] Intermediate 15

[0636]

[0637] N-(5-Bromo-2-(trifluoromethoxy)phenyl)propane-1-sulfonamide: 5-Bromo-2-(trifluoromethoxy)aniline (600 mg, 2.34 mmol) was dissolved in DCM (40 mL), and then DMAP (28.6 mg, 234 μmol), pyridine (371 mg, 378 μL, 4.69 mmol) and n-propylsulfonyl chloride (368 mg, 290 μL, 2.58 mmol) were added, and then the mixture was stirred at 20 ° C for 3 days. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel using CH2Cl2 / EtOAc mixture as eluent to give the title compound. [M–H] –=362.2. 1 H NMR(400MHz,DMSO-d6)δppm 10.03(s,1H),7.69(d,J=2.28Hz,1H),7.42-7.50(m,1H),7.32-7.41(m,1H),3.13-3.23(m,2H),1.64-1.81(m,2H),0.97(t,J=7.48Hz,3H).

[0638] N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)propane-1-sulfonamide: To a solution of N-(5-bromo-2-(trifluoromethoxy)phenyl)propane-1-sulfonamide (245 mg, 1 eq, 676 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolan) (344 mg, 1.35 mmol) in DMSO (5 mL) was added potassium acetate (199 mg, 2.03 mmol) while the mixture was purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (55.2 mg, 67.6 μmol) was added and the mixture was purged with argon for 5 min. The vial was sealed and the mixture was stirred at 90° C. for 9 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel using CH 2 Cl 2 / EtOAc mixtures as eluent to give the title compound. [M–H] – =408.4. 1 H NMR(400MHz,DMSO-d6)δppm 9.74(s,1H),7.77(d,J=1.5Hz,1H),7.57(dd,J=8.4,1.5Hz,1H),7.41(dd,J=8.4,1. 8Hz,1H),3.03-3.10(m,2H),1.68-1.80(m,2H),1.30(s,12H),0.96(t,J=7.5Hz,3H).

[0639] Intermediate 16

[0640]

[0641] N-(3-Bromo-5-(trifluoromethoxy)phenyl)propane-1-sulfonamide: 3-Bromo-5-(trifluoromethoxy)aniline (1.00 g, 3.91 mmol) was dissolved in DCM (40 mL), DMAP (47.7 mg, 391 μmol), pyridine (618 mg, 629 μL, 7.81 mmol) and n-propylsulfonyl chloride (613 mg, 483 μL, 4.30 mmol) were added, and the mixture was stirred at 20 °C for 3 days. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel using CH2Cl2 / EtOAc mixtures as eluent to give the title compound. [M–H] – =362.2. 1 HNMR(400MHz,DMSO-d6)δppm 10.40(s,1H),7.36-7.38(m,1H),7.33-7.37(m,1H),7.16-7.19(m,1H),3.17-3.24(m,2H),1.62-1.73(m,2H),0.95(t,J=7.48Hz,3H).

[0642] The following compounds were prepared following a procedure similar to that described for Intermediate 16.

[0643]

[0644] Intermediate 18

[0645]

[0646] N-(3-methoxy-2-methylphenyl)propane-1-sulfonamide: 3-methoxy-2-methyl-aniline was dissolved in CH2Cl2 (20 mL), then DIPEA (1.56 mL, 8.92 mmol) was added, followed by n-propylsulfonyl chloride (0.40 mL, 3.57 mmol) and DMAP (43.6 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 h. Additional DIPEA (1.56 mL, 8.92 mmol) was added, followed by n-propylsulfonyl chloride (0.40 mL, 3.57 mmol) and DMAP (43.6 mg, 0.36 mmol), and the mixture was stirred at room temperature for 88 h. The reactants were diluted with CH2Cl2 and water. The organic phase was separated and dried. The solvent was evaporated, and the residue was purified by flash column chromatography on silica gel to obtain the crude title compound. The compound was used in the next step without any further purification. [MH] - =242.3.

[0647] N-(3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide: Cyclooctadiene methanol iridium dimer (13.6 mg, 0.021 mmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (9.7 mg, 0.041 mmol) were dissolved in heptane (3 mL) and stirred at room temperature for 10 min. N-(3-methoxy-2-methylphenyl)propane-1-sulfonamide (200 mg, 0.622 mmol) and bis(pinacolato)diborane (417 mg, 1.64 mmol) were added and the mixture was heated to 80 °C for 16 h. The mixture was cooled to room temperature and diluted with EtOAc and brine. The organic phase was separated and dried. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel to give the title compound. The compound was used in the next step without any further purification. [MH] - =368.5.

[0648] The following compounds were prepared following a procedure similar to that described for Intermediate 18.

[0649]

[0650] Intermediate 21

[0651]

[0652] 2-(Difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: 2-(Difluoromethoxy)aniline, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (718 mg, 2.83 mmol, 1.5 equivalents), (1Z,5 A mixture of 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (50.6 mg, 189 μmol, 0.1 eq.) in dioxane (5 mL) was degassed and purged three times with N2, and then the mixture was stirred at 75 ° C. under N2 for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, PE:EA=1:1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm: 7.47 (d, J = 7.6Hz, 1H), 7.42 (s, 1H), 6.82-6.65 (m, 2H), 1.32 (s, 12H).

[0653] Intermediate 22

[0654]

[0655] 5-Bromo-3-fluoro-2-hydroxybenzoic acid: To a mixture of 3-fluoro-2-hydroxybenzoic acid (200 mg, 1.28 mmol, 1 eq) in ACN (4 mL) was added NBS (250 mg, 1.41 mmol, 1.1 eq) and the mixture was stirred at 25° C. under nitrogen for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO , DCM / MeOH = 1 / 0 to 10 / 1) to give the title compound. 1 HNMR (400MHz, DMSO-d6) δppm: 11.18-10.90 (m, 1H), 7.79 (dd, J = 2.4, 10.4Hz, 1H), 7.72-7.65 (m, 1H).

[0656] 5-bromo-3-fluoro-2-methoxybenzoic acid methyl ester: To a mixture of 5-bromo-3-fluoro-2-hydroxybenzoic acid (300 mg, 1.15 mmol, 1 eq.) and K2CO3 (874 mg, 6.32 mmol, 5.5 eq.) in DMF (7 mL) was added MeI (718 mg, 5.06 mmol, 0.315 mL, 4.40 eq.) at 0 ° C. The mixture was stirred at 0 ° C. under N2 atmosphere for 1 h, and then the mixture was stirred at 25 ° C. for 12 h. The reaction mixture was quenched with H2O (20 mL), extracted with DCM (20 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (DCM / MeOH=1 / 0) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm: 7.75-7.55 (m, 1H), 7.48-7.30 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H).

[0657] 3-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester: To a mixture of 5-bromo-3-fluoro-2-methoxybenzoic acid methyl ester (250 mg, 855 μmol, 1 eq.), B2Pin2 (434 mg, 1.71 mmol, 2 eq.) and KOAc (252 mg, 2.57 mmol, 3 eq.) in dioxane (3 mL), Pd(dppf)Cl2 (63 mg, 86 μmol, 0.1 eq.) was added. The mixture was degassed and purged three times with N2, and then the mixture was stirred at 100 °C under N2 atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0) to obtain the title compound. [M+H] + =311.1. 1 H NMR: (400MHz, CDCl3) δppm: 7.94 (s, 1H), 7.69-7.60 (m, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 1.33 (s, 12H).

[0658] Intermediate 23

[0659]

[0660] 5-bromo-3-fluoro-6-methylpyridine-2-amine: NBS (677.31 mg, 3.81 mmol, 1.2 equiv.) was added to a solution of 3-fluoro-6-methylpyridine-2-amine (400 mg, 3.17 mmol, 1 equiv.) in DCM (4 mL) at 0 ° C. The mixture was stirred for 1 h at 20 ° C. The reaction mixture was quenched by adding saturated Na2SO3 (10 mL) at 0 ° C. and then extracted with DCM (3x10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (PE / EtOAc=90 / 10 to 70 / 30) to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 7.60 (d, J = 10.4Hz, 1H), 6.35 (s, 2H), 2.32 (s, 3H).

[0661] Intermediate 24

[0662]

[0663] 5-Bromo-3-fluoro-2-hydroxybenzonitrile: To a solution of 3-fluoro-2-hydroxybenzonitrile (200 mg, 1.46 mmol, 1 eq.) in ACN (10 mL) was added NBS (260 mg, 1.46 mmol, 1 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 11.86 (br s, 1H), 7.87 (dd, J = 2.4, 10.8Hz, 1H), 7.82-7.73 (m, 1H).

[0664] 5-Bromo-3-fluoro-2-methoxybenzonitrile: To a solution of 5-bromo-3-fluoro-2-hydroxybenzonitrile (240 mg, 1.00 mmol, 1 eq.) in DMF (4 mL) was added NaH (80 mg, 2.00 mmol, 60% purity, 2 eq.). The mixture was stirred at 25 °C for 20 min, then iodomethane (284 mg, 2.00 mmol, 125 μL, 2 eq.) was added. The mixture was stirred at 25 °C for 12 h, then the reactants were quenched by adding H2O (10 mL). The resulting solid was collected by filtration and used directly without purification. [M+H] + =287.0. 1 H NMR (400MHz, DMSO-d6) δppm: 8.04 (dd, J = 2.3, 11.7Hz, 1H), 7.95 (d, J = 1.5Hz, 1H), 4.06 (d, J = 2.8Hz, 3H).

[0665] Intermediate 25

[0666]

[0667] 5-Bromo-3-fluoro-2-methoxybenzaldehyde: NaH (365 mg, 9.13 mmol, 60% purity, 2 eq.) was added to a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1 g, 4.57 mmol, 1 eq.) in DMF (15 mL) at 0 ° C. Then MeI (2.59 g, 18.3 mmol, 1.14 mL, 4 eq.) was added to the reaction mixture. The resulting mixture was stirred at 25 ° C. for 12 h. The reaction mixture was quenched by adding H2O (30 mL) at 0 ° C. and extracted with DCM (120 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase HPLC (H2O / ACN=0-56%) to obtain the title compound. 1 H NMR: (400MHz, DMSO-d6) δppm: 10.20 (s, 1H), 7.99 (dd, J = 2.4, 11.2Hz, 1H), 7.63 (s, 1H), 4.03 (s, 3H).

[0668] 5-Bromo-3-fluoro-2-methoxyphenol: A mixture of 5-bromo-3-fluoro-2-methoxybenzaldehyde (500 mg, 1.93 mmol, 1 eq.), m-CPBA (784 mg, 3.86 mmol, 85% purity, 2 eq.) in DCM (20 mL) was degassed and purged three times with N2, and then the mixture was stirred at 40 ° C for 12 h. The mixture was diluted with DCM (60 mL) and washed with saturated NaHCO3 aqueous solution (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Methanol (10 mL) was added, followed by NaOH (33% aqueous solution, 1 mL), and the mixture was stirred at 25 ° C for 2 h. The pH was adjusted to pH = 5 with HCl (1 N, 10 mL) at 0 ° C, and the mixture was extracted with EtOAc (90 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δppm: 6.96 (dd, J = 2.4, 10.0Hz, 1H), 6.91-6.85 (m, 1H), 3.76 (s, 3H).

[0669] Intermediate 26

[0670]

[0671] 5-bromo-1-fluoro-2,3-dimethoxybenzene: K2CO3 (600 mg, 4.35 mmol, 3 equiv) and MeI (617 mg, 4.35 mmol, 270 μL, 3 equiv) were added to a solution of 5-bromo-3-fluorobenzene-1,2-diol (300 mg, 1.45 mmol, 1 equiv) in DMF (2 mL). The mixture was stirred for 3 h at 25 ° C. The mixture was concentrated, and then water (30 mL) was added. The mixture was extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (SiO2, 0% to 10% ethyl acetate / petroleum ether) to obtain the title compound. 1 H NMR: (400MHz, CDCl3) δppm: 6.93-6.86 (m, 1H), 6.82 (t, J = 2.0Hz, 1H), 3.90 (d, J = 0.8Hz, 3H), 3.86 (s, 3H).

[0672] Intermediate 27

[0673]

[0674] (E)-5-bromo-1-fluoro-2-methoxy-3-(2-methoxyvinyl)benzene: To a solution of (methoxymethyl)triphenylphosphine chloride (1.10 g, 3.22 mmol, 1.5 eq) in THF (10 mL) was added LiHMDS (1 M, 3.43 mL, 1.6 eq) under N at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min, and then 5-bromo-3-fluoro-2-methoxybenzaldehyde (500 mg, 2.15 mmol, 1 eq) in THF (2 mL) was added to the reaction mixture, and the mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched at 0 °C by adding H2O (20 mL). The mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (eluting with petroleum ether) to give the title compound, which was used without further purification.

[0675] 2-(5-Bromo-3-fluoro-2-methoxyphenyl)acetaldehyde: To a solution of (E)-5-bromo-1-fluoro-2-methoxy-3-(2-methoxyvinyl)benzene (300 mg, 1.15 mmol, 1 eq.) in DCM (20 mL) was added HCl (1 mL, 12 N). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (2 mL), the pH was adjusted to 8 with saturated NaHCO3 at 0 °C, extracted with DCM (50 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 1 to 4 / 1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 9.66 (s, 1H), 7.58-7.50 (m, 1H), 7.35-7.29 (m, 1H), 3.83 (d, J = 1.6Hz, 2H), 3.78 (d, J = 2.0Hz, 3H).

[0676] 2-(5-bromo-3-fluoro-2-methoxyphenyl)ethan-1-ol: To a solution of 2-(5-bromo-3-fluoro-2-methoxyphenyl)acetaldehyde (150 mg, 607 μmol, 1 eq.) in MeOH (2 mL) was added NaBH4 (41.4 mg, 1.09 mmol, 1.8 eq.) at 0°C. The mixture was stirred at 25°C for 2 h. The reaction mixture was quenched at 0°C by addition of H2O (20 mL) and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 1 to 3 / 1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 7.43 (dd, J=2.4, 11.2Hz, 1H), 7.31-7.22 (m, 1H), 4.70 (t,J=5.6Hz,1H),3.82(d,J=1.6Hz,3H),3.61-3.52(m,2H),2.73(t,J=6.8Hz,2H).

[0677] Intermediate 28

[0678]

[0679] 1-Bromo-3-((methylsulfonyl)methyl)benzene: Sodium methanesulfinate (245 mg, 2.40 mmol, 3 eq.) was added to a solution of 1-bromo-3-(bromomethyl)benzene (200 mg, 800 μmol, 1 eq.) in DMF (2.5 mL). The mixture was stirred at 60 °C under N2 for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (petroleum ether / EtOAc=100 / 1 to 2 / 1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm: 7.64-7.49 (m, 2H), 7.40-7.34 (m, 1H), 7.34-7.27 (m, 1H), 4.21 (s, 2H), 2.80 (s, 3H).

[0680] Intermediate 29

[0681]

[0682] 1-Bromo-2-fluoro-4-methoxy-3-nitrobenzene: Br2 (1.87 g, 11.7 mmol, 602 μL, 4.0 eq.) was added to a solution of 1-fluoro-3-methoxy-2-nitrobenzene (500 mg, 2.92 mmol, 1 eq.) in AcOH (5.0 mL). The mixture was stirred at 60 ° C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (20 mL), the pH was adjusted to pH 8 with saturated NaHCO3 aqueous solution and the mixture was extracted with EtOAc (10 mLx3). The combined organic layers were concentrated under reduced pressure to obtain the title compound, which was used without further purification. 1 H NMR (400MHz, CDCl3) δppm: 7.64-7.55 (m, 1H), 6.80-6.74 (m, 1H), 3.93 (s, 3H).

[0683] 3-Bromo-2-fluoro-6-methoxyaniline: Fe (1.14 g, 20 mmol, 10 equiv) and NH4Cl (1.09 g, 20 mmol, 10 equiv) were added to a solution of 1-bromo-2-fluoro-4-methoxy-3-nitrobenzene (600 mg, 2.04 mmol, 1 equiv) in MeOH (6 mL) and H2O (6 mL). The mixture was stirred at 60 ° C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The mixture was then adjusted to pH = 8 with saturated NaHCO3 aqueous solution, then diluted with H2O (10 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound, which was used without further purification. 1 H NMR (400MHz, CDCl3) δppm: 6.94-6.77 (m, 1H), 6.49 (dd, J = 1.6, 8.8Hz, 1H), 3.85 (s, 3H).

[0684] Intermediate 30

[0685]

[0686] 5-Bromo-2-(difluoromethoxy)pyridin-3-amine: A mixture of 3-amino-5-bromopyridin-2-ol (50 mg, 265 μmol, 1 equivalent), compound 2-chloro-2,2-difluoroacetic acid sodium (121 mg, 794 μmol, 3 equivalents) and Cs2CO3 (172 mg, 529 μmol, 2 equivalents) in ACN (3 mL) was degassed and purged three times with N2, and then the mixture was stirred at 80 ° C under N2 for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound. [M+H] + =238.9). 1 H NMR (400MHz, DMSO-d6) δppm: 7.79-7.41 (m, 2H), 7.22 (d, J = 2.0Hz, 1H), 5.63 (s, 2H).

[0687] Intermediate 31

[0688]

[0689] 5-Bromo-2-methoxy-3-nitrobenzonitrile: To a solution of 5-bromo-2-methoxybenzonitrile (500 mg, 2.36 mmol, 1 eq.) in H2SO4 (5 mL) was added KNO3 (358 mg, 3.54 mmol, 1.5 eq.). The mixture was stirred at 25 °C for 2 h. The mixture was poured into ice and saturated NaHCO3 was added to adjust the pH to 7, then 10 mL of H2O was added and extracted with ethyl acetate (10 mLx2), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 0 to 67 / 33) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm: 8.14 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 4.18 (s, 3H).

[0690] 3-amino-5-bromo-2-methoxybenzonitrile: Fe (416 mg, 7.44 mmol, 5 equivalents) and NH4Cl (398 mg, 7.44 mmol, 5 equivalents) were added to a solution of 5-bromo-2-methoxy-3-nitrobenzonitrile (425 mg, 1.49 mmol, 1 equivalent) in EtOH (15 mL) and H2O (5 mL). The mixture was stirred at 80 ° C under N2 for 2 h. The reaction solution was filtered, and the filter cake was washed with EtOH (20 mL). The filtrate was concentrated under reduced pressure, dissolved in water (20 mL) and extracted with ethyl acetate (20 mLx2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=5 / 1 to 1 / 1) to obtain the title compound. [M+H] + =227.1. 1 H NMR (400MHz, DMSO-d6) δppm: 7.10 (d, J = 2.4Hz, 1H), 7.03 (d, J = 2.4Hz, 1H), 5.79 (s, 2H), 3.79 (s, 3H).

[0691] Intermediate 32

[0692]

[0693] 4-bromo-3,6-difluoro-2-nitrophenol: To a solution of 4-bromo-2,5-difluorophenol (0.6 g, 2.87 mmol, 1 equiv.) in AcOH (3 mL), HNO3 (221 mg, 3.45 mmol, 158 μL, 1.2 equiv.) was added. The mixture was stirred at 25 °C under N2 for 12 h. The reaction mixture was quenched by saturated NaHCO3 aqueous solution at 0 °C and extracted with EtOAc (20 mLx3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 8.02 (dd, J=6.8, 10.4Hz, 1H).

[0694] 1-Bromo-2,5-difluoro-4-methoxy-3-nitrobenzene: To a solution of 4-bromo-3,6-difluoro-2-nitrophenol (230 mg, 815 μmol, 1 eq.) in DMF (4 mL) was added KCO (338 mg, 2.45 mmol, 3 eq.) and iodomethane (231 mg, 1.63 mmol, 101 μL, 2 eq.). The mixture was stirred at 25 °C under N for 2 h. The mixture was diluted with water (100 mL), extracted with EtOAc (100 mL x 3), dried over NaSO, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δppm: 8.25 (dd, J=6.8, 11.6Hz, 1H), 4.05 (d, J=2.4Hz, 3H).

[0695] 3-bromo-2,5-difluoro-6-methoxyaniline: Fe (169 mg, 3.02 mmol, 5 equiv) and NH4Cl (162 mg, 3.02 mmol, 5 equiv) were added to a solution of 1-bromo-2,5-difluoro-4-methoxy-3-nitrobenzene (180 mg, 604 μmol, 1 equiv) in EtOH (3 mL) and H2O (1 mL). The mixture was stirred at 80 ° C under N2 for 2 h. The mixture was filtered and the filter cake was washed with EtOAc (30 mLx3). The filtrate was diluted with water (50 mL), extracted with EtOAc (50 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 1 to 4 / 1) to obtain the title compound. 1H NMR (400MHz, DMSO-d6) δppm: 6.77 (dd, J = 6.0, 10.4Hz, 1H), 5.58 (s, 2H), 3.76 (d, J = 0.8Hz, 3H).

[0696] Intermediate 33

[0697]

[0698] N-(6-chloro-4-methoxypyridin-2-yl)propane-1-sulfonamide: 2,6-dichloro-4-methoxypyridine (500 mg, 2.81 mmol, 1 equivalent), propane-1-sulfonamide (415 mg, 3.37 mmol,

[0699] A mixture of 4-nitropropene (2-nitropropene) (1.2 equiv.), Pd(OAc)2 (63 mg, 281 μmol, 0.1 equiv.), Cs2CO3 (1.83 g, 5.62 mmol, 2 equiv.) and Xantphos (195 mg, 337 μmol, 0.12 equiv.) in 1,4-dioxane (10 mL) was degassed and purged three times with N2, and then the mixture was stirred at 100 °C under N2 for 16 h. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. The residue was purified by column chromatography (SiO2, DCM / MeOH=100 / 0 to 100 / 3) to give the title compound. [M+H] + =265.0. 1 H NMR (400 MHz, DMSO-d6) δppm: 10.71 (s, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H), 3.83 (s, 3H), 3.45-3.36 (m, 2H), 1.77-1.62 (m, 2H), 0.96 (t, J = 7.2Hz, 3H).

[0700] Intermediate 34

[0701]

[0702] 4-bromo-2-methoxypyridine 1-oxide: A mixture of 4-bromo-2-methoxypyridine (1 g, 5.32 mmol, 1 eq.), hydrogen peroxide; urea (5.00 g, 53 mmol, 10 eq.) and TFAA (3.35 g, 16 mmol, 2.22 mL, 3 eq.) in DCM (3 mL) was degassed and purged three times with N2, and then the mixture was stirred at 25 ° C under N2 for 4 h. The reaction mixture was quenched by saturated Na2SO3 aqueous solution (10 mL), diluted with H2O (20 mL) and extracted with EtOAc (60 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δppm: 8.12 (d, J = 6.8 Hz, 1H), 7.29-7.00 (m, 2H), 4.08 (s, 3H).

[0703] 4- bromo-6-methoxypyridine-2-amine: Pyridine (154 mg, 1.94 mmol, 157 μL, 2 equivalents) was added dropwise to a solution of 4- bromo-2-methoxypyridine 1-oxide (220 mg, 970 μmol, 1 equivalent) in DCM (10 mL) at 0 ° C. Then a solution of Tf2O (301 mg, 1.07 mmol, 176 μL, 1.1 equivalents) in DCM (5 mL) was added dropwise to the mixture at 0 ° C. After addition, the mixture was stirred for 0.5 h at 0 ° C, and then ethanolamine (301 mg, 1.07 mmol, 176 μL, 1.1 equivalents) was added dropwise at 0 ° C. The mixture was slowly warmed to 25 ° C. The resulting mixture was stirred at 25 ° C for 14 h. The reaction mixture was quenched by adding H2O (20 mL) and then extracted with DCM (20 mLx3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 1 to 1 / 1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 6.24-6.15 (m, 3H), 6.07 (d, J = 1.2Hz, 1H), 3.73 (s, 3H).

[0704] Intermediate 35

[0705]

[0706] 3-Bromo-2,5-difluoro-6-nitroaniline: To a solution of 1-bromo-2,5-difluoro-4-nitrobenzene (2 g, 8.40 mmol, 1 eq.) in DMSO (40 mL) was added amino(trimethyl)ammonium at 15 °C; iodide (2.04 g, 10.1 mmol, 1.2 eq.) and t-BuOK (3.77 g, 33.6 mmol, 4 eq.). After addition, the mixture was stirred at 15 °C for 15 min. The reaction mixture was quenched with 10% HCl (20 mL) at 10 °C to pH = 4-5, and then the mixture was poured into water (150 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with water (50 mL x 3), brine (50 mL x 3) and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 7.19 (s, 2H), 7.00 (dd, J=5.6, 11.2Hz, 1H).

[0707] 4-Bromo-3,6-difluorobenzene-1,2-diamine: To a solution of 3-bromo-2,5-difluoro-6-nitroaniline (250 mg, 889 μmol, 1 eq) in EtOH (5 mL), THF (5 mL) and H2O (3 mL) was added Fe (500 mg, 8.89 mmol, 10 eq) and NH4Cl (476 mg, 8.89 mmol, 10 eq). The reaction mixture was stirred at 55 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound, which was used without further purification. [M+H] + =222.9. 1 H NMR (400MHz, DMSO-d6) δppm: 6.68-6.61 (m, 1H), 5.05 (s, 2H), 4.88 (s, 2H).

[0708] Intermediate 36

[0709]

[0710] 3-Bromo-5-(difluoromethoxy)aniline: A mixture of Fe (208 mg, 3.73 mmol, 10 eq.), NH4Cl (200 mg, 3.73 mmol, 10 eq.) and 1-bromo-3-(difluoromethoxy)-5-nitrobenzene (100 mg, 373 μmol, 1 eq.) in EtOH (5 mL) was stirred at 80 ° C for 2 h, and then the mixture was stirred at 90 ° C for 1 h. The mixture was heated to 100 ° C under N2 and stirred for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 7.15 (t, J = 74Hz, 1H), 6.61-6.57 (m, 1H), 6.43 (d, J = 1.6Hz, 1H), 6.38-6.22 (m, 1H), 5.71 (s, 2H).

[0711] Intermediate 37

[0712]

[0713] Tert-butyl (5-bromo-2-fluoro-3-methoxyphenyl)carbamate: By 5-bromo-2-fluoro-3-methoxybenzoic acid (200mg, 803μmol, 1 equivalent), Et3N (163mg, 1.61mmol, 224μL, 2 equivalents) and DPPA (265mg, 964μmol, 209μL, 1.2 equivalents) in t-BuOH (4mL) mixture N2 degassed and purged three times, and then the mixture was stirred at 90 ℃ under N2 for 6h. The reaction mixture was diluted with H2O (30mL) and extracted with EtOAc (30mLx3). The organic layer merged was washed with brine (30mL), through Na2SO4 dried, filtered and concentrated under reduced pressure, to obtain residue, by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 0 to 95 / 5) the residue was purified, to obtain the title compound. 1 HNMR (400MHz, CDCl3) δppm: 7.95 (d, J = 4.8 Hz, 1H), 6.77 (dd, J = 2.4, 7.6 Hz, 1H), 6.70 (s, 1H), 3.86 (s, 3H), 1.52 (s, 9H).

[0714] Intermediate 38

[0715]

[0716] 1-Bromo-3-(methoxymethyl)-5-nitrobenzene: NaH (310 mg, 7.76 mmol, 60% purity, 3 equivalents) was added to a solution of (3-bromo-5-nitrophenyl)methanol (0.6 g, 2.59 mmol, 1 equivalent) in THF (10 mL) at 0 ° C. After addition, the mixture was stirred for 0.5 h at 0 ° C, and then CH3I (880 mg, 6.21 mmol, 386 μL, 2.4 equivalents) was added dropwise. The resulting mixture was stirred for 3 h at 20 ° C. The reaction mixture was quenched by adding H2O (10 mL) and the mixture was extracted with EtOAc 30 mL (10 mLx3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether) to obtain the title compound.

[0717] 3-Bromo-5-(methoxymethyl)aniline: To a solution of 1-bromo-3-(methoxymethyl)-5-nitrobenzene (300 mg, 1.22 mmol, 1 eq.) in EtOH (20 mL) was added SnCl2.2H2O (2.20 g, 9.75 mmol, 8 eq.). The mixture was stirred at 90 °C under N2 for 1 h. The mixture was concentrated, diluted with water (50 mL), and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether gradient) to give the title compound. [M+H] + =217.6). 1 H NMR (400MHz, DMSO-d6) δppm: 6.64 (s, 1H), 6.57 (s, 1H), 6.49 (s, 1H), 4.24 (s, 2H), 3.25 (s, 3H).

[0718] Intermediate 39

[0719]

[0720] 3-(Bromodifluoromethoxy)-2-chloro-6-iodopyridine: To a solution of 2-chloro-6-iodopyridine-3-ol (2g, 7.83mmol, 1 equivalent) in DMF (15mL), NaH (1.67g, 41.7mmol, 60% purity, 5.32 equivalents) and dibromodifluoromethane (9.86g, 47.0mmol, 4.34mL, 6 equivalents) in DMF (5mL) were added. The mixture was stirred at 25 °C for 12h. The reaction mixture was diluted with water (80mL) and extracted with DCM (80mLx3). The combined organic layer was washed with water (80mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 0 to 99 / 1) to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 8.02 (d, J = 8.4Hz, 1H), 7.80-7.72 (m, 1H).

[0721] 2-Chloro-6-iodo-3-(trifluoromethoxy)pyridine: To a mixture of 3-(bromodifluoromethoxy)-2-chloro-6-iodopyridine (3.5 g, 8.20 mmol, 1 eq) in DCM (20 mL) was added AgBF4 (3.51 g, 18.0 mmol, 2.2 eq) at -78 °C under N2, and the mixture was then stirred at 20 °C under N2 for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound, which was used without further purification. [M+H] + =324.0. 1 H NMR (400MHz, DMSO-d6) δppm: 8.03 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 1.2, 8.4 Hz, 1H).

[0722] Intermediate 40

[0723]

[0724] 6-bromo-3-ethyl-2-fluoropyridine: LDA (2M, 5.68mL, 2 equivalents) was slowly added to a solution of 2-bromo-6-fluoropyridine (1g, 5.7mmol, 1 equivalent) in THF (20mL) at -78°C, and the mixture was stirred for 30min at -78°C. And EtI (2.66g, 17.0mmol, 1.36mL, 3 equivalents) was slowly added to the mixture, the mixture was stirred for 3h at -78°C, and then it was stirred for 1h at 25°C under N2. The reaction mixture was diluted with H2O (20mL) and extracted with EtOAc (20mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0) to obtain the title compound. [M+H] + =203.8.

[0725] 6-bromo-N-(2,4-dimethoxybenzyl)-3-ethylpyridin-2-amine: DMBNH2 (6.23g, 37.3mmol, 5.61mL, 10 equivalents) was added to a mixture of 6-bromo-3-ethyl-2-fluoropyridine (760mg, 3.72mmol, 1 equivalent) and DIEA (4.81g, 37.3mmol, 6.49mL, 10 equivalents) in DMSO (20mL), and then the mixture was degassed and purged three times with N2, and the mixture was stirred at 80°C under N2 for 12h. The reaction mixture was diluted with H2O (20mL), extracted with DCM (20mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to obtain the title compound. [M+H] + =351.1. 1 H NMR (400MHz, CDCl3) δppm: 7.31 (d, J = 8.0Hz, 1H), 7.01 (d, J = 7.2Hz, 1H), 6.66 (d, J = 7.6Hz, 1H), 6.49-6.42 (m, 2H), 4.86-4.73(m,1H),4.56(d,J=5.6Hz,2H),3.84(s,3H),3.80(s,3H),2.30(q,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H).

[0726] Intermediate 41

[0727]

[0728] 2-Bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-methoxypyridin-4-amine: To a solution of 2-bromo-6-methoxypyridin-4-amine (1.25 g, 4.93 mmol, 6.41 μL, 2 eq.) and (3-bromopropoxy)(tert-butyl)dimethylsilane (500 mg, 2.46 mmol, 1 eq.) in DMF (15 mL), CsCO (4.01 g, 12.3 mmol, 5 eq.) was added. The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 100 / 5) to give the title compound. [M+H] + =376.2. 1 H NMR (400MHz, CDCl3) δppm: 6.29 (d, J = 1.6 Hz, 1H), 5.74 (d, J = 1.6 Hz, 1H), 3.86 (s, 3H), 3. 76(t,J=5.2Hz,2H),3.22(t,J=6.4Hz,2H),1.85-1.74(m,2H),0.92(s,9H),0.07(s,6H).

[0729] N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-methoxy-6-(tributylstannyl)pyridin-4-amine: A mixture of 2-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-methoxypyridin-4-amine (620 mg, 1.49 mmol, 1 eq), Sn2Bu6 (2.59 g, 4.46 mmol, 2.23 mL, 3 eq) and PCy3Pd-G3 (109 mg, 149 μmol, 0.1 eq) in 1,4-dioxane (10 mL) was degassed and purged three times with N2, and then the mixture was stirred at 115 °C under N2 for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 100 / 15) to give the title compound.

[0730] Intermediate 42

[0731]

[0732] 5-Bromo-2-(difluoromethoxy)-1-fluoro-3-nitrobenzene: To a solution of 4-bromo-2-fluoro-6-nitrophenol (100 mg, 424 μmol, 1 eq.) in ACN (10 mL), 2-chloro-2,2-difluoroacetic acid sodium (194 mg, 1.27 mmol, 3.0 eq.) and Cs2CO3 (276 mg, 847 μmol, 2.0 eq.) were added. The mixture was stirred at 80 ° C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm: 7.90 (t, J = 2.0Hz, 1H), 7.64 (dd, J = 2.4, 8.8Hz, 1H), 6.88-6.43 (m, 1H).

[0733] 5-bromo-2-(difluoromethoxy)-3-fluoroaniline: Fe (178 mg, 3.19 mmol, 10 equiv) and NH4Cl (171 mg, 3.19 mmol, 10 equiv) were added to a solution of 5-bromo-2-(difluoromethoxy)-1-fluoro-3-nitrobenzene (114 mg, 319 μmol, 1 equiv) in EtOH (1.0 mL) and H2O (1.0 mL). The mixture was stirred at 80 ° C for 1 h. The reaction mixture was filtered under reduced pressure and the filtrate was adjusted to pH = 8 with saturated NaHCO3 aqueous solution, diluted with H2O (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 10: 1) to obtain the title compound.

[0734] Intermediate 43

[0735]

[0736] 6-bromo-2-fluoro-3-methylpyridine: LDA (2.0M, 8.52mL, 1.5 equivalents) was added to a solution of 2-bromo-6-fluoropyridine (2.0g, 11.36mmol, 1 equivalent) in THF (32mL). The mixture was stirred at -70 °C for 0.5h. MeI (9.68g, 68.2mmol, 4.24mL, 6.0 equivalents) was then added to the mixture and the mixture was stirred at -70 °C for 3h. The reaction mixture was diluted with H2O (50mL) and extracted with EtOAc (50mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 4 / 1) to obtain the title compound. [M+H] + =189.7. 1 H NMR (400MHz, DMSO-d6) δppm: 7.85-7.75 (m, 1H), 7.56-7.50 (m, 1H), 2.21 (s, 3H).

[0737] N-(6-bromo-3-methylpyridin-2-yl)propane-1-sulfonamide: To a mixture of 6-bromo-2-fluoro-3-methylpyridine (400mg, 1.89mmol, 1 equivalent) and CsCO (1.85g, 5.68mmol, 3 equivalents) in DMSO (8mL), propane-1-sulfonamide (700mg, 5.68mmol, 3 equivalents) was added, and the mixture was then degassed and purged three times with N. The mixture was stirred at 120 °C for 3h under microwave irradiation. The reaction mixture was diluted with H2O (30mL), extracted with EtOAc (30mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 4 / 1) to obtain the title compound. [M+H] + =294.8. 1 H NMR (400MHz, CDCl3) δppm: 7.31 (d, J = 8.0Hz, 1H), 7.12 (d, J = 8.0Hz, 1H), 3.73-3.60 (m, 2H), 2.20 (s, 3H), 1.98-1.85 (m, 2H), 1.10 (t, J = 7.6Hz, 3H).

[0738] The following compounds were prepared following procedures similar to that described for Intermediate 43.

[0739]

[0740] Intermediate 45

[0741]

[0742] 6- bromo-N- (2,4- dimethoxybenzyl) -3- methylpyridine -2- amine: 6- bromo-2- fluoro- 3- methylpyridine (1.5g, 7.10mmol, 1 equivalent), DMBNH2 (11.9g, 71.0mmol, 10.7mL, 10 equivalents) and DIEA (9.18g, 71.0mmol, 12.4mL, 10 equivalents) in DMSO (30mL) were degassed and purged three times with N2, and then the mixture was stirred at 80 ° C under N2 for 12h. The reaction mixture was diluted with H2O (100mL) and extracted with EtOAc (50mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain the title compound. 1 H NMR(400MHz, DMSO-d6)δppm:7.15(d,J=7.2Hz,1H),7.05(d,J=8.4Hz,1H),6.59(d,J=7.2Hz,1H),6.55(d,J=2.0Hz, 1H), 6.53-6.48 (m, 1H), 6.44 (dd, J=2.4, 8.4Hz, 1H), 4.41 (d, J=6.0Hz, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 2.04 (s, 3H).

[0743] Intermediate 46

[0744]

[0745] 5-Bromo-2-ethoxy-1-fluoro-3-nitrobenzene: K2CO3 (264 mg, 1.91 mmol, 3 equiv.) was added to a solution of 4-bromo-2-fluoro-6-nitrophenol (150 mg, 636 μmol, 1 equiv.) in DMF (2 mL). The mixture was stirred for 1 h at 25 ° C, and then EtI (496 mg, 3.18 mmol, 254 μL, 5 equiv.) was added to the reaction mixture. The mixture was stirred for 17 h at 25 ° C. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mLx2). The combined organic layers were washed with brine (10 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δppm: 8.08-8.06 (m, 1H), 8.05-8.03 (m, 1H), 4.27-4.18 (m, 2H), 1.30 (t, J = 6.8Hz, 3H).

[0746] 5-Bromo-2-ethoxy-3-fluoroaniline: A mixture of 5-bromo-2-ethoxy-1-fluoro-3-nitrobenzene (150 mg, 568 μmol, 1 eq.), NH4Cl (304 mg, 5.68 mmol, 10 eq.) and Fe (317 mg, 5.68 mmol, 10 eq.) in EtOH (10 mL) and H2O (5 mL) was degassed and purged three times with N2, and the mixture was then stirred at 80 °C under N2 for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mLx2). The combined organic layers were washed with brine (10 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δppm: 6.68-6.64 (m, 1H), 6.59-6.55 (m, 1H), 5.46 (s, 2H), 3.95-3.88 (m, 2H), 1.28 (t, J = 7.2Hz, 3H).

[0747] Intermediate 47

[0748]

[0749] 5-Bromo-1-chloro-2-methoxy-3-nitrobenzene: CH3I (562 mg, 3.96 mmol, 247 μL, 2 eq.) and K2CO3 (547 mg, 3.96 mmol, 2 eq.) were added to a solution of 4-bromo-2-chloro-6-nitrophenol (500 mg, 1.98 mmol, 1 eq.) in DMF (15 mL). The mixture was stirred at 60 ° C for 2 h. The reaction mixture was quenched by adding H2O (5 mL), diluted with brine (100 mL) and extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δppm: 8.21 (s, 2H), 3.93 (s, 3H).

[0750] 5-Bromo-3-chloro-2-methoxyaniline: To a solution of 5-bromo-1-chloro-2-methoxy-3-nitrobenzene (200 mg, 675 μmol, 1 eq.) in EtOH (2.5 mL) and H2O (0.5 mL) was added Fe (377 mg, 6.75 mmol, 10 eq.) and NH4Cl (361 mg, 6.75 mmol, 10 eq.). The mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (20 x 3 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δppm: 6.80 (d, J = 2.4Hz, 1H), 6.72 (d, J = 2.0Hz, 1H), 5.59 (s, 2H), 3.67 (s, 3H).

[0751] Intermediate 48

[0752]

[0753] 2-(Benzyloxy)-5-bromo-3-fluoroaniline: KCO (878 mg, 6.36 mmol, 3 eq.) and BnBr (1.81 g, 10.6 mmol, 1.26 mL, 5 eq.) were added to a solution of 4-bromo-2-fluoro-6-nitrophenol (500 mg, 2.12 mmol, 1 eq.) in DMF (6 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (petroleum ether / EtOAc=100 / 1 to 7 / 3) to give the title compound. 1 H NMR: (400MHz, DMSO-d6) δppm: 8.12-8.07 (m, 1H), 8.06-7.98 (m, 1H), 7.42-7.34 (m, 5H), 5.23 (d, J = 0.8Hz, 2H).

[0754] 2-(Benzyloxy)-5-bromo-3-fluoroaniline: To a solution of 2-(benzyloxy)-5-bromo-3-fluoroaniline (700 mg, 2.15 mmol, 1 eq.) in EtOH (6 mL) and H2O (6 mL), Fe (1.20 g, 21.5 mmol, 10 eq.) and NH4Cl (1.15 g, 21.5 mmol, 10 eq.) were added. The mixture was stirred at 80 °C under N2 for 1 h. The reaction mixture was diluted with H2O (45 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (petroleum ether / EtOAc=100 / 1 to 7 / 3) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 7.51-7.43(m,2H),7.42-7.33(m,3H),6.69-6.65(m,1H),6.62-6.53(m,1H),5.46(s,2H),4.94(s,2H).

[0755] N-(2-(Benzyloxy)-5-bromo-3-fluorophenyl)methanesulfonamide: To a solution of 2-(benzyloxy)-5-bromo-3-fluoroaniline (114 mg, 346 μmol, 1 eq.) in DCM (2 mL) was added pyridine (82 mg, 1.04 mmol, 84 μL, 3 eq.) and Ms2O (66.4 mg, 381 μmol, 1.1 eq.). The mixture was stirred at 25 °C under N2 for 1 h. To the reaction mixture was added Ms2O (60.4 mg, 346 μmol, 1 eq.). The mixture was stirred at 25 °C under N2 for 1 h. To the reaction mixture was added Ms2O (60.4 mg, 346 μmol, 1 eq.). The mixture was stirred at 25 °C under N2 for 1 h. The reaction mixture was diluted with H2O (15 mL) and extracted with DCM (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (petroleum ether / EtOAc=100 / 1 to 7 / 3) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 9.53 (s, 1H), 7.55-7.46 (m, 2H), 7.45-7.28 (m, 5H), 5.11 (s, 2H), 3.04 (s, 3H).

[0756] Intermediate 49

[0757]

[0758] 2-(4-Bromo-2-fluoro-6-nitrophenoxy)ethan-1-ol: To a solution of 4-bromo-2-fluoro-6-nitrophenol (1 g, 4.24 mmol, 1 eq) in MeCN (10 mL) was added KCO (1.17 g, 8.47 mmol, 2 eq) and 2-bromoethanol (1.20 mL, 16.95 mmol, 4 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo and the resulting crude material was purified via silica gel chromatography (PE / EtOAc=1 / 0 to 3 / 1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.78 (t, J = 2.4Hz, 1H), 7.53 (dd, J = 2.4, 10.0Hz, 1H), 4.40-4.37 (m, 2H), 3.93-3.88 (m, 2H).

[0759] 2-(2-amino-4-bromo-6-fluorophenoxy)ethan-1-ol: To a solution of 2-(4-bromo-2-fluoro-6-nitrophenoxy)ethan-1-ol (453 mg, 1.46 mmol, 1 eq.) in EtOH (4 mL) and H2O (2.4 mL), Zn (951.96 mg, 14.56 mmol, 10 eq.) and NH4Cl (778.72 mg, 14.56 mmol, 10 eq.) were added. The mixture was stirred at 80 °C for 10 m. The mixture was then stirred at 25 °C for 2 h. The reaction mixture was quenched by adding 1N HCl (1 mL). The reaction mixture was filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography (PE / EtOAc=8 / 1 to 7 / 2) to give the title compound. LCMS[M+H] + =249.9. 1 H NMR (400MHz, CDCl3) δppm 6.72-6.64(m,2H), 4.17-4.12(m,2H), 3.89-3.84(m,2H).

[0760] Intermediate 50

[0761]

[0762] N-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)propane-1-sulfonamide: Pyridine (389 mg, 4.93 mmol, 397 μL, 5 equiv.) was added to a solution of 3-amino-5-bromo-1-methylpyridin-2(1H)-one (200 mg, 985 μmol, 1 equiv.) and propane-1-sulfonyl chloride (702 mg, 4.93 mmol, 554 μL, 5 equiv.) in DCM (10 mL). The mixture was stirred at 25 ° C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 0 to 0 / 100) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.58 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 3.62 (s, 3H), 3.18-3.03 (m, 2H), 1.92-1.75 (m, 2H), 1.10-0.95 (m, 3H).

[0763] Intermediate 51

[0764]

[0765] 4-bromo-2-(difluoromethoxy)pyridine 1-oxide: urea-H2O2 (1.68 g, 17.9 mmol, 8 equiv.) was added to a mixture of 4-bromo-2-(difluoromethoxy)pyridine (500 mg, 2.23 mmol, 1 equiv.), TFA (1.41 g, 6.70 mmol, 931 μL, 3 equiv.) in DCM (5 mL), and stirred at 40 ° C under N2 for 12 h. The reaction mixture was quenched by adding saturated Na2SO3 aqueous solution (50 mL), diluted with H2O (50 mL) and extracted with EtOAc (50 mL x3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 2) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm: 8.10 (d, J = 7.2Hz, 1H), 7.70-7.34 (m, 2H), 7.32 (dd, J = 2.8, 6.8Hz, 1H).

[0766] 4-Bromo-6-(difluoromethoxy)pyridin-2-amine: To a mixture of 4-bromo-2-(difluoromethoxy)pyridine 1-oxide (150 mg, 563 μmol, 1 eq), pyridine (178 mg, 2.25 mmol, 182 μL, 4 eq) in acetonitrile (15 mL) was added Tf2O (238 mg, 844 μmol, 139 μL, 1.5 eq) at 0°C, and then stirred at 25°C under N2 for 3 h. To the mixture was added ethanolamine (344 mg, 5.62 mmol, 340 μL, 10 eq) at 0°C, and then stirred at 25°C under N2 for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give the title compound. [M+H] + =238. 1 H NMR (400MHz, CDCl3) δppm: 7.52-7.28 (m, 1H), 6.42 (d, J = 1.2 Hz, 1H), 6.41 (d, J = 1.2 Hz, 1H).

[0767] N-(4-bromo-6-(difluoromethoxy)pyridin-2-yl)propane-1-sulfonamide: To a mixture of 4-bromo-6-(difluoromethoxy)pyridin-2-amine (100 mg, 377 μmol, 1 eq), TEA (191 mg, 1.88 mmol, 262 μL, 5 eq) in DCM (10 mL) was added propane-1-sulfonyl chloride (268 mg, 1.88 mmol, 211 μL, 5 eq), and then degassed and purged three times with N, and then the mixture was stirred at 40 ° C under N for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm: 7.28-7.20 (m, 1H), 7.14 (s, 1H), 7.05 (d, J = 1.2Hz, 1H), 6 .81(d,J=1.2Hz,1H),3.40-3.30(m,2H),1.95-1.84(m,2H),1.08(t,J=7.2Hz,3H).

[0768] Intermediate 52

[0769]

[0770] 6-(tributylstannyl)pyridin-3-amine: A mixture of 6-bromopyridin-3-amine (200 mg, 1.16 mmol, 1 eq.), Sn2Bu6 (2.68 g, 4.62 mmol, 2.31 mL, 4 eq.) and PCy3Pd G3 (84.98 mg, 115.60 μmol, 0.1 eq.) in 1,4-dioxane (10 mL) was degassed and purged 3 times with N2, and the mixture was then stirred at 115 ° C under N2 atmosphere for 12 h. The reaction mixture was diluted with saturated KF (10 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / petroleum ether) to obtain the title compound. [M+H] + =382.8. 1 HNMR (400MHz, CDCl3) δppm 8.31 (d, J = 2.4Hz, 1H), 7.18 (d, J = 8.0Hz, 1H), 6.87 (dd, J = 8.0, 2.8Hz, 1H), 3.62 (br s,2H),1.58-1.47(m,6H),1.37-1.25(m,9H),1.12-1.05(m,3H),0.90-0.85(m,9H).

[0771] Intermediate 53

[0772]

[0773] 5-Bromo-6-fluoro-3-methoxypyridin-2-amine: NBS (130.23 mg, 731.72 μmol, 1.04 eq.) was added to a solution of 6-fluoro-3-methoxypyridin-2-amine (100 mg, 703.58 μmol, 1 eq.) in MeCN (5 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 30 min, and the reaction mixture was then warmed to 25 ° C. and stirred at 25 ° C. for 1 h, and the mixture was then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc=100 / 1 to 2 / 8) to obtain the title compound. [M+H] + =220.9. 1 H NMR (400MHz, CDCl3) δppm 7.08 (d, J=6.8Hz, 1H), 5.77-4.00 (m, 2H), 3.83 (s, 3H).

[0774] 6-Fluoro-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine: A mixture of 5-bromo-6-fluoro-3-methoxypyridin-2-amine (80 mg, 325.75 μmol, 1 eq), B2Pin2 (248.16 mg, 977.26 μmol, 3 eq), KOAc (95.91 mg, 977.26 μmol, 3 eq), Pd(dppf)Cl2 (23.84 mg, 32.58 μmol, 0.1 eq) in 1,4-dioxane (8 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 100° C. under N2 atmosphere for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether / EtOAc= to 3 / 1) to give the title compound. [M+H] + =269.0.

[0775] Intermediate 54

[0776]

[0777] 5-Bromo-3-chloro-6-methoxypyridin-2-amine: To a solution of 3-chloro-6-methoxypyridin-2-amine (50 mg, 315.29 μmol, 1 eq.) in DMF (2.5 mL) was added NBS (56.12 mg, 315.29 μmol, 1 eq.). The mixture was stirred at 0 ° C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=100 / 0 to 100 / 15) to give the title compound. 1 HNMR (400MHz, DMSO-d6) δppm 7.74 (s, 1H), 6.45 (s, 2H), 3.81 (s, 3H).

[0778] 3-Chloro-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine: A mixture of 5-bromo-3-chloro-6-methoxypyridin-2-amine (110 mg, 463.19 μmol, 1 eq), B2Pin2 (352.87 mg, 1.39 mmol, 3 eq), Pd2(dba)3 (42.42 mg, 46.32 μmol, 0.1 eq), KOAc (136.38 mg, 1.39 mmol, 3 eq) and PCy3 (12.99 mg, 46.32 μmol, 15.02 μL, 0.1 eq) in 1,4-dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / EtOAc=100 / 0 to 100 / 15) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.78 (s, 1H), 4.90 (s, 2H), 3.86 (s, 3H), 1.32 (s, 12H).

[0779] Intermediate 55

[0780]

[0781] 2-Amino-5-bromo-6-fluoronicotinonitrile: To a solution of 2-amino-6-fluoronicotinonitrile (230 mg, 1.68 mmol, 1 eq.) in MeCN (3.0 mL) was added NBS (597.11 mg, 3.35 mmol, 2.0 eq.). The mixture was stirred at 70 °C for 12 h, then the mixture was filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / EtOAc=1 / 0 to 4 / 1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.91 (d, J=8.0Hz, 1H), 5.32 (s, 2H).

[0782] 2-Amino-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile: A mixture of 2-amino-5-bromo-6-fluoronicotinonitrile (80 mg, 333.32 μmol, 1 eq), B2Pin2 (211.60 mg, 833.29 μmol, 2.5 eq), Pd(dppf)Cl2 (24.39 mg, 33.33 μmol, 0.1 eq), KOAc (81.78 mg, 833.29 μmol, 2.5 eq) in 1,4-dioxane (2.0 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 100° C. under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.

[0783] Intermediate 56

[0784]

[0785] Tert-butyl (3,6-difluoro-2-methylphenyl) carbamate: A mixture of 3,6-difluoro-2-methylbenzoic acid (790 mg, 4.13 mmol, 1 equivalent) and Et3N (836 mg, 8.26 mmol, 1.15 mL, 2 equivalents) in t-BuOH (20 mL) was degassed and purged 3 times with N2, and the mixture was then heated to 40 ° C, and DPPA (1.25 g, 4.54 mmol, 980.73 μL, 1.1 equivalents) was added to the mixture. The mixture was stirred at 90 ° C under N2 atmosphere for 12 h. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=100 / 0 to 3 / 1) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm 6.93-6.85 (m, 2H), 5.99 (br s, 1H), 2.20 (d, J = 2.4Hz, 3H), 1.50 (s, 9H).

[0786] 3,6-Difluoro-2-methylaniline: A mixture of tert-butyl (3,6-difluoro-2-methylphenyl)carbamate (500 mg, 1.85 mmol, 1 eq.) in 4M HCl in dioxane (25 mL) was stirred at 25° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / EtOAc=100 / 0 to 70 / 30) to give the title compound. 1H NMR (400MHz, DMSO-d6) δppm 6.89-6.82 (m, 1H), 6.33-6.27 (m, 1H), 3.57 (s, 2H), 2.01 (d, J = 2.0Hz, 3H).

[0787] 4-Bromo-3,6-difluoro-2-methylaniline: NBS (224 mg, 1.26 mmol, 1 eq) and Et3N (254.50 mg, 2.52 mmol, 350.07 μL, 2 eq) were added to a solution of 3,6-difluoro-2-methylaniline (200 mg, 1.26 mmol, 1 eq) in MeCN (18 mL). The mixture was stirred at 25 ° C for 2 h, then concentrated, diluted with water (20 mL) and extracted with EtOAc (3x60 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=100 / 0 to 90 / 10) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.10-7.01 (m, 1H), 3.78 (s, 2H), 2.13 (d, J = 2.0, 3H).

[0788] 3,6-Difluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: A mixture of 4-bromo-3,6-difluoro-2-methylaniline (240 mg, 972.84 μmol, 1 eq), B2Pin2 (741.13 mg, 2.92 mmol, 3 eq), Pd(dppf)Cl2 (71.18 mg, 97.28 μmol, 0.1 eq) and KOAc (286.43 mg, 2.92 mmol, 3 eq) in 1,4-dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C under N2 atmosphere for 3 h. The reaction mixture was filtered and the filtrate was then concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / EtOAc=100 / 0 to 70 / 30) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm: 7.21-7.15 (m, 1H), 2.06 (d, J = 1.6Hz, 3H), 1.33 (s, 12H).

[0789] Intermediate 57

[0790]

[0791] 5-Bromo-3,4-difluoropyridin-2-amine: To a solution of 5-bromo-4-fluoropyridin-2-amine (1 g, 5.24 mmol, 1 eq) in MeCN (40 mL) was added Selectfluor TM (11.13 g, 31.41 mmol, 6 eq.). The mixture was stirred at 40 °C under N2 atmosphere for 4 h, then diluted with H2O (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (SiO2, petroleum ether / EtOAc=1 / 0 to 5 / 1) to give the title compound. [M+H] + =210.9. 1 HNMR (400MHz, DMSO-d6) δppm 7.94 (dd, J=8.4, 1.2Hz, 1H), 6.79 (s, 2H).

[0792] 3,4-Difluoro-5-(tributylstannyl)pyridin-2-amine: To a solution of 5-bromo-3,4-difluoropyridin-2-amine (130 mg, 497.63 μmol, 1 eq) in 1,4-dioxane (15 mL) was added PCy3PdG3 (36.58 mg, 49.76 μmol, 0.1 eq) and Sn2Bu6 (3.79 g, 6.53 mmol, 3.27 mL, 13.13 eq). The mixture was stirred at 110 °C under N2 atmosphere for 16 h, then it was cooled to 25 °C, diluted with water (15 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=1 / 0 to 3 / 1) to give the title compound. [M+H] + =420.9. 1 HNMR (400MHz, DMSO-d6) δppm 7.56 (d, J = 6.0 Hz, 1H), 6.46 (s, 2H), 1.52-1.45 (m, 6H), 1.33-1.24 (m, 6H), 1.12-1.05 (m, 6H), 0.89-0.79 (m, 9H).

[0793] Intermediate 58

[0794]

[0795] 6-ethoxy-3-fluoropyridine-2-amine: At 0 ° C under N2 atmosphere, to 3,6-difluoropyridine-2-amine (200mg, 1.38mmol, 1 equivalent) and EtOH (127mg, 2.77mmol, 2 equivalents) in 1,4-dioxane (20mL) solution NaH (221.35mg, 5.53mmol, 60% mineral oil solution, 4 equivalents) was added. The mixture was stirred at 90 ° C for 2h, then quenched with MeOH (4mL) at 0 ° C, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc=20 / 1 to 6 / 1) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.15 (t, J = 9.2Hz, 1H), 5.97 (dd, J = 8.8, 2.0Hz, 1H), 4.39 (s, 2H), 4.24-4.13 (m, 2H), 1.35 (t, J = 7.2Hz, 3H).

[0796] 5-Bromo-6-ethoxy-3-fluoropyridin-2-amine: NBS (153.87 mg, 864.51 μmol, 1 eq.) was added to a solution of 6-ethoxy-3-fluoropyridin-2-amine (150 mg, 864.51 μmol, 1 eq.) in DMF (4 mL). The mixture was stirred at 0 ° C for 0.5 h, then diluted with H2O (20 mL) and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, petroleum ether / EtOAc=7 / 1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.39 (d, J = 8.8Hz, 1H), 4.41 (s, 2H), 4.34-4.27 (m, 2H), 1.38 (t, J = 7.2Hz, 3H).

[0797] 6-Ethoxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine: A mixture of 5-bromo-6-ethoxy-3-fluoropyridin-2-amine (100 mg, 382.89 μmol, 1 eq), B2Pin2 (291.69 mg, 1.15 mmol, 3 eq), Pd(dppf)Cl2 (28.02 mg, 38.29 μmol, 0.1 eq) and KOAc (112.73 mg, 1.15 mmol, 3 eq) in 1,4-dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C under N2 atmosphere for 12 h, then the mixture was diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / EtOAc=20 / 1 to 7 / 1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.50 (d, J = 10.4Hz, 1H), 4.59 (s, 2H), 4.29-4.23 (m, 2H), 1.36-1.33 (m, 3H), 1.31 (s, 12H).

[0798] Intermediate 59

[0799]

[0800] Tert-butyl (5-bromo-2-hydroxypyridin-3-yl)carbamate: 3-amino-5-bromopyridine-2-ol (200mg, 1.06mmol, 1 equivalent), Boc2O (577mg, 2.65mmol, 608μL, 2.5 equivalents), DMAP (12.9mg, 106μmol, 0.1 equivalent) and Et3N (107mg, 1.06mmol, 147μL, 1 equivalent) in DCM (5mL) are degassed and purged three times, and then the mixture is stirred for 1h at 25°C under N2. The reaction mixture is diluted with water (20mL), extracted with EtOAc (20mLx3). The combined organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure, to obtain a residue, which is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 1), to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 12.21 (s, 1H), 7.85 (d, J = 2.4Hz, 2H), 7.30 (d, J = 2.4Hz, 1H), 1.46 (s, 9H).

[0801] (5-bromo-1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamic acid tert-butyl ester: (5-bromo-2-hydroxypyridin-3-yl)carbamic acid tert-butyl ester (115mg, 358μmol, 1 equivalent), 2-chloro-2,2-difluoroacetic acid sodium (164mg, 1.07mmol, 3 equivalents), CsCO (233mg, 716μmol, 2 equivalents) in ACN (5mL) are degassed and purged three times with N, and then the mixture is stirred for 1h at 80°C under N. The reaction mixture is diluted with water (20mL) and extracted with EtOAc (20mLx3). The combined organic layer is dried over NaSO, filtered and concentrated under reduced pressure to obtain a residue, which is purified by column chromatography (SiO, petroleum ether / ethyl acetate=5 / 1) to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δppm: 8.34 (s, 1H), 8.03-7.73 (m, 3H), 1.47 (s, 9H).

[0802] Intermediate 60

[0803]

[0804] 5-bromo-3-fluoro-1-methylpyridin-2 (1H) -one: K2CO3 (720 mg, 5.21 mmol, 2 eq) and CH3I (407 mg, 2.86 mmol, 178 μL, 1.1 eq) were added to a solution of 5-bromo-3-fluoropyridine-2-ol (500 mg, 2.60 mmol, 1 eq) in DMF (5 mL). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (30 mL) and extracted with EtOAc 90 mL (30 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the title compound. [M+H] + =207.7). 1 H NMR (400MHz, DMSO-d6) δppm: 7.96-7.91 (m, 1H), 7.74-7.65 (m, 1H), 3.47 (s, 3H).

[0805] 5-Bromo-3-((3-hydroxypropyl)amino)-1-methylpyridin-2(1H)-one: A solution of 5-bromo-3-fluoro-1-methylpyridin-2(1H)-one (310 mg, 1.35 mmol, 1 equivalent) in 3-aminopropane-1-ol (3 mL) was stirred at 90 ° C for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to obtain the title compound. [M+H] + =260.7.

[0806] 1 H NMR (400MHz, DMSO-d6) δppm: 7.13 (d, J = 2.0Hz, 1H), 6.20 (d, J = 2.4Hz, 1H), 5.85-5.78 (m, 1H), 4.55(t,J=5.2Hz,1H),3.51-3.42(m,2H),3.41(s,3H),3.12-3.05(m,2H),1.73-1.62(m,2H).

[0807] Intermediate 61

[0808]

[0809] 3-Fluoro-6-isopropoxypyridine-2-amine: NaOH (138.35 mg, 3.46 mmol, 2.5 eq.) was added to a solution of 3,6-difluoropyridine-2-amine (200 mg, 1.38 mmol, 1 eq.) in i-PrOH (20 mL). The mixture was stirred at 150 ° C for 6 h, then diluted with H2O (20 mL) and extracted with EtOAc (3x10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc=1 / 0 to 5 / 1) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.14 (t, J = 8.4Hz, 1H), 5.95 (dd, J = 8.8, 2.4Hz, 1H), 5.10-4.96 (m, 1H), 4.39 (s, 2H), 1.30 (d, J = 6.4Hz, 6H).

[0810] 5-Bromo-3-fluoro-6-isopropoxypyridine-2-amine: NBS (60.99 mg, 342.69 μmol, 1.2 eq.) was added to a solution of 3-fluoro-6-isopropoxypyridine-2-amine (54 mg, 285.57 μmol, 1 eq.) in DMF (1.0 mL) at 0 ° C. The mixture was stirred for 2 h at 0 ° C., then diluted with H2O (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=10 / 1) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.38 (d, J = 9.2Hz, 1H), 5.21-5.08 (m, 1H), 4.39 (br s, 2H), 1.33 (d, J = 6.4Hz, 6H).

[0811] 3-Fluoro-6-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine: To a solution of 5-bromo-3-fluoro-6-isopropoxypyridin-2-amine (34 mg, 122.85 μmol, 1 eq) and B2Pin2 (62.39 mg, 245.70 μmol, 2.0 eq) in 1,4-dioxane (1.0 mL) was added Pd(dppf)Cl2 (8.99 mg, 12.29 μmol, 0.1 eq) and KOAc (30.14 mg, 307.13 μmol, 2.5 eq). The mixture was stirred at 100 °C under N2 atmosphere for 12 h, then it was diluted with H2O (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. [M+H] + =297.0.

[0812] Intermediate 62

[0813]

[0814] 5-Bromo-3-fluoro-N,N-bis(4-methoxybenzyl)-6-((4-methoxybenzyl)oxy)pyridin-2-amine: To a solution of (4-methoxyphenyl)methanol (83.03 mg, 600.95 μmol, 74.93 μL, 2 eq) in THF (0.5 mL) was added t-BuOK (1 M, 901.43 μL, 3 eq) dropwise at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 h, and then a solution of 5-bromo-3,6-difluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine (150 mg, 300.48 μmol, 1 eq) in THF (1.5 mL) was added dropwise at 25 °C. The resulting mixture was stirred at 90 °C for 11.5 h, then it was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound. 1 H NMR (400MHz, DMSO-d6) δppm 7.79 (d, J = 12.4Hz, 1H), 7.21-7.12 (m, 6H), 6.90-6.83 (m, 6H), 5.12 (s, 2H), 4.59 (s, 4H), 3.75-3.72 (m, 9H).

[0815] 5-Bromo-3-fluoro-N,N-bis(4-methoxybenzyl)-6-((4-methoxybenzyl)oxy)pyridin-2-amine: A mixture of 5-bromo-3-fluoro-N,N-bis(4-methoxybenzyl)-6-((4-methoxybenzyl)oxy)pyridin-2-amine (110 mg, 174.47 μmol, 1 eq), B2Pin2 (132.91 mg, 523.40 μmol, 3 eq), KOAc (51.37 mg, 523.40 μmol, 3 eq) and Pd(dppf)Cl2 (12.77 mg, 17.45 μmol, 0.1 eq) in 1,4-dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C under N2 atmosphere for 2 h. The solids were removed by filtration and the filter cake was washed with 1,4-dioxane (3 x 5 mL). The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound. 1H NMR (400MHz, DMSO-d6) δppm7.41(d,J=14.0Hz,1H),7.29(d,J=8.8Hz,2H),7.15(d,J=8. 4Hz,4H),6.88-6.82(m,6H),5.11(s,2H),4.65(s,4H),3.74-3.70(m,9H),1.26(s,12H).

[0816] Intermediate 63

[0817]

[0818] N-(5-bromo-2-ethylphenyl)methanesulfonamide: Pyridine (119 mg, 1.50 mmol, 121 μL, 3 eq.) was added to a mixture of 5-bromo-2-ethylaniline (100 mg, 500 μmol, 1 eq.) and Ms2O (174 mg, 1 mmol, 2 eq.) in DCM (3 mL). The mixture was stirred at 20 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove DCM and obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain the title compound. 1 HNMR (400MHz, DMSO-d6) δppm: 9.24 (s, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.41-7.37 (m, 1 H), 7.23 (d, J = 8.4Hz, 1H), 3.03 (s, 3H), 2.70-2.61 (m, 2H), 1.13 (t, J = 8.8Hz, 3H).

[0819] Intermediate 64

[0820]

[0821] N-(5-bromo-3-fluoro-2-methoxyphenyl)propane-1-sulfonamide: To a solution of 5-bromo-3-fluoro-2-methoxyaniline (200 mg, 909 μmol, 1 eq) in DCM (5 mL) was added propane-1-sulfonyl chloride (1.30 g, 9.09 mmol, 1.02 mL, 10 eq) and pyridine (719 mg, 9.09 mmol, 734 μL, 10 eq). The mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (SiO2, 0% to 10% ethyl acetate / petroleum) to give the title compound. 1H NMR (400MHz, CDCl3) δppm: 7.49 (t, J=2.0Hz, 1H), 7.03 (dd, J=2.4, 10.8Hz, 1H), 6.92 (s, 1H), 3.99 (d, J = 2.4Hz, 3H), 3.18-3.02 (m, 2H), 1.96-1.77 (m, 2H), 1.05 (t, J = 7.2Hz, 3H).

[0822] Intermediate 65

[0823]

[0824] 5-bromo-3,6-difluoropyridine-2-amine: NBS (124.50 mg, 699.49 μmol, 0.7 eq.) was added to a mixture of 3,6-difluoropyridine-2-amine (130 mg, 999.27 μmol, 1 eq.) in MeCN (15 mL). The mixture was stirred at 25 °C in the dark for 30 min, and then a solution of additional NBS (124.50 mg, 699.49 μmol, 0.7 eq.) in MeCN (5 mL) was added. The mixture was stirred at 25 °C in the dark under N2 atmosphere for another 12 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to obtain the title compound. 1 H NMR (400MHz, CDCl3) δppm 7.58-7.34 (m, 1H), 4.98-4.37 (m, 2H).

[0825] 3,6-Difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine: To a mixture of 5-bromo-3,6-difluoropyridin-2-amine (140 mg, 602.90 μmol, 1 eq), B2Pin2 (459.29 mg, 1.81 mmol, 3 eq) and KOAc (177.50 mg, 1.81 mmol, 3 eq) in dioxane (10 mL) was added Pd(dppf)Cl2 (44.11 mg, 60.29 μmol, 0.1 eq). The mixture was degassed and purged with N2 for 3 times, and then it was stirred at 100° C. under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, 0-30% EtOAc / petroleum ether) to give the title compound. 1 H NMR (400MHz, CDCl3) δppm7.63-7.55(m,1H),4.89(s,2H),1.33(s,12H).

[0826] Intermediate 66

[0827]

[0828] 5-(tert-Butylsulfonyl)-3-(2,6-difluoropyridin-3-yl)pyrazolo[1,5-a]pyridine and 5-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)pyrazolo[1,5-a]pyridine: 3-Bromo-5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridine (0.200 g, 0.631 mmol, 1 equivalent, prepared as described in U.S. Published Application No. US2018 / 0072717, the application A stirred solution of 1,4-dioxane (1.6 mL) and a 1.6:1.0 mixture of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.226 g, 0.946 mmol, 1.2 eq) was purged with N. Bis(triphenylphosphine)palladium(II) dichloride (0.046 g, 0.063 mmol, 0.1 eq), sodium carbonate (0.133 g, 1.26 mmol, 2.0 eq) and water (0.4 mL) were added to the reaction mixture. The reaction mixture was stirred for 1h at 100 ℃, then diluted with water (10mL) and extracted with EtOAc (2x15mL). The organic layer merged was dried over anhydrous MgSO and concentrated under reduced pressure. 5-15% ethyl acetate / petroleum ether was used as eluent to purify the crude product by silica gel (100-200 mesh) flash column chromatography to obtain a mixture of positional isomers 5-(tert-butylsulfonyl)-3-(2,6-difluoropyridine-4-yl)pyrazolo[1,5-a]pyridine and 5-(tert-butylsulfonyl)-3-(2,6-difluoropyridine-3-yl)pyrazolo[1,5-a]pyridine in a 3:1 ratio.

[0829] Intermediate 67

[0830]

[0831] 6-(tert-Butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine: In the first batch, 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (612 mg, 2.54 mmol), 6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine (1.00 g, 1.95 mmol, prepared as described in ACS Med. Chem. Lett. 2017, 8, 1048, which is incorporated herein by reference in its entirety) and aqueous sodium carbonate (2.9 mL, 2M, 5.86 mmol) were combined in a mixture of ethanol (9 mL) and 1,4-dioxane (9 mL), and argon was bubbled through the mixture for 2 min. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (160 mg, 195 μmol) was added. The mixture was stirred in a microwave oven at 100 °C for 60 min. The second batch was carried out in the same manner, but using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (120 mg, 146 μmol). The two mixtures were combined and filtered through a celite pad. Water and saturated aqueous sodium chloride solution were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were filtered, concentrated, and purified by flash chromatography (silica gel, hexane / ethyl acetate / ethanol gradient) to give the title compound. [M+H] + =382.6. 1 H NMR (400MHz, DMSO-d6) δppm 8.89 (s, 1H), 8.18 (s, 1H), 7.48 (s, 2H), 7.37 (s, 1H), 3.96 (s, 3H), 1.33 (s, 9H).

[0832] Exemplary compounds of formula (I)

[0833] Example 1

[0834]

[0835] 6-(tert-Butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)imidazo[1,2-a]pyridine: 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (430 mg, 1.78 mmol), 6-(tert-butylsulfonyl)-3-iodoimidazo[1,2-a]pyridine (500 mg, 1.37 mmol) and sodium carbonate (437 mg, 4.12 mmol) were combined in a mixture of ethanol (4 mL), 1,4-dioxane (4 mL) and water (2 mL), and argon was bubbled through the mixture for 3 min. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (112 mg, 137 μmol) was added, and argon was bubbled through the mixture for another 2 min. The mixture was stirred in a microwave oven at 100° C. for 90 min. The mixture was filtered and concentrated, and the crude product was purified by flash chromatography (silica gel, dichloromethane / ethanol gradient) to give the title compound. [M+H] + =352.4. 1 H NMR(400MHz,DMSO-d6)δppm 8.95(dd,J=1.6,0.9Hz,1H),8.31(s,1H),7.93(dd,J=9.4,0.8Hz,1H),7.66(dd,J=9.4,1.8Hz,1H),7.56(s,2H),1.33(s,9H).

[0836] Example 2

[0837]

[0838] 3-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: A mixture of 5-bromo-3-fluoro-2-methoxyaniline (240 mg, 1.09 mmol, 1 eq.), B2Pin2 (831 mg, 3.27 mmol, 3 eq.), KOAc (321 mg, 3.27 mmol, 3 eq.) and Pd(dppf)Cl2 (80 mg, 109 μmol, 0.1 eq.) in 1,4-dioxane (3 mL) was degassed and purged three times with N2, and then the mixture was stirred at 100° C. under N2 for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (petroleum ether / EtOAc=100 / 1 to 3 / 1) to provide the title compound. [M+H] + =268.3.1 H NMR (400MHz, DMSO-d6) δppm6.87(s,1H),6.58-6.51(m,1H),5.19(s,2H),3.75(s,3H),1.26(s,12H).

[0839] 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyaniline: 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (150 mg, 505 μmol, 1 equivalent), 6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a ] A mixture of pyridine (332 mg, 758 μmol, 1.5 eq.), K2CO3 (210 mg, 1.52 mmol, 3 eq.), Pd(dppf)Cl2 (37 mg, 51 μmol, 0.1 eq.) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was degassed and purged three times with N2, and the mixture was then stirred at 90 ° C under N2 for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue that was purified by preparative HPLC to obtain the title compound. [M+H] + =408.0. 1 H NMR (400MHz, DMSO-d6) δppm 8.69(s,1H),7.64(s,1H),7.24(s,1H),6.67-6.60(m,2H),5.54(s,2H),3.92(s,3H),3.81(s,3H),1.31(s,9H).

[0840] The following compounds were prepared following procedures similar to those described for Example 1 and Example 2.

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877] Embodiment 159

[0878]

[0879] 6-(tert-Butylsulfonyl)-3-(2-chloro-5-methylpyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine: 4-Bromo-2-chloro-5-methylpyridine (157 mg, 0.761 mmol) was dissolved in dioxane (4 mL). Bis(triphenylphosphine)palladium(II) dichloride (53.4 mg, 76.1 μmol) and 1,1,1,2,2,2-hexamethyldistanane (333 μL, 1.60 mmol) were added and the mixture was heated to 100 °C for 0.5 h. 6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine (300 mg, 761 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (62.1 mg, 76.1 μmol) were added and the mixture was heated to 100 °C for 12 h. The mixture was diluted with EtOAc and brine. The organic phase was separated and dried. The residue was purified by silica gel flash column chromatography using CH2Cl2 / EtOH as eluent to obtain the title compound. [M+H] + =394.4. 1 H NMR (400MHz, DMSO-d6) δppm 8.49(s,1H),8.42(s,1H),7.91(s,1H),7.67(s,1H),7.34(s,1H),3.95(s,3H),2.24(s,3H),1.31(s,9H).

[0880] The following compounds were prepared following procedures similar to that described for Example 159.

[0881]

[0882]

[0883]

[0884] Embodiment 165

[0885]

[0886] Tert-butyl (4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate: 6-(tert-butylsulfonyl)-3-iodo-7-methoxyimidazo[1,2-a]pyridine (117 mg, 267 μmol, 0.7 equivalent), (4-methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol ... A mixture of tert-butyl thiazol-2-yl)carbamate (170 mg, 381 μmol, 1 eq), K PO (243 mg, 1.14 mmol, 3 eq) and Pd(dppf)Cl (27.9 mg, 38.1 μmol, 0.1 eq) in 1,4-dioxane (4 mL) and H O (1 mL) was degassed and purged three times with N, and then the mixture was stirred at 80° C. under N atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.

[0887] 4-(6-(tert-Butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)thiazol-2-amine: A mixture of tert-butyl (4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (220 mg, 375 μmol, 1 eq) in TFA (10 mL) was stirred at 70 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue that was purified by RP-HPLC to give the title compound. [M+H] + =367.0. 1 H NMR (400MHz, DMSO-d6) δppm 9.65 (s, 1H), 8.21 (s, 0.14H), 7.89 (s, 1H), 7.21 (d, J = 3.2Hz, 3H), 6.94 (s, 1H), 3.92 (s, 3H), 1.32 (s, 9H).

[0888] The following compounds were prepared following procedures similar to that described for Example 165.

[0889]

[0890] Embodiment 168

[0891]

[0892] 4-(6-(tert-Butylsulfonyl)imidazo[1,2-a]pyridin-3-yl)-6-fluoro-N-(4-methoxybenzyl)pyridin-2-amine: 6-(tert-Butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)imidazo[1,2-a]pyridine (180 mg, 92 wt%, 1 eq, 471 μmol) and (4-methoxyphenyl)methanamine (129 mg, 123 μL, 2 eq, 943 μmol) were dissolved in 2-propanol (4.6 mL). DIPEA (91.4 mg, 123 μL, 1.5 eq, 707 μmol) was added and the resulting mixture was heated to 120 °C for 2 h. The solvent was evaporated. A partial amount of the residue was dissolved in DMSO (2 mL) and submitted to HPLC purification (basic method) to give the title compound. [M+H] + =469.4. 1 H NMR (400MHz, DMSO-d6) δppm 8.82 (dd, J=1.8, 0.8Hz, 1H), 8.09 (s, 1H), 7.88 (dd, J=9.4, 0.8Hz, 1H), 7.78 (br t,J=5.7Hz,1H),7.58(dd,J=9.4,1.8Hz,1H),7.29(d,J=8.6Hz,2H),6.84-6.94(m ,2H),6.63(s,1H),6.46(s,1H),4.40(d,J=5.8Hz,2H),3.72(s,3H),1.32(s,9H).

[0893] Examples 169 and 170

[0894]

[0895] 4-((4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)butan-2-ol: 6-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine (110 mg, 98% weight, 1 eq, 280 μmol) and 4-aminobutan-2-ol (52.4 mg, 56 μL, 2.1 eq, 588 μmol) were dissolved in 2-propanol (4 mL) and DIPEA (54.2 mg, 73.1 μL, 1.5 eq, 420 μmol) was added. The vial was sealed and heated to 120 °C for 4 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was redissolved in DMSO (2.5 mL) and submitted to HPLC purification on a chiral stationary column to give two resolved enantiomers of arbitrarily specified stereochemistry.

[0896] (R)-4-((4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)butan-2-ol[M+H] + =451.5. 1 H NMR(400MHz,DMSO-d6)δppm 8.81(s,1H),7.92(s,1H),7.31(s,1H),7.21(br s,1H),6.50(s,1H),6.35(s,1H),4.50(d,J=4.8Hz,1H),3.94(s,3H),3.66-3.75( m,1H),3.19-3.30(m,2H),1.51-1.67(m,2H),1.32(s,9H),1.09(d,J=6.1Hz,3H).

[0897] (S)-4-((4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)butan-2-ol[M+H] + =451.5. 1 H NMR(400MHz,DMSO-d6)δppm 8.81(s,1H),7.92(s,1H),7.31(s,1H),7.14-7.27(m,1H),6.50(s,1H),6.35(s,1H),4.50(d,J=4.8Hz,1H) ,3.94(s,3H),3.64-3.76(m,1H),3.20-3.30(m,2H),1.54-1.69(m,2H),1.32(s,9H),1.09(d,J=6.1Hz,4H).

[0898] The following compounds were prepared following procedures similar to those described for Examples 168, 169 and 170.

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920] Embodiment 253

[0921]

[0922] N-(2-amino-5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)pyridin-3-yl)-N-(propylsulfonyl)propane-1-sulfonamide: To a solution of 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)pyridine-2,3-diamine (50 mg, 106.54 μmol, 1 eq) and propane-1-sulfonyl chloride (75.97 mg, 532.70 μmol, 59.82 μL, 5 eq) in DCM (3 mL) was added Et3N (53.90 mg, 532.70 μmol, 74.15 μL, 5 eq). The mixture was stirred at 25 °C for 4 h, then it was filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.

[0923] N-(2-amino-5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)pyridin-3-yl)propane-1-sulfonamide: To a solution of N-(2-amino-5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)pyridin-3-yl)-N-(propylsulfonyl)propane-1-sulfonamide (70 mg, 119.10, crude purity, 1 eq) in THF (2 mL) was added TBAF (1 M, 476.41 μL, 4 eq). The mixture was stirred at 25 °C for 4 h, then the mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by RP-HPLC to give the title compound. [M+H] + =482.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.55(s,1H),8.04-7.86(m,1H),7.62(s,1H),7.56(d,J=2.0Hz,1H),7.25-7.20(m,1H),6.34-6.1 3(m,2H),3.92(s,3H),3.08-3.03(m,2H),1.76-1.65(m,2H),1.31(s,9H),0.96(t,J=5.2Hz,3H).

[0924] The following compounds were prepared following procedures similar to that described for Example 253.

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935] Examples 296 and 297

[0936]

[0937] 3-((4-(5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)propan-1-ol (Example 296) and 3-((5-(5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)propan-1-ol (Example 297): 5-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)pyrazolo[1,5-a To a stirred solution of a 3:1 mixture of 5-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-3-yl)pyrazolo[1,5-a]pyridine (0.160 g, 0.455 mmol, 1 eq) in acetonitrile (1.6 mL) was added anhydrous potassium carbonate (0.157 g, 1.14 mmol, 2.5 eq) followed by 3-aminopropan-1-ol (0.376 g, 0.501 mmol, 1.1 eq) at room temperature. The reaction mixture was stirred at 90 ° C for 2 h, then it was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous MgSO and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (100-200 mesh) eluting with 60-80% ethyl acetate / petroleum ether to give a mixture of positional isomers, which was then subjected to achiral SFC purification to give Example 296 and Example 297.

[0938] Example 296: [M+H] + =407.41. 1 H NMR (400MHz, DMSO-d6) δ9.02(d,J=7.2Hz,1H),8.70(s,1H),8.26(d,J=0.8Hz,1H),7.27(dd,J=7.2,5.6Hz,1H),7.17(br s,1H),6.63(s,1H),6.46(s,1H),4.49(t,J=5.2Hz,1H),3.50(q,J=5.2Hz,2H),3.28(m,2H),1.70(t,J=2Hz,2H),1.34(s,9H).

[0939] Example 297: [M+H] + =407.41. 1H NMR (400MHz, DMSO-d6) δ8.98(d,J=8.0Hz,1H),8.30(s,1H),7.77(s,1H),7.56(t,J=8.4Hz,1H),7.20(dd,J=7.2,2.0Hz 1H),6.33(s,1H),6.27(dd,J=8.0,2.8Hz 1H),4.38(t,J=5.2Hz,1H),3.41(q,J=6Hz,2H),3.25(m,2H),1.65(m,2H),1.30(s,9H),1.17(t,J=7.2Hz,1H)

[0940] Examples 298, 299 and 300

[0941]

[0942] 4-(5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridin-3-yl)-6-fluoropyridin-2-amine (Example 298), 3-(5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridin-3-yl)-6-fluoropyridin-2-amine (Example 299), 5-(5-(tert-butylsulfonyl)pyrazolo[1,5-a]pyridin-3-yl)-6-fluoropyridin-2-amine (Example 300): 5-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)pyrazolo[1,5-a]pyridine and 5-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-3-yl)pyrazolo[1,5-a]pyridine (60 mg, 0.171 mmol, 1 equiv) and 25% A 3:1 mixture of NH3 in H2O was combined in a steel reactor. The reaction mixture was stirred at 110°C for 15h and then concentrated under reduced pressure. The crude residue was purified by flash chromatography on neutral alumina eluting with 50-60% EtOAc / petroleum ether. The material was then further purified by achiral SFC to separate three positional isomers, namely:

[0943] Example 298 [M+H] + =349.32. 1 H NMR(400MHz,DMSO-d6)δ9.01(d,J=7.2Hz,1H),8.70(s,1H),8.26(d,J=0.8Hz,1H ),7.27(dd,J=7.2,2.0Hz,1H),6.61(s,2H),6.51(d,J=17.2Hz,2H),1.34(s,9H),

[0944] Example 299 [M+H] + =349.40. 1HNMR (400MHz, DMSO-d6) δ8.95(d,J=7.2Hz,1H),8.31(s,1H),7.84(d,J=0.8Hz,1H),7.57(t,J= 8.2Hz,1H),7.17(dd,J=7.2,2.0Hz,1H),6.31(dd,J=7.6,2.8Hz,1H),6.19(s,2H),1.30(s,9H),

[0945] Embodiment 300

[0946] Embodiment 301

[0947]

[0948] Tert-Butyl 4-(((4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)methyl)piperidine-1-carboxylate: 6-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine (200 mg, 97% wt, 1 eq, 509 μmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (236 mg, 233 μL, 97% wt, 2.1 eq, 1.07 mmol) were dissolved in 2-propanol (10 mL). DIPEA (98.6 mg, 133 μL, 1.5 eq, 763 μmol) was added and the resulting mixture was heated to 120 °C for 4 h. The solvent was evaporated and the residue was used without further purification.

[0949] 4-(6-(tert-Butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoro-N-(piperidin-4-ylmethyl)pyridin-2-amine: tert-Butyl 4-(((4-(6-(tert-Butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)methyl)piperidine-1-carboxylate (509 mg, 82% weight, 1 eq, 725 μmol) was dissolved in dioxane (10 mL) and hydrogen chloride (264 mg, 1.81 mL, 4 moles in dioxane, 10 eq, 7.25 mmol) was added dropwise. The mixture was stirred at room temperature for 16 h. The solvent and all volatiles were evaporated. A portion of the crude material was dissolved in DMSO (2 mL) and submitted to HPLC purification (basic method) to give the title compound. [M+H] + =476.4. 1H NMR(400MHz,DMSO-d6)δppm 8.81(s,1H),8.38(s,1H),7.92(s,1H),7.35-7.46(m,1H),7.31(s,1H),6.54(s,1H), 6.37(s,1H),3.94(s,3H),3.12-3.20(m,4H),2.67-2.75(m,2H),2.54(s,1H),1.79(br d,J=11.7Hz,2H),1.32(s,9H),1.16-1.29(m,2H).

[0950] Embodiment 302

[0951]

[0952] 6-(tert-Butylsulfonyl)-3-(2-fluoro-6-methoxypyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine: 6-(tert-Butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine (45 mg, 75% weight, 1 eq, 88.5 μmol) was dissolved in methanol (2 mL). Sodium methoxide (10.0 mg, 11.0 μL, 2.1 eq, 186 μmol) was added and the resulting mixture was heated to 70 °C for 16 h. The solvent was evaporated and the residue was dissolved in DMSO (2 mL) and submitted to HPLC purification to give the title compound. [M+H] + =394.4. 1 H NMR (400MHz, DMSO-d6) δppm 8.85 (s, 1H), 8.08 (s, 1H), 7.34 (s, 1H), 7.03 (dd, J = 1.9, 1.1Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 1.32 (s, 9H).

[0953] Embodiment 303

[0954]

[0955] 4-(6-(tert-Butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2(1H)-one: 6-(tert-Butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine (45 mg, 97% weight, 1 eq, 114 μmol) and sodium hydroxide (18 mg, 17 μL, 4 eq, 458 μmol) were dissolved in dioxane (1.2 mL) and water (0.6 mL) and heated to 120 °C for 16 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in DMSO (2 mL) and submitted to HPLC purification (basic method) to give the title compound. [M+H] + =380.4. 1 HNMR(400MHz,DMSO-d6)δppm 9.02(s,1H),8.28-8.40(m,1H),7.20(s,1H),6.44(br s,1H),6.12(br s,1H),3.89(s,3H),1.31(s,9H).

[0956] Embodiment 304

[0957]

[0958] N-(4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-yl)propane-1-sulfonamide: Propane-1-sulfonamide (19.0 mg, 1 eq, 154 μmol) and potassium tert-butoxide (17.3 mg, 1 eq, 154 μmol) were dissolved in DMF (2 mL) and stirred at room temperature for 20 min. 6-(tert-butylsulfonyl)-3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine (60 mg, 98% weight, 1 eq, 154 μmol) was added and the mixture was stirred at 80 °C for 4 h. The solvent was evaporated under reduced pressure and at elevated temperature. The residue was redissolved in DMSO (2 mL) and submitted to HPLC purification (basic method) to give the title compound. [M+H] + =485.3. 1 H NMR(400MHz,DMSO-d6)δppm10.98(br s,1H),9.12(s,1H),8.60(s,1H),7.44(s,1H),7.26(s,1H),7.21(s,1H),3.92(s,3 H), 3.40-3.52 (m, 2H), 1.74 (sxt, J = 7.5Hz, 2H), 1.32 (s, 9H), 0.98 (t, J = 7.4Hz, 3H).

[0959] Embodiment 305

[0960]

[0961] 3-(3-Bromo-5-fluoro-4-methoxyphenyl)-6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine: To a solution of 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyaniline (20 mg, 39.3 μmol, 1 eq) in HBr (0.1 mL) was added HO (1 mL). The mixture was cooled to 0°C, and an ice-cold solution of NaNO (2.71 mg, 39.3 μmol, 1 eq) in HO (1 mL) was added dropwise. CuBr (11.3 mg, 79 μmol, 2.39 μL, 2 eq) was added to the mixture, and the resulting mixture was stirred at 70°C for 1 h. The mixture was diluted with water (50 mL), extracted with DCM (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give the title compound. [M+H] + =472.9. 1 H NMR (400MHz, DMSO-d6) δppm: 8.67 (s, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 7.67 (d, J = 11.6Hz, 1H), 7.27 (s, 1H), 3.97-3.90 (m, 6H), 1.32 (s, 9H).

[0962] Embodiment 306

[0963]

[0964] 2-(2-Bromo-4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluorophenoxy)ethan-1-ol: A solution of 2-(2-amino-4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluorophenoxy)ethan-1-ol (20 mg, 41.1 μmol, 1 eq) in HBr (0.2 mL) was cooled to 0°C. A cooled solution of NaNO2 (2.84 mg, 41.14 μmol, 1 eq) in H2O (0.5 mL) was added dropwise over 0.2 h, and then CuBr (2.51 μL, 82.3 μmol, 2 eq) was added to the mixture. The resulting mixture was stirred at 0°C for 1 h. The reaction mixture was quenched by adding saturated NaHCO (10 mL), then diluted with water (20 mL) and extracted with DCM / MeOH (60 mL). The combined organic layers were dried over NaSO, filtered and concentrated in vacuo. The resulting crude material was purified via preparative RP-HPLC (neutral conditions) to give the title compound. LCMS [M+H] + =503.0. 1 H NMR(400MHz,DMSO-d6)δppm 8.67(s,1H),7.81(s,1H),7.74(s,1H),7.66(d,J=12.0Hz,1H),7.27(s,1H),4.89(t ,J=5.2Hz,1H),4.16(t,J=4.8Hz,2H),3.94(s,3H),3.78-3.73(m,2H),1.32(s,9H).

[0965] Embodiment 307

[0966]

[0967] (R)-1-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyphenyl)-3-hydroxypyrrolidin-2-one: 3-(3-bromo-5-fluoro-4-methoxyphenyl)-6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine (50 mg, 95 μmol, 1 equivalent), (R)-3-hydroxy-1λ2-pyrrolidin-2-one (48 mg, 477 μmol, 5 equivalents), BrettPhos Pd A mixture of G3 (8.65 mg, 9.55 μmol, 0.1 eq.), Cs2CO3 (93.3 mg, 286 μmol, 3 eq.) in 1,4-dioxane (2 mL) was degassed and purged three times with N2, and the mixture was then stirred at 100 ° C under N2 for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue that was purified by preparative HPLC to obtain the title compound. [M+H] + =492.1. 1 H NMR(400MHz,DMSO-d6)δppm:8.69(s,1H),8.46(br s,0.6H),7.76(s,1H),7.63-7.54(m,1H),7.42(s,1H),7.27(s,1H),5.85-5.73(m,1H),4.37-4.24(m, 1H),3.93(s,3H),3.90(s,3H),3.72-3.66(m,2H),2.45-2.40(m,1H),1.99-1.89(m,1H),1.32(s,9H).

[0968] Embodiment 308

[0969]

[0970]

[0136] tert-Butyl (2-((5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyphenyl)amino)ethyl)carbamate: To a solution of tert-butyl (2-aminoethyl)carbamate (76.5 mg, 477 μmol, 75.3 μL, 5 equiv), Cs2CO3 (93.3 mg, 286 μmol, 3 equiv), PEPPSI IHPET-Cl (9.29 mg, 9.6 μmol, 0.1 equiv) in 1,4-dioxane (1 mL) was added 3-(3-bromo-5-fluoro-4-methoxyphenyl)-6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine. The mixture was stirred at 100 °C under N2 for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the title compound. [M+H] + =551.0. 1 H NMR(400MHz,DMSO-d6)δppm:8.75(s,1H),7.71(s,1H),7.25(s,1H),7.01-6.92(m,1H),6. 72-6.64(m,2H),5.83-5.76(m,1H),3.93(s,3H),3.82(s,3H),3.14(s,4H),1.32(s,18H).

[0971] Embodiment 309

[0972]

[0973] 3-({4-[7-methoxy-6-(2-methylpropane-2-sulfonyl)imidazo[1,2-a]pyridin-3-yl]-5-methylpyridin-2-yl}amino)propan-1-ol: 6-(tert-butylsulfonyl)-3-(2-chloro-5-methylpyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine (70.0 mg, 178 μmol), cesium carbonate (116 mg, 355 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20.6 mg, 35.5 μmol) and tris(dibenzylideneacetone)dipalladium (16.3 mg, 17.8 μmol) were combined in toluene (3.0 mL). 3-Aminopropan-1-ol (40.0 mg, 533 μmol) was added and the mixture was stirred at 100 °C under argon for 6 h. Brine was added to the mixture and the aqueous layer was extracted with EtOAc. The combined organics were dried and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound. [M+H] + =433.5. 1H NMR (400MHz, DMSO-d6) δppm8.30(s,1H),8.02(s,1H),7.72(s,1H),7.28-7.33(m,1H),6.53(t,J=5.70Hz,1H),6.48(s,1H),4 .49(t,J=5.20Hz,1H),3.91-3.96(m,3H),3.44-3.50(m,2H),3.21-3.30(m,2H),1.96(s,3H),1.62-1.75(m,2H),1.30(s,9H).

[0974] The following compounds were prepared following procedures similar to those described for Example 309.

[0975]

[0976]

[0977] Embodiment 313

[0978]

[0979] N-(6-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-(trifluoromethoxy)pyridin-2-yl)propane-1-sulfonamide: 6-(tert-butylsulfonyl)-3-(6-chloro-5-(trifluoromethoxy)pyridin-2-yl)-7-methoxyimidazo[1,2-a]pyridine (50 mg, 97.0 μmol, 1 equivalent), propane-1-sulfonamide (36 mg, A mixture of (291 μmol, 3 equivalents), Pd(OAc)2 (2.18 mg, 9.70 μmol, 0.1 equivalent), Xantphos (11.2 mg, 19.4 μmol, 0.2 equivalent) and Cs2CO3 (94.8 mg, 291 μmol, 3 equivalents) in dioxane (3 mL) was degassed and purged three times with N2, and then the mixture was stirred at 100 ° C under N2 for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by preparative HPLC to obtain the title compound. [M+H] + =551.0. 1H NMR: (400MHz, DMSO-d6) δppm: 10.78(s,1H),9.79(s,1H),8.38(s,1H),7.97-7.90(m,1H),7.82-7.70(m, 1H),7.35(s,1H),3.95(s,3H),3.55-3.46(m,2H),1.82-1.72(m,2H),1.33(s,9H),0.95(t,J=7.6Hz,3H).

[0980] The following compounds were prepared following procedures similar to that described for Example 313.

[0981]

[0982] Embodiment 315

[0983]

[0984] Tert-butyl(3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridin-6-yl)(imino)-λ 6 -Thiolanone: 6-(tert-butylthio)-3-(2,6-difluoropyridin-4-yl)-7-methoxyimidazo[1,2-a]pyridine (100 mg, 1 eq., 286 μmol) was dissolved in methanol (5 mL). Ammonia (12 eq.) and iodophenyldiacetic acid (PIDA) (461 mg, 5 eq., 1.43 mmol) in methanol were added, and the mixture was stirred at 40 °C for 16 h. Water was added, and the aqueous phase was extracted twice with EtOAc and CH2Cl2. The combined organic phases were dried, and the solvent was evaporated. The residue was dissolved in DMSO (2 mL) and submitted to HPLC purification to obtain the title compound. [M+H] + =381.4. 1 H NMR (400MHz, DMSO-d6) δppm9.00(s,1H),8.20(s,1H),7.52(s,2H),7.30(s,1H),4.53(s,1H),3.94(s,3H),1.31(s,9H).

[0985] The following compounds were prepared following procedures similar to that described for Example 315.

[0986]

[0987] Embodiment 317

[0988]

[0989] 1-(4-(((4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-yl)amino)methyl)piperidin-1-yl)ethan-1-one: 4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-fluoro-N-(piperidin-4-ylmethyl)pyridin-2-amine hydrochloride (290 mg, 1 eq, 566 μmol) was dissolved in CH2Cl2 (10 mL). Acetic anhydride (72 mg, 66.8 μL, 1.25 eq 708 μmol) and DIPEA (220 mg, 292 μL, 3 eq, 1.70 mmol) were added and the resulting mixture was stirred at room temperature for 22 h. The solvent was evaporated. The residue was dissolved in DMSO (2 mL) and submitted to HPLC purification (basic method) to give the title compound. [M+H] + =518.5. 1 H NMR(400MHz,DMSO-d6)δppm 8.81(s,1H),7.92(s,1H),7.32-7.42(m,1H),7.31(s,1H),6.54(s,1H),6.36(s,1H),4.32-4.43(m,1H),3.94(s,3H),3.81(br d,J=13.7Hz,1H),3.13(br s,2H),2.93-3.04(m,1H),2.47(br s,1H),1.98(s,3H),1.66-1.88(m,3H),1.32(s,9H),0.91-1.19(m,2H).

[0990] The following compounds were prepared following procedures similar to that described for Example 317.

[0991]

[0992] Embodiment 319

[0993]

[0994] 3-((5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyphenyl)amino)propan-1-ol: To a solution of 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyaniline (50 mg, 98 μmol, 1 eq) in DMF (1 mL) was added 3-bromopropan-1-ol (68 mg, 491 μmol, 44.4 μL, 5 eq), K3PO4 (63 mg, 295 μmol, 3 eq) and KI (49 mg, 295 μmol, 3 eq). The mixture was stirred at 80 °C for 5 h. The mixture was filtered to give a residue, which was purified by preparative HPLC to give the title compound. [M+H] + =466.1. 1 H NMR (400MHz, DMSO-d6) δppm: 8.76 (s, 1H), 7.70 (s, 1H), 7.24 (s, 1H), 6.68-6.58 (m, 2H), 5.75 (t, J = 5.6Hz, 1H), 4.51 (t,J=4.8Hz,1H),3.92(s,3H),3.82(s,3H),3.52-3.45(m,2H),3.21-3.13(m,2H),1.76-1.68(m,2H),1.32(s,9H).

[0995] Embodiment 320

[0996]

[0997] N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)aniline was prepared according to a procedure similar to that described for Example 319.

[0998] 3-((3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)phenyl)amino)propan-1-ol: To a solution of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)aniline (60 mg, 113 μmol, 1 eq) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at 25 °C under N2 for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by preparative HPLC to give the title compound. [M+H] + =418.2. 1H NMR (400MHz, DMSO-d6) δppm:8.77(s,1H),7.67(s,1H),7.29-7.19(m,2H),6.75-6.61(m,3H),5.92-5.81(m,1H),4.47(br s,1H),3.93(s,3H),3.55-3.46(m,2H),3.14-3.04(m,2H),1.76-1.66(m,2H),1.31(s,9H).

[0999] The following compounds were prepared following procedures similar to that described for Example 320.

[1000]

[1001] Embodiment 322

[1002]

[1003] N-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-2-methoxy-3-methylaniline: A mixture of 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-2-methoxy-3-methylaniline (50 mg, 111 μmol, 1 eq), 3-((tert-butyldimethylsilyl)oxy)propanal (42 mg, 223 μmol, 2 eq) and NaBH(OAc)3 (14.0 mg, 223 μmol, 2 eq) in MeOH (8 mL) was degassed and purged three times with N2, and then the mixture was stirred at 25°C under N2 for 12 h. The mixture was concentrated and then water (10 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, DCM / MeOH=100 / 0 to 9 / 1) to give the title compound.

[1004] 3-((5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-2-methoxy-3-methylphenyl)amino)propan-1-ol: To a solution of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-2-methoxy-3-methylaniline (60 mg, 93.8 μmol, 1 eq) in THF (12 mL) was added TBAF (1 M, 281 μL, 3 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give the title compound. [M+H] + =462.1. 1 H NMR(400MHz,DMSO-d6)δppm:8.77(s,1H),7.65(s,1H),7.24(s,1H),6.63(s,1H),6.58(s,1H),5.43-5.40(m,1H),4.56-4 .45(s,1H),3.93(s,3H),3.68(s,3H),3.51-3.46(m,2H),3.18-3.11(m,2H),2.23(s,3H),1.77-1.67(m,2H),1.32(s,9H).

[1005] Embodiment 323

[1006]

[1007] 3-(4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1H-pyrazol-1-yl)propan-1-ol: To a solution of 6-(tert-butylsulfonyl)-7-methoxy-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (50 mg, 135 μmol, 1 eq) in DMF (10 mL) was added CsCO (43.9 mg, 135 μmol, 1 eq) and then 3-bromopropan-1-ol (18.7 mg, 135 μmol, 12.2 μL, 1 eq). The mixture was stirred at 60 °C under N for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound. [M+H] + =393.1. 1H NMR(400MHz,DMSO-d6)δppm:8.53(s,1H),8.15(s,1H),7.79(s,1H),7.63(s,1H),7.23(s,1H),4.6 6-4.61(m,1H),4.32-4.23(m,2H),3.92(s,3H),3.47-3.39(m,2H),2.02-1.92(m,2H),1.31(s,9H).

[1008] Embodiment 324

[1009]

[1010] 2-(4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1H-pyrazol-1-yl)ethan-1-ol: A mixture of 6-(tert-butylsulfonyl)-7-methoxy-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (70 mg, 188.40 μmol, 1 eq) and KCO (78.11 mg, 565.20 μmol, 3 eq) in DMF (10 mL) was degassed and purged with N (3x). 2-Iodoethanol (29.45 μL, 376.80 μmol, 2 eq) was added, and the reaction mixture was stirred at 80 °C under N atmosphere for 12 h. The reaction mixture was filtered and concentrated in vacuo. The resulting crude material was purified via preparative RP-HPLC (neutral conditions) to give the title compound. LCMS [M+H] + =379.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.56(s,1H),8.12(s,1H),7.80(s,1H),7.63(s,1H),7.23(s,1H),5.03-4. 88(m,1H),4.28-4.22(m,2H),3.92(s,3H),3.82-3.77(m,2H),1.31(s,9H).

[1011] Embodiment 325

[1012]

[1013] N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-methoxy-2-methylphenyl)-N-methylpropane-1-sulfonamide: N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-methoxy-2-methylphenyl)propane-1-sulfonamide (20.0 mg, 39.2 μmol), iodomethane (7.62 μL, 118 μmol) and potassium carbonate (10.9 mg, 78.5 μmol) were combined in DMF (2.0 mL). DMAP (479 μg, 3.92 μmol) was added and the mixture was stirred at 50 °C for 20 h. The mixture was concentrated under reduced pressure. The crude was purified by high throughput preparative HPLC using an acidic method to give the title compound. [M+H] + =524.2. 1 H NMR(400MHz,DMSO-d6)δppm 8.76(s,1H),7.83(s,1H),7.29-7.34(m,1H),7.28(s,1H),7.25–7.23(m,1H),3.94(s,3H),3.86(s, 3H), 3.16-3.20 (m, 5H), 2.19 (s, 3H), 1.70-1.82 (m, 2H), 1.29-1.33 (m, 9H), 1.01 (t, J = 7.48Hz, 3H).

[1014] Embodiment 326

[1015]

[1016] 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-2,3-dimethoxy-N-methylaniline: To a solution of 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-2,3-dimethoxyaniline (40 mg, 86 μmol, 1 eq) and pyridine (23.8 mg, 300 μmol, 24.2 μL, 3.5 eq) in 1,4-dioxane (2 mL) was added Cu(OAc)2 (39 mg, 215 μmol, 2.5 eq) and MeB(OH)2 (12.8 mg, 215 μmol, 2.5 eq). The mixture was stirred at 100 °C under air atmosphere for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound. [M+H] + =434.1. 1HNMR(400MHz,DMSO-d6)δppm:8.91(s,1H),8.30-8.10(m,1H),7.37-6.95(m,1H),6.53(s,1H),6.39( s,1H),5.57-5.50(m,1H),3.93(s,3H),3.79(s,3H),3.70(s,3H),2.71(d,J=4.8Hz,3H),1.32(s,9H).

[1017] Embodiment 327

[1018]

[1019] 3-((4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-chloropyridin-2-yl)amino)propan-1-ol: To a mixture of tert-butyl (3-((tert-butoxycarbonyl)oxy)propyl)(4-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-6-chloropyridin-2-yl)carbamate (76.0 mg, 116 μmol) in 1,4-dioxane (1160 μL) was added hydrochloric acid (4M, 1.16 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by high throughput preparative HPLC using a basic method, followed by preparative HPLC using an acidic method and flash chromatography (silica gel, DCM / ethanol gradient) to give the title compound. [M+H] + =453.5. 1 H NMR(400MHz,DMSO-d6)δppm 8.79(s,1H),7.93(s,1H),7.30(s,1H),7.25(br t,J=5.32Hz,1H),6.75(d,J=1.01Hz,1H),6.58(d,J=1.01Hz,1H),4.49(t,J=5.20Hz,1H),3 .94(s,3H),3.45-3.52(m,2H),3.25-3.32(m,2H),1.70(quin,J=6.65Hz,2H),1.32(s,9H).

[1020] The following compound was prepared by a procedure similar to that described for Example 327

[1021]

[1022] Embodiment 330

[1023]

[1024] 4-(6-(tert-Butylsulfonyl)imidazo[1,2-a]pyridin-3-yl)-6-fluoropyridin-2-amine: 4-(6-(tert-Butylsulfonyl)imidazo[1,2-a]pyridin-3-yl)-6-fluoro-N-(4-methoxybenzyl)pyridin-2-amine (280 mg, 87% weight, 1 eq, 520 μmol) was dissolved in CH2Cl2 (8 mL). Trifluoroacetic acid (1.96 g, 1.31 mL, 33 eq, 17.2 mmol) was added dropwise and the mixture was stirred at room temperature for 3 h. The mixture was diluted with additional CH2Cl2 and then washed with saturated aqueous NaHCO3. The organic phase was dried and evaporated. The residue was dissolved in DMSO (2 mL) and submitted to HPLC purification to give the title compound. [M+H] + =349.4. 1 H NMR(400MHz,DMSO-d6)δppm 8.75-8.84(m,1H),8.09(s,1H),7.88(dd,J=9.4,0.8Hz,1H),7.58(dd,J=9.4,1.8Hz,1H),6.70(s,2H),6.53(s,1H),6.45(s,1H),1.33(s,9H).

[1025] Embodiment 331

[1026]

[1027] 6-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-ethylpyridin-2-amine: To a solution of 6-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(2,4-dimethoxybenzyl)-3-ethylpyridin-2-amine (100 mg, 167 μmol, 1 eq) in DCM (5 mL) was added TFA (1.78 g, 15.6 mmol, 1.15 mL). The mixture was stirred at 25 °C under N2 for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound. [M+H] + =388.9. 1H NMR (400MHz, DMSO-d6) δppm: 10.34 (s, 1H), 8.14 (s, 1H), 7.38 (d, J = 7.6Hz, 1H), 7.24 (s, 1H), 7.12 ( d,J=7.6Hz,1H),5.54(s,2H),3.93(s,3H),2.49-2.45(m,2H),1.34(s,9H),1.17(t,J=7.2Hz,3H).

[1028] The following compounds were prepared following procedures similar to those described for Example 331.

[1029]

[1030] Embodiment 334

[1031]

[1032] 6-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(2,4-dimethoxybenzyl)-3-(trifluoromethoxy)pyridin-2-amine: 6-(tert-butylsulfonyl)-3-(6-chloro-5-(trifluoromethoxy)pyridin-2-yl)-7-methoxyimidazo[1,2-a]pyridine (55 mg, 107 μmol, 1 equivalent), DMBNH2 (178.43 mg, 1. A mixture of 4-(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2- 1H NMR (400MHz, DMSO-d6) δppm: 10.40 (s, 1H), 8.32 (s, 1H), 7.62 (dd, J = 1.6, 8.4Hz, 1H), 7.29 (s, 1H), 7.17 (d, J = 8.4Hz, 1H), 7.10 (d, J = 8.4Hz, 1H), 6. 83(t,J=5.6Hz,1H),6.50(d,J=2.4Hz,1H),6.42(dd,J=2.4,8.0Hz,1H),4 .64(d,J=5.2Hz,2H),3.93(s,3H),3.73(s,3H),3.71(s,3H),1.21(s,9H).

[1033] 6-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-(trifluoromethoxy)pyridin-2-amine: To a solution of 6-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(2,4-dimethoxybenzyl)-3-(trifluoromethoxy)pyridin-2-amine (55 mg, 83 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL). The mixture was stirred at 20 °C for 2 h. The mixture was evaporated on a water bath under reduced pressure. The residue was dissolved in MeOH (1.5 mL) and the pH was adjusted to about 8 at 0 °C by stepwise addition of NH3.H2O. The crude product was purified by preparative HPLC to give the title compound. [M+H] + =444.9. 1 H NMR (400MHz, DMSO-d6) δppm: 10.16 (s, 1H), 8.25 (s, 1H), 7.63 (dd, J = 1.2, 8.4Hz, 1H), 7.29 (s, 1H), 7.17 (d, J = 8.4Hz, 1H), 6.28 (s, 2H), 3.94 (s, 3H), 1.35 (s, 9H).

[1034] The following compounds were prepared following procedures similar to that described for Example 334.

[1035]

[1036]

[1037] Embodiment 337

[1038]

[1039] 2-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyphenyl)propan-2-ol: To a solution of methyl 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxybenzoate (20 mg, 40 μmol, 1 eq) in THF (5 mL) was added methylmagnesium bromide (3 M, 133 μL, 10 eq) dropwise at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched at 0 °C by adding saturated NH4Cl (10 mL) aqueous solution, and then diluted with H2O (20 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by preparative HPLC to give the title compound. [M+H] + =451.1. 1 H NMR (400MHz, DMSO-d6) δppm: 8.72 (s, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.68 (dd, J = 2 .0,12.4Hz,1H),7.27(s,1H),5.21(s,1H),3.94(s,6H),1.53(s,6H),1.32(s,9H).

[1040] Embodiment 338

[1041]

[1042] 2-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyphenoxy)ethan-1-ol: To a mixture of 5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyphenol (20 mg, 44.1 μmol, 1 eq) and 2-bromoethanol (13.8 mg, 110 μmol, 7.81 μL, 2.5 eq) in DMF (1 mL) was added CsCO (43.1 mg, 132 μmol, 3 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give the title compound. [M+H] + =452.9. 1H NMR(400MHz,DMSO-d6)δppm:8.72(s,1H),7.77(s,1H),7.27(s,1H),7.19-7.12(m,2H),4.94(t, J=5.6Hz,1H),4.09(t,J=4.8Hz,2H),3.93(s,3H),3.89(s,3H),3.78-3.74(m,2H),1.32(s,9H).

[1043] The following compounds were prepared following procedures similar to that described for Example 338.

[1044]

[1045] Embodiment 340

[1046]

[1047] A mixture of 3-(3-bromo-5-fluoro-4-methoxyphenyl)-6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridine (50.00 mg, 106.08 μmol, 1 eq), cyclopropylboronic acid (27.34 mg, 318.24 μmol, 3 eq), PCy3 (5.95 mg, 21.22 μmol, 6.88 μL, 0.2 eq), Pd(OAc)2 (4.76 mg, 21.22 μmol, 0.2 eq) and K3PO4 (78.81 mg, 371.28 μmol, 3.5 eq) in toluene (2 mL) and H2O (0.5 mL) was degassed and purged with N2 (3x). The mixture was stirred at 100°C under N2 atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative RP-HPLC (acidic conditions) to give the title compound. [M+H] + =433.1. 1 H NMR (400MHz, DMSO-d6) δppm: 8.64 (s, 1H), 7.74 (s, 1H), 7.34 (dd, J = 1.6, 12.0Hz, 1H), 7.25 (s, 1H) ,6.91(s,1H),3.93(s,6H),2.29-2.18(m,1H),1.32(s,9H),1.08-0.95(m,2H),0.85-0.70(m,2H).

[1048] Example 341 (N-(5-(6-(ethylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2-methoxyphenyl)propane-1-sulfonamide) and Example 342 (N-(3-fluoro-2-methoxy-5-(7-methoxy-6-(methylsulfonyl)imidazo[1,2-a]pyridin-3-yl)phenyl)propane-1-sulfonamide) can be prepared following procedures analogous to those described herein.

[1049]

[1050] Biological data

[1051] RIPK2 binding competition assay

[1052] The ability of selected compounds of formula (I) to inhibit the binding of Alexa647-labeled ATP-competitive kinase inhibitors to GST-RIPK2 fusion protein was quantified using a TR-FRET based RIPK2 binding competition assay as described in the following paragraphs.

[1053] A recombinant fusion protein of N-terminal glutathione-S-transferase (GST) and a human RIPK2 fragment (amino acids 1-310 of accession number O43353) was expressed in baculovirus-infected Sf9 cells, purified via glutathione affinity chromatography, and used as a GST-RIPK2 fusion protein. Tracer 199 (Catalog No. PR9115B) from Life Technologies was used as an Alexa647-labeled ATP-competitive kinase inhibitor.

[1054] For the assay, 50 nL of a 100-fold concentrated solution of each test compound in DMSO was pipetted into a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany) and tracer 199 (16.7 nM => 10 nM final concentration in 5 μL assay volume) was added 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 Then, 2 μL of GST-RIPK2 fusion protein (2.5 nM => final concentration of 1 nM in 5 μL assay volume) and anti-GST-Tb (from PerkinElmer) were added. Binding competition was started with a solution of -Tb cryptate conjugated anti-GST antibody) (1.25 nM => final concentration 0.5 nM in 5 μL assay volume) (Cat. No. 61 GSTTAH) in assay buffer.

[1055] The resulting mixture was incubated at 22°C for 45 min to allow complex formation between tracer 199, fusion protein and Anti-GST-Tb. Subsequently, the amount of this complex was assessed by measuring the resonance energy transfer from the Tb-cryptate to the tracer 199. Therefore, the fluorescence emission at 620 nm and 665 nm after excitation at 337 nm was measured in a TR-FRET reader such as Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or Viewlux (PerkinElmer). The emission ratio at 665 nm and 620 nm was used as a measure of the amount of complex. The data have been normalized (assay reaction without inhibitor = 0% activity, all other assay components except the GST-RIPK2 fusion protein = -100% activity). Typically, test compounds were tested in the same microtiter plate at 11 different concentrations ranging from 20 μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM), in a dilution series prepared individually by serial dilution of a 100-fold concentrated solution in DMSO prior to the assay; the exact concentration may vary depending on the pipette used, replicates were taken for each concentration, and the assay was performed using Genedata Screener TM Software Computing IC 50 value.

[1056] THP-1Dual cell SEAP and viability assay

[1057] THP1-Dual TM Cells (InvivoGen Cat#thpd-nfis) were simultaneously evaluated for the NF-κΒ pathway by monitoring the activity of secreted embryonic alkaline phosphatase (SEAP), and for the IRF pathway by evaluating 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 x 10 in assay medium (RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% fetal bovine serum (heat inactivated at 56°C for 30 min), Pen-Strep (100 U / mL)). 5Cells / mL were added to each well of a flat-bottom 384-well plate (white opaque) at 300 g. The plate was centrifuged for 2 min at 300 g, compounds were added in a serial dilution series according to the plate layout (volume was approximately 500 nL–0.0152 nL), and the plate was incubated at 37° C. in 5% CO2 for 30 min. Using assay medium, a L18-MDP stock solution was prepared, which had a final concentration of 10 ng / mL L18-MDP in each well when 15 μL was added to each well. 15 μL of the L18-MDP stock solution was added to each well, while 15 μL of assay medium was added to the negative control well. The plate was then incubated overnight (20-24 h) at 37° C. in 5% CO2.

[1058] For SEAP assay: without disturbing the cells at the bottom of the well, 15 μL of supernatant was transferred to a clear 384-well flat bottom plate and 35 μL of QUANTI-Blue solution was added per well. After incubation at 37°C for 2 h, the optical density (OD) at 620-655 nm was measured using a microplate reader (PheraStar FS microplate reader with OD 620-655 nm protocol).

[1059] For viability assay: use the remaining cells in the plate to assess cell viability. For this reason, allow CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate to balance to room temperature, and reconstruct lyophilized CellTiter-Glo substrate according to the manufacturer's advice. An equal volume of CTG (here 35 μL) is added to each well, and the contents are mixed on an orbital shaker for 2 min to induce lysis, followed by incubation at room temperature for 10 min. Luminescent signal is subsequently measured in a microplate reader (PheraStar).

[1060] analyze:

[1061] The values ​​of the medium-only wells were subtracted and the % inhibition was calculated for each compound concentration relative to the DMSO / L18-MDP treated control. The inhibition values ​​+ / - SD were fitted by nonlinear regression using Prism software (GraphPad PRISM software) to calculate the IC 50 value.

[1062] Table A below lists the IC values ​​of selected compounds of formula (I) measured in RIPK2 binding competition assay and THP-1 Dual cell SEAP and viability assays. 50 IC values ​​for RIPK2 competition assay 50 Value, "A" means IC 50 <1nM; "B" indicates IC 50For 1 nM ≤ B ≤ 2.5; "C" represents IC 50 For 2.5 nM < C ≤ 20; and "D" represents IC 50 For 20 nM < D. For the THP assay of IC 50 value, "A" represents IC 50 For < 50 nM; "B" represents IC 50 For 50 nM ≤ B ≤ 250; "C" represents IC 50 For 250 nM < C ≤ 1,000; and "D" represents IC 50 For 1,000 nM < D.

[1063] Table A

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic group; One of X and Y is N, and the other of X and Y is C; Each is a single bond or a double bond, so that the bicyclic ring system of formula (I) is imidazo[1,2-a]pyridine or pyrazolo[1,5-a]pyridine; m is 0, 1, 2, 3 or 4; Each R 1 Independently selected from the group consisting of: (i) halogen, (ii) cyano, (iii) C1-C6 alkyl optionally substituted by hydroxy, C1-C6 alkoxy or -S(O2)C1-C6 alkyl, (iv) C1-C6 haloalkyl, (v) C1-C6 haloalkoxy, (vi) C3-C6 cycloalkyl, (vii)–NR A R B , (viii) a C1-C6 alkoxy group optionally substituted by a hydroxyl group or a phenyl group, (ix) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl, (x) – S(O2) C1-C6 alkyl, (xi) hydroxyl group, (xii) nitro, (xiii) –S(O2)C3-C6 cycloalkyl, and (xiv) When ring A is phenyl, R 1 Further selected from –S(O2)NR A R A ; R A is hydrogen or C1-C6 alkyl; R B for (i)Hydrogen, (ii) –S(O2)C1-C6 alkyl, (iii) a C3-C6 cycloalkyl group optionally substituted by a hydroxyl group or a C1-C6 alkoxy group, (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl, or (v) C1-C6 alkyl optionally substituted by 1 to 4 substituents independently selected from the following: (a) halogen, (b) hydroxyl groups, (c)-NR C R D , (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group, (g) phenyl optionally substituted by C1-C6 alkoxy, (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group, (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl, (k) C1-C6 thioalkyl, and (l) – S(=NR E )(=O)C1-C6 alkyl; R 2 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 haloalkoxy; R 3 for (i) C1-C6 thioalkyl, (ii) (iii) (iv) a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl, (v) optionally NR E R F or a C1-C6 alkyl group substituted with hydroxyl, (vi) -CO2H, (vii)-C(=O)NR E R F , (viii) C1-C6 alkoxy optionally substituted by a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by a C1-C6 alkoxy group, (ix) hydrogen; Z is O or NR 4 ; R 3A is C1-C6 haloalkyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by C3-C6 cycloalkyl; R 3B and R 3C Each is independently a C3-C6 cycloalkyl group or a C1-C6 alkyl group optionally substituted by a C3-C6 cycloalkyl group; R 4 is hydrogen or C1-C6 alkyl; and Each R C and R D Each is independently hydrogen, -C(=O)OC1-C6 alkyl or C1-C6 alkyl optionally substituted by oxo; Each R E and R F are each independently hydrogen or C1-C6 alkyl; and in (i) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is C1-C6 alkoxy, R 3 When -S(O2)-C1-C6 alkyl and m is 1, then R 1 Not –NH2 or –NH(C=O)CH3; (ii) 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, m is 2, and one R 1 When it is fluorine, -NH-(p-methoxybenzyl) or -NH2, the other R 1 Not halogen; (iii) When X is C, Y is N, ring A is phenyl, R 2 is C1-C6 alkoxy, R 3 When it is –S(O2)-C1-C6 alkyl and m is 1, R 1 It is not fluorine, cyano or unsubstituted C1-C6 alkoxy; (iv) When X is C, Y is N, ring A is phenyl, R 2 is a C1-C6 alkoxy group, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is a halogen, the other R 1 is not an unsubstituted C1-C6 alkoxy group; (v) When X is C, Y is N, Ring A is 4-pyridyl, R 2 is C1-C6 haloalkoxy, R 3 is –S(O2)-C1-C6 alkyl, m is 2, and one R 1 When it is –NH2, the other R 1 Not halogen; (vi) When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When -S(O2)-C1-C4 alkyl, ring A is phenyl, and m is 1, R 1 It is not halogen, -NH2, cyano or unsubstituted C1-C6 alkoxy; (vii) When X is C, Y is N, R 2 is ethoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not –NH2 or unsubstituted alkoxy; (viii) When X is C, Y is N, R 2 is C1-C2 haloalkoxy, R 3 is –S(O2)-C1-C4 alkyl, and m is 2, and one R 1 When it is a halogen, the other R 1 is not –NH2; and (ix) When X is C, Y is N, R 2 is C1-C3 alkoxy, R 3 When the ring A is -S(O2)-C1-C4 alkyl and m is 0, then the ring A is not 1H-indazole or 1H-benzo[d]imidazole.

2. The compound according to claim 1, wherein X is C, Y is N, and the bicyclic ring system of formula (I) is imidazo[1,2-a]pyridine.

3. The compound according to claim 1, wherein X is N, Y is C, and the bicyclic ring system of formula (I) is pyrazolo[1,5-a]pyridine.

4. The compound according to any one of claims 1 to 3, wherein ring A is a 5-6 membered heteroaryl group.

5. The compound according to any one of claims 1 to 3, wherein ring A is a 5-6 membered heterocyclic group. The compound according to any one of claims 1 to 3, wherein ring A is phenyl.

7. The compound according to any one of claims 1 to 7, wherein 1 to 3 R 1 are independently halogen.

8. The compound according to any one of claims 1 to 7, wherein one R 1 It is cyano.

9. The compound according to any one of claims 1 to 8, wherein one R 1 It is a C1-C6 alkyl group optionally substituted by a hydroxy group, a C1-C6 alkoxy group or a -S(O2)C1-C6 alkyl group.

10. The compound of any one of claims 1 to 9, wherein one R 1 It is a C1-C6 haloalkyl group.

11. The compound of any one of claims 1 to 10, wherein one R 1 It is a C1-C6 haloalkoxy group.

12. The compound of any one of claims 1 to 11, wherein one R 1 It is a C3-C6 cycloalkyl group.

13. The compound of any one of claims 1 to 12, wherein one R 1 is a C1-C6 alkoxy group optionally substituted by a hydroxy group or a phenyl group.

14. The compound of any one of claims 1 to 13, wherein one R 1 is a 4- to 8-membered heterocyclic group optionally substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl and C1-C6 haloalkyl.

15. The compound of any one of claims 1 to 14, wherein one R 1 It is –S(O2)C1-C6 alkyl.

16. The compound of any one of claims 1 to 15, wherein one R 1 It is hydroxyl.

17. The compound of any one of claims 1 to 16, wherein one R 1 For –NR A R B .

18. The compound of any one of claims 1 to 17, wherein one R 1 For nitro.

19. The compound of any one of claims 1 to 18, wherein one R 1 It is –S(O2)C3-C6 cycloalkyl.

20. A compound as claimed in any one of claims 1 to 19, wherein R A For hydrogen.

21. A compound as described in any one of claims 1 to 19, wherein R A It is a C1-C6 alkyl group.

22. A compound as described in any one of claims 1 to 21, wherein R B For hydrogen.

23. A compound as described in any one of claims 1 to 22, wherein R B It is –S(O2)C1-C6 alkyl.

24. A compound as described in any one of claims 1 to 22, wherein R B It is a C3-C6 cycloalkyl group which is optionally substituted by a hydroxy group or a C1-C6 alkoxy group.

25. A compound as described in any one of claims 1 to 22, wherein R B is a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from hydroxy and C1-C6 haloalkyl.

26. A compound as described in any one of claims 1 to 22, wherein R B is a C1-C6 alkyl group optionally substituted by 1 to 4 substituents independently selected from the following: (a) halogen, (b) hydroxyl groups, (c)-NR C R D , (d) C1-C6 alkoxy, (e) C1-C6 haloalkoxy, (f) a C3-C6 cycloalkyl group optionally substituted by a hydroxy group, (g) phenyl optionally substituted by C1-C6 alkoxy, (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group, (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl, (k) C1-C6 thioalkyl, and (l) – S(=NR E )(=O)C1-C6 alkyl.

27. A compound as described in any one of claims 1 to 22, wherein R B is a C1-C6 alkyl group optionally substituted by 1 to 4 substituents independently selected from the following: (h) a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group, and (j) a 4- to 8-membered heterocyclic group optionally substituted by hydroxy, -C(=O)C1-C6 alkyl or C1-C6 alkyl.

28. A compound as described in any one of claims 1 to 27, wherein R C For hydrogen.

29. A compound as described in any one of claims 1 to 27, wherein R C It is a C1-C6 alkyl group which is optionally substituted by oxo.

30. A compound as described in any one of claims 1 to 29, wherein R D For hydrogen.

31. A compound as described in any one of claims 1 to 29, wherein R D It is a C1-C6 alkyl group which is optionally substituted by oxo.

32. The compound of any one of claims 1 to 31, wherein m is 1.

33. The compound of any one of claims 1 to 31, wherein m is 2.

34. The compound of any one of claims 1 to 31, wherein m is 3.

35. The compound of any one of claims 1 to 31, wherein m is 4.

36. The compound of any one of claims 1 to 6, wherein m is 0.

37. A compound as described in any one of claims 1 to 36, wherein R 2 For hydrogen.

38. A compound as described in any one of claims 1 to 36, wherein R 2 It is a halogen.

39. A compound as described in any one of claims 1 to 36, wherein R 2 It is a C1-C6 alkoxy group.

40. A compound as described in any one of claims 1 to 36, wherein R 2 It is a C1-C6 haloalkoxy group.

41. A compound as described in any one of claims 1 to 40, wherein R 3 For hydrogen.

42. A compound as described in any one of claims 1 to 40, wherein R 2 is not hydrogen and R 3 Not hydrogen.

43. A compound as described in any one of claims 1 to 40, wherein R 3 It is a C1-C6 thioalkyl group.

44. A compound as described in any one of claims 1 to 40, wherein R 3 It is -CO2H.

45. A compound as described in any one of claims 1 to 40, wherein R 3 It is a C1-C6 alkoxy group optionally substituted by a 4-10-membered heterocyclic group, and the 4-10-membered heterocyclic group is optionally substituted by a C1-C6 alkoxy group.

46. ​​A compound as described in any one of claims 1 to 40, wherein R 3 is a 4-8 membered heterocyclic group optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl.

47. A compound as described in any one of claims 1 to 40, wherein R 3 for 48. A compound as described in any one of claims 1 to 40 or 47, wherein R 3A It is a C1-C6 haloalkyl group.

49. A compound as described in any one of claims 1 to 40 or 47, wherein R 3A It is a C3-C6 cycloalkyl group.

50. A compound as described in any one of claims 1 to 40 or 47, wherein R 3A It is a C1-C6 alkyl group which is optionally substituted by a C3-C6 cycloalkyl group.

51. A compound as described in any one of claims 1 to 40 or 47 to 50, wherein Z is NR 4 .

52. A compound as described in any one of claims 1 to 40 or 47 to 51, wherein R 4 For hydrogen.

53. A compound as described in any one of claims 1 to 40 or 47 to 51, wherein R 4 It is a C1-C6 alkyl group.

54. A compound as described in any one of claims 1 to 40 or 47 to 50, wherein Z is O.

55. A compound as described in any one of claims 1 to 40, wherein R 3 for 56. A compound as described in any one of claims 1 to 40 or 55, wherein R 3B It is a C3-C6 cycloalkyl group.

57. A compound as described in any one of claims 1 to 40 or 55, wherein R 3B It is a C1-C6 alkyl group which is optionally substituted by a C3-C6 cycloalkyl group.

58. A compound as described in any one of claims 1 to 40 or 55 to 57, wherein R 3C It is a C3-C6 cycloalkyl group.

59. A compound as described in any one of claims 1 to 40 or 55 to 57, wherein R 3C It is a C1-C6 alkyl group which is optionally substituted by a C3-C6 cycloalkyl group.

60. A compound as described in any one of claims 1 to 40, wherein R 3 For optionally NR E R F or a C1-C6 alkyl group substituted with a hydroxy group.

61. A compound as described in any one of claims 1 to 40, wherein R 3 -C(=O)NR E R F .

62. A compound selected from Examples 1 to 340 or a pharmaceutically acceptable salt of any of the foregoing.

63. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

64. A method of treating a RIPK2-related disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 62 or a pharmaceutical composition as described in claim 63.

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